Derivatives of benzopyrane substituted with secondary amines comprising tetrazole, method for their preparing and pharmaceutical compositions comprising thereof

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

SUBSTANCE: invention relates to novel derivatives of benzopyrane substituted with secondary amines comprising tetrazole, their stereoisomers or their pharmaceutical acceptable salts of the formula (I): wherein R1 represents hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom, -CF3, -NO2, -CN, -ORa, -NH2, or -OS(O)lRa under condition that Ra represents hydrogen atom (H) or unbranched or branched (C1-C4)-alkyl; l means a whole number 0-2; R2 represents -CH2ORa, under condition that Ra has values given above; Rb and Rc represent independently unbranched or branched (C1-C4)-alkyl; R3 represents -OH or under condition that Ra has values given above; R4 and R5 represent independently H, F, Cl, Br, unbranched or branched (C1-C3)-alkyl, -ORa, -CF3, -OCF3, -NO2, or -SO3Ra under condition that Ra has values given above; R6 represents H, unbranched or branched (C1-C3)-alkyl; n and m mean independently a whole number 0-2; * represents chiral carbon atom. Also, invention relates to a method of synthesis of these compounds and a pharmaceutical composition based on thereof. Invention provides preparing novel derivatives of benzopyrane possessing antioxidant activity.

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

15 cl, 14 tbl, 118 ex

 

TECHNICAL AREA

The present invention relates to the derivatives of benzopyran, substituted secondary amines, including tetrazol, and is represented by the following formula 1, a method of receiving and containing pharmaceutical compositions.

where R1, R2, R3, R4, R5, R6, n, m, and * have the values listed in the description.

BACKGROUND of INVENTION

Neurons in the CNS (Central nervous system) mammals are very sensitive to oxygen availability. It is well known that temporary critical reduction of oxygen levels in healthy brain runs various pathological processes and, eventually, leads to a fatal brain damage [.Nieber, Pharmacol. Ther. 1999, 82, 71]. Oxygen may become unavailable to the brain due to loss of blood flow (ischemia) after cardiac arrest or occlusion of intracranial vessels due to thrombosis and embolism or due to a lack of oxygen in the blood (hypoxia).

Ischemic cell damage may be the result of biochemical cascades of complex interactions, which include abnormalities in electrophysiological, hemodynamic, and energy metabolism [W. Paschen and B. Djuricic, J. Neurochem. 1995, 65, 1692], and modifications in gapticheskoi transmission [H. J. Luhmann, Prog. Neurobiol. 1996, 48, 131]. Disturbed ion homeostasis, characterized by increased cellular expiration To+and the flow of Na+and CA2+, accompanied by extracellular acidosis, free radical formation, swelling of the cells and the inhibition of the synthesis of proteins that are associated with receptor excitatory amino acids, CA-dependent or ATP-dependent K-channel, etc. As explained above, ischemic cell damage occurs due to a cascade of biochemical events, not individual events. So, for the development of neuroprotective agents proposed several strategies and also assumes that an effective intervention in several key stages during the ischemic cascade is necessary for effective therapeutic agent for cerebral ischemia [De Keyser et al. Trends Neurosci., 1999, 22, 535; Dirnagl et al. Trends Neurosci., 1999, 22, 391; Gladstont et al. Stroke, 2002, 33, 2123].

Even after blood flow is restored, the oxygen can also enhance biochemical reactions that generate free radicals, which can lead to opportunities that will take place "reperfusion injury". It is known that, both acute and chronic damage to tissues and organs caused by ischemia-reperfusion or endotoxins due to bacterial infection. In order predot is atiti brain damage, caused by ischemia-reperfusion, the brain must be protected during the ischemic period, to avoid additional damage and pathological progressive cellular changes need to be minimized.

For this goal is the development of several neuroprotective means, such as antagonists of excitatory amino acids, antioxidants, agonists of adenosine and openers ToATPchannels.

It is known that the damage or death of neurons is the main cause of various neurological disorders such as stroke, head trauma, Alzheimer's disease, Parkinson's disease, asphyxia infants, glaucoma and diabetic neuropathy etc [G. J. Zoppo et al., Drugs 1997, 54, 9: I. Sziraki et al., Neurosci, 1998, 85, 1101].

Neurons are damaged by various factors, including the increase in the concentration of iron, reactive oxygen species and procyclical in neurons [M. P. Mattson et al., Methods Cell Biol. 1995, 46, 187; Y. Goodman et al., Brain Res. 1996, 706, 328].

Free radicals are generated in cells by oxidative stress. Excess oxygen free radicals promotes lipid perechislenie, so procyclical accumulates in neurons and this also causes a change in protein synthesis and DNA. It is known that reactive free radicals accumulated in the cells that are responsible for RA is a personal disease [J. M. McCord, J. Am Med. 2000, 108, 652], including inflammatory diseases such as arthritis; atherosclerosis; myocardial infarction of the heart muscle and neurodegenerative disease, such as dementia, allergies, cancer, and acute and chronic damage to tissues and organs.

Therefore, the continued therapeutic approaches to minimize damage or death of neurons, including inhibition of lipid perechisleniya, the formation of NO and reactive oxygen particles induced by endotoxins. Today it is known that antioxidants reduce the damage and death of neurons caused by the increase of iron concentration in neurons. Many efforts were made to develop pharmaceutical drugs that can prevent neuronal damage oxidative stress (Y. Zhang et al., J. Cereb. Blood Flow Metab. 1993, 13, 378).

There are reports that the opening To theATPchannel is associated with induction of antioxidant enzymes [S. Okubo et al., Mol. and cell Biochem., 1999, 196, 3] and reducing the release of excitatory amino acids [J-L Moreau, G. Huber, Brain Res., 1999, 31, 65].

It has been described that diazoxide, an opener of KATPchannels reversibly oxidizes flavoprotein in mitochondria, which leads to inhibition of the formation of oxygen free radicals, such inhibition may protect cells from damage acyclical the m stress [A. A. Starkov, Biosci, Rep. 1997, 17, 273; V. P. Skulachev, Q. Rev. Biophus. 1996, 29, 169].

Described that asphyxia infants (IA), due to a temporary lack of supply of oxygen during birth, caused by reduced production of energy, damage to cell membranes due to oxygen free radicals, release of excitatory neurotransmitters, changes in intracellular concentrations of ions, including calcium, zinc, etc. IA is a major problem worldwide, because, if IA is heavy, the deaths are high (approximately 1/3 of the total mortality of infants). In addition, it can cause long-term consequences, such as violations of movements, loss of ability to learn, epilepsy, dystonia, mental retardation and muscle spasticity [C. F. Loid et al. Discrimination and Behavior, 2000, 68, 263-269].

Antioxidant enzymes, allopurinol, vitamins C and E, scavengers of free radicals, inhibitors of excitatory neurotransmitters, calcium channel blockers, such as nimodipine and flunarizin, inhibitors of NO formation, hyperglycemic and hypothermic therapy can be useful to protect the brain from damage, but their clinical application is still limited.

Glaucoma, one of the major causes of blindness, defined as ocular neuropathy, associated with a characteristic change in enemy in the optic nerve. People the optic nerve consists of 1 million oxonol neurons, perikaryon which are mainly in the layer of ganglion cells and to a lesser extent in the inner part of the inner nuclear layer. It is believed that dissected the appearance of the optic disc in glaucoma is caused by death and then the loss of ganglion cells and their axons [N.N. Osborne, et al., Survey of Ophthalmology, 43; suppl. 1999, S102-128].

Neuroprotective agents in glaucoma can be protected from the death of retinal neurons, in particular ganglion cells, either directly or indirectly. To protect against the death of retinal neurons, caused by ischemia, and protection from damage to the optic nerves can be used by various agents, such as receptor antagonist NMDA (N-methyl-D-aspartate), α-blockers, calcium antagonists and antioxidants.

Although the pathogenesis of diabetic neuropathy has not been clearly established, were offered two main hypotheses for this. One of them is a metabolic disorder and the other is the disadvantages of blood flow in peripheral nerves [K. Naka et al. Diabetes Research and Clinical Practice, 1995, 30, 153-162]. In clinical studies used acetyl-L-carnitine (ALC), acting through stimulation of lipid metabolism and repair weakened nociceptive reactions of neurons, or acetyl, acting through vysvobozhdeny the neurotrophic factors. In addition, conduct clinical research with Nemanjina providing a good effect on vascular dementia through regulation of the NMDA receptor. Then for the treatment of diabetic neuropathy can be developed neuroprotective agents that have different mechanisms of action.

Ischemic heart disease is usually caused by myocardial ischemia, when the oxygen flow is significantly reduced compared to the oxygen demand due to the imbalance between them [G. J. Grover, Can. J. Physiol., 1997, 75, 309; G. D. Lopaschuk et al. Science and Medicine, 1997, 42]. Myocardial ischemia causes various pathophysiological changes in a progressive manner that will ultimately lead to irreversible myocardial damage, cell death and tissue necrosis. At the stage where cell damage is reversible, this process can be prevented by early reperfusion of the myocardium. However, there is a possibility that will be damaged by reperfusion" [D. J. Hearse, Medicographia, 1996, 18, 22].

To slow the ischemic cascade and minimize damage during reperfusion investigated the use of adenosine agonists, inhibitors of Na+-K+-antiporta, scavengers of oxygen free radicals and discoverers ToATP(ATP-sensitive potassium channel)and ACE inhibitors (enzyme, reverseimage angiotensin) and calcium antagonists. In addition, total ischemia occurs during heart surgery or during storage of the heart prior to transplantation. In recent studies described that the addition of openers ToATPto gipercalziemicescoy, cardioplegic solution helps restore polisomaticheskoi contractile function after normothermal ischemia or short periods of hypothermic ischemia [D. J. Chamders, D. J. Hearse, Ann. Thoar. Surg., 1999, 68, 1960]. Studies on the use of these compounds as protective agents or therapeutic agents for bodies associated with damage due to ischemia and reperfusion", such as the retina and skeletal muscle, in addition to the heart and brain.

As described above, so as ischemic cascades evolve through complex interactions, this may be a useful strategy for the development of compounds acting at more than one target site in the ischemic cascade.

ToATPdetected in various tissues, including cardiac muscle, smooth muscle, skeletal muscle, kidney, pancreatic β-cells, the brain and the Central nervous system that make it promising as a target of the drug. However, this diversity leads to the difficulty of finding selective agents for fabrics.

Described, is that unlike conventional openers potassium channels, derived bezoperatsionnaya (BMS-180448)represented by the following formula 4, and derived benzoperylene (BMS-191095)represented by the following formula 5, show a moderate anti-ischemic activity with excellent cardiac selectivity. Although the compound represented by formula 5, had all the desirable properties to serve as the primary connection, it still retains a certain degree of vasodilator and hypotensive activity [K. S. Atwal et al., J. Med. Chem., 1995, 38, 3236; K. S. Atwal et al., J. Med. Chem., 1996, 40, 24; K. S. Atwal et al., Current Pharmaceutical Design, 1996, 2, 585]. Therefore, a more cardioselektivee compounds that have cardiotoxins activity without a significant reduction in blood pressure, yet give hope to develop a new cardioboxing tools.

FORMULA 4

FORMULA 5

The proportion of cancer among human diseases gradually increases. Angiogenesis, the formation of new blood vessels, recognized as the main process for the growth and metastasis of solid tumors (Folkma, J. et al., J. Biol. Chem. 1992, 267, 10931-10934). Angiogenesis is regulated by inducers and inhibitors of angiogenesis. When the balance between them is violated, i.e. when the inducers of angiogenesis outweigh the inhibitors of angiogenesis, the image is carried out a large number of new blood vessels. Angiogenesis is closely associated with various physiological phenomena, such as embryonic development, wound healing, chronic inflammation, hemangiomas, diabetic retinopathy, rheumatoid arthritis, psoriasis, complications from the AIDS and the growth and metastasis of malignant tumors (Forkman, J., and Klagsbrun, M. Science, 1987, 235, 442-447). Angiogenesis involves a number of processes, such as migration, proliferation and differentiation of endothelial cells, and is an important prerequisite for the growth and metastasis of cancerous tumors. In detail, since the growth of tumor cells requires the formation of blood vessels from the host cells, the promoters of angiogenesis, formed of tumors, stimulate the induction of angiogenesis in the tumor mass. Subsequently, blood vessels formed around malignant tumors, contribute to the metastasis of tumor cells in other places. Therefore, inhibition of angiogenesis leads to the prevention of the growth and metastasis of cancerous tumors. As one of the important research areas for the development of anti-cancer drugs, focusing on the presence of inducers of angiogenesis and angiogenesis inhibitors and to establish the mechanisms of their actions.

To date, it was established that proteins, such as prostasin and necrotic factors of tumors derived from Cana cartilage, and called cortisones angiostatic steroids and various derivatives of steroids can play a role as inhibitors of angiogenesis. In particular, hydrocortisone exhibits antiangiogenic activity when combined treatment with heparin (Lee, A. et al., Science, 1983, 221, 1185-1187; Crum, R. et al., Science, 1985, 230, 1375-1378). However, use of these compounds for the effective treatment of cancer can be a problem because of their toxicity.

Description of the INVENTION

The present invention relates to the derivatives of benzopyran, substituted secondary amine, including tetrazol, their stereoisomers or their pharmaceutically acceptable salts.

The present invention relates further to the way they are received.

The present invention further relates to pharmaceutical compositions containing the derivatives of benzopyran, substituted secondary amine, including tetrazol, their stereoisomers or pharmaceutically acceptable salt as an effective ingredient.

In order to achieve the above objective, the present invention provides derivatives of benzopyran, substituted secondary amine, including tetrazol, and is represented by the following formula 1, their stereoisomers or their pharmaceutically acceptable salts.

where R1represents H, F, Cl, Br, CF3 , NO2CN, -ORa,, COORa, NH2NHS(O)lRa,or S(O)1Raprovided that Rarepresents H, an unbranched or branched C1-C4alkyl or aryl, l is an integer 0-2;

R2represents CH2ORa,orprovided that Ramatter mentioned above, Rband Rcrepresents, independently, an unbranched or branched C1-C4alkyl, Z is an unbranched or branched C1-C5-alkyl;

R3is a HE, F, Cl, Br, ONO2orprovided that Rahas the values listed above;

R4and R5represent, independently, H, F, Cl, Br, unbranched or branched C1-C3alkyl, ORa, CF3, OCF3, NO2,,,or SO3Raprovided that Rahas the values listed above;

R6represents H, an unbranched or branched C1-C3alkyl,

n and m is, independently, an integer of 0-2;

* represents a chiral atom in which laroda.

Preferably, in the compound of formula 1, R1represents NO2CN or NH2;

R2representsorprovided that Rband Rcrepresent, independently, an unbranched or branched C1-C3alkyl, Z is an unbranched or branched C2-C3alkyl;

R3HE is a orprovided that Randrepresents an unbranched or branched C1-C3alkyl;

R4and R5represent, independently, H, F, Cl, unbranched or branched C1-C3alkyl, ORa, CF3, OCF3or NO2provided that Randrepresents an unbranched or branched C1-C3alkyl;

R6represents an unbranched or branched C1-C3alkyl;

n and m is an integer of 0-1.

The present invention also includes derivatives of benzopyran formula 1 and their pharmaceutically acceptable salts of all of the solvate and hydrate, which can be obtained from the derivatives of benzopyran, substituted secondary amines, including tetrazol.

In addition, the present invention also includes racemic with the Yessei or diastereomeric mixtures derived benzopyran formula 1 all individual stereochemical isomers, i.e. diastereomers pure or enantiomerically pure compounds that have one or more chiral centers in the 2-, 3 - and 4-positions.

Preferably, the compounds of formula 1 contain:

1) (2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

2) (2S,3R,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

3) (2S,3S,4R)-6-nitro-4-[N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

4) (2S,3R,4S)-6-nitro-4-[N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

5) (2S,3S,4R)-6-nitro-4-[N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

6) (2S,3R,4S)-6-nitro-4-[N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

7) (2S,3S,4R)-6-nitro-4-[N-benzyl-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

8) (2S,3R,4S)-6-nitro-4-[N-benzyl-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

9) (2S,3S,4R)-6-nitro-4-[N-(4-nitrophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-,4-dihydro-2H-1-benzopyran,

10) (2S,3S,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

11) (2S,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

12) (2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(1-methyl-1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

13) (2S,3S,4R)-6-nitro-4-[N-(1-methyl-1H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

14) (2S,3S,4R)-6-nitro-4-[N-(4-forfinal)-N-(1-methyl-1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

15) (2S,3S,4R)-6-nitro-4-[N-benzyl-N-(1-methyl-1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

16) (2S,3R,4S)-6-nitro-4-[N-benzyl-N-(1-methyl-1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

17) (2S,3S,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(1-methyl-1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

18) (2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

19) (2S,3S,4R)-6-nitro-4-[N-(1H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

20) (2S,3S,4R)-6-nitro-4-[N-benzyl-N-(1H-tetrazol-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

21) (2S,3S,4R)-6-nitro-4-[N-(3-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

22) (2S,3S,4R)-6-amino-4-[N-(3-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

23) (2S,3S,4R)-6-nitro-4-[N-(4-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

24) (2S,3S,4R)-6-amino-4-[N-(4-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

25) (2S,3R,4S)-6-nitro-4-[N-(3-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

26) (2S,3R,4S)-6-amino-4-[N-(3-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

27) (2S,3R,4S)-6-nitro-4-[N-(4-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

28) (2S,3R,4S)-6-amino-4-[N-(4-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

29) (2S,3R,4S)-6-nitro-4-[N-(2-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

30) (2S,3R,4S)-6-amino-4-[N-(2-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-banter is h,

31) (2S,3R,4S)-6-nitro-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

32) (2S,3R,4S)-6-amino-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

33) (2S,3R,4S)-6-nitro-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

34) (2S,3R,4S)-6-amino-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

35) (2S,3R,4S)-6-nitro-4-[N-(3-acetylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

36) (2S,3R,4S)-6-amino-4-[N-[3-(1-hydroxyethyl)phenyl]-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

37) (2S,3R,4S)-6-nitro-4-[N-(2-methyl-4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

38) (2S,3R,4S)-6-amino-4-[N-(2-methyl-4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

39) (2S,3R,4S)-6-nitro-4-[N-(4-methoxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

40) (2S,3R,4S)-6-amino-4-[N-(4-methoxyphenyl)-N-(2-methyl-2H-tetrazol-5-ILM is Tyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

41) (2S,3R,4S)-6-nitro-4-[N-(2-methyl-4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

42) (2S,3R,4S)-6-amino-4-[N-(2-methyl-4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

43) (2S,3R,4S)-6-nitro-4-[N-(2-methoxy-5-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

44) (2S,3R,4S)-6-amino-4-[N-(2-methoxy-5-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

45) (2S,3R,4S)-6-nitro-4-[N-(2,4-dimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

46) (2S,3R,4S)-6-amino-4-[N-(2,4-dimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

47) (2S,3R,4S)-6-nitro-4-[N-(2,6-dimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

48) (2S,3R,4S)-6-amino-4-[N-(2,6-dimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

49) (2S,3R,4S)-6-nitro-4-[N-(2,3-dimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

50) (2S,3R,4S)-6-amino-4-[N-(2,3-dimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

51) (2S,3R,4S)-6-nitro-4-[N-(2-isopropylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

52) (2S,3R,4S)-6-amino-4-[N-(2-isopropylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

53) (2S,3R,4S)-6-nitro-4-[N-(4-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

54) (2S,3R,4S)-6-amino-4-[N-(4-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

55) (2S,3R,4S)-6-amino-4-[N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

56) (2S,3R,4S)-6-amino-4-[N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

57) (2S,3R,4S)-6-amino-4-[N-benzyl-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

58) (2S,3R,4S)-6-nitro-4-[N-[(3-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

59) (2S,3R,4S)-6-amino-4-[N-[(3-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-methoxymethyl-3,4-dihydro-2H-1-benzopyran,

60) (2S,3R,4S)-6-nitro-4-[N-(2-hydroxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-meth is l-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

61) (2S,3R,4S)-6-amino-4-[N-(2-hydroxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

62) (2S,3R,4S)-6-nitro-4-[N-[(2-methoxy-4-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

63) (2S,3R,4S)-6-amino-4-[N-[(2-methoxy-4-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

64) (2S,3R,4S)-6-nitro-4-[N-[(2-methyl-4-hydroxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

65) (2S,3R,4S)-6-amino-4-[N-[(2-methyl-4-hydroxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

66) (2S,3R,4S)-6-nitro-4-[N-(2-ethylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

67) (2S,3R,4S)-6-amino-4-[N-(2-ethylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

68) (2S,3R,4S)-6-nitro-4-[N-(2-methyl-5-(ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

69) (2S,3R,4S)-6-amino-4-[N-(2-methyl-5-(ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

70) (2S,3R,4S)-6-nitro-4-[-(2-hydroxy-5-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

71) (2S,3R,4S)-6-amino-4-[N-(2-hydroxy-5-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

72) (2S,3R,4S)-6-nitro-4-[N-(2,4,6-trimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

73) (2S,3R,4S)-6-amino-4-[N-(2,4,6-trimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

74) (2S,3S,4R)-6-nitro-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

75) (2S,3S,4R)-6-amino-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

76) (2R,3S,4R)-6-nitro-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

77) (2R,3S,4R)-6-amino-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

78) (2R,3R,4S)-6-nitro-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

79) (2R,3R,4S)-6-amino-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

80) (2S,3S,4R)-6-nitro-4-[N-(4-trifloromethyl)-N-(2-methyl-2 is-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

81) (2S,3S,4R)-6-amino-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

82) (2R,3R,4S)-6-nitro-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

83) (2R,3R,4S)-6-amino-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

84) (2R,3S,4R)-6-nitro-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

85) (2R,3S,4R)-6-amino-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

86) (2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-acetoxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

87) (2S,3S,4R)-6-atsetamino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-acetoxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

88) (2S,3S,4R)-6-atsetamino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

89) (2S,3S,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-acetoxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

90) (2S,3R,4S)-6-bromo-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

91) (2R,3R,4S)-6-bromo-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

92) (2S,3R,4S)-6-bromo-4-[N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

93) (2R,3R,4S)-6-bromo-4-[N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

94) (2R,3R,4S)-6-bromo-4-[N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

95) (2R,3R,4S)-6-methansulfonate-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

96) (2S,3S,4R)-6-methansulfonate-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

97) (2S,3S,4R)-6-hydroxy-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

98) (2S,3S,4R)-6-nitro-5-methyl-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

99) (2S,3S,4R)-6-nitro-4-[N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

100) (3R,4S)-6-cyano-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-be sopian,

101) (3R,4S)-6-cyano-4-[N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran,

102) (2S,3S,4R)-6-hydroxy-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

103) (2S,3S,4R)-8-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

104) (2S,3S,4R)-8-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

105) (2R,3S,4R)-8-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

106) (2R,3S,4R)-8-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

107) (2R,3R,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

108) (2R,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

109) (2R,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

110) (2R,3S,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

111) (2S,3R,4R)-6-neither the ro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

112) (2S,3R,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

113) (2S,3S,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

114) (2S,3S,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

115) (2R,3R,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

116) (2R,3R,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

117) (2R,3S,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

118) (2R,3S,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran.

More preferably the compounds of formula 1 contain:

1) (2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

10) (2S,3S,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

11) (2S,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

17) (2S,3S,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(1-methyl-1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

22) (2S,3S,4R)-6-amino-4-[N-(3-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

24) (2S,3S,4R)-6-amino-4-[N-(4-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

26) (2S,3R,4S)-6-amino-4-[N-(3-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

28) (2S,3R,4S)-6-amino-4-[N-(4-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

30) (2S,3R,4S)-6-amino-4-[N-(2-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

32) (2S,3R,4S)-6-amino-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

34) (2S,3R,4S)-6-amino-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

42) (2S,3R,4S)-6-amino-4-[N-(2-methyl-4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

52) (2S,3R,4S)-6-amino-4-[N-(2-isopropylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimetix the methyl-3,4-dihydro-2H-1-benzopyran,

54) (2S,3R,4S)-6-amino-4-[N-(4-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

55) (2S,3R,4S)-6-amino-4-[N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

56) (2S,3R,4S)-6-amino-4-[N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

57) (2S,3R,4S)-6-amino-4-[N-benzyl-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

59) (2S,3R,4S)-6-amino-4-[N-[(3-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-methoxymethyl-3,4-dihydro-2H-1-benzopyran,

60) (2S,3R,4S)-6-nitro-4-[N-(2-hydroxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

61) (2S,3R,4S)-6-amino-4-[N-(2-hydroxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

70) (2S,3R,4S)-6-nitro-4-[N-(2-hydroxy-5-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

75) (2S,3R,4S)-6-amino-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

77) (2R,3S,4R)-6-amino-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-METI the-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

79) (2R,3R,4S)-6-amino-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

81) (2S,3S,4R)-6-amino-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

83) (2R,3R,4S)-6-amino-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

85) (2R,3S,4R)-6-amino-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

89) (2S,3S,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-acetoxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

107) (2R,3R,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

108) (2R,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

109) (2R,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

110) (2R,3S,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

111) (2S,3R,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

112) (2S,3R,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

113) (2S,3S,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

114) (2S,3S,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

115) (2R,3R,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

116) (2R,3R,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

117) (2R,3S,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

118) (2R,3S,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran.

With regard pharmaceutically acceptable salt, this salt preferably is an acid additive salt, obtained using a pharmaceutically acceptable free acid. The free acid can be used, if it is pharmaceutically acceptable, regardless of whether it is inorganic or organic. Examples of inorganic free the ne acids include chloride-hydrogen acid, Hydrobromic acid, sulfuric acid and phosphoric acid. Examples of suitable organic free acids are citric acid, acetic acid, lactic acid, tartaric acid, malic acid, fumaric acid, formic acid, propionic acid, oxalic acid, triperoxonane acid, benzoic acid, gluconic acid, methanesulfonate acid, glycolic acid, succinic acid, 4-toluensulfonate acid, galacturonic acid, albanova acid, glutamic acid and aspartic acid.

Salts with acids of the compounds of the present invention can be obtained in the usual way, for example by dissolving the compounds of formula 1 in excess aqueous acid and precipitation of salts dissolved in water with an organic solvent, such as methanol, ethanol, acetone or acetonitrile. It can also be obtained by heating equivalent amounts of the compounds of formula 1 and acid in water or alcohol, such as onomatology ether glycol, and then the evaporation of the mixture to dryness or vacuum filtration of precipitated salt.

In addition, the compounds of formula 1 can be in the form of pharmaceutically acceptable salts of alkali metals or alkaline-earth metals. Salts of compounds of formula 1 alkali metals or alkaline-earth metals can be obtained, for example, by dissolving the soedineniya formula 1 in a solution of an excess of hydroxide of alkali metal or alkaline earth metal, filtering nerastvorim substances and evaporation of the filtrate to dryness.

Salts of sodium, potassium or calcium are pharmaceutically acceptable. The corresponding silver salt is produced by interaction of salts of alkaline metal or alkaline-earth metal with a suitable silver salt such as silver nitrate.

In accordance with another aspect of the present invention, a method for obtaining substituted tetrazoles derived benzopyran formula 1, as shown in the following chemical scheme 1.

More specifically, the present invention provides a method containing stage of the interaction between epoxy compounds of formula 2 with a secondary amine compounds comprising a heterocycle of formula 3 in the presence of a metal salt to obtain the compounds of formula 1A, in which R3HE is a-group. In addition, the present invention provides the following method containing the stage of interaction of the compounds of formula 1A according to the chemical scheme 2 to obtain the compounds of formula 1, and this method is used with different substituents at R3.

where R1, R2, R3, R4, R5, R6, n, m, and * have the values specified above.

In the chemical scheme 1 salt of metal selected from the group, with the standing of Mg(ClO 4)2, CoCl2, LiClO4, NaClO4, CaCl2, ZnCl2, LiBF4and Zn(Tf)2.

The solvent is selected from the group consisting of acetonitrile, tetrahydrofuran and dimethylformamide, preferred is acetonitrile.

Reaction conditions can be modified in accordance with different values of the substituents R1, R2, R3, R4, R5and R6method and reagent for the reaction. The reaction temperature may be in the range from room temperature to the boiling point of the used solvent.

In addition, the substituents R1, R2, R3, R4, R5and R6can be modified according to the chemical scheme 2, and the stereochemistry of the carbon atom at the 3-position may be determined by the reaction represented by the chemical scheme 1.

Epoxy compounds of formula 2 can be obtained by the production method, described in U.S. patent No. 5236935 and patent of the Republic of Korea No. 094546, which were obtained by the authors of the present invention (chemical scheme 3).

where R1and R2have the meanings specified above (OZ) represents a leaving group, Hal represents a halogen atom.

In addition, the olefinic compound of the formula 2 can be obtained by the method described in the patent of the Republic of Korea No. 0192083,according to the authors of the present invention, and stereoisomer can be allocated ordinary chiral column chromatography or recrystallization.

Epoxy compounds of formulas 2A-2d can be separated from the corresponding stereoisomer, all of the selected epoxy compounds or mixtures thereof can be used in the next stage.

In the case of racemic mixtures of compounds of formula 2 as a synthetic intermediate compounds of formula 1 are in the form of racemic or diastereomeric mixture which can be separated with the separation of each stereoisomer.

More specifically, the compounds of formula 1, which have the original properties of the stereochemistry of the starting materials, can be obtained from each stereoisomer epoxy compounds represented by formula 2A to formula 2d.

FORMULA 2a

FORMULA 2b

FORMULA 2c

FORMULA 2d

where R1and R2have the values specified above.

You can also get stereoisomers epoxy compounds of the formula 2, respectively, of olefinic compounds using (salen) Mn (III) as catalyst for the epoxidation [E. N. Jacobsen et al., Tetrahedron Lett. 1991, 38, 5055].

Secondary amine compounds, vkluchaysya themselves tetrazol, described in the chemical scheme 1 as the other starting compounds can be obtained by means of chemical schemes 4.

The chemical scheme 4

where n is 0, m is 1, R6represents methyl, R4and R5have the values specified above.

In stage 1 connection type metal azide selected from the group consisting of sodium azide, ammonium azide, azide of trialkylamine, trialkylsilyl and azide triamcinolone, preferably sodium azide, ammonium azide.

The solvent for the reaction selected from the group consisting of tetrahydrofuran, dimethylformamide, toluene and dimethoxyethane. The reaction temperature may vary from room temperature to the boiling point of the used solvent.

In stage 3 base selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydride or sodium methoxide, and the solvent is selected from the group consisting of solvent type simple ether such as tetrahydrofuran or dioxane; solvent type ketone, such as acetone, and dimethylformamide. The reaction temperature can vary from room temperature to the boiling point of the used solvent.

Several methods of preparing compounds of formula 1 depending on the values of the substituents R1, R2, R3, R4, R5 and R6described in detail below. But we should not assume that the description of the methods, reagents and reaction conditions limit the present invention.

(1) Introduction acetoxy when R3

As described in the chemical scheme 5, the compound of formula 1b with the entered acetoxypropionyl position R3can be obtained from compounds of formula 1A, obtained according to the chemical scheme 1, in the presence of a suitable solvent and base.

The CHEMICAL SCHEME 5

where R1, R2, R4, R5, R6, n, m, and * have the values specified above.

In the chemical scheme 5 acetyl group can be introduced using acetic anhydride (°C2O) or acetylchloride (AcCl), and all organic and inorganic bases can be used as bases. The preferred organic base is selected from the group consisting of triethylamine, pyridine and N,N-diisopropylethylamine, and the preferred inorganic base is selected from the group consisting of sodium carbonate, sodium hydroxide and calcium carbonate. At the same time, the preferred amount of base is 1-3 equivalent relative to the amount of compounds of formula 1a.

The preferred catalyst is 4-(dimethylamino)pyridine and the preferred amount of catalyst having aetsa 0.05 to 0.5 equivalent relative to the amount of compounds of formula 1A.

The solvent is selected from the group consisting of methylene chloride, chloroform, tetrahydrofuran, acetonitrile. At the same time, the reaction temperature can vary from 0°C to 40°C.

(2) the Introduction of NH2as R1

The compound (1d) of formula 1, in which R1represents NH2can be obtained by reduction of compound (1C)in which R1represents NO2as shown in the diagram below, 6.

where R2, R3, R4, R5, R6, n, m, and * have the values specified above.

Group NO2can be restored in the group of NH2by hydrogenation using a metal catalyst, such as platinum, palladium on coal (Pd/C, Raney Nickel, etc. in a suitable solvent. The reduction is performed using conventional reducing agents. Solvents are alcohols, such as methanol, ethanol, etc. and ethyl acetate.

In addition, recovery group NO2in the group of NH2can be carried out using a reducing agent such as NaBH4in the presence of CuSO4, Cu(OAc)2, CoCl2, SnCl2or NiCl2. At the same time, the solvent is a mixture of water and methanol, and the preferred reaction temperature is room temperature.

as R1

The compound of formula 1E, in which R1represents NHC(O)Racan be obtained by the coupling of compounds of formula 1d, obtained according to the chemical scheme 6, with acylchlorides or acid anhydride in the presence of a solvent and base.

Base selected from the group consisting of triethylamine, N,N-diisopropylethylamine, pyridine and 4-(dimethylamino)pyridinium.

The solvent is selected from the group consisting of methylene chloride, chloroform, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran and dioxane.

(4) Introduction-NHS(O)lRaas R1

The compound of formula 1f, in which R1represents-NHS(O)mRacan be obtained by the coupling of compounds of formula 1d, obtained according to the chemical scheme 6, with alkylsulfonamides or arylsulfonamides in the presence of a solvent and base.

At the same time base selected from the group consisting of triethylamine, N,N-diisopropylethylamine, pyridine and 4-(dimethylamino)pyridine. The solvent is selected from the group consisting of methylene chloride, chloroform, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran and dioxane.

In accordance with the following aspect of the present invention, the proposed pharmaceutical composition comprising a derivative of benzopyrene, substituted Deut is CNAME amines, includes tetrazol, formula 1, their stereoisomers or pharmaceutically acceptable salt as an effective ingredient.

More specifically, the present invention provides a pharmaceutical composition comprising a derivative of benzopyrene, substituted secondary amines, including tetrazol, their stereoisomers or their pharmaceutically acceptable salts, for protection from damage to nerve cells, brain, heart, retinal ganglion cells and organs during storage or during surgical operations on the cardiovascular system, antioxidant activity, inhibition of NO generation or suppression of angiogenesis.

The present invention provides pharmaceutical compositions containing the derivatives of benzopyran, substituted secondary amines, including tetrazol, their stereoisomers or their pharmaceutically acceptable salts, for the protection of nerve cells.

Compounds (pharmaceutical composition) of the present invention find a neuroprotective action on protection against induced oxidative stress cell death under the influence of iron or hydrogen peroxide.

In addition, the compounds of the present invention protects against ischemic-hypoxic and hypoxic damage to the brain of newborn rats, the which is often used to study asphyxia infants because the maturity of the brain is similar to the maturity of the babies person and easy to get a sufficient number of animals required to determine the action of the compounds according to the decrease of the ratio of lipid/NAA (N-acetylaspartic acid) and lipid/Cr (creatine) in proton Mrs (magnetic resonance spectroscopy), and these relationships are an important index for apoptosis, as well as improve morphological assessments and mortality. In addition, the compounds of the present invention protects acetominoven retinal ganglion cells and exert a neuroprotective action by improving the condition of damaged cells.

In addition, the compounds of the present invention exert a neuroprotective action by increasing the speed of conduction of a damaged nerve in animal models of diabetic neuropathy. Thus, the compounds of the present invention can be used as a neuroprotective tools and can also be used for the prevention and treatment of asphyxia infants, glaucoma, diabetic neuropathy and head injuries caused by damage to or destruction of nerve cells.

In addition, the compounds of the present invention inhibit perechislenie lipids induced by iron or copper, and inhibit the action of intracellular reactive color is-breaking varieties in AG (cell lines smooth muscles of the thoracic aorta, ATSS)induced by H2About2. Therefore, compounds of the present invention can be used as an antioxidant and can be effectively used for drug treatment of neurodegenerative disorders caused by perechislenie lipids and accumulation of varieties of free radicals in neurons, such as aging and senile dementia.

In addition, the compounds of the present invention inhibit the production of NO (nitric oxide), induced by endotoxins, such as lipopolysaccharides (LPS), a dose-dependent manner. Therefore, compounds of the present invention can be used as inhibitors of NO formation and can be used effectively for the treatment of inflammatory diseases such as arthritis, heart attack, heart muscle, arterioles and dementia caused by damage to tissues or organs in the apoptotic or necrotic cell death due to the accumulation of NO in the cells.

In addition, the compounds of the present invention effectively protects the brain from damage during ischemia-reperfusion. Coronary heart diseases are the result of complex interactions between different types of neurotransmitters, ion channels, enzymes, etc. Then it is assumed that the compounds of the present invention that the possession is tons of various pharmacological actions, such as the regulation of ion channels, protection from neurotoxicity resulting from the action of iron, hydrogen peroxide, etc., inhibition of perechisleniya lipids and protect the brain from damage and so on, prevent or treat stroke caused by cerebral ischemia.

On the model removed the ischemic rat heart using the apparatus of Langendorf compounds of the present invention significantly prolong the time to contracture (TTC, time to contracture), increased recovery polisomaticheskoi contractile function [LVDP x HR (left ventricular developed pressure) x (heart rate)] and reduce the release of lactate dehydrogenase (LDH), which is a marker enzyme for cell damage, then show cardiotoxin action similar to cardiostim the action of BMS-180448. In addition, the compounds of the present invention showed antiischemic activity similar to the anti-ischemic activity of BMS-180448, in models of ischemic myocardial damage shot rats. In addition, in contrast to BMS-180448, the compounds of the present invention have markedly low vasodilator activity and, thus, they are superior to conventional medicines as heart selective cardiotoxin funds.

As described the above, compounds of the present invention have excellent anti-ischemic activity in vivo and in vitro, at the same time find low vasodilator activity, so that they can be used as cardiotoxin means for the prevention and treatment of myocardial infarction, congestive heart failure and angina.

In addition, the compounds of the present invention to inhibit angiogenesis in a dose-dependent manner in vascular endothelial cells, so that they can be used to inhibit angiogenesis and the prevention and treatment of rheumatic arthritis, psoriasis, complications from AIDS, cancer or diabetic retinopathy, caused by angiogenesis.

The present invention includes pharmaceutical compositions which contain, in addition to non-toxic, inert pharmaceutically acceptable additives, one or more than one active ingredient of the present invention, and the method of obtaining these drugs.

Non-toxic, inert pharmaceutically acceptable suitable carrier materials include solid, semi-solid or liquid diluents, fillers and additives drugs of all types.

Preferred pharmaceutical preparations are tablets, tablet coatings, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, MAZ is, gels, creams, lotions, powders and sprays.

Tablets, coated tablets, capsules, pills and granules can contain more than one additive, in addition to the active ingredient or ingredients, such as (a) fillers and diluents, for example starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, for example carboxymethylcellulose, alginates, gelatin and polyvinylpyrrolidone, (C) humectants, for example glycerol, (d) dezintegriruetsja agents, for example agar-agar, calcium carbonate and sodium carbonate, (e) the dissolution retarders, for example paraffin, and (f) moderators absorption, for example Quaternary ammonium compounds, (g) wetting agents, for example cetyl alcohol and glycerol monostearate, (h) adsorbents, for example kaolin and bentonite, and (i) lubricants, for example talc, calcium stearate, magnesium stearate and solid polyethylene glycols, or mixtures of the substances listed in paragraphs (a) through (i).

Tablets, coated tablets, capsules, pills and granules can be provided with the customary coatings and shells, optionally containing agents, giving the drug opacity, and may be of such composition that releases the active ingredient or ingredients only or predominantly in a particular part of the intestine, if necessary, slow way, and when the apostrophes compositions which can be used are polymeric substances and waxes.

If necessary, the active ingredient or ingredients may also be present in microencapsulated form with one or more of the above excipients.

Suppositories can contain, in addition to the active ingredient or ingredients, conventional water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cocoa butter, and higher esters (for example, esters With14-alcohol and18-fatty acid) or mixtures of these substances.

Ointments, pastes, creams and gels may contain, in addition to the active ingredient or ingredients, conventional excipients, for example animal and vegetable fats, waxes, paraffins, starch, tragakant, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.

Powders and dusty may contain, in addition to the active ingredient or ingredients, conventional excipients, for example lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorocarbons.

Solutions and emulsions can contain, in addition to the active ingredient or ingredients, conventional excipients, so is e as solvents, solubilizing agents and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, germ oil corn, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters and sorbitan or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also be in a sterile form, which is isotonic with blood.

Suspensions can contain, in addition to the active ingredient or ingredients, conventional excipients, such as liquid diluents, for example water, ethyl alcohol and propylene glycol, and suspendresume agents, for example ethoxylated isostearyl alcohols, polyoxyethylenated and esters sorbitan, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant, or mixtures of these substances.

These forms of drugs can also contain coloring agents, preservatives and additives which improve the smell and taste, for example peppermint oil and eucalyptus oil, and sweetening agents such as saccharin.

Therapeutically active ingredients should preferably prists who participate in the above-mentioned pharmaceutical preparations in a concentration of approximately 0.1-99,5, preferably, about 0.5 to 95 wt.% the total mixture.

The abovementioned pharmaceutical preparations may contain in addition to the compounds according to the present invention with other pharmaceutically active compounds.

The above pharmaceutical drugs get in the usual manner by known methods, for example by mixing the active ingredient or ingredients with fillers.

The above drugs can be used for the introduction of humans and animals either orally, rectally, parenterally (intravenous, intramuscular or subcutaneous), intracavitary, intravaginal, intraperitoneal, or by local (powders, ointments, drops) and for the treatment of infectious diseases in hollow places, and body cavities. Possible suitable drugs are injection solutions, solutions and suspensions for oral therapy and gels, products for infusion, emulsions, ointments or drops, for local therapy may be used in emulsions, ointments or drops, ophthalmic and dermatological preparations of silver salts and other salts, eye drops, eye ointments, powders or solutions. In the case of animals introduction can be carried out in suitable drugs through feed and drinking water.

For humans and animals, in addition, can be used gels, powders, powders, tablets is etki, slow release tablets, premixes, concentrates, granules, pills, capsules, aerosols, sprays and pharmaceutical forms for inhalation. Compounds of the present invention, moreover, can be incorporated into other materials-media, such as, for example, patches (the number of patches for local therapy), collagen or bone cement.

In General, proved suitable for the treatment of people is the introduction of the active ingredient or ingredients of the present invention in total amounts of from about 0.1 to about 20 mg/kg, preferably 0.5 to 10 mg/kg of body weight every 8 hours, if necessary, in the form of several individual doses, to achieve the desired results. However, it may be necessary deviation from the indicated doses and, in particular, it may be necessary to make them a function of the nature and mass of the body being treated of the subject, the nature and severity of the disease, the nature of the drug and route of administration of the medicinal product and the period or interval at which carry out the introduction.

In the tests for acute oral toxicity in rats it was shown that the derivatives of benzopyran, substituted secondary amines, including tetrazol, their stereoisomers or their pharmaceutically acceptable salts exhibit no toxicity to rats at doses up to 2000 mg/kg Thus, the connection is in the present invention can be safely administered in vivo.

The present invention will be explained in more detail with reference to the following examples. However, the following examples are presented only to illustrate the present invention, and the present invention is not limited to them. The structure of the compounds of the present invention detect infrared spectroscopy, spectroscopy nuclear magnetic resonance, mass spectroscopy, liquid chromatography, x-ray crystallography, x-ray diffraction method, rotating crystal, analytical comparison of the calculated data with the found values of the connection.

<EXAMPLE 1> Obtain (2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Stage 1: Obtain (2S,3S,4R)-6-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran

0.05 M aqueous solution of Na2HPO4(16.6 ml) are added to 0.55 M aqueous solution of NaOCl at 41.5 ml of 22.8 mmol) at 0°C. To the aqueous solution is added slowly a solution of (2S)-6-nitro-2-methyl-2-dimethoxymethyl-2H-1-benzopyran (1.5 g, 5.7 mmol) and catalyst (S,S)-Mn (III) (salen) (155 mg, 0.28 mmol) for enantioselective epoxidation developed Jacobsen, in dichloromethane (8.5 ml). The solution was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture is altroot to remove catalyst and the filtrate is extracted with dichloromethane (200 ml). The dichloromethane layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated to remove dichloromethane. The crude product is purified by chromatography (developing solution is n-hexane:ethyl acetate, 4:1)to give (2S,3S,4R)-6-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran, the compound of formula 2 (1.4 g, yield: 88%).

1H NMR (CDCl3, 200 MHz): δ of 1.53 (s, 3H), of 3.25 (s, 3H), 3,49 (s, 3H), 3,79 (d, 1H), 3.96 points (d, 1H), 4,19 (s, 1H), PC 6.82 (d, 1H), 8,09 (DD, 1H), 8,24 (d, 1H).

Stage 2: Obtain N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)Amin

A. Getting 5-chloromethyl-1H-tetrazole

Sodium azide (1,72 g of 26.4 mmol) is added to THF (30 ml)to the mixture is added aluminum chloride (0.88 g, 6.6 mmol) and chloroacetonitrile (0,42 ml, 6.6 mmol) at 0°C. the Reaction mixture is heated to boiling under reflux for 48 hours. After completion of the reaction, the reaction mixture is acidified to pH 3 n HCl solution at 0°and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate. The solvent is removed and the resulting white solid is washed with a mixture of ethyl acetate and n-hexane (1:4), while receiving 5-chloromethyl-1H-tetrazol (1.7 g, yield: 89%).

1H NMR (CDCl3, 200 MHz): δ a 4.86 (s, 2H), 5,10 (user. s, 1H).

b. Getting 5-chloromethyl-1-methyl-1H-tetraza the a and 5-chloromethyl-2-methyl-2H-tetrazol

5-Chloromethyl-1H-tetrazol (300 mg, 2,53 mmol)obtained above, dissolved in DMF (10 ml)solution was added To the2CO3(455 mg, 3,29 mmol). Then to the mixture slowly dropwise for 4 hours at room temperature add MeI (0.16 ml, of 2.53 mmol), the reaction mixture was stirred at room temperature. After the specified reaction to the reaction mixture are added water (30 ml). The reaction mixture was extracted with ether (50 ml), then the organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and concentrate. The residue is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 4:1), while receiving 5-chloromethyl-1-methyl-1H-tetrazol (88,1 mg, 26%) and 5-chloromethyl-2-methyl-2H-tetrazol (184,2 mg, yield: 55%).

5-Chloromethyl-2-methyl-2H-tetrazol:1H NMR (CDCl3, 200 MHz): δ 4,37 (s, 3H), 4,51 (s, 2H),

5-chloromethyl-1-methyl-1H-tetrazol:1H NMR (CDCl3, 200 MHz): δ of 4.05 (s, 3H), to 4.52 (s, 2H).

C. Obtain N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)Amin

p-Chloroaniline (14 g, 13,2 mmol) dissolved in DMF (120 ml), the solution is added To a2CO3(9,49 g, only 68.6 mmol) and 5-chloromethyl-2-methyl-2H-tetrazol (7 g, to 34.4 mmol)obtained in the above stage 2, to the mixture of NaI (4.9 g, to 34.3 mmol). The reaction mixture is stirred for 4 hours at 80°C. After completion shall provide a response to the mixture is added water (60 ml). The reaction mixture was extracted with ether (20 ml) and the organic layer was washed with saturated salt solution, dried over anhydrous MgSO4and concentrate. The residue is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 4:1), thus obtaining N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine, the compound of formula 3 (3.9 g, yield: 61%).

1H NMR (CDCl3, 200 MHz): δ 4,30 (s, 3H), 4,47 (user. s, 1H), 4,56 (s, 2H), only 6.64 (d, 2H), 7,11 (d, 2H).

Stage 3: Obtain (2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

The compound obtained in stage 1 (450 mg, 1.6 mmol), dissolved in acetonitrile (0.5 ml). To the solution add a secondary amine compound containing tetrazole and obtained in the above stage 2 (363 mg, 1.6 mmol), and magnesium perchlorate ((MgClO4)2) (357 mg, 1.6 mmol). The reaction mixture was stirred at room temperature for 10 hours, there was added an aqueous solution of NaHCO3(20 ml). The reaction mixture was extracted with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired with the unity (435 mg, yield: 54%).

1H NMR (CDCl3, 200 MHz): δ of 1.62 (s, 3H), 3,49 (s, 3H)and 3.59 (s, 3H), of 3.95 (DD, 1H), 4,32 (d, 1H), 4,48 (s, 3H), 4.72 in (s, 1H), a 4.83 (d, 1H), ceiling of 5.60 (d, 1H), PC 6.82 (d, 2H), 6,95 (d, 1H), 7,16 (d, 2H), to 7.99 (d, 1H), of 8.06 (DD, 1H).

<EXAMPLE 2> Obtain (2S,3R,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Stage 1: obtain (2S,3R,4R)-6-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 1 of example 1, except using (2S)-6-nitro-2-methyl-2-dimethoxymethyl-2H-1-benzopyran (2.5 g, 9.4 mmol) and (R,R)-Mn (III) (salen). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 4:1), thus obtaining the desired compound (2.1 g, yield: 80%).

1H NMR (CDCl3, 200 MHz): δ of 1.28 (s, 3H), of 3.60 (s, 3H), 3,68 (s, 3H), 3,80 (d, 1H), 3,97 (d, 1H), 4,47 (s, 1H), 6,95 (d, 1H), 8,16 (DD, 1H), 8,31 (d, 1H).

Stage 2: obtain (2S,3R,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (250 mg, 0.9 mmol)obtained in the above stage 1. The crude product is purified column chromatography on silica gel (manifesting the solvent mixture is n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (359 mg, yield: 87%).

1H NMR (CDCl3, 200 MHz): δ to 1.48 (s, 3H), to 3.58 (s, 3H), of 3.64 (s, 3H), 4,29 (s, 3H), 4,42 (DD, 1H), to 4.52 (d, 1H), br4.61 (s, 1H), 4,82 (d, 1H), 5,13 (d, 1H), 5,18 (d, 1H), at 6.84 (d, 2H), 7,05 (d, 1H), 7,15 (d, 2H), 8,08 (DD, 1H), 8,10 (d, 1H).

<EXAMPLE 3> Obtain (2S,3S,4R)-6-nitro-4-[N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (450 mg, 1.6 mmol)obtained in the above stage 1 of example 1, and N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamine (302 mg, 1.6 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (484 mg, yield: 64%).

1H NMR (CDCl3, 200 MHz): δ for 1.49 (s, 3H), of 3.57 (s, 3H), of 3.64 (s, 3H), or 4.31 (s, 3H), 4,32 (DD, 1H), 4,39 (d, 1H), 4,82 (d, 1H), total of 5.21 (d, 1H), 4,63 (s, 1H), 5,27 (d, 1H), 6,79-6,92 (m, 3H), 7,05 (d, 1H), 7,16-7,25 (m, 2H), 8,07 (DD, 1H), of 8.09 (s, 1H).

<4> Obtain (2S,3R,4S)-6-nitro-4-[N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (225 mg, 0.8 mmol)obtained in the above stage 1 of example 2, and N-(2-methyl-2H-tetrazol-5 is methyl)phenylamine (151 mg, 0.8 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (134 mg, yield: 56%).

1H NMR (CDCl3, 200 MHz): δ and 1.63 (s, 3H), 3,51 (s, 3H), 3,55 (s, 3H), 3,91 (DD, 1H), 4,29 (d, 1H), 4,33 (s, 3H), and 4.75 (s, 1H), 4,88 (d, 1H), the 5.45 (d, 1H), 5,69 (d, 1H), 6,80-6,97 (m, 4H), 7,20 (m, 2H), 8,01 (d, 1H), 8,07 (DD, 1H).

<EXAMPLE 5> Obtain (2S,3S,4R)-6-nitro-4-[N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (450 mg, 1.6 mmol)obtained in stage 1 of example 1, and N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamine (332 mg, 1.6 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:1), thus obtaining the desired compound (661 mg, yield: 86%).

1H NMR (CDCl3, 200 MHz): δ of 1.62 (s, 3H), of 3.48 (s, 3H), 3,53 (s, 3H), 3,91 (DD, 1H), 4,33 (s, 3H), 4,35 (d, 1H), 4,71 (s, 1H), 4,82 (d, 1H), 5,38 (d, 1H), 5,50 (d, 1H), 6,85-of 6.96 (m, 5H), 8,03 (s, 1H), with 8.05 (DD, 1H).

<EXAMPLE 6> Obtain (2S,3R,4S)-6-nitro-4-[N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except COI is whether epoxy compound (450 mg, 1.6 mmol)obtained in stage 1 of example 2, and N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (332 mg, 1.6 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:1), thus obtaining the desired compound (528 mg, yield: 69%).

1H NMR (CDCl3, 200 MHz): δ of 1.46 (s, 3H), of 3.57 (s, 3H), 3,63 (s, 3H), or 4.31 (s, 3H), 4,32 (d, 1H), 4,39 (DD, 1H), 4,60 (s, 1H), 4,80 (d, 1H), 5,10 (d, 1H), 5,19 (d, 1H), 6.87 in (d, 2H), 6.90 to (d, 2H), 7,03 (d, 1H), 8,08 (DD, 1H), 8,14 (d, 1H).

<EXAMPLE 7> Obtain (2S,3S,4R)-6-nitro-4-[N-benzyl-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (300 mg, 1.07 mmol)obtained in stage 1 of example 1 and N-benzyl-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (217 mg, 1.07 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:2), thus obtaining the desired compound (282 mg, yield: 55%).

1H NMR (CDCl3, 200 MHz): δ 1,24 (s, 3H), 3,61 (s, 3H), 3,63 (s, 3H), 3,94-4,30 (m, 5H), 4,30 (s, 3H), 4,32 (d, 1H), 4,45 (s, 1H), 4,50 (d, 1H), at 6.84 (d, 1H), 7,20-7,33 (m, 3H), 7,43 (d, 2H), to 7.99 (DD, 1H), total of 8.74 (d, 1H).

<EXAMPLE 8> Obtain (2S,3R,4S)-6-nitro-4-[N-benzyl-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-banter is on

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (200 mg, 0.71 mmol)obtained in stage 1 of example 2 and N-benzyl-N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamine (145 mg, 0.71 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:2), thus obtaining the desired compound (165 mg, yield: 48%).

1H NMR (CDCl3, 200 MHz): δ was 1.58 (s, 3H), 3,30 (s, 3H), 3,34 (s, 3H), 3,89-4,12 (m, 6H), 4,27-to 4.33 (m, 5H), 6,83 (d, 1H), 7.23 percent-7,38 (m, 3H), 7,45 (d, 2H), 8,01 (DD, 1H), 8,73 (d, 1H).

<EXAMPLE 9> Obtain (2S,3S,4R)-6-nitro-4-[N-(4-nitrophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (200 mg, 0.71 mmol)obtained in stage 1 of example 1, and N-(4-nitrophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (167 mg, 0.71 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:1), thus obtaining the desired compound (162 mg, yield: 45%).

1H NMR (CDCl3, 200 MHz): δ to 1.59 (s, 3H), 3,65-to 3.49 (m, 7H), 4,32-and 4.40 (m, 4H), to 4.62 (s, 1H), a 4.86 (d, 1H), 5,14 (d, 1H), the 5.45 (d, 1H), 6,98 (d, 2H), 7,07 (d, 1H), 7,99-8,15 (m, 4H).

<EXAMPLE 10> Obtain (2S,3S,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-shall tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

(2S,3S,4R)-6-Nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran obtained in example 1 (100 mg, 0.2 mmol), dissolved in methanol (2 ml), to the solution was added an aqueous solution of Cu(OAc)2(0,38 ml, 0.4 M aqueous solution, 0.15 mmol). The solution for 30 min at room temperature, slowly add borohydride sodium (NaBH4) (113 mg, 3.0 mmol), the reaction mixture is stirred for 1 hour, after which the reaction mixture are added ethyl acetate (5 ml). The resulting mixture is filtered to remove the precipitated black solid. To the filtrate is added a saturated aqueous solution of NaHCO3(5 ml) and extracted with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel (manifesting the solvent is n-hexane:ethyl acetate, 1:3), thus obtaining the desired compound, which R1represents an amino group (62 mg, yield: 67%).

1H NMR (CDCl3, 200 MHz): δ of 1.34 (s, 3H), 3,51 (s, 3H), 3,61 (s, 3H), was 4.02 (s, 3H), 4,10 (DD, 1H), 4,33 (d, 1H), 4,47 (s, 1H), and 4.68 (d, 1H), 4.80 to equal to 4.97 (m, 2H), 6.35mm (d, 1H), is 6.54 (DD, 1H), 6,74 (d, 1H), for 6.81 (d, 2H), 7,14 (d, 2H).

<EXAMPLE 11> Obtain (2S,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl the -3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (150 mg, 0.3 mmol)obtained in example 2. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:3), thus obtaining the desired compound (74 mg, yield: 52%).

1H NMR (CDCl3, 200 MHz): δ and 1.54 (s, 3H), 3,49 (s, 3H), 3,52 (s, 3H), of 3.95 (DD, 1H), 4,30 (d, 1H), 4,32 (s, 3H), to 4.41-4,70 (m, 3H), 5,33 (d, 1H), 6,45 (s, 1H), 6,55 (DD, 1H), of 6.68 (d, 1H), PC 6.82 (d, 2H), 7,13 (d, 2H).

<EXAMPLE 12> Obtain (2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(1-methyl-1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Stage 1: obtain N-(4-chlorophenyl)-N-(1-methyl-1H-tetrazol-5-ylmethyl)Amin

Perform the same procedure as in stage 2 of example 1, except for using p-Chloroaniline (5.8 g, 45,3 mmol) and 5-chloromethyl-1-methyl-1H-tetrazole (6 g, of 45.3 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (3,68 g, yield: 36%).

Stage 2: obtain (2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(1-methyl-1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (15 mg, of 0.53 mmol)obtained in stage 1 of example 1, and N-(4-chlorophenyl)-N-(1-methyl-1H-tetrazol-5-ylmethyl)amine (121 mg, of 0.53 mmol)obtained in the above stage 1. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:1), thus obtaining the desired compound (194 mg, yield: 72%).

1H NMR (CDCl3, 200 MHz): δ the 1.44 (s, 3H), 3,52 (s, 3H), 3,63 (s, 3H), 4,08 (s, 3H), 4,20 (DD, 1H), 4,35 (d, 1H), 4,58 (s, 1H), 4,84 (d, 1H), 5,08 (d, 1H), 5,58 (d, 1H), for 6.81 (d, 2H), 7,17 (d, 2H), 7,03 (d, 1H), 8,02 (d, 1H), 8,04 (DD, 1H).

<EXAMPLE 13> Obtain (2S,3S,4R)-6-nitro-4-[N-(1-methyl-1H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (150 mg, of 0.53 mmol)obtained in stage 1 of example 1, and N-(1-methyl-1H-tetrazol-5-ylmethyl)amine (101 mg, of 0.53 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (203 mg, yield: 81%).

1H NMR (CDCl3, 200 MHz): δ to 1.47 (s, 3H), of 3.54 (s, 3H), of 3.64 (s, 3H), 4,08 (s, 3H), 4,18 (DD, 1H), 4,37 (d, 1H), br4.61 (s, 1H), 4,84 (d, 1H), 5,18 (d, 1H), to 5.66 (d, 1H), 6,86-was 7.08 (m, 4H), from 7.24 (d, 2H), with 8.05 (s, 1H), 8,10 (DD, 1H).

<14> Obtain (2S,3S,4R)-6-nitro-4-[N-(4-forfinal)-N-(1-methyl-1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-meth is l-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (150 mg, of 0.53 mmol)obtained in stage 1 of example 1, and N-(4-forfinal)-N-(1-methyl-1H-tetrazol-5-ylmethyl)amine (111 mg, of 0.53 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:1), thus obtaining the desired compound (198 mg, yield: 76%).

1H NMR (CDCl3, 200 MHz): δ of 1.43 (s, 3H), of 3.56 (s, 3H), of 3.64 (s, 3H), 4,08 (s, 3H), 4,19 (DD, 1H), 4,37 (d, 1H), 4,57 (s, 1H), 4,84 (d, 1H), 4,99 (d, 1H), vs. 5.47 (d, 1H), 7,03 (d, 1H), 7,94 (DD, 4H), of 8.06 (DD, 1H), of 8.09 (s, 1H).

<EXAMPLE 15> Obtain (2S,3S,4R)-6-nitro-4-[N-benzyl-N-(1-methyl-1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (200 mg, 0.71 mmol)obtained in stage 1 of example 1 and N-benzyl-N-(1-methyl-1H-tetrazol-5-ylmethyl)amine (145 mg, 0.71 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:2), thus obtaining the desired compound (192 mg, yield: 56%).

1H NMR (CDCl3, 200 MHz): δ of 1.30 (s, 3H), 3,63 (s, 3H), of 3.65 (s, 3H), to 3.67 (s, 3H), 3,80-4,10 (m, 4H), 4,37-to 4.62 (m, 4H), 6.89 in (d, 1H), 7,26-to 7.35 (m, 5H), of 8.00 (DD, 1H), to 8.57 (d, 1H).

<EXAMPLE 16> Obtain (2S,3R,4S)-6-nitro-4-[N-benzyl-N-(methyl-1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (200 mg, 0.71 mmol)obtained in stage 1 of example 2 and N-benzyl-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (145 mg, 0.71 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:2), thus obtaining the desired compound (70 mg, yield: 20%).

1H NMR (CDCl3, 200 MHz): δ and 1.60 (s, 3H), 3,39 (s, 3H), 3,41 (s, 3H), of 3.56 (DD, 1H), 3,74-of 3.97 (m, 4H), was 4.02-to 4.33 (m, 6H), at 6.84 (d, 1H), 7.24 to 7,38 (m, 5H), 8,03 (DD, 1H), charged 8.52 (d, 1H).

<EXAMPLE 17> Obtain (2S,3S,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(1-methyl-1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using the epoxy compound (100 mg, 0.2 mmol)obtained in example 12. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (62 mg, yield: 67%).

1H NMR (CDCl3, 200 MHz): δ of 1.34 (s, 3H), 3,51 (s, 3H), 3,61 (s, 3H), was 4.02 (s, 3H), 4,10 (DD, 1H), 4,33 (d, 1H), 4,47 (s, 1H), and 4.68 (d, 1H), 4.80 to equal to 4.97 (m, 2H), 6.35mm (d, 1H), is 6.54 (DD, 1H), 6,74 (d, 1H), for 6.81 (d, 2H), 7,14 (d, 2H).

<EXAMPLE 18> Obtain (2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihyd the on-2H-1-benzopyran

Stage 1: obtain (2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-[2-(1-ethoxyethyl)-2H-tetrazol-5-ylmethyl]amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (900 mg, 3.2 mmol)obtained in stage 1 of example 1, and N-(4-chlorophenyl)-N-[2-(1-ethoxyethyl)-2H-tetrazol-5-ylmethyl)amine (900 mg, 3.2 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (566 mg, yield: 31%).

1H NMR (CDCl3, 200 MHz): δ of 1.12 (m, 3H), of 1.48 (s, 3H), equal to 1.82 (d, 3H), 3,26-to 3.34 (m, 1H), 3,49-3,59 (m, 1H), only 3.57 (s, 3H), of 3.64 (s, 3H), 4,43-4,10 (m, 2H), to 4.62 (s, 1H), a 4.86 (d, 1H), 5,15 (d, 1H), 5,20 (d, 1H), 6,00 (square, 1H), 6,85 (d, 2H), 7,05 (d, 1H), 7,13 (d, 2H), of 8.06 (DD, 1H), 8,10 (d, 1H).

Stage 2: obtain (2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

The compound obtained in the above stage 1 (300 mg, of 0.53 mmol), dissolved in methanol (2 ml)to the solution add 3% aqueous HCl solution (1 ml). The reaction mixture was stirred at room temperature for 12 hours. To the reaction mixture are added water (20 ml). The reaction mixture was extracted with ethyl acetate (30 ml). The organic layer is dried over anhydrous magnesium sulfate and concentrated. Not the shelled product is purified column chromatography on silica gel (manifesting solvent - a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (160 mg, yield: 61%).

1H NMR (CDCl3, 200 MHz): δ for 1.49 (s, 3H), 3,63 (s, 6H), 4,60-and 4.40 (m, 3H), 5,20-of 4.95 (m, 3H), 6,78-6,50 (m, 3H), of 7.00 (d, 1H), 7,10 (d, 2H), to 7.99 (d, 1H), 8,10 (DD, 1H).

<EXAMPLE 19> Obtain (2S,3S,4R)-6-nitro-4-[N-(1H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 1 of example 18, except for using N-[2-(1-ethoxyethyl)-2H-tetrazol-5-ylmethyl]phenylamine, while receiving the connection tetryzoline group of which is protected. Using this compound (272 mg, 0.52 mmol) perform the same procedure as in step 2 of example 18. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (119 mg, yield: 50%).

1H NMR (CDCl3, 200 MHz): δ for 1.49 (s, 3H), 3,62 (s, 6H), 4.75 V-4,43 (m, 3H), to 5.21-equal to 4.97 (m, 3H), 6,84-of 6.73 (m, 3H), of 6.99 (d, 1H), 7,20 for 7.12 (m, 2H), 8,03 (d, 1H), 8,11 (DD, 1H).

<EXAMPLE 20> Obtain (2S,3S,4R)-6-nitro-4-[N-benzyl-N-(1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 1 of example 18, except for using the epoxy compound obtained in stage 1 of example 1 and N-benzyl-N-[2-(1-ethoxyethyl)-2H-tetrazol-5-ylmethyl]Amin is, while receiving specified in the title compound (254 mg, 0.47 mmol). After that, perform the same procedure as in step 2 of example 18. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (107 mg, yield: 48%).

1H NMR (CDCl3, 200 MHz): δ 1,25 (s, 3H), of 3.64 (s, 6H), 3,85 (m, 2H), 4.16 the (d, 1H), to 4.52-to 4.41 (m, 4H), 6.90 to (d, 1H), 7,25-7,17 (m, 5H), with 8.05 (DD, 1H), to 8.41 (d, 1H).

<EXAMPLE 21> Obtain (2S,3S,4R)-6-nitro-4-[N-(3-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (150 mg, of 0.53 mmol)obtained in stage 1 of example 1, and N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:1), thus obtaining the desired compound (249 mg, yield: 9.3 per cent).

1H NMR (CDCl3, 200 MHz): δ a 1.50 (s, 3H), 4,10 (s, 3H), to 4.41-4,34 (m, 4H), to 4.62 (s, 1H), 4,81 (d, 1H), 5,20 (d, 2H), 6,80 (DD, 2H), 6.89 in (s, 1H), 7,07 (m, 2H), 8,08 (m, 2H).

<EXAMPLE 22> Obtain (2S,3S,4R)-6-amino-4-[N-(3-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as the example 10, except for using compound (148 mg, 0.3 mmol)obtained in example 21. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (106 mg, yield: 74%).

1H NMR (CDCl3, 200 MHz): δ of 1.41 (s, 3H), 3,55 (s, 3H), 3,61 (s, 3H), 4,20-and 4.40 (m, 6H), of 4.57 (s, 1H), and 4.68 (d, 1H), 5,09 (d, 1H), 6,40 (d, 1H), is 6.54 (DD, 1H), 6,70-to 6.80 (m, 3H), 6.87 in (s, 1H), was 7.08 (t, 1H).

<EXAMPLE 23> Obtain (2S,3S,4R)-6-nitro-4-[N-(4-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (300 mg, 1.1 mmol)obtained in stage 1 of example 1, and N-(4-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (463 mg, yield: 69%).

1H NMR (CDCl3, 200 MHz): δ to 1.48 (s, 3H), 2,02 (s, 3H), of 3.57 (s, 3H), of 3.64 (s, 3H), of 4.38-or 4.31 (m, 5H), to 4.62 (s, 1H), 4,84 (d, 1H), 5,16 (s, 1H), total of 5.21 (s, 1H), PC 6.82 (d, 2H), 6,99-7,06 (m, 3H), of 8.06 (DD, 1H), 8,12 (, 1H).

<EXAMPLE 24> Obtain (2S,3S,4R)-6-amino-4-[N-(4-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same technique to the to in example 10, except for using the epoxy compound (263 mg, 0.54 mmol)obtained in example 23. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (176 mg, yield: 72%).

1H NMR (CDCl3, 200 MHz): δ of 1.41 (s, 3H), of 2.23 (s, 3H), 3,55 (s, 3H), 3,61 (s, 3H), 4,30 (s, 3H), 4,42 (s, 1H), 4,59 (s, 1H), 4,70 (s, 1H), is 4.93 (s, 1H), 5,11 (d, 1H), 6,44 (d, 1H), 6,53 (DD, 1H), 6,79 (DD, 3H), of 7.00 (d, 2H).

<EXAMPLE 25> Obtain (2S,3R,4S)-6-nitro-4-[N-(3-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (150 mg, of 0.53 mmol)obtained in stage 1 of example 2, and N-(3-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:1), thus obtaining the desired compound (124 mg, yield: 46%).

1H NMR (CDCl3, 200 MHz): δ and 1.63 (s, 3H), 3,52 (s, 3H), 3,55 (s, 3H), 3,95 (square, 1H), 4,36 (m, 4H), and 4.75 (s, 1H), around 4.85 (d, 1H), vs. 5.47 (s, 1H), 5,70 (d, 2H), 6,78 (DD, 1H), 6.90 to (s, 1H), 6,95 (d, 1H), 7,12 (t, 1H), of 7.96 (s, 1H), 8,08 (DD, 1H).

<EXAMPLE 26> Obtain (2S,3R,4S)-6-amino-4-[N-(3-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (180 mg, of 0.37 mmol)obtained in example 25. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (95 mg, yield: 54%).

1H NMR (CDCl3, 200 MHz): δ and 1.54 (s, 3H), 3,40 (s, 1H), 3,50 (s, 3H), 3,53 (s, 3H), 3,92 (square, 1H), 4,32-4,50 (m, 4H), with 4.64 (s, 1H), 4.63 to-to 4.73 (m, 2H), 5,41 (d, 1H), 6.42 per (s, 1H), 6,56 (DD, 1H), 6,68-of 6.78 (m, 3H), 6,91 (s, 1H), 7,05 (t, 1H).

<EXAMPLE 27> Obtain (2S,3R,4S)-6-nitro-4-[N-(4-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (300 mg, 1.1 mmol)obtained in stage 1 of example 2, and N-(4-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (388 mg, yield: 75%).

1H NMR (CDCl3, 200 MHz): δ of 1.62 (s, 3H), 2,24 (s, 3H), 3,49 (s, 3H), 3,55 (s, 3H), 3,92 (square, 1H), 4.26 deaths (m, 4H), 4,74 (s, 1H), a 4.86 (d, 1H), of 5.40 (d, 1H), of 5.55 (d, 1H), for 6.81 (d, 2H),? 7.04 baby mortality-6,91 (m, 3H), 8,02 (s, 3H), of 8.06 (d, 1H).

<EXAMPLE 28> Obtain (2S,3R,4S)-6-amino-4-[N-(4-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-Dima is oxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (238 mg, 0.49 mmol)obtained in example 27. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (168 mg, yield: 69%).

1H NMR (CDCl3, 200 MHz): δ of 1.53 (s, 3H), of 2.23 (s, 3H), of 3.48 (s, 3H), 3,52 (s, 3H), 3,92 (d, 1H), 4,30 (s, 3H), 4,39 (d, 1H), with 4.64 (s, 1H), 4,65-4,74 (m, 2H), 5,35 (d, 1H), 6.48 in (d, 1H), of 6.52 (d, 1H), 6,69 (d, 1H), PC 6.82 (d, 2H), 7,00 (d, 2H).

<EXAMPLE 29> Obtain (2S,3R,4S)-6-nitro-4-[N-(2-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (450 mg, 1.6 mmol)obtained in stage 1 of example 2, and N-(2-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (118 mg, yield: 15%).

1H NMR (CDCl3, 200 MHz): δ and 1.63 (s, 3H), 3,42 (s, 3H), 3,53 (m, 3H), 4,13 (d, 1H), 4,22 (s, 3H), of 4.45 (d, 1H), 4,54 (s, 1H), 4,63 (d, 1H), 5,12 (d, 1H), 6,88-6,93 (m, 2H), 7,16 (t, 1H), 7,34 (DD, 1H), to 7.67 (DD, 1H), 8,08 (DD, 1H), 9,12 (DD, 1H).

<30> Obtain (2S,3R,4S)-6-amino-4-[N-(2-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-m is Teal-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (108 mg, 0.21 mmol)obtained in example 29. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (78 mg, yield: 78%).

1H NMR (CDCl3, 200 MHz): δ for 1.49 (s, 3H), and 3.16 (user. s, 1H), 3,35 (s, 3H), of 3.48 (s, 3H), 4,19 (s, 3H), 4,30 (d, 1H), 4,50 (s, 1H), 4,82 (d, 1H), 4,94 (d, 1H), return of 6.58 (DD, 1H), to 6.67 (d, 1H), 6,85 (t, 1H), 7,10 (t, 1H), 7,28 (d, 1H), 7,45 (d, 1H), 7,74 (d, 1H).

<EXAMPLE 31> Obtain (2S,3R,4S)-6-nitro-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (300 mg, 1.07 mmol)obtained in stage 1 of example 2, and N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (248 mg, yield: 42%).

1H NMR (CDCl3, 200 MHz): δ and 1.63 (s, 3H), 3,50 (s, 3H), 3,55 (s, 3H), 3,92 (square, 1H), 4,30 (user. s, 1H), 4,35 (s, 3H), 4,73 (s, 3H), around 4.85 (d, 1H), vs. 5.47 (s, 1H), 5,62 (d, 2H), 6,86 (d, 2H), of 6.96 (d, 1H), 7,07 (d, 2H), to 7.99 (s, 1H), 8,07 (DD, 1H).

<EXAMPLE 32> Obtain (2S,3R,4S)-6-amino-4-[N-(4-trifloromethyl)-N-(2-what ethyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (165 mg, 0.30 mmol)obtained in example 31. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (117 mg, yield: 75%).

1H NMR (CDCl3, 200 MHz): δ and 1.54 (s, 3H), of 3.48 (s, 3H), 3,52 (s, 3H), 3,95 (square, 1H), 4,32 (s, 1H), to 4.41 (d, 1H), 4,66-4,74 (m, 3H), are 5.36 (d, 1H), 6,46 (s, 1H), is 6.54 (DD, 1H), 6,70 (d, 1H), 6,86 (d, 2H), 7,03 (d, 2H).

<EXAMPLE 33> Obtain (2S,3R,4S)-6-nitro-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (300 mg, 1.07 mmol)obtained in stage 1 of example 2, and N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-yl)methyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (92 mg, yield: 16%).

1H NMR (CDCl3, 200 MHz): δ and 1.63 (s, 3H), 3,51 (s, 3H), of 3.54 (s, 3H), 3,98 (user. s, 1H), 4,35 (m, 4H), 4,74 (s, 1H), 4.92 in (d, 1H), 5,80 (s, 1H), 6,72 (d, 1H), of 6.96 (d, 2H), 7,40-7,47 (m, 2H), 7,95 (m, 1H), of 8.06 (DD, 1H).

<EXAMPLE 34> Obtain (2S,3R,4S)-6-amino-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-meth is l-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (92 mg, 0,17 mmol)obtained in example 33. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (26 mg, yield: 30%).

1H NMR (CDCl3, 200 MHz): δ of 1.55 (s, 3H), 3,50 (s, 3H), 3,53 (s, 3H), 3,99 (user. s, 1H), 4,32-and 4.40 (m, 4H), with 4.64-4.80 to (m, 3H), 5.56mm (s, 1H), 6,40 (s, 1H), 6,55 (DD, 1H), of 6.71 (d, 1H), 6,95 (d, 2H), 7,42 (d, 2H).

<EXAMPLE 35> Obtain (2S,3R,4S)-6-nitro-4-[N-(3-acetylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (300 mg, 1.07 mmol)obtained in stage 1 of example 2, and N-(3-acetylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:1), thus obtaining the desired compound (232 mg, yield: 42%).

1H NMR (CDCl3, 200 MHz): δ and 1.63 (s, 3H), of 2.54 (s, 3H), of 3.56 (s, 6H), of 3.97 (s, 1H), 4,33 (m, 4H), was 4.76 (s, 1H), 4.92 in (d, 1H), 5,43 (s, 1H), 5,80 (s, 1H), of 6.96 (d, 1H),? 7.04 baby mortality (d, 1H), 7.24 to 7,38 (m, 2H), 7,60 (d, 1H), of 7.96 (d, 1H).

<EXAMPLE 36> Obtain (2S,3R,4S)-6-amino-4-[N-[3-(1-hydroxyethyl)phenyl]-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-Dimitar imethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (151 mg, 0.29 mmol)obtained in example 35. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (90 mg, yield: 64%).

1H NMR (CDCl3, 200 MHz): δ 1,43 (DD, 3H), and 1.54 (s, 3H), 3,51 (s,3 H), of 3.54 (s, 3H), of 3.97 (d, 1H), 4,30-4,45 (m, 4H), 4,65-4,78 (m, 3H), vs. 5.47 (d, 1H), 6,47-6,56 (m, 2H), 6,68-6,77 (m, 3H), of 6.99 (d, 1H), 7,16 (t, 1H)

<EXAMPLE 37> Obtain (2S,3R,4S)-6-nitro-4-[N-(2-methyl-4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (450 mg, 1.6 mmol)obtained in stage 1 of example 2, and N-[(2-methyl-4-fluoro)phenyl]-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (323 mg, yield: 40%).

1H NMR (CDCl3, 200 MHz): δ and 1.63 (s, 3H), 2,47 (s, 3H), 3,38 (s, 3H), 3,40 (s, 3H), 3,99 (d, 1H), 4,12 (d, 1H), 4,23 (s, 1H), 4,33 (d, 1H), 4,47 (s, 1H), 4,67 (d, 1H), 4,78 (d, 1H), 6.75 in-6,85 (m, 2H), 7,55 (DD, 1H), of 8.06 (DD, 1H), 9,02 (d, 1H).

<EXAMPLE 38> Obtain (2S,3R,4S)-6-amino-4-[N-(2-methyl-4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (205 mg, 0.41 mmol)obtained in example 37. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (143 mg, yield: 74%).

1H NMR (CDCl3, 200 MHz): δ for 1.49 (s, 3H), 2,43 (s, 3H), 2,98 (d, 1H), 9,31 (s, 3H), 3.46 in (s, 3H), 4,19 (s, 3H), 4,23 (d, 1H), 4,37 (d, 1H), 4,43 (s, 3H), to 4.81 (d, 1H), return of 6.58 (DD, 1H), 6,65-to 6.80 (m, 3H), 7,40 (DD, 1H), to 7.68 (d, 1H).

<EXAMPLE 39> Obtain (2S,3R,4S)-6-nitro-4-[N-(4-methoxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (300 mg, 1.07 mmol)obtained in stage 1 of example 2, and N-(4-methoxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (417 mg, yield: 78%).

1H NMR (CDCl3, 200 MHz): δ of 1.62 (s, 3H), of 3.48 (s, 3H), of 3.54 (s, 3H), 3,74 (s, 3H), 3,93 (DD, 1H), 4,32 (m, 4H), 4.72 in (s, 1H), a 4.83 (d, 1H), of 5.34 (d, 1H), 5,46 (d, 2H), 6,76-to 6.95 (m, 3H), 8,03 (d, 1H), 8,08 (DD, 1H).

<EXAMPLE 40> Obtain (2S,3R,4S)-6-amino-4-[N-(4-methoxy-phenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimetix the methyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10 except for using the compound (300 mg, 0.6 mmol)obtained in example 39. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (270 mg, yield: 96%).

1H NMR (CDCl3, 200 MHz): δ of 1.53 (s, 3H), 3,39 (s, 2H), 3,48 (s, 3H), 3,51 (s, 3H), of 3.73 (s, 3H), 3,93 (DD, 1H), 4,30 (s, 3H), of 4.44 (d, 1H), br4.61 (m, 1H), 4,67 (d, 1H), 5,17 (d, 1H), 6,54 (m, 1H), 6,69 (d, 1H), 6,77 (d, 2H), 6.89 in (d, 2H)

<EXAMPLE 41> Obtain (2S,3R,4S)-6-nitro-4-[N-(2-methyl-4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (450 mg, 1.6 mmol)obtained in stage 1 of example 2, and N-[(2-methyl-4-chlorophenyl)]-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (235 mg, yield: 28%).

1H NMR (CDCl3, 200 MHz): δ and 1.63 (s, 3H), of 2.46 (s, 3H), 3,38 (s, 3H), 3,41 (s, 3H), 3,99-4,18 (m, 2H), 4,23 (s, 3H), 4,33 (d, 1H), 4,48 (6, 1H), 4,67 (d, 1H), 4,87 (s, 1H), 6.90 to (d, 1H), 7,01-to 7.09 (m, 2H), 7,50 (d, 1H), 8,07 (DD, 1H), 8,99 (d, 1H).

<EXAMPLE 42> Obtain (2S,3R,4S)-6-amino-4-[N-(2-methyl-4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)and the Ino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (164 mg, 0.31 mmol)obtained in example 41. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (86 mg, yield: 57%).

1H NMR (CDCl3, 200 MHz): δ a 1.50 (s, 3H), 2,42 (s, 3H), 2,99 (d, 1H), 3,32 (s, 3H), 3.46 in (s, 3H), 4,03-to 4.23 (m, 4H), 4,19 (s, 3H), 4,43 (s, 1H), 4,48 (d, 1H), 4,81 (d, 1H), return of 6.58 (DD, 1H), of 6.68 (d, 1H), of 6.96? 7.04 baby mortality (m, 2H), 7,34 (d, 1H), 7,65 (d, 1H).

<EXAMPLE 43> Obtain (2S,3R,4S)-6-nitro-4-[N-(2-methoxy-5-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (400 mg, 1.4 mmol)obtained in stage 1 of example 2, and N-[(2-methoxy-5-methyl)phenyl]-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (615 mg, yield: 85%).

1H NMR (CDCl3, 200 MHz): δ of 1.64 (s, 3H), 3,37 (s, 3H), 3,50 (s, 3H), 3,93 (s, 3H), 4,13 (d, 1H), 4,23 (s, 1H), 4.75 in (s, 1H), around 4.85 (d, 1H), and 4.68 (s, 1H), 4,99 (d, 1H), USD 5.76 (d, 1H), 5,79 (d, 1H), 6,80 (s, 2H), 6.87 in (d, 1H), 7,35 (s, 1H), 8,02 (DD, 1H), 8,83 (d, 1H).

<EXAMPLE 44> Obtain (2S,3R,4S)-6-amino-4-[N-(2-methoxy-5-were)-N-(2-m is Teal-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (414 mg, 0.8 mmol)obtained in example 43. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (285 mg, yield: 74%).

1H NMR (CDCl3, 200 MHz): δ of 1.53 (s, 3H), of 2.21 (s, 3H), 3,41 (s, 3H), 3,44 (s, 3H), 3,83 (s, 3H), 4,00-4,11 (m, 2H), 4,20 (s, 3H), of 4.49 (d, 1H), 4.53-in (s, 1H), br4.61 (d, 1H), to 4.98 (d, 1H), is 6.54 (DD, 1H), 6,64-6,76 (m, 3H), 7,18 (s, 1H), 7,25 (s, 1H).

<EXAMPLE 45> Obtain (2S,3R,4S)-6-nitro-4-[N-(2,4-dimethyl-phenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (250 mg, 0.89 mmol)obtained in stage 1 of example 2, and N-(2,4-dimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (256 mg, yield: 57%).

1H NMR (CDCl3, 200 MHz): δ of 1.62 (s, 3H), of 2.23 (s, 3H), of 2.46 (s, 3H), 3,39 (s, 3H), 3,40 (s, 3H), 4,12-4,16 (m, 2H), 4,22 (s, 3H), and 4.40 (d, 1H), 4,51 (s, 1H), with 4.64 (d, 1H), 4,89 (d, 1H), 6.87 in-6,94 (m, 3H), of 7.48 (d, 1H), with 8.05 (DD, 1H), 8,99 (DD, 1H).

<EXAMPLE 46> Obtain (2S,3R,4S)-6-amino-4-[N-(2,4-dimethyl-phenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)and the Ino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (180 mg, 0.36 mmol)obtained in example 45. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (155 mg, yield: 92%).

1H NMR (CDCl3, 200 MHz): δ for 1.49 (s, 3H), of 2.20 (s, 3H), 2,42 (s, 3H), 3,10 (users, 3H), of 3.32 (s, 3H), of 3.45 (s, 3H), of 4.12 (d, 1H), 4.16 the (s, 3H), 4,20 (d, 1H), 4,45 (s, 1H), 4,49 (d, 1H), 4,82 (d, 1H), 6,56 (DD, 1H), to 6.67 (d, 1H), 6,83 (s, 1H), to 6.88 (s, 1H), 7,33 (d, 1H), to 7.67 (d, 1H).

<EXAMPLE 47> Obtain (2S,3R,4S)-6-nitro-4-[N-(2,6-dimethyl-phenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (300 mg, 1.1 mmol)obtained in stage 1 of example 2, and N-(2,6-dimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (153 mg, yield: 29%).

1H NMR (CDCl3, 200 MHz): δ and 1.63 (s, 3H), 2,55 (user. s, 6H), 3,13 (d, 1H), 3,30 (s, 3H), 3,40 (s, 3H), 3,62 (d, 1H), 4,15 (d, 1H), 4,22 (s, 3H), 4,37 (s, 1H), to 4.62 (d, 1H), is 4.93 (d, 1H), 6.89 in-6,94 (m, 4H), with 8.05 (DD, 1H), 9,17 (d, 1H).

<EXAMPLE 48> Obtain (2S,3R,4S)-6-amino-4-[N-(2,6-dimethyl-phenyl)-N-(2-methyl-2H-those whom razol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (107 mg, 0.21 mmol)obtained in example 47. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (78 mg, yield: 80%).

1H NMR (CDCl3, 200 MHz): δ is 1.51 (s, 3H), of 2.53 (s, 6H), 2.91 in (d, 1H), or 3.28 (s, 3H), of 3.45 (s, 3H), 3,54 (s, 1H), 3,60 (d, 1H), 3,98 is 4.13 (m, 1H), 4,15 (s, 3H), 4,29 (d, 1H), 4,46 (s, 1H), 4,87 (d, 1H), 6,59 (d, 1H), only 6.64 (d, 1H), 6,68-6,86 (m, 3H), to 7.84 (s, 1H).

<EXAMPLE 49> Obtain (2S,3R,4S)-6-nitro-4-[N-(2,3-dimethyl-phenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (300 mg, 1.07 mmol)obtained in stage 1 of example 2, and N-(2,3-dimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (253 mg, yield: 47%).

1H NMR (CDCl3, 200 MHz): δ and 1.63 (s, 3H), and 2.26 (s, 3H), 2.40 a (s, 3H), 3,38 (s, 3H), 3,39 (s, 3H), Android 4.04 (d, 1H), 4,13 (d, 1H), 4,21 (s, 3H), and 4.40 (d, 1H), 4,49 (s, 1H), 4,67 (d, 1H), 4,89 (d, 1H), 6,85 (d, 1H), 6,89 (d, 1H), 7,02 (t, 1H), 7,47 (d, 1H), of 8.06 (DD, 1H), 9,00 (d, 1H).

<EXAMPLE 50> Obtain (2S,3R,4S)-6-amino-4-[N-2,3-dimethyl-phenyl]-N-(2-meth is l-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (177 mg, 0.35 mmol)obtained in example 49. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (131 mg, yield: 80%).

1H NMR (CDCl3, 200 MHz): δ to 1.48 (s, 3H), of 2.23 (s, 3H), of 2.35 (s, 3H), 2,90 (s, 1H), 3,30 (s, 3H), of 3.45 (s, 3H), 4,07-of 4.25 (m, 2H), 4,18 (s, 3H), of 4.44 (s, 1H), 4,51 (d, 1H), a 4.83 (d, 1H), return of 6.58 (DD, 1H), of 6.68 (d, 1H), is 6.78 (d, 1H), of 6.96 (t, 1H), 7,31 (d, 1H), 7,71 (d, 1H).

<EXAMPLE 51> Obtain (2S,3R,4S)-6-nitro-4-[N-(2-isopropylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (300 mg, 1.07 mmol)obtained in stage 1 of example 2, and N-(2-isopropylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (192 mg, yield: 35%).

1H NMR (CDCl3, 200 MHz): δ of 1.27 (d, 3H), and 1.63 (s, 3H), 3,38 (s, 3H), on 3.36 (s, 3H), 4,15 (d, 1H), 4,20 (s, 3H), or 4.31 (d, 1H), 4,45 (s, 1H), 4.75 in (d, 1H), 4,82 (d, 1H), 6.90 to (d, 1H), 7,02 for 7.12 (m, 2H), 7.23 percent (d, 1H), 7,60 (DD, 1H), 8,07 (DD, 1H), 9,02 (DD, 1H).

<EXAMPLE 52> Obtain (2S,3R,4S)-6-amino-4-[N-(2-isopropylphenyl)-N-(2-methyln-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (140 mg, 0.27 mmol)obtained in example 51. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (83 mg, yield: 64%).

1H NMR (CDCl3, 200 MHz): δ of 1.23 (d, 3H), of 1.27 (d, 3H), 1,49 (s, 3H), 2,90 (user. s, 1H), 3.27 to (s, 3H), 3,44 (s, 3H), 3,61 (m, 1H), 4,10-4,20 (m, 4H), to 4.41 (s, 1H), of 4.44 (d, 1H), 4,88 (d, 1H), 6,59 (DD, 1H), of 6.68 (d, 1H), 6,95-7,06 (m, 2H), 7,19 (DD, 1H), of 7.48 (DD, 1H), 7,65 (d, 1H).

<EXAMPLE 53> Obtain (2S,3R,4S)-6-nitro-4-[N-(4-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (400 mg, of 1.42 mmol)obtained in stage 1 of example 2, and N-[(2-etoxycarbonyl)phenyl]-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (161 mg, yield: 33%).

1H NMR (CDCl3, 200 MHz): δ to 1.35 (t, 3H), and 1.63 (s, 3H), 3,52 (s, 3H), 3,55 (s, 3H), 3,92 (s, 1H), 4,33 (m, 6H), 4,51-of 4.75 (m, 2H), 4,91 (d, 1H), 5,49 (s, 1H), of 5.81 (d, 1H), 6.89 in - 6,99 (m, 3H), 7,87-8,10 (m, 4H).

<EXAMPLE 54> Obtain (2S,3R,4S)-6-amino-4-[N-(4-ethoxycarbonylphenyl)-N-(2-methyl-2 is-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (118 mg, 0.22 mmol)obtained in example 53. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (49 mg, yield: 44%).

1H NMR (CDCl3, 200 MHz): δ of 1.33 (t, 3H), and 1.54 (s, 3H), 3,25 (s, 1H), 3,49 (s, 3H), 3,52 (s, 3H), 3,99 (s, 1H), 4,24 was 4.42 (m, 5H), with 4.64-to 4.81 (m, 3H), to 5.58 (s, 1H), 6,53 (DD, 1H), 6,70 (d, 1H), 6.89 in (d, 2H), 7,87 (d, 2H).

<EXAMPLE 55> Obtain (2S,3R,4S)-6-amino-4-[N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (217 mg, 0.46 mmol)obtained in example 4. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (157 mg, yield: 77%).

1H NMR (CDCl3, 200 MHz): δ and 1.54 (s, 3H), 3,30 (s, 1H), 3,49 (s, 3H), 3,52 (s, 3H), 3.96 points (d, 1H), 4,30 (s, 3H), of 4.45 (d, 1H), with 4.64 (s, 1H), 4,71 (d, 1H), 5,43 (d, 1H), 6,46 (s, 1H), of 6.52 (DD, 1H), 6,69 (d, 1H), 6,76 (d, 1H), 6.90 to (d, 1H), 7,25 (m, 2H).

<EXAMPLE 56> Obtain (2S,3R,4S)-6-amino-4-[N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10,except for using compound (104 mg, 0.21 mmol)obtained in example 6. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (85 mg, yield: 88%).

1H NMR (CDCl3, 200 MHz): δ of 1.53 (s, 3H), of 3.48 (s, 3H), 3,51 (s, 3H), 3.96 points (d, 1H), 4,29 (s, 3H), of 4.44 (d, 1H), br4.61 (s, 1H), 4,67 (d, 1H), 5,26 (d, 1H), 6,53 (d, 2H), 6,69 (d, 1H), 6,85 (d, 2H), to 6.88 (d, 2H).

<EXAMPLE 57> Obtain (2S,3R,4S)-6-amino-4-[N-benzyl-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (75 mg, 0.15 mmol)obtained in example 8. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (57 mg, yield: 87%).

1H NMR (CDCl3, 200 MHz): δ is 1.51 (s, 3H), up 3.22 (s, 3H), 3,39 (s, 3H), 3,61 (d, 1H), 3,83 (d, 1H), 3,92 (d, 1H), was 4.02 (d, 1H), 4,12-4,27 (m, 3H), or 4.31 (s, 3H), of 6.52 (DD, 1H), 6,59 (d, 1H), 7,22-7,37 (m, 4H), of 7.48 (d, 2H).

<EXAMPLE 58> Obtain (2S,3R,4S)-6-nitro-4-[N-(3-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (460 mg, of 1.65 mmol)obtained in stage 1 of example 2,and N-[(3-methoxycarbonyl)phenyl]-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (360 mg, yield: 40%).

1H NMR (CDCl3, 200 MHz): δ 1,22 (s, 3H), of 3.57 (s, 3H), with 3.89 (s, 3H), of 4.13 (m, 2H), 4,30 (s, 3H), 4,88 (s, 1H), 6,98 (m, 2H), 7,27 (d, 1H), 7,30 (d, 1H), 7,69 (1H), of 7.96 (m, 1H), 8,07 (DD, 1H).

<EXAMPLE 59> Obtain (2S,3R,4S)-6-amino-4-[N-(3-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (520 mg, or 0.57 mmol)obtained in example 58. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:2), thus obtaining the desired compound (360 mg, yield: 40%).

1H NMR (CDCl3, 200 MHz): δ of 1.53 (s, 3H)and 3.59 (d, 6H), of 3.84 (s, 3H), 3,98 (m, 2H), 4,12 (s, 3H), 4,15 (m, 1H), 4,78 (s, 1H), of 5.55 (m, 1H), 6,66 (m, 2H), of 6.71 (d, 1H), 7,01 (m, 1H), 7,17 (t, 1H), 7,38 (m, 1H), to 7.68 (m, 1H).

<EXAMPLE 60> Obtain (2S,3R,4S)-6-nitro-4-[N-(2-hydroxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (370 mg, of 1.32 mmol)obtained in stage 1 of example 2, and N-(2-hydroxyphenyl)-N-(2-methyl-2 is-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (140 mg, yield: 21%).

1H NMR (CDCl3, 200 MHz): δ of 1.66 (s, 3H), 3,44 (d, 6N), of 4.13 (m, 2H), 4,33 (s, 3H), to 4.81 (s, 1H), 4,91 (m, 1H), 4,99 (m, 1H), 6,99 (m, 1H), 7,55 (m, 1H), 8,02 (DD, 1H), 8,54 (DD, 1H).

<EXAMPLE 61> Obtain (2S,3R,4S)-6-amino-4-[N-(2-hydroxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (210 mg, 0.42 mmol)obtained in example 60. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (71 mg, yield: 37%).

1H NMR (CDCl3, 200 MHz): δ of 1.57 (s, 3H), 3,55 (d, 6H), to 4.15 (m, 2H), 4,33 (s, 3H), of 4.44 (8, 1H), and 4.75 (m, 1H), 4,84 (m, 1H), 6,86 (m, 6H), 7,49 (m, 1H).

<EXAMPLE 62> Obtain (2S,3R,4S)-6-nitro-4-[N-(2-methoxy-4-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (380 mg, of 1.36 mmol)obtained in stage 1 of example 2, and N-[(2-methoxy-4-methoxycarbonyl)phenyl]-N-(2-methyl-2H-tetrazol-5-ileti is)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:3), thus obtaining the desired compound (250 mg, yield: 48%).

1H NMR (CDCl3, 200 MHz): δ of 1.64 (s, 3H), 3,48 (d, 6H), 3,90 (s, 3H), 4,01 (s, 3H), 4,33 (m, 2H), 4,66 (s, 1H), 4,99 (m, 1H), 5,19 (m, 1H), 6,92 (d, 1H), 7,55 (m, 3H), 8,02 (DD, 1H), total of 8.74 (m, 1H).

<EXAMPLE 63> Obtain (2S,3R,4S)-6-amino-4-[N-(2-methoxy-4-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10 except for using the compound (200 mg, and 0.37 mmol)obtained in example 62. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (90 mg, yield: 45%).

1H NMR (CDCl3, 200 MHz): δ of 1.52 (s, 3H), 3,42 (d, 6H), to 3.58 (m, 1H, in), 3.75 (s, 3H), of 3.77 (s, 3H), 3,98 (m, 1H), 4,49 (s, 1H), 4,57 (m, 1H), and 4.68 (m, 1H), 5,26 (d, 1H), to 6.57 (m, 1H), 7,27 (m, 2H), 7,55 (m, 2H).

<EXAMPLE 64> Obtain (2S,3R,4S)-6-nitro-4-[N-(2-methyl-4-hydroxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (350 mg, of 1.26 mmol)obtained in stage 1 of example 2, and N-[(2-methyl-4-HYDR which XI)phenyl]-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (190 mg, yield: 30%).

1H NMR (CDCl3, 200 MHz): δ to 1.61 (s, 3H), 2,43 (s, 6H), 3,39 (d, 6H,) to 3.64 (m, 1H), 3.96 points (m, 1H), 4.16 the (s, 1H), 4,46 (s, 1H), and 4.68 (m, 1H), 4.72 in (m, 1H), 5,81 (user. s, 1H), 6,59 (DD, 1H), is 6.61 (m, 1H), 6,91 (d, 1H), 7,27 (d, 1H), 8,04 (DD, 1H), 9,05 (m, 1H).

<EXAMPLE 65> Obtain (2S,3R,4S)-6-amino-4-[N-(2-methyl-4-hydroxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (140 mg, 0.29 mmol)obtained in example 64. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (70 mg, yield: 53%).

1H NMR (CDCl3, 200 MHz): δ to 1.48 (s, 3H), 2,32 (s, 3H), and 3.31 (d, 6H,) 3,63 (m, 1H), 3,78 (m, 1H), 4,10 (s, 3H), 4,23 (m, 1H), 4,33 (s, 1H), 4,82 (m, 1H), 6,34 (DD, 1H), 6,59 (m, 3H), 7,26 (m, 1H), 7,71 (m, 1H).

<EXAMPLE 66> Obtain (2S,3R,4S)-6-nitro-4-[N-(2-ethylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (270 mg, 0.98 mmol)obtained in stage 1 of example 2 and N-(2-ethylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (100 mg, yield: 22%).

1H NMR (CDCl3, 200 MHz): δ of 1.27 (t, 3H), of 1.62 (s, 3H), 2,89 (t, 2H,) to 3.36 (d, 6H), 3,82 (d, 1H), 4,10 (d, 1H), 4,18 (s, 3H), 4,28 (d, 1H), 4,35 (s, 1H), 4,84 (d, 1H), 7,10 (m, 4H), to 7.59 (DD, 1H), 8,08 (DD, 1H), of 9.02 (m, 1H).

<EXAMPLE 67> Obtain (2S,3R,4S)-6-amino-4-[N-(2-ethylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (190 mg, 0,39 mmol)obtained in example 66. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (30 mg, yield: 14%).

1H NMR (CDCl3, 200 MHz): δ to 1.24 (t, 3H), 1,49 (s, 3H), 2,65 (m, 1H), 2.91 in (m, 1H), 3.27 to (d, 6H), 4.09 to (m, 2H), 4,14 (s, 3H), 4,42 (s, 1H), 4,45 (m, 1H), 4.92 in (m, 1H), 6,70 (m, 2H), 7,05 (m, 3H), 7,45 (d, 1H), to 7.67 (m, 1H).

<EXAMPLE 68> Obtain (2S,3R,4S)-6-nitro-4-[N-(2-methyl-5-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (420 mg, 1.48 mmol)obtained in stage 1 of example 2, and N-(2-IU the Il-5-(methoxycarbonyl)phenyl]-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (520 mg, yield: 51%).

1H NMR (CDCl3, 200 MHz): δ 1,64 (s, 1H), has 2.56 (s, 3H), 3,41 (d, 6H,) a 3.87 (s, 3H), 4,07 (m, 2H), 4,10 (s, 3H), 4,48 (s, 1H), 4,80 (d, 1H), is 4.93 (d, 1H), 6,93 (d, 1H), 7,17 (d, 1H), to 7.61 (m, 1H), 8,07 (DD, 1H), of 8.25 (m, 1H), 8,97 (m, 1H).

<EXAMPLE 69> Obtain (2S,3R,4S)-6-amino-4-[N-(2-methyl-5-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (220 mg, 0.40 mmol)obtained in example 68. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (90 mg, yield: 44%).

1H NMR (CDCl3, 200 MHz): δ to 1.48 (s, 3H), 2.49 USD (s, 3H), 3,44 (d, 6H), and 3.72 (m, 1H), 3,83 (m, 1H), of 4.05 (s, 3H), 4,49 (s, 1H), 4,54 (d, 1H), 4,96 (d, 1H), of 6.68 (m, 2H), 7,25 (d, 1H), 7,49 (m, 2H), with 8.05 (m, 1H).

<EXAMPLE 70> Obtain (2S,3R,4S)-6-nitro-4-[N-(2-hydroxy-5-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (400 mg, was 1.43 mmol)obtained in stage 1 the example is 2, and N-(3-hydroxy-5-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (280 mg, yield: 39%).

1H NMR (CDCl3, 200 MHz): δ to 1.67 (s, 3H), of 2.33 (s, 3H), 3.46 in (d, 6H), 4,07 (m, 2H), 4,25 (s, 3H), 4,87 (s, 1H), a 4.86 (d, 1H), is 4.93 (d, 1H), 6,80 (s, 1H), 6,94 (d, 1H), 7,39 (m, 1H), 8,07 (DD, 1H), 8,33 (m, 1H), 8,53 (m, 1H).

<EXAMPLE 71> Obtain (2S,3R,4S)-6-amino-4-[N-(2-hydroxy-5-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (140 mg, 0.29 mmol)obtained in example 70. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (70 mg, yield: 53%).

1H NMR (CDCl3, 200 MHz): δ of 1.62 (s, 3H), of 2.33 (s, 3H), 3,30 (d, 6H,) 3,62 (m, 1H), 3,74 (m, 1H), of 3.78 (s, 3H), 4,17 (m, 1H), 4,33 (s, 1H), 4,82 (d, 1H), 6.35mm (m, 1H), 6,59 (m, 3H), 7,22 (m, 1H), 7,71 (m, 1H).

<EXAMPLE 72> Obtain (2S,3R,4S)-6-nitro-4-[N-(2,4,6-trimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (400mg, of 1.43 mmol)obtained in stage 1 of example 2, and N-(2,4,6-trimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (260 mg, yield: 35%).

1H NMR (CDCl3, 200 MHz): δ of 1.62 (s, 3H), of 2.20 (s, 3H), 2.49 USD (m, 6H), 3,30 (d, 6H), 3,68 (m, 2H), 4,10 (m, 1H), 4,17 (s, 3H), 4,20 (s, 1H), and 4.68 (m, 1H), is 4.93 (m, 1H), to 6.88 (m, 2H), 6,93 (d, 1H), 8,07 (DD, 1H), 9,14 (m, 1H).

<EXAMPLE 73> Obtain (2S,3R,4S)-6-amino-4-[N-(2,4,6-trimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (190 mg, of 0.37 mmol)obtained in example 73. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (90 mg, yield: 52%).

1H NMR (CDCl3, 200 MHz): δ of 1.64 (s, 3H), 2,17 (s, 3H), 2,52 (m, 6H), and 3.31 (d, 6H), of 3.65 (m, 2H), 4,07 (s, 3H), 4,30 (m, 1H), 4,47 (s, 1H), 4,89 (m, 1H), 6,56 (m, 1H), 6.73 x (m, 3H), to 7.84 (m, 1H).

<EXAMPLE 74> Obtain (2S,3S,4R)-6-nitro-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using epoksidnogo compound (340 mg, to 1.21 mmol), obtained in stage 1 of example 1, and N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (522 mg, yield: 82%).

1H NMR (CDCl3, 200 MHz): δ a 1.50 (s, 3H)and 3.59 (s, 3H), 3,63 (s, 3H,) to 4.38 (s, 5H), 4,60 (s, 1H), 4,90 (m, 1H), and 5.30 (m, 2H), 7,00 (m, 3H), 7,43 (m, 2H), 8,10 (m, 2H).

<EXAMPLE 75> Obtain (2S,3S,4R)-6-amino-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10 except for using the compound (200 mg, and 0.37 mmol)obtained in example 74. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:2), thus obtaining the desired compound (155 mg, yield: 81%).

1H NMR (CDCl3, 200 MHz): δ a 1.50 (s, 3H), 3,63 (s, 3H), 3,68 (s, 3H), and 4.40 (s, 5H), 4,63 (s, 1H), 4,80 (m, 1H), to 4.98 (m, 1H), 5,20 (m, 1H), 6,50 (m, 1H), 6,63 (m, 1H), 6.90 to (d, 1H), 7,00 (m, 2H), 7,50 (m, 2H).

<EXAMPLE 76> Obtain (2R,3S,4R)-6-nitro-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Stage 1: obtain (2R,3S,4S)-6-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran

You anaut the same technique, as in stage 1 of example 1, except using (2R)-6-nitro-2-methyl-2-dimethoxymethyl-2H-1-benzopyran (1.5 g, 5.7 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 4:1), thus obtaining the desired compound (1.3 g, yield: 82%).

1H NMR (CDCl3, 200 MHz): δ of 1.28 (s, 3H), of 3.60 (s, 3H), 3,61 (s, 3H), 3,80 (d, 1H), 3,97 (d, 1H), 4,47 (s, 1H), 6,94 (d, 1H), 8,15 (DD, 1H), 8.30 to (d, 1H).

Stage 2: obtain (2R,3R,4R)-6-nitro-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (426 mg and 1.51 mmol)obtained in the above stage 1, and N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (391 mg and 1.51 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (111 mg, yield: 14%).

1H NMR (CDCl3, 200 MHz): δ and 1.63 (s, 3H), 3,50 (s, 3H), 3,55 (s, 3H) 3,92 (square, 1H), 4,30 (user. s, 1H), 4,35 (s, 3H), 4,73 (s, 1H), around 4.85 (d, 1H), vs. 5.47 (s, 1H), 5,62 (d, 2H), 6,86 (d, 2H), of 6.96 (d, 1H), 7,07 (d, 2H), to 7.99 (s, 1H), 8,07 (DD, 1H).

<EXAMPLE 77> Obtain (2R,3S,4R)-6-amino-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-34-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (93 mg, 0,17 mmol)obtained in example 76. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (73 mg, yield: 84%).

1H NMR (CDCl3, 200 MHz): δ and 1.54 (s, 3H), of 3.48 (s, 3H), 3,52 (s, 3H) 3,95 (square, 1H), 4,32 (s, 1H), to 4.41 (d, 1H), 4,66-4,74 (m, 3H), are 5.36 (d, 1H), 6,46 (s, 1H), is 6.54 (DD, 1H), 6,70 (s, 1H), 6,86 (d, 2H), 7,03 (d, 2H).

<EXAMPLE 78> Obtain (2R,3R,4S)-6-nitro-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Stage 1: obtain (2R,3R,4R)-6-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 1 of example 1, except using (2R)-6-nitro-2-methyl-2-dimethoxymethyl-2H-1-benzopyran (2.5 g, 9.4 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 4:1), thus obtaining the desired compound (2.3 g, yield: 87%).

1H NMR (CDCl3, 200 MHz): δ and 1.56 (s, 3H), of 3.28 (s, 3H), 3,49 (s, 3H), 3,82 (d, 1H), 3,99 (d, 1H), 4,21 (s, 1H), 6,85 (d, 1H), 8,13 (DD, 1H), 8,28 (d, 1H).

Stage 2: obtain (2R,3R,4S)-6-nitro-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimetix the methyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (604 mg, of 2.15 mmol)obtained in the above stage 1, and N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (555 mg, of 2.15 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (700 mg, yield: 60%).

1H NMR (CDCl3, 200 MHz): δ a 1.50 (s, 3H), to 3.58 (s, 3H), of 3.65 (s, 3H,) to 4.38 (m, 5H), 4,60 (s, 1H), 4,90 (m, 1H), and 5.30 (m, 2H), 7,05 (d, 1H), 7,01 (m, 1H), 7,43 (d, 2H), 8,10 (DD, 1H).

<EXAMPLE 79> Obtain (2R,3R,4S)-6-amino-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (376 mg, 0.70 mmol)obtained in example 78. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:3), thus obtaining the desired compound (284 mg, yield: 80%).

1H NMR (CDCl3, 200 MHz): δ of 1.42 (s, 3H), of 3.56 (s, 3H), 3,62 (s, 3H), and 4.40 (s, 5H), 4,63 (s, 1H), 4,80 (m, 1H), to 4.98 (m, 1H), 5,20 (m, 1H), 6,50 (m, 1H), 6,63 (m, 1H), 6.90 to (d, 1H), 7,00 (m, 2H), 7,50 (m, 2H).

<EXAMPLE 80> Obtain (2S,3S,4R)-6-nitro-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-di is ethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (293 mg, 1.04 mmol)obtained in stage 1 of example 1, and N-(4-trifloromethyl)-N-(2-methyl-1H-tetrazol-5-ylmethyl)amine (285 mg, 1.04 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (433 mg, yield: 75%).

1H NMR (CDCl3, 200 MHz): δ 1,45 (s, 3H)and 3.59 (s, 3H), 3,63 (s, 3H), 4,34 (s, 3H), and 4.40 (m, 2H), 4,63 (s, 1H), a 4.83 (d, 1H), 5,19 (m, 2H), 6.87 in (m, 2H),? 7.04 baby mortality (m, 3H), 8,08 (m, 2H).

<EXAMPLE 81> Obtain (2S,3S,4R)-6-amino-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (240 mg, 0.43 mmol)obtained in example 80. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (189 mg, yield: 83%).

1H NMR (CDCl3, 200 MHz): δ of 1.43 (s, 3H), of 3.60 (s, 3H), 3,63 (s, 3H), 4,39 (s, 3H), and 4.40 (m, 2H), 4,60 (s, 1H), amounts to 4.76 (d, 2H), 4,90 (s, 1H), 5,16 (m, 1H), gold 6.43 (s, 1H), 6,59 (m, 1H), to 6.88 (m, 3H), 7,18 (m, 2H).

<EXAMPLE 82> Obtain (2R,3R,4S)-6-nitro-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-DIMET kemetyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (260 mg, of 0.92 mmol)obtained in the above stage 1 of example 78, N-(4-trifloromethyl)-N-(2-methyl-1H-tetrazol-5-ylmethyl)amine (253 mg, of 0.92 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (406 mg, yield: 80%).

1H NMR (CDCl3, 200 MHz): δ 1,45 (s, 3H)and 3.59 (s, 3H), 3,63 (s, 3H), 4,34 (d, 3H), and 4.40 (m, 2H), 4,63 (s, 1H), a 4.83 (d, 1H), 5,19 (m, 2H), 6.87 in (m, 2H),? 7.04 baby mortality (m, 3H), 8,08 (m, 2H).

<EXAMPLE 83> Obtain (2R,3R,4S)-6-amino-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (240 mg, 0.43 mmol)obtained in example 82. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (176 mg, yield: 78%).

1H NMR (CDCl3, 200 MHz): δ of 1.40 (s, 3H), of 3.56 (s, 3H), 3,61 (s, 3H), 4,37 (s, 3H), and 4.40 (m, 2H), 4,60 (s, 1H), amounts to 4.76 (d, 2H), 4,90 (s, 1H), 5,16 (m, 1H), gold 6.43 (s, 1H), 6,59 (m, 1H), to 6.88 (m, 3H), 7,18 (m, 2H).

<EXAMPLE 84> Obtain (2R,3S,4R)-6-nitro-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroc and-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (504 mg, to 1.79 mmol)obtained in the above stage 1 of example 76, and N-(4-trifloromethyl)-N-(2-methyl-1H-tetrazol-5-ylmethyl)amine (490 mg, to 1.79 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (645 mg, yield: 65%).

1H NMR (CDCl3, 200 MHz): δ and 1.63 (s, 3H), 3,50 (s, 3H), 3,55 (s, 3H), 3,92 (square, 1H), 4,30 (user. s, 1H), 4,35 (s, 3H), 4,73 (s, 1H), around 4.85 (d, 1H), vs. 5.47 (s, 1H), 5,62 (d, 2H), 6,86 (d, 2H), of 6.96 (d, 1H), 7,07 (d, 2H), to 7.99 (s, 1H), 8,09 (DD, 1H).

<EXAMPLE 85> Obtain (2R,3S,4R)-6-amino-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (295 mg, of 0.53 mmol)obtained in example 84. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:3), thus obtaining the desired compound (225 mg, yield: 81%).

1H NMR (CDCl3, 200 MHz): δ and 1.54 (s, 3H), of 3.48 (s, 3H), 3,52 (s, 3H), 3,95 (square, 1H), 4,32 (s, 1H), to 4.41 (d, 1H), 4,66-4,74 (m, 3H), are 5.36 (d, 1H), 6,46 (s, 1H), is 6.54 (DD, 1H), 6,70 (d, 1H), 6,86 (d, 2H), 7,03 (d, 2H).

<EXAMPLE 86> Obtain (2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-METI is-2N-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

The compound (700 mg, of 1.43 mmol)obtained in the above example 21 were dissolved in dichloromethane (5 ml), the solution is added triethylamine (0.3 ml) and acetic anhydride (160 ml). To the reaction mixture 4-dimethylaminopyridine (50 mg). The reaction mixture was stirred at room temperature for 5 hours. To the reaction mixture are added water (30 ml). The reaction mixture was extracted with ethyl acetate (30 ml) and the organic layer was washed with saturated salt solution (20 ml), dried over anhydrous magnesium sulfate and concentrated. The crude product is purified column chromatography on silica gel (manifesting the solvent is n-hexane:ethyl acetate, 1:1), thus obtaining the desired compound (652 mg, 83%).

1H NMR (CDCl3, 200 MHz): δ of 1.41 (s, 3H), of 1.65 (d, 3H), 3,52 (s, 3H), of 3.57 (s, 3H), 4,25 (s, 5H), was 4.76 (d, 1H), 5,24 (d, 1H), 5,71 (d, 1H), 6.90 to (d, 2H), 7,00 (d, 1H), 7,15 (d, 2H), 8,08 (DD, 1H), 8,71 (d, 1H).

<EXAMPLE 87> Obtain (2S,3S,4R)-6-acetamido-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-acetoxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

The compound (150 mg, 0.32 mmol), obtained in the above example 10, dissolved in dichloromethane (3 ml), the solution is added triethylamine (0,11 ml) and acetic anhydride (65 ml). To the reaction mixture 4-dimethylaminopyridine (11 mg). The reaction mixture was stirred at room temperature for 12 hours. The reaction is ionic mixture is added water (20 ml). The reaction mixture was extracted with ethyl acetate (20 ml) and the organic layer was washed with saturated salt solution (20 ml), dried over anhydrous magnesium sulfate and concentrated. The crude product is purified column chromatography on silica gel (manifesting the solvent is n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (158 mg, 88%).

1H NMR (CDCl3, 200 MHz): δ to 1.32 (s, 3H), of 1.65 (s, 3H), of 2.08 (s, 3H), 3,47 (s, 3H), of 3.56 (s, 3H), 4,33-4,21 (user. s, 5H), and 4.68 (d, 1H), 5,13 (d, 1H), 5,62 (d, 1H), 6,86 (d, 3H), 7,11 (d, 2H), 7,39 (user. s, 1H), 7,49 (s, 1H), 7,63 (d, 1H).

<EXAMPLE 88> Obtain (2S,3S,4R)-6-atsetamino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 86, except for using compound (359 mg, from 0.76 mmol)obtained in example 10. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:4), thus obtaining the desired compound (376 mg, yield: 96%).

1H NMR (CDCl3, 200 MHz): δ of 1.41 (s, 3H), 2,07 (s, 3H), of 3.56 (s, 3H), 3,61 (s, 3H), or 4.31 (user. s, 4H), of 4.57 (s, 1H), 4.72 in (d, 1H), 4,94 (user. s, 1H), is 5.06 (d, 1H), 6,83 (user. s, 1H), 6.90 to (d, 2H), 7,10 (d, 3H), 7,20 (user. s, 1H), 7,38 (DD, 1H).

<EXAMPLE 89> Obtain (2S,3S,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-acetoxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-Ben is apirana

Perform the same procedure as in example 10, except for using compound (150 mg, 0.28 mmol)obtained in example 86. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:3), thus obtaining the desired compound (102 mg, yield: 77%).

1H NMR (CDCl3, 200 MHz): δ of 1.30 (s, 3H), of 1.62 (s, 3H), of 3.45 (s, 3H), of 3.56 (s, 3H), 4,18 (s, 1H), 4,23 (s, 1H), or 4.31 (d, 1H), and 4.68 (d, 1H), 5,12 (d, 1H), 5,58 (d, 1H), to 6.57 (DD, 1H), 6,72 (d, 1H), 6.87 in (d, 2H), 7,03 (d, 1H), 7,11 (d, 2H).

<EXAMPLE 90> Obtain (2S,3R,4S)-6-bromo-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using (2S,3R,4R)-6-bromo-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (192 mg, 0.61 mmol) and N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (136 mg, of 0.60 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:2), thus obtaining the desired compound (55 mg, yield: 17%).

1H NMR (CDCl3, 200 MHz): δ of 1.26 to 1.31 (m, 3H), of 1.57 (s, 3H), of 3.48 (s, 3H), 3,52 (s, 3H), 3.96 points-3,91 (m, 1H), 4,32 (s, 3H), and 4.68 (d, 1H), 4,78 (d, 1H), of 5.05 (user. s, 1H), 5,49 (d, 1H), 6,88-6,74 (m, 3H), 7,27 for 7.12 (m, 5H).

<EXAMPLE 91> Obtain (2R,3R,4S)-6-bromo-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-g is droxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except using (2R,3R,4R)-6-bromo-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (232 mg, of 0.74 mmol) and N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (164 mg, of 0.74 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 3:1), thus obtaining the desired compound (165 mg, yield: 41%).

1H NMR (CDCl3, 200 MHz): δ 1,28-to 1.25 (t, 3H), of 1.42 (s, 3H), 3,55 (s, 3H), 3,61 (s, 3H), 4,33-4,30 (user. s, 5H), 4,58 (s, 1H), 4.75 in (d, 1H), 5,14-of 5.05 (user. s, 1H), 6.87 in-PC 6.82 (m, 3H), 7,12 (d, 2H), 7,28-of 7.23 (m, 2H).

<EXAMPLE 92> Obtain (2S,3R,4S)-6-bromo-4-[N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using (2S,3R,4R)-6-bromo-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (209 mg, 0.66 mmol) and N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (138 mg, 0.66 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 6:1), thus obtaining the desired compound (165 mg, yield: 51%).

1H NMR (CDCl3, 200 MHz): δ 1,28-to 1.21 (m, 3H), and 1.56 (s, 3H), 3,47 (d, 3H), 3,51 (s, 3H), 4.92 in (d, 1H), 4,30 (d, 3H), and 4.40 (s, 1H), 4,66 (d, 1H), amounts to 4.76 (d, 1H), 5,00 (user. s, 1H), 5,41 (d, 1H), 6,94-6,72 (m, H), 7,21-7,26 (m, 2H).

<EXAMPLE 93> Obtain (2R,3R,4S)-6-bromo-4-[N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except using (2R,3R,4R)-6-bromo-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (198 mg, to 0.63 mmol) and N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (130 mg, to 0.63 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 4:1), thus obtaining the desired compound (175 mg, yield: 53%).

1H NMR (CDCl3, 200 MHz): δ 1,20-of 1.27 (m, 3H), of 1.40 (s, 3H), 2,03 (d, 3H), 3,55 (s, 3H), of 3.60 (s, 3H), 4,28-to 4.33 (m, 5H), 4,56 (s, 1H), 4,73 (d, 1H), 5,02 (d, 1H), 6,80-to 6.88 (m, 5H), 7,22-7,26 (m, 2H).

<EXAMPLE 94> Obtain (2R,3R,4S)-6-bromo-4-[N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except using (2R,3R,4R)-6-bromo-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (204 mg, of 0.65 mmol) and N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamine (123 mg, of 0.65 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 3:1), thus obtaining the desired compound (196 mg, yield: 60%).

1NMR (CDCl 3, 200 MHz): δ 1,27-of 1.39 (m, 3H), 1,60 (s, 3H), 3,50 (d, 3H), 3,53 (s, 3H), 3,91 (d, 1H), 4,30-4,50 (user. s, 3H), of 4.77 (d, 1H), 4,80 (d, 1H), 5,02 (user. s, 1H), of 5.40 (d, 1H), 6,62-6,89 (m, 5H), 7,10-7,40 (m, 5H).

<EXAMPLE 95> Obtain (2R,3S,4R)-6-methansulfonate-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except using (2R,3S,4S)-6-methansulfonate-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (231 mg, 0.70 mmol) and N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (187 mg, 0.84 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:1), thus obtaining the desired compound (104 mg, yield: 27%).

1H NMR (CDCl3, 200 MHz): δ was 1.58 (s, 3H), 3,06 (s, 3H), 3,52 (d, 6H), 4,07 (m, 2H), 4,32 (s, 3H), of 4.67 (s, 1H), 5,10 (s, 1H), 5,50 (d, 1H), 6,78-to 7.15 (m, 7H).

<EXAMPLE 96> obtain (2S,3S,4S)-6-methansulfonate-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 95. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:1), thus obtaining the desired compound (64 mg, yield: 17%).

1H NMR (CDCl3, 200 MHz): δthe 1.44 (s, 3H), 3.04 from (s, 3H)and 3.59 (d, 6N), 4,32 (s, 3H), of 4.57 (s, 1H), 4,78 (d, 1H), 5,10 (d, 1H), 6,94-7,14 (m, 7H).

<EXAMPLE 97> Obtain (2S,3S,4R)-6-hydroxy-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

The compound (50 mg, 0.09 mmol)obtained in example 96, dissolved in ethanol (2 ml), to the solution was added 6 n KOH (1 ml). The reaction mixture is heated to boiling under reflux for 1 hour, to the mixture was added 1 N. HCl (10 ml). The reaction mixture was extracted with ethyl acetate (20 ml). The organic layer is dried over anhydrous magnesium sulfate and concentrated, thus obtaining the crude product. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:1), thus obtaining the desired compound (40 mg, yield: 93%).

1H NMR (CDCl3, 200 MHz): δ to 1.38 (s, 3H), of 3.56 (d, 3H), 4,28 (s, 3H), 4,55 (s, 1H), 4,90 (s, 1H), 5,10 (d, 1H), 6.75 in-7,10 (m, 7H).

<EXAMPLE 98> Obtain (2S,3S,4R)-6-nitro-5-methyl-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using (2S,3S,4S)-6-nitro-5-methyl-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran (100 ml, 0.34 mmol). The crude product is purified column of chromatographie the on silica gel (manifesting solvent - a mixture of n-hexane:ethyl acetate, 1:1), thus obtaining the desired compound (80 mg, yield: 45%).

1H NMR (CDCl3, 200 MHz): δ of 1.30 (s, 3H), 2,12 (s, 3H), 3,60 (d, 6N), 4,10 (s, 3H), 4,23 (s, 3H), 4,30 (s, 2H), to 4.62 (d, 1H), 5,08 (d, 1H), 6,80-7,80 (m, 6N).

<EXAMPLE 99> Obtain (2S,3S,4R)-6-nitro-4-[N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-methoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using (2S,3S,4S)-6-nitro-2-methyl-2-methoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (100 ml, 0.40 mmol) and amine compound (116 mg, 0.52 mmol)obtained in step 2 of example 1. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:1), thus obtaining the desired compound (110 mg, yield: 58%).

1H NMR (CDCl3, 200 MHz): δ of 1.40 (s, 3H), 3.43 points (s, 3H), 3,70 (DD, 2H), 4,28 (s, 2H), 4,90 (d, 1H), 5,12 (d, 1H), 6,80-7,20 (m, 5H), with 8.05 (m, 2H).

<EXAMPLE 100> Obtain (3R,4S)-6-cyano-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using (3R,4R)-6-cyano-2,2-dimethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (300 mg, 1,49 mmol) and amine compound (270 mg, 1,19 mmol)obtained in step 2 of example 1. The crude product Colo cleanse the face-to-face chromatography on silica gel (manifesting solvent - a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (109 mg, yield: 22%).

1H NMR (CDCl3, 200 MHz): δ of 1.42 (s, 3H), 1,58 (s, 3H), 3,85 (d, 1H), 4,13 (s, 3H), 4,22 (DD, 1H), 4,77 (d, 1H), 5,10 (d, 1H), 5,20 (d, 1H), for 6.81-6,93 (m, 3H), 7,15 (d, 1H), was 7.36 (s, 1H), 7,46 (DD, 1H).

<EXAMPLE 101> Obtain (3R,4S)-6-cyano-4-[N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using (3R,4R)-6-cyano-2,2-dimethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (200 mg, 0,99 mmol) and N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamine (188 mg, 0,99 mmol). The crude product is distilled, thus obtaining the desired compound (229 mg, yield: 77%).

1H NMR (CDCl3, 200 MHz): δ of 1.43 (s, 3H), of 1.59 (s, 3H), 3,88 (d, 1H), 4,32 (DD, 1H), 4,33 (s, 3H), 4,80 (d, 1H), 5,19 (d, 1H), 5,39 (d, 1H), 6,92-6,70 (m, 4H), 7,20 (m, 2H), 7,40 (s, 1H), 7,45 (DD, 1H).

<EXAMPLE 102> Obtain (2S,3S,4R))-6-hydroxy-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-3-methyl-2,2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

The compound (64 mg, 0.1 mmol)obtained in example 96, dissolved in ethanol (2 ml), to the solution was added 6 n KOH (1 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture is neutralized 1 N. HCl and extracted with ethyl acetate (20 ml). The organic layer is dried over anhydrous magnesium sulfate and the concentration of irout. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:2), thus obtaining the desired compound (45 mg, yield: 82%).

1H NMR (CDCl3, 200 MHz): δ to 1.38 (s, 3H), 3,53 (s, 3H), of 3.56 (s, 3H), 4,28 (s, 3H), 4,55 (s, 1H), 4,90 (s, 1H), 5,10 (d, 1H), 6.75 in-7,10 (m, 7H).

<EXAMPLE 103> Obtain (2S,3S,4R)-8-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using (2S,3S,4S)-8-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (751 mg, 0.67 mmol) and N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (597 mg, to 2.67 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (691 mg, yield: 51%).

1H NMR (CDCl3, 200 MHz): δ of 1.41 (s, 3H), 3,49 (s, 3H), 3,53 (s, 3H), 4,24 (s, 3H), 4,46-4,72 (m, 4H), of 5.06 (d, 1H), 6,79 (d, 1H), 6,91 (t, 1H),? 7.04 baby mortality (d, 2H), 7,45 (d, 1H), to 7.67 (d, 1H).

<EXAMPLE 104> Obtain (2S,3S,4R)) 8-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10, except for using compound (170 mg, 0.34 mmol)obtained in example 103. Neocis the config product was then purified column chromatography on silica gel (manifesting solvent - a mixture of n-hexane:ethyl acetate, 1:2), thus obtaining the desired compound (128 mg, yield: 80%).

1H NMR (CDCl3, 200 MHz): δ of 1.43 (s, 3H), 3,55 (s, 3H), of 3.60 (s, 3H), 4,29 (s, 3H), 4,35 (d, 1H), to 4.62 (s, 2H), 4,89 (user. s, 1H), 5,12 (d, 1H), 6,45 (d, 1H), 6,60-6,72 (m, 2H), PC 6.82 (d, 2H), 7,10 (d, 2H).

<EXAMPLE 105> Obtain (2R,3S,4R)-8-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except using (2R,3S,4S)-8-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (75 mg, or 2.67 mmol) and N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (597 mg, to 2.67 mmol). The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (200 mg, yield: 15%).

1H NMR (CDCl3, 200 MHz): δ and 1.63 (s, 3H), 3.46 in (s, 6H), 4.00 points (d, 1H), or 4.31 (s, 3H), amounts to 4.76 (s, 2H), and 5.30 (user. s, 1H), 5,59 (d, 1H), 6,78-6,94 (m, 3H), 7,13 (d, 2H), 7.23 percent (d, 1H), 7,66 (d, 1H).

<EXAMPLE 106> Obtain (2R,3S,4R))-8-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 10 except for using the compound (100 mg, 0.20 mmol)obtained in example 105. The crude product is purified column chromatography on silica the Le (the solvent - a mixture of n-hexane:ethyl acetate, 1:1), thus obtaining the desired compound (70 mg, yield: 74%).

1H NMR (CDCl3, 200 MHz): δ and 1.60 (s, 3H), of 3.48 (s, 3H), 3,53 (s, 3H), 4.00 points (d, 1H), 4,30 (s, 3H), 4,42 (user. s, 1H), 4,63 (s, 2H), of 5.40 (d, 1H), 6,45 (d, 1H), 6,61-6,70 (m, 2H), 6,83 (d, 2H), 7,11 (d, 2H).

<EXAMPLE 107> Obtain (2R,3R,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in stage 3 of example 1, except for using the epoxy compound (250 mg, 0.9 mmol), obtained in stage 1 of example 2. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (340 mg, yield: 82%).

1H NMR (CDCl3, 200 MHz): δ to 1.67 (s, 3H), 3,49 (s, 3H)and 3.59 (s, 3H), of 3.95 (DD, 1H), 4,32 (d, 1H), 4,48 (s, 3H), of 4.83 (d, 1H), 4.72 in (s, 1H), ceiling of 5.60 (d, 1H), PC 6.82 (d, 2H), 6,95 (d, 1H), 7,16 (d, 2H), to 7.99 (d, 1H), of 8.06 (DD, 1H).

<EXAMPLE 108> Obtain (2R,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

(2R,3R,4S)-6-Nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran (100 mg, 0.2 mmol)obtained in example 107, dissolved in methanol (2 ml), to the solution was added an aqueous solution of Cu(OAc)2(0,38 ml, 0.4 M water R is the target, 0.15 mmol). To the solution is added slowly at room temperature for 30 min borohydride sodium (NaBH4, 113 mg, 3.0 mmol). The reaction mixture is stirred for 1 hour, to the mixture are added ethyl acetate (5 ml). The reaction mixture was filtered to remove a black precipitate. To the resulting filtrate is added an aqueous solution of NaHCO3(5 ml). The filtrate is extracted with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:3), thus obtaining the desired compound (60 mg, yield: 63%).

1H NMR (CDCl3, 200 MHz): δ of 1.34 (s, 3H), 3,51 (s, 3H), 3,61 (s, 3H), was 4.02 (s, 3H), 4,10 (DD, 1H), 4,33 (d, 1H), 4,47 (s, 1H), and 4.68 (d, 1H), 4.80 to equal to 4.97 (m, 2H), 6.35mm (d, 1H), is 6.54 (DD, 1H), 6,74 (d, 2H), for 6.81 (d, 2H), 7,14 (d, 2H).

<EXAMPLE 109> Obtain (2R,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Epoxy compound (450 mg, 1.6 mmol)obtained in stage 1 of example 1, dissolved in acetonitrile (0.5 ml). To the solution add a secondary amine (363 mg, 1.6 mmol)containing tetrazole group, obtained in stage 2 of example 1, with magnesium perchlorate (Mg(ClO4)2, 357 mg, 1.6 mmol). The reaction mixture was stirred at those who tell 10 hours, to this mixture an aqueous solution of NaHCO3(20 ml). The reaction mixture was extracted with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 2:1), thus obtaining the desired compound (480 mg, yield: 60%).

1H NMR (CDCl3, 200 MHz): δ to 1.48 (s, 3H), to 3.58 (s, 3H), 4,29 (s, 3H), 4,42 (DD, 1H), br4.61 (s, 1H), 4,82 (d, 1H), 5,13 (d, 1H), 5,18 (d, 1H), at 6.84 (d, 1H), 7,05 (d, 1H), 7,15 (d, 2H), 8,08 (DD, 1H), 8,10 (d, 1H).

<EXAMPLE 110> Obtain (2R,3S,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

(2R,3S,4R)-6-Nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran (100 mg, 0.2 mmol)obtained in example 109, dissolved in methanol (2 ml), to the solution was added an aqueous solution of Cu(OAc)2(0,38 ml, 0.4 M aqueous solution, 0.15 mmol). To the solution is added slowly at room temperature for 30 min borohydride sodium (NaBH4, 113 mg, 3.0 mmol). The reaction mixture is stirred for 1 hour, to the mixture are added ethyl acetate (5 ml). The reaction mixture was filtered to remove a black precipitate. To the resulting filtrate is added an aqueous solution of NaHCO3(5 ml). The filter is t extracted with ethyl acetate (30 ml). The organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate and concentrated. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:3), thus obtaining the desired compound (58 mg, yield: 62%).

1H NMR (CDCl3, 200 MHz): δ and 1.54 (s, 3H), 3,49 (s, 3H), 3,52 (s, 3H), 4,30 (d, 1H), 4,32 (s, 3H), to 4.41-4,70 (m, 3H), 5,33 (d, 1H), 6,45 (s, 1H), 6,55 (DD, 1H), of 6.68 (d, 1H), PC 6.82 (d, 2H), 7,13 (d, 2H).

<EXAMPLE 111> Obtain (2S,3R,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

(2S,3S,4R)-6-Nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran (100 mg, 0.20 mmol) was dissolved in a mixed solvent (3.8 ml toluene/tetrahydrofuran, 1/1). To the solution at 0°add triphenylphosphine (268 mg, 0,99 mmol) and 4-nitrobenzoic acid (149 mg, 0.87 mmol). Then to the reaction mixture via syringe slowly add diethylazodicarboxylate (156 μl, 0,99 mmol). The reaction mixture is stirred for 3 days at room temperature. The solvent is removed under reduced pressure, thus obtaining the crude product. The crude product is purified by chromatography on a short column of silica gel to give the intermediate. More clear is not carried out. The crude product is dissolved in dichloromethane. To the solution at -20°With dropwise slowly added DiBAL-H (1M solution in hexane, of 1.36 mmol). The reaction mixture was stirred for 20 min. To complete the reaction, to the reaction mixture is added a saturated solution of salt. The organic layer is separated. The solvent is removed under reduced pressure, thus obtaining the crude product. The crude product is purified column chromatography on silica gel (manifesting the solvent is a mixture of n-hexane:ethyl acetate, 1:2), thus obtaining the desired compound (18 mg, yield: 19%).

1H NMR (CDCl3, 200 MHz): δ of 1.52 (s, 3H), 3,63 (s, 3H), of 3.69 (s, 3H), 4,32 (s, 3H), 4,48 (d, 1H), 4.53-in (m, 2H), 4,74 (s, 1H), 5,32 (d, 1H), the 5.45 (d, 1H), 6,85 (d, 2H), 7,03 (d, 1H), 7,16 (d, 2H), 8,11 (DD, 1H).

<EXAMPLE 112> Obtain (2S,3R,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 110, except for using (2S,3R,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran (100 mg, 0.2 mmol)obtained in example 111. Get the desired compound (62 mg, yield: 67%).

1H NMR (CDCl3, 200 MHz): δ to 1.48 (s, 3H), 3,52 (s, 3H), of 3.56 (s, 3H), 4,01 (s, 3H), of 4.13 (m, 1H), 4,48 (d, 1H), and 4.75 (m, 1H), 4,90 (m, 3H), 6.42 per (d, 1H), 6,62 (DD, 1H), PC 6.82 (d, 2H), 6,94 (d, 2H), 7,18 (d, 2H).

Perform the same procedure as in example 111, except for using (2S,3R,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran (100 mg, 0.20 mmol)obtained in example 2. Get the desired compound (14 mg, yield: 14%).

1H NMR (CDCl3, 200 MHz): δ of 1.57 (s, 3H), 3,53 (s, 3H), 3,62 (s, 3H), 4,34 (s, 3H), to 4.52 (d, 1H), 4,67 (m, 2H), 4,82 (m, 1H), 5,41 (d, 1H), vs. 5.47 (d, 1H), 6,86 (d, 2H), 7,12 (d, 1H), 7,18 (d, 2H), 8,12 (d, 1H), to 8.14 (DD, 1H).

<EXAMPLE 114> Obtain (2S,3S,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 110, except for using (2S,3S,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran (100 mg, 0.20 mmol)obtained in example 113. Get the desired compound (55 mg, yield: 57%).

1H NMR (CDCl3, 200 MHz): δ to 1.48 (s, 3H), 3,53 (s, 3H), to 3.58 (s, 3H), was 4.02 (DD, 3H), 4,35 (m, 1H), to 4.38 (d, 1H), 4.92 in (m, 2H), 5,35 (m, 2H), 6.42 per (d, 1H), 6,59 (d, 1H), 6.73 x (d, 1H), 6,92 (d, 2H), 7,19 (d, 2H).

<EXAMPLE 115> Obtain (2R,3R,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-methoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 111, except using (2R,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran (100 mg, 0.20 mmol)obtained in example 2. Get the desired compound (11 mg, yield: 11%).

1H NMR (CDCl3, 200 MHz): δ of 1.57 (s, 3H), 3,53 (s, 3H), 3,62 (s, 3H), 4,34 (s, 3H), to 4.52 (d, 1H), 4,67 (m, 2H), 4,82 (m, 1H), 5,41 (d, 1H), vs. 5.47 (d, 1H), 6,86 (d, 2H), 7,12 (d, 1H), 7,18 (d, 2H), 8,12 (d, 1H), to 8.14 (DD, 1H).

<EXAMPLE 116> Obtain (2R,3R,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 110, except using (2R,3R,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran (100 mg, 0.20 mmol)obtained in example 115. Get the desired compound (51 mg, yield: 55%).

1H NMR (CDCl3, 200 MHz): δ to 1.48 (s, 3H), 3,53 (s, 3H), to 3.58 (s, 3H), was 4.02 (DD, 3H), 4,35 (m, 1H), to 4.38 (d, 1H), 4.92 in (m, 2H), 5,35 (m, 2H), 6.42 per (d, 1H), 6,59 (DD, 1H), 6.73 x (d, 1H), 6,92 (d, 2H), 7,19 (d, 2H).

<EXAMPLE 117> Obtain (2R,3S,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 111, except using (2R,3R,4S)-6-nitro-4-[N-(4-harfe who yl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran (100 mg, 0.20 mmol)obtained in example 107. Get the desired compound (13 mg, yield: 13%).

1H NMR (CDCl3, 200 MHz): δ of 1.52 (s, 3H), 3,63 (s, 3H), of 3.69 (s, 3H), 4,32 (s, 3H), 4,48 (d, 1H), 4.53-in (m, 2H), 4,74 (m, 1H), 5,32 (d, 1H), the 5.45 (d, 1H), 6,85 (d, 2H), 7,03 (d, 1H), 7,16 (d, 2H), of 8.09 (d, 1H), 8,11 (DD, 1H).

<EXAMPLE 118> Obtain (2R,3S,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran

Perform the same procedure as in example 110, except using (2R,3S,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran (100 mg, 0.20 mmol)obtained in example 117. Get the desired compound (55 mg, yield: 59%).

1H NMR (CDCl3, 200 MHz): δ to 1.48 (s, 3H), 3,52 (s, 3H), of 3.56 (s, 3H), 4,01 (s, 3H), of 4.13 (m, 1H), 4,48 (d, 1H), and 4.75 (m, 1H), 4,90 (m, 3H), 6.42 per (d, 1H), 6,62 (DD, 1H), PC 6.82 (d, 1H), 6,94 (d, 2H), 7,18 (d, 2H).

Compounds of the present invention obtained in the above examples, shown in table 1.

TABLE 1A

TABLE 1b

TABLE 1C

The experiment confirming the pharmacological action of the compounds of formula 1 according to the present invention, is performed as described below.

<EXPERIMENTAL EXAMPLE 1> Vasodilator action on the blood from the UD, deformed in rats

The experiment confirming whether the compounds of formula 1 according to the present invention vasodilatory effect on blood vessel, performed as described below.

Rats (350 ˜ 450 g, obtained from the Experimental Animal Team of The Korea Research Institute of Chemical Technology) brought to unconsciousness stroke in the occipital region, were killed by dislocation of vertebra and subjected thoractomy. After a quick removal of the thoracic aorta were deprived of adipose tissue, and cut in aortae ring width of 3 mm, the Aorta was gently wiped with a cotton swab dipped in a modified buffer Krebs Henseleit (saline) to remove from her inner epithelial layer. When the suspension in the bath for bodies containing physiological buffer, vascular smooth muscle gave the opportunity to balanced in tension at rest 2 g and then kept for 1 hour at 37°to stabilize, feeding Carbogen, consisting of 95% O2and ˜ 5% CO2.

After that vascular smooth muscle was reduced 10-5M phenylephrine and washed several times with saline. This procedure was repeated again to ensure a stable response of vascular smooth muscle to repetitive cycle contraction/relaxation.

Then applied 3 x 10-6M labels the amine to induce intense contraction in vascular smooth muscle. When vasoconstriction induced by methoxamine, reached a maximum and remained at this level, compound and control the cumulative material was added to the bath for the body at a concentration of 1, 3, 10 and 30 μm, respectively, to study the effect of salts. Cromakalim, BMS-180448 (compound of formula 4) and BMS-191095 (compound of formula 5), known as the first discoverers of generation QUATRE with a strong vasodilator activity, was used as control materials.

The change of speed reduction by the addition of drugs compared with the maximum contraction induced by methoxamine, calculate for application chart to plot curve concentration-contraction. Using the method of least squares linear regression analysis for each drug was obtained the value of the IC50that is the concentration of drug at which the vascular tissue is reduced to 50% of the maximum degree of reduction.

/tr>
TABLE 2

Salts of compounds of formula 1
ConnectionConcentration for inhibition of the contraction induced by methoxamine in rat aorta

(IC50microns)
BMS-180448 (compound of formula 4)1,38
BMS-191095 (compound of formula 5)2,14
Example 17,14
Example 75,59
Example 10> 30
Example 11> 30
Example 17> 30
Example 22> 30
Example 24> 30
Example 2527,45
Example 2624,6
Example 28> 30
Example 31> 30
Example 32> 30
Example 34> 30
Example 61> 30
Example 65> 30
Example 70> 30
Example 75> 30
Example 77> 30
Example 81> 30
Example 83> 30
Example 85> 30
Example 987,34

As shown in the above table 2, cromakalim found a strong vasodilator action, with IC500,067 μm, extracted aorta of the rat, concise what examina (3 μm), while IC50BMS-180448 and BMS-191095 were to 1.38 μm and 2.14 ám, respectively, in the twenty and thirty times is a much weaker effect on vasodilatation than cromakalim. On the other hand, the values of the IC50compounds of the present invention varied from 5,59 μm to more than 30 μm, so that their vasodilator actions were considerably weaker than the action of the controls, chromagranin, BMS-180448 and BMS-191095.

Providing steps on ToATPpresent in the heart, the compounds of the present invention play a role in protecting the heart. On the other hand, the openers ToATPacting on KATPpresent in peripheral vascular smooth muscle, expand blood vessels, reducing blood pressure. Hypotension may mask any cardiotoxin as a result of the pressure reduction in perfusion of the coronary arteries and may limit the usefulness in the treatment of myocardial ischemia. Thus, the compounds of the present invention may be more optimal as cardiotoxin funds due to their weak vasodilating activity.

<EXPERIMENTAL EXAMPLE 2> Protective effect against induced iron damage to nerve cells

The experiment confirming inhibit whether the compounds of formula 1 according to the present invention induzirovanny the e iron nerve cell damage, performed, as described below.

From the brain 17˜18-day-old embryos were isolated cortical nerve cells and then cultured at 37°C for 7˜9 days in an incubator with 5% CO2. Culture of these cortical cells were washed twice in MEM (minimal supportive environment to reduce the level of serum to 0.2%. Compound serially diluted four times to obtain a final concentration of 30, 7,5, 1,875 and 0,469 μm, respectively. Then the connection with the high concentration of pre-treated for 30 min, respectively. For the experiment, the test compound was dissolved in DMSO and diluted in the environment. At this time, the final concentration of DMSO should not exceed 0.1%. For the control group used only the filler.

After this pre-processing to the medium was added FeSO4so that the final concentration was 50 μm. The medium was cultured in an incubator with CO2within 24 hours. During incubation under the action of iron was released lactate dehydrogenase (LDH). The level of serum lactate dehydrogenase released into the medium was measured to assess necrosis of nerve cells under the action of oxidative toxicity of iron. A protective effect on nerve cells of the tested compounds was evaluated by calculating the degree of reduction of the content of LDH in group treatments is key in comparison with the degree of decrease in the content of LDH in the control group. Built curve based concentration-protective effect and the value of the IC50the drug concentration corresponding to 50% of maximum action, was calculated using least squares linear regression analysis. The results are shown below in table 3.

TABLE 3

Protective effect exerted on induced iron nerve cell damage
ConnectionA protective effect for nerve cells
Inhibition (%, adding 30 μm compound)IC50(µm)
Example 17118,1
Example 75934,1
Example 101032,2
Example 11932,0
Example 171102,0
Example 22975,9
Example 24986,1
Example 2583-
Example 26972,2
Example 281034,1
Example 30103 -
Example 31861,8
Example 321081,6
Example 33916,0
Example 341111,5
Example 421032,6
Example 52913,0
Example 54981,5
Example 561005,3
Example 57943,1
Example 59771,8
Example 60870,7
Example 61891,2
Example 70851,4
Example 71890,9
Example 74905,3
Example 751251,8
Example 7652the 5.7
Example 771111,9
Example 78694,4
Example 791071,7
Example 80955,0
Example 81120 1,5
Example 82691,3
Example 83803,7
Example 84485,6
Example 851191,8
Example 988510,5
Example 996920,8

As shown in table 3, the compounds of the present invention have a protective effect for induced iron damage to nerve cells. Preferably, the IC50compounds obtained in examples 11, 17, 31, 32, 54, 59, 61, 70, 75, 77, 79, 81, 82 and 85 were below 2 microns. More preferably, the IC50compounds obtained in examples 60 and 71, were below 1 μm. Thus, the compounds of the present invention have a strong protective effect for induced iron damage to nerve cells.

Since the derivatives of benzopyran, substituted secondary amine containing tetrazole group, according to the present invention have a strong protective effect against induced by iron toxicity of nerve cells, they can be used as agents for the prevention or treatment of neurological disorders caused by neural damage, such as cerebral stroke and dementia, as well as inflammatory diseases, that the CSOs as arthritis, infarction of the heart muscle and acute/chronic tissue damage (S. Miranda et al., The role of oxidative stress in the toxicity induced by amyloid-peptide in Alzheimer's disease Progress in Neurobiology, 2000, 62, 633-648; S.A. Cook, P.H. Sugden, A. Clerk, Regulation of Bcl-2 Family Proteins During Development and in Response to Oxidative Stress in Cardiac Myocytes Association with Changes in Mitochondrial Membrane Potential Circulation Research, 1999, 85, 940-949; J.M. McCord, The Evolution of Free Radicals and Oxidative Stress. Am J Med, 2000, 108, 652-659).

<EXPERIMENTAL EXAMPLE 3> Protective effect against the damage of nerve cells caused by hydrogen peroxide

The experiment confirming inhibit whether the compounds of formula 1 according to the present invention induced by hydrogen peroxide damage to the nerve cells, was performed as described below.

Performed the same procedure as in example 2, except that the concentration of added test compound was 30 μm and the final concentration of hydrogen peroxide was 30 μm. The results are shown in table 4.

TABLE 4

Protective effect against the damage of nerve cells induced by hydrogen peroxide
ConnectionAdd (µm)Inhibition (%)
Example 113096
BMS-18044830-5
BMS-19195 3027
Propylgallate1094
Promethazine597

As shown above, the reference compound of formula 5 (BMS-191095) showed a protective effect (27%) at a concentration of 30 μm. However, the compound of formula 11 according to the present invention have a high degree of inhibition (96%). Thus, the derivatives of benzopyran, substituted secondary amine containing tetrazole group, according to the present invention have a protective effect similar to the action of conventional antioxidants, such as propylgallate and promethazine. In addition, the compounds of the present invention have a strong protective effect against the toxicity of nerve cells induced by hydrogen peroxide, they can be used as a therapeutic agent for the prevention or treatment of neurological disorders caused by neuronal loss induced oxidative stress induced by hydrogen peroxide damage or necrosis of neurons, such as cerebral stroke and dementia, as well as inflammatory diseases such as arthritis, heart attack, heart muscle and acute/chronic tissue damage (S. Miranda et al., The role of oxidative stress in the toxicity induced by amyloid-peptide in Alzheimer's disease Progress in Neurobiology, 2000, 62, 633-648; S.A. Cook, P.H. Sugden, A. Clerk, Regulation of Bcl2 Family Proteins During Development and in Response to Oxidative Stress in Cardiac Myocytes Association with Changes in Mitochondrial Membrane Potential Circulation Research, 1999, 85, 940-949; J.M. McCord, The Evolution of Free Radicals and Oxidative Stress. Am J Med, 2000, 108, 652-659).

<EXPERIMENTAL EXAMPLE 4> Inhibitory effect against perechisleniya lipids caused by iron

The experiment confirming inhibit whether the compounds of formula 1 according to the present invention induced iron perechislenie lipids was performed as described below.

The brain of rats homogenized in Krebs buffer (15 mm HEPES, 10 mm glucose, 140 mm NaCl, 3.6 mm KCl, 1.5 mm CaCl2, 1.4 mm KN2RHO4, 0.7 mm MgCl2, pH 7.4), and the supernatant separated by centrifugation at 12000 rpm for 10 min, was used for further experiments. Added FeCl2to achieve a final concentration of 400 μm. Then the homogenate brain kept at 37°C for 30 min to facilitate the oxidation. Each test compound was added at a concentration of 100 μm. For the control group used only the filler.

Iron promotes the oxidation of the specified homogenate brain with the formation of malonic aldehyde (MDA), a product of perechisleniya lipids. Thus, perechislenie lipids were quantified using MDA. The inhibitory activity of the test compounds against perechisleniya lipids was assessed by calculating the degree of decrease in the content of MDA caused examinees joint is mi, compared with the degree of decrease in the content of MDA in the control group.

Usually quantitative determination of MDA was achieved by the interaction of the samples with 2-thiobarbituric acid (TBA) and measuring the absorption at 530 nm. However, this method is unsuitable for processing samples on a large scale due to the stage of boiling. Therefore, in this experiment instead of the TBA used N-methyl-2-phenylindol. In this case, one molecule of MDA interacts with two molecules of N-methyl-2-phenylindole education chromagen, which detects the maximum absorption at 586 nm and does not require the stages of boiling. Kit BioxytechRLPO-586 used for the quantitative determination of MDA. The results are shown below in table 5.

TABLE 5

Inhibitory effect against perechisleniya lipid-induced iron
ConnectionInhibitory effect against perechisleniya lipid-induced iron

(%, 100 µm)
Example 1090
Example 1191
Example 1787
Example 22108
Example 2494
Example 26101
Por the measures 28 83
Example 3084
Example 3289
Example 34103
Example 4285
Example 5288
Example 5487
Example 5676
Example 5795
Example 5970
Example 6085
Example 6187
Example 6479
Example 7095
Example 7193
Example 8189
Example 8397
Example 85101
Example 8981

As shown above, the compounds obtained in examples 10, 11, 22, 24, 26, 34, 57, 70, 71, 83, 85 and 108, had a very strong inhibitory effect against induced iron perechisleniya lipids with more than 90% inhibitory effect. In addition, the compounds obtained in examples 11, 17, 32, 54, 59, 60, 70, 71, 81 and 85, had simultaneously inhibiting action against perechisleniya lipids, as well as a protective effect against induced oxidative stress damage to nerve cells under the action of iron or the edit (tables 3 and 4). Thus, the compounds of the present invention can be used as a therapeutic agent for the prevention or treatment of neurological disorders caused by the accumulation of oxidation product promotion perechislenie lipids, such as cerebral stroke and dementia, as well as inflammatory disease, such as arthritis, heart attack, heart muscle and acute/chronic tissue damage (Chul Lee, Antioxidant ability of caffein and its metabolites based on the study of oxygen radical absorbing capacity and inhibition of LDL peroxidation, Clinica Chimica Acta, 2000, 295, 141-154; P-E. Chabrier et al FBN 80933, a dual inhibitor of neuronal nitric oxide synthase and lipid peroxidationL A promising neuroprotective strategy. Pro. Natl. Acad Sci USA, 1999, 96, 10824-10829).

<EXPERIMENTAL EXAMPLE 5> Inhibitory effect against perechisleniya lipids induced by copper

The experiment confirming inhibit whether the compounds of formula 1 according to the present invention induced by copper oxidation of low-density lipoprotein (LDL), was performed as described below.

Low-density lipoprotein person (LDL person, sigma) was dissolved in water to a final concentration of 1 mg/ml To remove EDTA (ethylenediaminetetraacetic acid) aqueous solution were dialyzed in phosphate buffer at 4°C for 18 hours. In this dialysis phosphate buffer was replaced three times. Phosphate buffer was added to LDL (100 μg LDL protein/ml)from the aqueous solution which was the Dalen EDTA, in addition to the solution was added 10 μm CuSO4as oxidant. Thus, the final concentration of tocopherol for test compounds and control material was 10-9, 10-7and 10-5M, respectively. The group to which the CuSO4was not added, was used as the blind experience. The group to which the filler was added instead of the test compounds, was used as the control experiment. The mixture is incubated at 37°C for 18 hours. 200 μm EDTA was added to the mixture to terminate the reaction of oxidation.

As shown in example 4, Cu2+promotes oxidation reactions with the formation of malonic aldehyde (MDA), a product of perechisleniya lipids. Quantitative formation of MDA is achieved by the interaction of the samples with 2-thiobarbituric acid (TBA) and measuring the absorption at 530 nm. In addition, 1,1,3,3-tetramethoxypropane purchased from sigma, was used as standard material. The inhibitory activity of the tested compounds against lipid perechisleniya measured by the number of NMA (nmol) protein (mg). To calculate the decrease in MDA regarding the reduction of MDA in the control group. The result is shown in the following table 6.

TABLE 6

Inhibitory effect against lipid peroxyl the tion, induced copper
Add (M)The inhibitory activity (%)
Example 11TocopherolProbucol
10-727,321,333,7
10-654,958,7
10-563,929,766,7

As shown in table 6, the compound of example 11 of the present invention had a significant inhibitory effect against lipid perechisleniya induced by copper, depending on the concentration of such compounds. In addition, the compound of the present invention possessed inhibitory action, twice the inhibitory effect of tocopherol (reference compound) at a concentration of 10-5M. in Addition, the compound of the present invention has an inhibitory effect similar to the inhibitory action of probucol.

Since the derivatives of benzopyran, substituted secondary amine containing tetrazole group, according to the present invention have a very strong inhibitory effect against induced copper lipid perechisleniya, they can be used as an agent for preventing or treating neurologist who mental disorders, due to the accumulation of oxidation products with promoting lipid perechislenie, such as cerebral stroke and dementia, as well as inflammatory disease, such as arthritis, heart attack, heart muscle and acute/chronic tissue damage (Chul Lee, Antioxidant ability of caffein and its metabolites based on the study of oxygen radical absorbing capacity and inhibition of LDL peroxidation. Clinica Chimica Acta, 2000, 295, 141-154; P-E, Chabrier et al FBN 80933, a dual inhibitor of neuronal nitric oxide synthase and lipid peroxidation, A promising neuroprotective strategy. Pro. Natl. Acad Sci USA, 1999, 96, 10824-10829).

<EXPERIMENTAL EXAMPLE 6> Inhibitory effect against the accumulation of reactive oxygen species induced by hydrogen peroxide

The experiment confirming inhibit whether the compounds of formula 1 according to the present invention induced by hydrogen peroxide reactive oxygen species was performed, as described below.

For measurement of the content of reactive oxygen species used H2DCFDA (diacetate 2',7'-DICHLORODIFLUOROMETHANE, Molecular Probes, Eugene, OR, USA). If H2DCFDA, non-polar material is transferred through the cell membrane, it becomes in the H2DCF (2',7'-DICHLORODIFLUOROMETHANE), a material that is impermeable to the membrane due to the intracellular esterase. H2DCF becomes highly fluorescent DCF (2',7'-dichlorofluorescein) through the m having low fluorescence perechislennogo oxygen or hydroxyl radical. A solution of H2DCFDA (10 mm), obtained by dissolving in DMSO, was used before the experiment. A7r5 (cell line smooth muscle of the thoracic aorta of the rat, ATSS) in smooth muscle cells were incubated in DMEM (modified by way of Dulbecco Wednesday Needle)containing 10% FBS (fetal bovine serum). After that, cells were incubated in 48-hole tablet for two days, then incubated in DMEM without serum for 24 hours to use for the experiment. The Krebs buffer-linger (Krebs-Ringer (K-R), 99,01 mm NaCl, 4,69 mm KCl, 1,87 mm CaCl2, 1.2 mm MgSO4, of 1.03 mm To2NRA4, 25 mm NaHCO3, 20 mm Hepes, 11,1 mm D-glucose, pH 7.4) was used for washing and processing of cell monolayers. After removing the medium from the cell monolayers each of the tested compounds (0.2 ml) was pre-treated with medium, then incubated at 37°C for 15 minutes the Final concentration was 50 μm, was added hydrogen peroxide. The environment was kept for 30 minutes Then the specified solution from the medium was removed. Wednesday was washed once. To the medium was added to 20 μm H2DCFDA. The environment was kept for 30 minutes Wednesday was washed two times. After that, the oxidation of N2DCFDA was measured fluorescence tablet reader (FL600, Biotech Instruments, excitation at 485 nm, emission at 530). The results are shown in table 7.

TABLE 7

The inhibitory effect exerted against the accumulation of reactive oxygen species
ConnectionAdd (µm)Inhibition (%)
Example 1130124
Example 111082
Example 1136
Propylgallate30108
Propylgallate1094
Propylgallate357

If A7r5 cells were added to hydrogen peroxide, cellular damage were induced reactive oxygen species, which led to the increase in DCF fluorescence. However, the increase in DCF fluorescence induced by hydrogen peroxide, inhibited by treatment with a compound of formula 11 of the present invention in a dose-dependent manner. Most preferably, the fluorescence of DCF completely inhibited by treatment of 30 μm compound of formula 11. Since the compound of the formula 11 of the present invention had a strong inhibitory effect against the accumulation of reactive oxygen species induced by hydrogen peroxide, they can be used as a therapist is ical agent for prevention or treatment of neurological disorders, due to the accumulation of oxidation products with the assistance of lipid perechislenie, such as cerebral stroke and dementia, as well as inflammatory disease, such as arthritis, heart attack, heart muscle and acute/chronic tissue damage (G. J. Gross, J. R. Kersten, D.C. Warltier Mechanism of post-ischemic contractile dysfunction Ann Thoar Sur, 1999, 68, 1898-1904; S. Okubo, Myocardial preconditioning: Basic concepts and potential mechanisms. Molecular and Cellular Biochemistry, 1999, 196, 3-12; I Cantuti-Castelvetri, B. Shukitt-HAle, J.A.Joseph, Neurobehavioral aspects of antioxidants in aging Int. J. Neuroscience, 2000, 18, 267-381).

<EXPERIMENTAL EXAMPLE 7> Protective effect against brain damage induced by the process of ischemia-reperfusion injury brain

The experiment confirming, do the compounds of formula 1 according to the present invention a protective effect against brain damage induced by the process of ischemia-reperfusion was performed, as described below.

Male rats (rat Sprague-Dawley, 350 ± 50 g, Samyook) was anestesiologi the introduction of 40 mg/kg pentobarbital sodium. Tube RE-19 was inserted into the femoral vein and artery, the left carotid artery was exposed. Before the operation in the peritoneal cavity were injected with 20 µg of heparansulfate. Device for measuring blood pressure was inserted into the femoral artery for continuous blood pressure measurement. Blood (10 ml) were collected from the femoral vein to lower blood pressure d is 30 mm Hg. If blood pressure was reduced to 100 mm Hg by collecting blood (7 ml), this meant that sympathetic tone is very high. This case was excluded from the experiment because the mortality rate of rats is high in blood pressure of 30 mm Hg or even after the success in lowering blood pressure, these rats were found high mortality after the operation.

When blood pressure is supported at 30 mm Hg, the left carotid artery was closed aneurysm clip for 20 min to induce ischemia. The reperfusion was performed collected blood and 0.84% physiological bicarbonate solution (5 ml). The body temperature of rats during ischemia was maintained constant at 37 ± 0,5°by applying thermal coverings and electric light fixtures. After surgery in the recovery period, the body temperature was maintained constant for more than 2 hours. If rats were fully recovered, transferred to the laboratory for animals. Conditions in the laboratory animal, such as temperature, humidity and light cycle was maintained constant at the level of 27°C, 60% and 12-21 hours, respectively.

24 hours after surgery, rats were killed. Then within 3 min in rats was nucleosomal the brain. Enableireland.ie the brain was dissected on ice into sections with an interval of 2 mm with ISOE what Itanium matrix brain to get six coronal slices. These coronal sections were stained in 2 % solution of chloride 2,3,5-triphenyltetrazolium at 37°C for 30 minutes Specified stained coronal section was shown and marked with numbers. After that, the ratio of the area of necrosis to the area of the brain was measured using image analyzer.

Otherwise, the compound was injected four times into the abdominal cavity at a dose of 30 mg/kg, In particular, the compound was administered 30 min before surgery, and after 2, 4 and 16 hours after the closure of the carotid artery. For the control group instead of the tested compounds were administered only filler. In the comparative group of rats was administered gidromolot (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) as a non-competing NMDA (N-methyl-D-aspartate).

Protective effect against brain damage induced by the process of ischemia-reperfusion brain was assessed by calculating the decrease of the area of necrosis regarding the area of necrosis of the brain in the control group. The results are shown in table 8.

TABLE 8

Protective effect against brain damage induced by the process of ischemia-reperfusion injury brain
The test connection is out Dose (mg/kg)NThe volume of infarction
Average (%)Reduction (%)
Control1340,3 ± 5,5
Comparative (MK 801)301129,8 ± and 4.925,9
Example 11301421,5 ± 2,646,3

As shown in table 8, the volume of infarction comparative group, which was administered MK-801 at a dose of 30 mg/kg, was 29.8 per cent, which was the reduction of heart attack by 24.8% relative to the volume of the infarction control group.

In another case, the volume of infarction of the test group was administered the compound of formula 11 with a dose of 30 mg/kg, was 21.5 per cent, which was the reduction of heart attack by 46.3% relative to the volume of the infarction control group. Thus, the connection of the present invention had a protective effect against brain damage induced by the process of ischemia-reperfusion brain, two times higher than had reference compound MK-801.

In addition, in the group treated with MK-801, as a comparative group observed side effects, such as reduced motility in rats. However, in the group, which centuries the Dili compound of formula 11, side effects, including changes in mobility were observed. As shown in table 2, due to the weak vasodilating activity (IC50> 30 μm) of the compounds of the present invention, the side effects induced by the reduction of perfusion in the ischemic brain, decreased significantly.

Since the derivatives of benzopyran, substituted secondary amine containing tetrazole group, have excellent protective effect against brain damage induced by the process of ischemia-reperfusion brain, they can be used as agents for the prevention or treatment of diseases caused by brain damage, such as cerebral stroke and dementia (E.V. Golanov, J.D. Christensen, D.J. Reis, Role of Potassium Channels in the central neurogenic neuroprotection elicited by cerebellar stimulation in the rat. Brain Research, 1999, 842, 496-500).

<EXPERIMENTAL EXAMPLE 8> Protective effect against ischemic-hypoxic brain damage

The experiment confirming, do compound of formula 1 of the present invention a protective effect against ischemic-hypoxic brain damage, was performed, as described below, using CMP (magnetic resonance spectrum).

Described that in ischemic-hypoxic rat models result histological tested is of significantly correlated with the change in the spectrum of magnetic resonance. Using this description was investigated protective effects against brain damage induced by hypoxia in vitro. [A. Van der Toorn et al. Magnetic Resonance in Medicine, 1996, 36, 914-9220]. Described that the peak of lipid increased in IDA due to ischemic damage of nerve cells due to the destruction of cellular membranes, including the blood-brain barrier. It also describes that the increased concentration of lipids correlated with apoptosis. [A. Bizzi et al., Magnetic Resonance Imaging, 1996, 14, 581-592]. Thus, it was described that the ratio of lipid/NAA and lipid/Cr obtained by comparing the lipid N-acetylaspartate (NAA) and creatine (Cr) as a marker of nerve cells, correlated with morphological changes and severity of apoptosis in hypoxic brain damage.

In newborn rats (age 7 days, 10 ˜ 15 g) left carotid artery was blocked for 3 hours to induce hypoxia. Compound were injected with intraperitoneal way 1 hour before hypoxia. The left eye, the carotid artery which is blocked, used as ischemic-hypoxic model, right eye, carotid artery which was not blocked, used as a hypoxic model. Spectrum of magnetic resonance was obtained from the two models after histological tests performed through one day after the behavior is idania. From this result, calculate the ratio of lipid/NAA or lipid/Cr. In addition, to calculate the viability and morphological indicator macroscopic examination volume of a heart attack. The results are shown in table 9.

TABLE 9

Protective effect against hypoxic brain damage
ControlExample 11 (50 mg/kg)
Ischemic-hypoxicHypoxicIschemic-hypoxicHypoxic
Limes./NAA11,554,635,431,69
Limes./Cr13,904,115,161,55
Survival13/26 (50%)19/24 (79%)
Morphological evaluation3,01,4

As shown in table 9, the compound of formula 11 of the present invention reduces the ratio of lime trees./NAA and Limes./Cr obtained from the spectrum of magnetic resonance in ischemic-hypoxic or hypoxic model of newborn rat, not less than twice or three times about the relative relationship of the control group, respectively. Thus, the connection of the present invention has a protective effect against brain damage. In addition, comparison of the viability showed that the compound of formula 11 was significantly increased vitality, more than 79% of the viability of the control group (50%). The compound of formula 11 was reduced morphological evaluation obtained from macroscopic examination volume of a heart attack two times in comparison with the morphological evaluation of the control group.

As derivatives of benzopyran, substituted secondary amine containing tetrazole group, according to the present invention have a protective effect against brain damage induced by ischemia-hypoxia or hypoxia, therefore, the connection of the present invention can be used as an agent for prevention or treatment of neonatal hypoxia (C. C Huang et al Measurement of the urinary laktate:creatinine ratio for the early identification of newborn infants at risk for hypoxic-ischemic encephalopathy. New England J. Of Medicine, 1999, 341 (5), 328-335).

<EXPERIMENTAL EXAMPLE 9> Protective effect against the damage of the nerve cells axotomy optic nerve

The experiment confirming, does the compound of formula 1 according to the present invention a protective effect against damage to the nervous cleto is, induced axotomy the optic nerve was performed, as described below.

Compound was dissolved in DMSO to obtain the initial solution (100 mm), which was diluted with saline to 20 μm. 10 μl of the original solution is injected into the glass body.

Adult rats were anestesiologi chloralhydrate (400 mg/kg), then optic nerve was exposed conjunctiva of the eyeball. Then did a cut nerve at a distance corresponding to 0.5 mm or 3 mm from the eyeball, respectively. Or through the upper eyelid was performed amputation of skin, then deleted the part of the lacrimal gland. Eyeball the front straight muscle was dissected in the eye muscles to exposure of the optic nerve. Optic nerve was dissected approximately 5 mm behind the eyeball. The blood vessels of the retina, which supply blood to the retina is not damaged. The condition of the blood vessels of the retina controlled by the Ophthalmoscope. Versolato (Fluorochrome Inc., 5% solution in PBS (solution with phosphate buffer)) was administered to half of the rats of the test group during the backward motion after axotomy optic nerve. To study the survival of ganglion cells after axotomy the eyes of the rats were removed, then the retina was isolated after 3 days, 1 week, 2 weeks, 4 weeks, 2 months, 4 months and 6 months. Isolated retina was studied by transmission electron mikros the ops. For quantitative analysis at the same time received the tissue of the retina. The obtained fabric was investigated immunochemical staining or fluorescence microscope, which is mounted 530 ˜ 560 nm filter. The results are shown in table 10.

TABLE 10

Protective effect on nerve cell damage induced by axotomy optic nerve
The survival of ganglion cells (%)
Control22%
Example 11 (20 μm)43%

As shown in table 10, after axotomy optic nerve survival ganglion cells of the retina relative to the control group was 22%. However, the degree of survival of ganglion cells of the retina from the group tests, which compound of formula 11 was injected at a concentration of 20 μm, was 43%. Thus, the compound of formula 1 was significantly improved survival.

Since the derivatives of benzopyran, substituted secondary amine containing tetrazole group, have a protective effect against the loss of ganglion cells of the retina from damage induced by axotomy optic nerve, they can be used as an agent for the prophylaxis is whether the treatment of glaucoma, induced damage to the ganglion cells (P. Hardy et al. Oxidant, nitric oxid and prostanoids in the developing ocular Vasculature: a basis for ischemic retinopathy Car diovascular Research, 2000, 47, 489-509).

<EXPERIMENTAL EXAMPLE 10> Effects on the conduction velocity of motor nerve in diabetic rats

The experiment confirming improve if the compounds of formula 1 conduction velocity weakened motor nerve from diabetic rats was performed as described below.

Diabetes was induced by injecting rats streptozotocin (65 mg/kg), then oral was administered once a day the test compound, dissolved in 2 ml of medium (a mixture of saline: ethanol: tween 80, 1:1:1). Rats were anestesiologi the pentothal, then the sciatic nerve was exposed for speed measurement of motor nerve conduction. The nerve was stimulated at two points. The first stimulating electrode was inserted at the proximal end and the second stimulating electrode was inserted at the distal incision. Coaxial needle electrode was inserted in the interdigital muscle, then the action potential of the muscle induced by stimulation at two points. Conduction velocity was calculated by dividing the distance between two points incentive to differences in the latent state. Lipoic acid (100 mg/kg) was used for comparison with the compound of the present invention to restore the MSE of the spine of the motor nerve conduction (MNCV) in diabetic rats. Recovery (%) of motor nerve conduction was calculated by the following mathematical formula 1. The results are shown in table 11.

MATHEMATICAL FORMULA 1

TABLE 11

The effect on the conduction velocity of motor nerve in diabetic rats
MNCV (msec)Recovery (%)
Normal59,78100-
Diabetic49,03-
Example 11 (50 mg/kg)53,9545,8

As shown in table 11, MNCV in diabetic rats were significantly reduced compared with MNCV group normal control rats. Introduction the compounds of formula 11 at a dose of 50 mg/kg significantly increased MNCV in diabetic rats.

Since the derivatives of benzopyran, substituted secondary amine containing tetrazole group, according to the present invention increase MNCV in diabetic rats, they can be used as an agent for the prophylaxis or treatment of diabetic neuropathy or diabetic disorders of the peripheral nerves (K. Naka et al. Effects of stazol on development of experimental diabetic neuropathy: functional and structural studies, and Na+-K+-ATPase acidity in peripheral nerve in rats ith streptozocin-induced diabetes. Diabetes Res. and Clinical Practice, 1995, 30, 153-162).

<EXPERIMENTAL EXAMPLE 11> Inhibitory effect on the production of NO

The experiment confirming whether the compounds of formula 1 inhibitory effect on the formation of NO (nitric oxide), was performed as described below.

Using RPMI1640 medium, supplemented with 10% fetal bovine serum (FBS), cells RAW 264.7 (obtained from American Type Culture Collection)cell line murine macrophages were cultured at 37°C incubator with 5% CO2. Cells RAW 264,7 collected and cell density was adjusted to 5 x 105cells/ml in RPMI1640 medium, supplemented with 0.5% FBS, and were sown at a density of 5x104cells/well in 96-well-plates, cells were then cultured for 20 hours in CO2-incubator. After removal of the medium the cells were pre-treated for 1 h with fresh medium containing 30 μm. Compound was dissolved in DMSO and diluted to the appropriate concentration in the environment. To minimize the influence of DMSO on the formation of nitric oxide by cells RAW 264.7, holes were made so that the medium containing DMSO at a concentration of 0.1% or below.

After a one-hour pre-treatment to activate the cells were added lipopolysaccharide (E. coli, serotype 055:B5) at a final concentration of 1 μg/ml, the cells were kept for 24 hours in CO2the incubator is. The activated cells RAW 264.7 using LPS was NO education. The release of NO in the medium was in the form of nitrate (NO2-and quantitative measurement of NO was performed using the Griess reagent. The control group was treated with only the filler instead of the tested compounds. When using nitrite standard was shown that subjects medicines do not prevent the quantitative determination NO.

The inhibitory activity of the tested compounds against the formation of NO was determined as the reduction in the number of NO compared to the amount of NO in the control group. The results are shown in table 12.

TABLE 12

The inhibitory activity shown against education NO
ConnectionAdd (µm)Inhibition (%)
Example 13027
Example 293079
Example 453075
Example 473062
Example 513096
Example 533096
Example 583076
Example 603086
Example 683064
Example 703075

As shown in table 12, derivatives benzopyrane, substituted secondary amine containing tetrazole group, according to the present invention have inhibitory activity shown against the formation of NO, induced by endotoxin, such as LBS. Preferably, the compounds obtained in examples 29, 45, 58, 60, and 70, to possess inhibitory action, constituting more than 75% at a concentration of 30 μm. Most preferably, the compounds obtained in examples 51 and 53, have inhibitory action, constituting more than 90% at the same concentration.

Since the derivatives of benzopyran, substituted secondary amine containing tetrazole group, according to the present invention have inhibitory activity shown against the formation of NO, they can be used as an agent for the prophylaxis or treatment of neurological disorders caused by excessive production of NO, such as cerebral stroke and dementia, as well as inflammatory diseases such as arthritis, heart attack, heart muscle and acute/chronic tissue damage (J.F. Kerwin Jr. Nitric Oxide: A New Paradigm for second Messengers J. Med. Chem, 1995, 38, 4343-4362).

<EXPERIMENTAL USE is 12> Cardiotoxin action in models of ischemic rat heart

The experiment confirming whether the compounds of formula 1 protective action (antiischemic effect) on ischemic heart was performed, as described below.

Male rats (300 ˜ 450 g, obtained from the experimental animal team of the Korea Research Institute of Chemical Technology) was anestesiologi intraperitoneal injection nutrientebisa at the dose of 100 mg/kg of Heparin (1000 U/kg) were injected with the tail vein and then the heart was nucleosomal. Specifically, in this body inserted a cannula (PE 240). Rats were subjected to artificial lung ventilation with automatic breathing apparatus for rats, in situ in their aorta inserted a cannula to the aorta. When reverse reperfusion heart they were nucleosomal, then immediately placed on the apparatus Langendorf. The fabric is attached to the heart, were removed. Through the heart was perfesional oxygenated, modified bicarbonate buffered Krebs-Henseleit (composition in mmol/l: 116 NaCl, A 4.7 KCl, 1,1 MgSO4, 1,17 KH2PO4, 24,9 NaHCO3, 2,52 CaCl2, 8,32 glucose, 2.0 pyruvate) at a constant perfusion pressure (85 mm Hg). The metal cannula attached to a latex balloon filled with solvent (ethanol:water, 1:1 (vol./vol.), drove into the left ventricle through the pulmonary vein and connected with isovolumetric pressure sensor (H.S.E., Germany) for measuring the left of ventry is warnowo pressure (LVP). The heart was allowed to balanced for 15 min, and at this time, the left ventricular end-diastolic pressure (EDP) was adjusted to 5 mm Hg and the volume of the container was maintained throughout the experiment.

Measured baseline cardiac contractile function, heart rate (HR) and coronary flow (CF). Cardiac contractile function was calculated by subtracting LVSP, left ventricular peak sistolicheskogo pressure) LVEDP (left ventricular end-diastolic pressure), while receiving LVDP (left ventricular developed pressure). Double product RPP (the product of the frequency-pressure (DP), another important parameter for the indirect assessment of cardiac activity in the heart of Langendorf unsuitable for measuring cardiac output, calculated by multiplying the HR in LVDP.

Throughout the experiment the total coronary flow was measured by use of the probe in coronary blood flow (diameter: 1.0 mm)installed in aortas the cannula with an electromagnetic velocity meter blood flow. The temperature of the heart was maintained constant immersion of the heart in a physiological solution with a temperature of 37°to which routinely submitted gaseous mixture of 95% O2/5% CO2. After stabilization for 15 min heart pre-clicks sativali for 10 min filler (0.04% DMSO) or a mixture containing the compound of the present invention or a control material. After re-measured cardiac contractile function, HR and CF. Global ischemia was induced by complete shutdown of the perfusion solution during 30 minutes the Severity of ischemia was defined as the time to contracture (IDT, min) during total ischemia, where watched the first 5 mm Hg increase in EDP. Then the heart was subjected to reperfusion after 30 min re-measured contractility (LVDP, HR and CF). After performing reperfusion for 30 min level of LDH (lactate dehydrogenase) was measured as the ratio of sensitivity to the loss of viability of cells using the set. The results are shown in table 13.

td align="center"> 24,8
TABLE 13

Cardiotoxin action, manifested in models of ischemic rat heart
Test connectionCardiotoxin action in models of ischemic rat heart (10 μm)
LVDP x HR (%)EDP (mm Hg)TTC (min)LDH (µg/g)
Filler23,043,420,329,9
BMS-18044867,616,527,817,2
Example 146,829,315,2
Example 1124,847,6to 19.916,5
Example 3264,7of 17.027,915,7
Example 6152,723,020,022,4
Example 7031,937,022,018,4

In the group treated filler, DP reperfusion (LVDP X HR), index of contractile function, decreased to 23.0% DP before pre-treatment, and EDP was increased from 5 mm Hg to 43.3 mm Hg and TTC was a 20.3 min, and LDH release during reperfusion was only 29.9 µg/g, as shown above.

The group treated with BMS-180448, the function of reperfusion contractile (DP, LVDP x HR) was 67.6% of the DP pre-treatment, which was significantly increased compared with the group treated filler. EDP was 16.5 mm Hg, significantly lower than the control, and TTC was up 27.8 min, prolonged compared to the control, and the release of LDH by reperfusion was 17,2 E/g, i.e. higher than the control. In this case, all parameters of the group treated with BMS-180448, found a significant protective effect on the ischemic heart.

When comparing only the antiischemic action among these parameters, cardiac contractile function is AI, EDP, TTC and release of LDH, the compounds of the present invention were similar to BMS-180448 or surpassed it. However, since the compounds of the present invention have extremely low vasodilator effect than dose of BMS-180448, they are much superior to such conventional medicine in cardioselektivee antiischemic activity. The compound of example 30 was found especially good cardiotoxin action despite the fact that the contractile function (LVDP x HR) was increased to 64.7% of the index before treatment and EDP was 17.0 mm Hg and TTC was 27,9 min, and the level of LDH release during reperfusion was to 17.7 G/g at a very low vasodilator activity. Thus, this compound finds the best cardioselectivity with a weak vasodilator action than BMS-180448. Therefore, the compounds of the present invention can be used to treat ischemic heart disease due to their excellent selectivity and protective activity against ischemic cardiovascular diseases. In addition, the compounds obtained in examples 1, 11 and 32 of the present invention, had excellent protective effect manifested against cell damage caused by reperfusion after ischemia by reducing the release of LDH by reperfusion.

Since the derivatives of benzopyran, for amennye secondary amine, containing tetrazole group, according to the present invention have a protective effect on the heart during ischemia, similar to the action of BMS-180448 or superior, in addition, they have, more preferably, lower vasodilator compared with BMS-180448, they can be used as an agent for the prophylaxis or treatment of heart attack, heart muscle, heart failure or angina due to their excellent selectivity and protective activity (T. Miura etal. Roles of Mitochondrial ATP-sensitive K Channels and PKC in Anti-lnfarct Tolerance afforded by Adenosine Al receptor Activation. J Am Coll Cardiol, 1999,35,238-45; D. J. Chambers, D. J. Hearse Developments in Cardioprotection: "Polarized" Arrest as an Alternative to "Depolarized" Arrest Ann. Thorc. Surg, 1999,68,1960-6).

<EXPERIMENTAL EXAMPLE 13> the Inhibitory activity shown against the formation of HUVEC tubes

The experiment confirming whether the compounds of formula 1 inhibitory activity shown against the formation of tubules HUVEC was performed, as described below.

HUVEC (endothelial cells of the umbilical vein) was cultured and topologies" (the formation of tubules) in vascular endothelial cells induced by placing them on the surface of Matrigel for a few hours. The effect of the tested compounds on the formation of tubules compared with the treated filler control group, then ihateamerenue action was confirmed directly in vitro. The results are shown in table 14.

TABLE 14

The inhibitory activity shown against education

tubes HUVEC
The formation of blood vessels
Control10 µm100 mm
Example 2+++
Example 28+/-+
-: no activity; +/-: weak action

+: average effect: ++: strong

As shown in table 14, there was inhibition of the formation of HUVEC tubes concentration-dependent manner at concentrations of 10 μm and a strong inhibition occurred at a concentration of 100 μm in the case of compound obtained in example 2. In addition, the compound obtained in example 28, possessed inhibitory activity shown against the formation of tubules, thus inhibiting angiogenesis.

Since the derivatives of benzopyran, substituted secondary amine containing tetrazole group, according to the present invention possess a strong inhibitory activity against angiogenesis, they can be used for medical treatment of various diseases related to angiogenesis, such as rheumatoid arthritis, psoriasis, OS is onanie AIDS, cancer, diabetic retinopathy, etc. (P. A. Burke, S.J. DeNardo Antiangiogenic agents and their promising potential in combined therapy. Critical Reviews in Oncology/Hematology, 2001, 39, 155-171).

<EXPERIMENTAL EXAMPLE 14> Test on rats acute oral toxicity

The experiment confirming whether the compound of formula 1 of the present invention acute oral toxicity was performed as described below.

In this test, six rats SPF SD used with distribution groups. Each group consisted of two rats. The compounds obtained in examples 1, 7, 11, 17, 22, 24, 26, 28, 30, 32, 34, 42, 52, 54, 55, 56, 57, 59, 60, 61, 70, 75, 77, 79, 81, 83, 85 and 89, suspended in 0.5% methylcellulose, respectively. Then the suspension was administered orally at a dose of 1 g/kg/15 ml After injection animals were examined for clinical signs of toxicity or mortality, and measured the change in body mass. In addition, he performed hematological testing and biochemical analysis. After sacrifice of the animals performed the autopsy for macroscopic examination of organs and tissues. In the result, did not observe significant changes in clinical symptoms, body weight and mortality. In addition, observed no changes in Hematology, chemical parameters, serum, macroscopic examination and the changes associated with the drug. As a result, in the e tested compounds did not show toxicity in rats at a dose up to 2 g/kg, and it was determined that the lethal dose (LD50for oral administration is more than 2 g/kg

1. Derivatives benzopyrane, substituted secondary amines, including tetrazol, and is represented by the following formula 1, their stereoisomers or pharmaceutically acceptable salts

where R1represents H, F, Cl, Br, CF3, NO2CN, -ORa, NH2,or OS(O)lRaprovided that Rarepresents H or unbranched or branched C1-C4alkyl, l is an integer 0-2;

R2represents CH2ORa,provided that Ramatter mentioned above, Rband Rcrepresents, independently, an unbranched or branched C1-C4alkyl;

R3is a HE, orprovided that Rahas the values listed above;

R4and R5represent, independently, H, F, Cl, Br, unbranched or branched C1-C3alkyl, ORa, CF3, OCF3, NO2,,or SO3Raprovided that Ramatter, you mentioned the e;

R6represents H, an unbranched or branched C1-C3alkyl,

n and m is, independently, an integer of 0-2;

* is a chiral carbon atom.

2. Derivatives benzopyrane, their stereoisomers or pharmaceutically acceptable salt according to claim 1, R1represents NO2CN or NH2;

R2representsprovided that Rband Rcrepresent, independently, an unbranched or branched C1-C3alkyl;

R3HE is a orprovided that Rarepresents an unbranched or branched C1-C3alkyl;

R4and R5represent, independently, H, F, Cl, unbranched or branched C1-C3alkyl, ORa, CF3, OCF3or NO2provided that Rarepresents an unbranched or branched C1-C3alkyl;

R6represents an unbranched or branched C1-C3alkyl;

n and m is an integer of 0-1.

3. Derivatives benzopyrane, their stereoisomers or pharmaceutically acceptable salt according to claim 1, and the compounds of formula 1 include :

1) (2S,3S,4R)-6-nitro-4-[N-(4-chlorp the Nile)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

2) (2S,3R,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

3) (2S,3S,4R)-6-nitro-4-[N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

4) (2S,3R,4S)-6-nitro-4-[N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

5) (2S,3S,4R)-6-nitro-4-[N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

6) (2S,3R,4S)-6-nitro-4-[N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

7) (2S,3S,4R)-6-nitro-4-[N-benzyl-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

8) (2S,3R,4S)-6-nitro-4-[N-benzyl-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

9) (2S,3S,4R)-6-nitro-4-[N-(4-nitrophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

10) (2S,3S,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

11) (2S,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-d the hydro-2H-1-benzopyran,

12) (2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(1-methyl-1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

13) (2S,3S,4R)-6-nitro-4-[N-( 1-methyl-1 H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

14) (2S,3S,4R)-6-nitro-4-[N-(4-forfinal)-N-(1-methyl-1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

15) (2S,3S,4R)-6-nitro-4-[N-benzyl-N-(1-methyl-1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

16) (2S,3R,4S)-6-nitro-4-[N-benzyl-N-(1-methyl-1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

17) (2S,3S,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(1-methyl-1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

18) (2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

19) (2S,3S,4R)-6-nitro-4-[N-(1H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

20) (2S,3S,4R)-6-nitro-4-[N-benzyl-N-(1H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

21) (2S,3S,4R)-6-nitro-4-[N-(3-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,/p>

22) (2S,3S,4R)-6-amino-4-[N-(3-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

23) (2S,3S,4R)-6-nitro-4-[N-(4-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

24) (2S,3S,4R)-6-amino-4-[N-(4-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

25) (2S,3R,4S)-6-nitro-4-[N-(3-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

26) (2S,3R,4S)-6-amino-4-[N-(3-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

27) (2S,3R,4S)-6-nitro-4-[N-(4-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

28) (2S,3R,4S)-6-amino-4-[N-(4-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

29) (2S,3R,4S)-6-nitro-4-[N-(2-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

30) (2S,3R,4S)-6-amino-4-[N-(2-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

31) (2S,3R,4S)-6-nitro-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ileti is)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

32) (2S,3R,4S)-6-amino-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

33) (2S,3R,4S)-6-nitro-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

34) (2S,3R,4S)-6-amino-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

35) (2S,3R,4S)-6-nitro-4-[N-(3-acetylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

36) (2S,3R,4S)-6-amino-4-[N-[3-(1-hydroxyethyl)phenyl]-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

37) (2S,3R,4S)-6-nitro-4-[N-(2-methyl-4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

38) (2S,3R,4S)-6-amino-4-[N-(2-methyl-4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

39) (2S,3R,4S)-6-nitro-4-[N-(4-methoxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

40) (2S,3R,4S)-6-amino-4-[N-(4-methoxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

41) (2S,3R,4S)-6-neither the ro-4-[N-(2-methyl-4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

42) (2S,3R,4S)-6-amino-4-[N-(2-methyl-4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

43) (2S,3R,4S)-6-nitro-4-[N-(2-methoxy-5-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

44) (2S,3R,4S)-6-amino-4-[N-(2-methoxy-5-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

45) (2S,3R,4S)-6-nitro-4-[N-(2,4-dimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

46) (2S,3R,4S)-6-amino-4-[N-(2,4-dimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

47) (2S,3R,4S)-6-nitro-4-[N-(2,6-dimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

48) (2S,3R,4S)-6-amino-4-[N-(2,6-dimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

49) (2S,3R,4S)-6-nitro-4-[N-(2,3-dimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

50) (2S,3R,4S)-6-amino-4-[N-(2,3-dimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

51) (2S,3R,4S)-6-nitro-4-[N-(2-what isopropylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

52) (2S,3R,4S)-6-amino-4-[N-(2-isopropylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

53) (2S,3R,4S)-6-nitro-4-[N-(4-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

54) (2S,3R,4S)-6-amino-4-[N-(4-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

55) (2S,3R,4S)-6-amino-4-[N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

56) (2S,3R,4S)-6-amino-4-[N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

57) (2S,3R,4S)-6-amino-4-[N-benzyl-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

58) (2S,3R,4S)-6-nitro-4-[N-[(3-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

59) (2S,3R,4S)-6-amino-4-[N-[(3-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-methoxymethyl-3,4-dihydro-2H-1-benzopyran,

60) (2S,3R,4S)-6-nitro-4-[N-(2-hydroxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

61) (2S,3R,4S)-6-amino-4-[N-(2-hydroxyphenyl the)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

62) (2S,3R,4S)-6-nitro-4-[N-[(2-methoxy-4-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

63) (2S,3R,4S)-6-amino-4-[N-[(2-methoxy-4-ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

64) (2S,3R,4S)-6-nitro-4-[N-[(2-methyl-4-hydroxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

65) (2S,3R,4S)-6-amino-4-[N-[(2-methyl-4-hydroxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

66) (2S,3R,4S)-6-nitro-4-[N-(2-ethylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

67) (2S,3R,4S)-6-amino-4-[N-(2-ethylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

68) (2S,3R,4S)-6-nitro-4-[N-(2-methyl-5-(ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

69) (2S,3R,4S)-6-amino-4-[N-(2-methyl-5-(ethoxycarbonylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

70) (2S,3R,4S)-6-nitro-4-[N-(2-hydroxy-5-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-Dima is oxymethyl-3,4-dihydro-2H-1-benzopyran,

71) (2S,3R,4S)-6-amino-4-[N-(2-hydroxy-5-were)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

72) (2S,3R,4S)-6-nitro-4-[N-(2,4,6-trimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

73) (2S,3R,4S)-6-amino-4-[N-(2,4,6-trimetilfenil)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

74) (2S,3S,4R)-6-nitro-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

75) (2S,3S,4R)-6-amino-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

76) (2R,3S,4R)-6-nitro-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

77) (2R,3S,4R)-6-amino-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

78) (2R,3R,4S)-6-nitro-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

79) (2R,3R,4S)-6-amino-4-[N-(4-triptoreline)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

80) (2S,3S,4R)-6-nitro-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

81) (2S,3S,4R)-6-amino-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

82) (2R,3R,4S)-6-nitro-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

83) (2R,3R,4S)-6-amino-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

84) (2R,3S,4R)-6-nitro-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

85) (2R,3S,4R)-6-amino-4-[N-(4-trifloromethyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

86) (2S,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-acetoxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

87) (2S,3S,4R)-6-atsetamino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-acetoxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

88) (2S,3S,4R)-6-atsetamino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

89) (2S,3S,4R)6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-acetoxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

90) (2S,3R,4S)-6-bromo-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

91) (2R,3R,4S)-6-bromo-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

92) (2S,3R,4S)-6-bromo-4-[N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

93) (2R,3R,4S)-6-bromo-4-[N-(4-forfinal)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

94) (2R,3R,4S)-6-bromo-4-[N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

95) (2R,3R,4S)-6-methansulfonate-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

96) (2S,3S,4R)-6-methansulfonate-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

97) (2S,3S,4R)-6-hydroxy-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

98) (2S,3S,4R)-6-nitro-5-methyl-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

99) (2S,3S,4R)-6-nitro-4-[N-(4-forfinal)-N-(2-methyl-2H-tetraz is l-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

100) (3R,4S)-6-cyano-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran,

101) (3R,4S)-6-cyano-4-[N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamino]-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran,

102) (2S,3S,4R)-6-hydroxy-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

103) (2S,3S,4R)-8-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

104) (2S,3S,4R)-8-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

105) (2R,3S,4R)-8-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

106) (2R,3S,4R)-8-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

107) (2R,3R,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

108) (2R,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

109) (2R,3S,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-is ihydro-2H-1-benzopyran,

110) (2R,3S,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

111) (2S,3R,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

112) (2S,3R,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

113) (2S,3S,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

114) (2S,3S,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

115) (2R,3R,4R)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

116) (2R,3R,4R)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

117) (2R,3S,4S)-6-nitro-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran,

118) (2R,3S,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran.

4. The method of obtaining derivatives of benzopyran according to claim 1, comprising a stage of mutual the steps of epoxy compounds of formula 2

with a secondary amine compounds comprising a heterocycle of formula 3

in the presence of a metal salt to obtain the compounds of formula 1A

where R1, R2, R4, R5, R6, n, m, and * have the meanings indicated in claim 1.

5. The method according to claim 4, further comprising the stage of interaction of the compounds of formula 1A

obtaining the compounds of formula 1

replaced byas Deputy R3where R1, R2, R4, R5, R6, n, m, and * have the meanings indicated in claim 1.

6. The method according to claim 4, where the salt of a metal selected from the group consisting of Mg(ClO4)2, CoCl2, LiClO4, NaClO4, CaCl2, ZnCl2, LiBF4and Zn(Tf)2.

7. The method of obtaining derivatives of benzopyran, including the stage of recovery of the compounds of formula 1C

where R1represents NO2in the compound of formula 1a according to claim 4 in the presence of a solvent for the reaction to obtain compounds of formula 1d

where R1,R 3, R4, R5, R6n and m have the meanings indicated in claim 1.

8. The method according to claim 7, where the recovery is carried out using a reducing agent such as NaBH4in the presence of a metal catalyst selected from the group consisting of platinum, palladium on coal (Pd/C) and Raney Nickel; CuSO4, Cu(SLA)2, CoCl2; SnCl2or NiCl2.

9. The method according to claim 7, where the solvent for the reaction are alcohols, such as methanol, ethanol; and ethyl acetate.

10. Pharmaceutical composition for the protection of nerve cells that are useful for the prevention and treatment of asphyxia infants, glaucoma, diabetic neuropathy, head injury, spinal cord injury, which contains the derivatives of benzopyran according to claim 1, their stereoisomers or their pharmaceutically acceptable salts.

11. Pharmaceutical composition for protecting the brain from damage, useful for the prevention and treatment of stroke, which contains the derivatives of benzopyran according to claim 1, their stereoisomers or their pharmaceutically acceptable salts.

12. Pharmaceutical composition for anticyclone, useful for the prevention and treatment of neurodegenerative diseases, including aging and dementia, and atherosclerosis, which contains the derivatives of benzopyran according to claim 1, their stereoisomers or their pharmaceutically acceptable salts.

13. Pharma is eticeskaja composition for inhibiting the generation of NO, useful for the prevention and treatment of arthritis, atherosclerosis, myocardial infarction, stroke, dementia, which contains the derivatives of benzopyran according to claim 1, their stereoisomers or their pharmaceutically acceptable salts.

14. Pharmaceutical composition for protection of the heart that are useful for the prevention and treatment of myocardial infarction, heart failure, angina, congestive heart failure, angina, which contains the derivatives of benzopyran according to claim 1, their stereoisomers or their pharmaceutically acceptable salts.

15. Pharmaceutical composition for suppression of angiogenesis for the prevention and treatment of cancer and diabetic retinopathy, which contains the derivatives of benzopyran according to claim 1, their stereoisomers or their pharmaceutically acceptable salts.



 

Same patents:

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

45 cl, 1 tbl, 57 ex

FIELD: organic chemistry, chemical technology, medicine, endocrinology, biochemistry.

SUBSTANCE: invention relates to a method for preparing compound of the formula (I) wherein R1 and R2 represent independently of one another hydrogen atom or methyl; R3, R4, R5 and R6 represent independently of one another hydrogen atom (H), halogen atom, formyl group, (C1-C6)-alkyl substituted optionally with fluorine atoms in amount up to three, (C1-C6)-alkoxy-group substituted optionally with fluorine atoms in amount up to three, (C1-C6)-alkylenyloxycarbonyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C1-C4)-alkylcarbonylamido-group, (C3-C7)-cycloalkylcarbonylamido-group, phenylcarbonylamido-group, benzyl, phenyl or naphthyl wherein benzyl, phenyl and naphthyl are substituted optionally and independently of one another with substitutes in amount up to two and chosen independently from halogen atom, (C1-C6)-alkyl substituted optionally with fluorine atoms in amount up to three, (C1-C6)-alkoxy-group substituted optionally with fluorine atoms in amount up to three and (C1-C4)-alkoxy-(C1-C4)-alkyl. Proposed method involves the following successive stages: (a) interaction of compound of the formula (II) wherein R3, R4, R5 and R6 are determined independently as given above with lithium-organic compound in the presence of sulfur source in medium of the first reactively inert solvent to form the reactive intermediate compound of the formula (IIa) (b) interaction of indicated reactive intermediate compound of the formula (IIa) with compound of the formula (III) to form compound of the formula (IV) (c) interaction of indicated compound of the formula (IV) with alkaline (C1-C2)-alkoxide in (C1-C2)-alkanol medium to form derivative of simple ether of the formula (V) wherein Alk represents (C1-C2)-alkyl; (d) interaction of indicated compound of the formula (V) with mineral acid to form compound of the formula (VI) and (e) oxidation of compound of the formula (VI) in the second reactively inert solvent to form compound of the formula (I). Prepared pyridazinone compounds are effective inhibitors of aldose reductase activity and can be used in prophylaxis and/or treatment of diabetes mellitus complications, such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic microangiopathy and diabetic macroangiopathy in mammals. Also, invention relates to new intermediate compounds of the formula (IV) used in synthesis of indicated inhibitors of aldose reductase, to a method for synthesis of compound of the formula (IV) and a method for synthesis of preferable pyridazinone compound of the formula (XI) .

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

10 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of aminoquinoline and aminopyridine. Invention describes compounds of the general formula (I): wherein R1 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R2 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R3 means hydrogen atom or direct or branched (C1-C4)-alkyl group or phenyl group, thienyl group or furyl group optionally substituted with one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group or halogen atom; R4 and R5 form in common 1,3-butadienyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group or halogen atom; R6 means hydrogen atom or cyano-group; R7 means hydrogen atom or direct or branched (C1-C4)-alkyl group, phenyl group, benzyl group, thienyl group, or furyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group, trifluoromethyl group, cyano-group or halogen atom; X means -NH-group, -NR8-group or sulfur atom, or oxygen atom, or sulfo-group, or sulfoxy-group wherein R8 means direct or branched (C1-C4)-alkyl group or (C3-C6)-cycloalkyl group; n = 0, 1 or 2, and their salts. Also, invention describes a method for preparing compounds of the formula (I). a pharmaceutical composition based on thereof, using compounds of the formula (I) as antagonists of A3 receptors for preparing a pharmaceutical composition used in treatment of different diseases (variants), compounds of the formula (IA), (II), (III) and (IV) given in the invention description. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

15 cl, 6 tbl, 6 dwg, 172 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes new derivatives of triazole of the general formula (I): wherein X represents group of the general formula (II): wherein R' means halogen atom; R4 means (C1-C6)-alkyl; L means group of the formula: -La-Lb wherein La means a simple bond, oxygen atom, phenyl group that can be optionally substituted with halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group or (C1-C6)-alkyl substituted with a single group -O-P(=O)(OH)2, naphthyl group, 5-membered heteroaryl group comprising as a heteroatom oxygen (O) or sulfur (S) atom, or (C3-C7)-cycloalkyl group that is substituted with carboxyl group; and Lb means (C1-C5)-alkylene group that can be optionally substituted with (C1-C6)-alkyl, carboxyl group or di-[(C1-C6)-alkyl]-amino-(C1-C6)-alkyl group; R means hydrogen atom, (C1-C6)-alkanoyl that can be optionally substituted with group: -Q-NR2'R3' wherein Q means a simple bond or carbonyl group, and R2' and R3' in common with nitrogen atom with that they are bound form piperazinyl ring substituted with (C1-C6)-alkyl and/or carboxyl group, or group: -O-P(=O)(OH)2; or their pharmacologically acceptable salts, pharmaceutical composition based on thereof, and a method for treatment of fungal infections.

EFFECT: valuable medicinal properties of compounds and composition, improved method for treatment of infections.

24 cl, 14 tbl, 1 dwg, 45 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to quinazoline derivatives of the formula (I) or their pharmaceutically acceptable salts wherein m = 0 or 1; each group R1 can be similar or different and represents halogen atom, hydroxy- and (C1-C6)-alkoxy-group, or group of the formula Q3-X1 wherein X1 represents oxygen atom (O); Q3 represents phenyl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl, and wherein heteroaryl group represents aromatic 5- or 6-membered monocyclic rings with one or two nitrogen heteroatoms, and any heterocyclyl group defined as the group R1 represents non-aromatic saturated or partially saturated 3-6-membered monocyclic ring with one or two heteroatoms chosen from oxygen and nitrogen atoms, and wherein adjacent carbon atoms in any (C2-C6)-alkylene chain in the substitute R1 are separated optionally by incorporation of oxygen atom (O) in the chain, and wherein any group CH2 or CH3 in the substitute R1 comprises optionally in each of indicated groups CH2 or CH3 one or some halogen substitutes or a substitute chosen from hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkylsulfonyl or pyridyloxy-group, and wherein any heteroaryl or heterocyclyl group in the substitute R1 comprises optionally 1, 2 or 3 substitutes that can be similar or different and chosen from hydroxy-group, carbamoyl, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]-carbamoyl, (C1-C6)-alkoxy-(C1-C6)-alkyl and cyano-(C1-C6)-alkyl, or among group of the formula -X5-Q6 wherein X5 represents a direct bond or -CO, and Q6 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that comprises optionally (C1-C6)-alkyl as a substitute wherein heterocyclyl group represents non-aromatic, fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from nitrogen and oxygen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; Z represents a direct bond or oxygen atom; Q1 represents phenyl, (C3-C7)-cycloalkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl wherein heteroaryl group represents 5- or 6-membered aromatic monocyclic ring with I, 2 or 3 heteroatoms of nitrogen, and any heterocyclyl group represents non-aromatic fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from oxygen, nitrogen or sulfur atom, or when Z represents oxygen atom (O) then Q1 can represent (C1-C6)-alkyl or (C1-C6)-alkoxy-(C1-C6)-alkyl and wherein any heterocyclyl group in the group -Q1-Z- comprises substitutes chosen from (C1-C6)-alkyl, (C1-C)-alkoxycarbonyl and pyridylmethyl, and wherein any heterocyclyl group in the group -Q1-Z- comprises optionally 1 or 2 oxo-substitutes; Q2 represents aryl group of the formula (Ia): wherein G1 represents halogen atom, trifluoromethyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C2-C6)-alkanoyl, pyrrolyl, pyrrolidinyl, piperidinyl and morpholinomethyl, and each G2, G3, G4 and G5 that can be similar or different represents hydrogen, halogen atom, cyano-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group, or G1 and G2 form in common group of formulae -CH=CH-CH=CH-, -CH=CH-O- or -O-CH=CH- being each group carries optionally halogen atom as a substitute, or G1 and G2 form in common group of formulae -O-CH2-O- or -O-CH2-CH2-O-, or -O-CH2-CH2-O-, and each among G3 and G4 represents hydrogen atom, and G5 is chosen from hydrogen and halogen atom. Proposed compounds possess anti-tumor activity and designated for preparing a medicine preparation for its using as an anti-tumor agent for suppression and/or treatment of solid tumors. Also, invention relates to a pharmaceutical composition based on abovementioned compounds.

EFFECT: valuable medicinal properties of compounds.

20 cl, 7 tbl, 57 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine. Method involves reaction of 4,6-dichloro-2-(methylthio)-1,3-pyrimidine with alkaline metal methoxide in inert organic solvent, transfer of prepared 4,6-dimethoxy-2-(methylthio)-1,3-pyrimidine in aqueous acid medium and the following oxidation of this compound in the presence of catalyst if necessary, preferably, with an interphase catalyst, such as tricaprylmethylammonium chloride. Then method involves carrying out the purification stage wherein pH value of the aqueous acid reaction mixture is brought about to the value from 5 to 8 with aqueous base, such as alkaline metal hydroxide, for example, sodium hydroxide at temperature 10-90°C and stirring in the presence of absence of organic solvent, for example, aromatic hydrocarbon, such as benzene, toluene or isomeric xylenes, or alcohol, such as methanol or ethanol. Also, invention relates to using the prepared compound as an intermediate substance for synthesis of herbicide, in particular, 7-[(4,6-dimethoxypyrimidin-2-yl)thio]-3-methylphthalide by reaction of 7-mercapto-3-methylphthalide of compound in preparing herbicides, for example, 7-[(4,6-dimethoxypyrimidin-2-yl)thio]-3-methylphthalide.

EFFECT: improved preparing method.

24 cl, 2 sch, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of benzene or its salt of the formula (I): wherein X1 means -C(=O)-NR5-, -NR5-C(=O)-; X2 means -NR6-C(=O)-, -NR6-CH2-; R1 means halogen atom, lower alkyl or lower alkoxy-group; R2 and R3 mean hydrogen or halogen atom; R4 means hydrogen atom, -SO3H- or sugar residue; ring A represents benzene or pyridine ring; ring B represents piperidine ring, and a pharmaceutical composition based on thereof. Proposed compounds possess anti-coagulating effect based on inhibition of blood coagulation activated factor X that are useful as anti-coagulants or prophylactic agents against diseases caused by thrombosis and embolism.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

5 cl, 9 tbl, 38 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing aminoxyl ethers, for example, N-hydrocarbyloxy-derivatives of steric hindranced amines that can be used as light- and/or thermostabilizing organic materials and/or a regulator in the polymerization reaction. Invention describes a method for preparing aminoxyl ethers by interaction of the corresponding N-oxyl derivative with hydrocarbon organic solvent in the presence of organic peroxide and a catalyst representing copper or copper compound, preferably, inorganic compound Cu (I) or Cu (II) as a solution in suitable solvent chosen in the catalytically effective amount. Method provides preparing the end product with the high yield by simplified technological schedule and without using high temperatures.

EFFECT: improved method of synthesis.

15 cl, 2 tbl, 27 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new derivatives of quinazoline of the formula (I):

wherein m = 0, 1, 2 or 3; each group R1 that can be similar or different is taken among halogen atom, trifluoromethyl, hydroxy-, amino-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-, (C2-C6)-alkynyloxy-, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino- and (C2-C6)-alkanoylamino-group, or among the group of the formula: Q1-X1- wherein X1 represents oxygen atom (O); Q1 represents aryl-(C1-C6)-alkyl, heteroaryl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl and wherein neighboring carbon atoms in any (C2-C6)-alkylene chain in substitute at R1 are separated optionally by insertion to the chain the group taken among oxygen atom (O) and N(R5) wherein R5 represents hydrogen atom or (C1-C6)-alkyl, or when the inserted group represents N(R5); R5 can represent also (C2-C6)-alkanoyl and wherein any group -CH2 or -CH3 in substitute R1 carries one or more substitutes in each indicated group -CH2 or -CH3 and wherein these substitutes are taken among halogen atom or (C1-C6)-alkyl, or substitute taken among hydroxy-, amino-group, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino-, (C2-C6)-alkanoyloxy, (C2-C6)-alkanoylamino- and N-(C1-C6)-alktyl-(C2-C6)-alkanoylamino-group, or among the group of the formula: -X3-Q3wherein X3 represents oxygen atom (O) and Q3 represents heteroaryl, and wherein any aryl, heteroaryl or heterocyclyl group in substitute at R1 carries optionally 1, 2 or 3 substitutes that can be similar or different and taken among halogen atom, trifluoromethyl, cyano-, hydroxy-, amino-group, carbamoyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy, (C2-C6)-alkynyloxy,(C1-C6)-alkylthio-group, (C1-C)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino-group, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]carbamoyl, (C2-C6)-alkanoyl, (C2-C6)-alkanoyloxy-, (C2-C)-alkanoylamino- and N-(C1-C6)-alkyl-(C2-C6)-alkanoylamino-group, or among the group of the formula: -X4-R8 wherein X4 represents a simple bond and R8 represents hydroxy-(C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, cyano-(C1-C6)-alkyl, amino-(C1-C6)-alkyl, (C1-C6)-alkylamino-(C1-C6)-alkyl or di-[(C1-C6)-alkyl]amino-(C1-C6)-alkyl, or among the group of the formula: -X5-Q4 wherein X5 represents a simple bond or -CO, and Q4 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that carries optionally 1 or 2 substitutes that can be similar or different and taken among halogen atom, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group and wherein any heterocyclyl group in substitute at R1 carries optionally 1 or 2 oxo-substitutes, and wherein any aryl group in the group R1 represents phenyl; any heteroaryl group in the group R1 is taken among pyrrolyl, imidazolyl, triazolyl and pyridyl, and any heterocyclyl group in the group R1 is taken among oxyranyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, 1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl; R2 represents hydrogen atom; n = 0, 1, 2 or 3; R3 represents halogen atom, trifluoromethyl, cyano-, hydroxy-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or (C1-C6)-alkoxy-group, or its pharmaceutically acceptable salt. Also, invention relates to methods for preparing compounds of the formula (1) and to pharmaceutical composition based on thereof for using as an anti-tumor agent. Invention provides preparing new derivatives of quinazoline possessing an anti-tumor activity.

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

17 cl, 7 tbl, 7 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 3-aminomethylquinolone-2 of the general formula (1)

(2)

or (3) wherein R1 means hydrogen atom (H) or Alk; R2 is taken among Alk; -OAlk, -SCH3, -Hal, -CF3, 3,4-OCH2CH2O-, 3,4-OCH2O-, 4-OCF3, 2-Ph, -OPh, -NHCOR, 2-OCH3, 5-Ph, 4-Obzk, 3-NO2, 2-CH3, 5-iPr, di-OAlk, di-Hal; or R2 represents halogen atom and alkyl group, or halogen atom and alkoxy-group taken simultaneously and independently of one another; or R2 represents the group -CONR4R5 wherein each R4 and R5 means independently of one another the group Alk, or they form the group -(CH2)n- wherein n = 2-6. R means -CH3; R3 means hydrogen atom (H); X is taken among hydrogen atom (H), 6-(C1-C3)-Alk, 6-iPr, 6-iBu; 7-(C1-C2)-Alk, 8-(C1-C2)-Alk, 6-(C1-C2)-OAlk, 6-OCF3, 7-(C1-C2)-Alk, 7-SCH3, 6,7-OCH2O-, 6,7-OCH2CH2O-, 5,6,7-OCH3, 6-F; X and Y are similar or different and taken among 7,8-CH3, 6,8-CH3, 5,8-CH3, 5,7-CH3, 6,7-CH3, 6,7-OCH3, 6-CH3, 7-Cl. Also, invention relates to a method for preparing indicated compounds and to pharmaceutical composition inhibiting activity of NO-synthetase based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof for aims preparing medicinal agents for treatment diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

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

19 cl, 1 tbl, 95 ex

FIELD: medicine.

SUBSTANCE: method involves carrying out intracerebral implantation of spinal marrow stem cells during neurosurgical intervention in the injured area. Transplantation is carried out in early and late recovery period after stroke. The whole autologic mononuclear cells complex is introduced as the stem cells separated from spinal marrow aspirate without selecting individual cell fractions and their culturing.

EFFECT: simplified treatment course; reduced neurological deficiency.

2 tbl

FIELD: chemical and pharmaceutical industry.

SUBSTANCE: claimed agent represents aqueous solution of microelements such as copper, zinc, indium, cobalt, manganese, chromium and silicium in concentration approximately being equal to concentration of same elements in drinking water. Hydrochloric acid in introduced into solution to activate microelement action and to produce pH 3-5. Metals are introduced in form of chlorides, and silicium is introduced in form of sodium or potassium silicate. Said aqueous solution of microelements is administrated orally 3 times per day for 1.5-2 months in single dose of 20-40 ml.

EFFECT: high effective agent for treatment of hypertension without side effects.

2 cl, 3 ex

FIELD: medicine, cardiology.

SUBSTANCE: invention relates to prophylaxis of disorders of the cardiac activity rhythm. Method involves simultaneous administration of para-aminobenzoic acid β-diethylaminoethylamide and 3-(2,2,2-trimethylhydrazinium)propionate dihydrate, 30-40 min before the suggested development of disorders of cardiac activity rhythm. Such performance of method allows carrying out the effective prophylactic of disorders of cardiac rhythm caused by arhythmogenic factor of different etiology.

EFFECT: improved method of prophylaxis.

2 cl, 4 ex

FIELD: medicine, gynecology.

SUBSTANCE: invention relates to a method for correction of vegetative symptoms in climacteric syndrome in women with ischemic disorders in cerebral circulation. Method involves administration of mexidol in the dose 125 mg, 3 times per a day for 8 weeks, and alzolam in the dose 0.25 mg, once per a day, 30 min before sleeping for 4 weeks. Method represents the alternative substitution hormonal therapy and provides the simultaneous correction of vegetative disorders in climacteric period and ischemic damages of the cerebral circulation.

EFFECT: improved method of syndrome correction.

1 tbl

FIELD: medicine, pharmaceutical technology, pharmacy.

SUBSTANCE: invention relates to producing solid combined medicinal formulations of preparations exhibiting an antihypertensive effect, increasing heart blow-out index and enhancing tolerance to physical load in patient with the congestive cardiac insufficiency. The proposed medicinal agent comprises the following components, wt.-%: perindopril erbumine, 0.6-7.0; microcrystalline cellulose, 12.0-35.0; magnesium stearate, 0.3-1.7; aerosil, 0.1-1.0; croscarmelose-sodium, 1.1-7.0, and lactose, the balance. Also, invention discloses a method for preparing the medicinal formulation. Invention reduces loss of perindopril in process for the formulation preparing, retaining the parent properties of perindopril erbumine and enhancing biological availability of agent.

EFFECT: enhanced and valuable properties of agent, improved preparing method.

3 cl, 2 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to an enantiomer in S-configuration at position 4 of its 4,5-dihydropyrazole ring, compound of the formula (I): wherein R and R1 are similar or different and represent 3-pyridyl or 4-pyridyl, or phenyl that can be substituted with halogen atom or methoxy-group; R2 and R3 are similar or different and represent hydrogen atom, (C1-C3)-alkyl or dimethylamino-group; R4 represents phenyl that can be substituted with 1, 2 or 3 substitutes chosen among group comprising halogen atoms, trifluoromethyl, methoxy-group and (C1-C3)-alkyl, and to its tautomers and salts also. Compounds possess antagonistic activity with respect to CB1-cannabis. Also, invention relates to a pharmaceutical composition possessing the abovementioned activity, method for preparing the pharmaceutical composition, method for synthesis of compounds of the formula (I), method for antagonistic effect on CB1-receptors and method for treatment of cardiovascular diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

7 cl, 4 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a medicinal formulation consisting of a core comprising the following components, wt.-%: trimetazidine dihydrochloride, 9.0-32.0; hydroxypropylcellulose, 3.0-10.5; hydroxyethylcellulose, 18.5-67.2; sodium alginate, 0.1-0.6; calcium phosphate dihydrate, 19.0-28.5; magnesium stearate, 0.5-2.0; talc, 0.5-2.0, and envelope comprising the following components, wt.-%: one component chosen from the group including hydroxypropylcellulose, water-soluble methylcellulose or hydroxypropylcellulose, 0.6-2.7; Tween-80, 0.3-1.2; pigment titanium dioxide, 0.1-1.0 and red iron oxide, 0.1-0.8. Method for preparing the medicinal formulation is carried out by wet granulation, tabletting prepared granules and applying the envelope from an aqueous suspension by spraying preferably. Release of trimetazidine dihydrochloride in the body from the new proposed formulation is carried out for 8 h that provides the constant level of the preparation in blood.

EFFECT: improved preparing method, valuable pharmaceutical properties of formulation.

3 cl, 2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to a method for treatment of cerebral ischemia on its model in mammal. Method involves administration in mammal the effective doses of bis-[(2-hydroxyethyl)-N,N,N-trimethylaminium] succinate. This provides prophylaxis of development of unfavorable results of cerebral ischemia and/or insult based on prevention of cerebral neurons death, reducing rate of pathological decreasing the energetic metabolism in ischemia being without by-side effects.

EFFECT: improved and enhanced method of treatment of cerebral ischemia.

3 tbl, 2 ex

FIELD: medicine, endocrinology.

SUBSTANCE: invention proposes a medicinal agent for reducing the blood sugar content after food intake and representing a compound included in meglytinides and, if necessary, a pharmaceutically acceptable carrier. Nateglynide is the preferable compound. The complication associated with diabetes mellitus is chosen among nephropathy, retinopathy, neuropathy and angiopathy. At least one agent chosen among antihypertensive agent, vasodilating agent and antihyperlipidemic agent can be used with agent used simultaneously for reducing the blood content after food intake. Invention provides realization of indicated prescription.

EFFECT: valuable medicinal properties of drugs.

15 cl, 2 dwg, 5 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to improved methods for modulation of diabetes mellitus type II in mammal and modulation of resistance to insulin. Methods involve administration to indicated mammal needing in this treatment of (-)-stereoisomer of compound of the formula (I): wherein R is chosen from group including hydroxy-, lower araloxy-, d-(lower)-alkylamino-(lower)-alkoxy-, (lower)-alkylamido-(lower)-alkoxy-, benzamido-(lower)-alkoxy-, ureido-(lower)-alkoxy-, N'-(lower)-alkyl-ureido-(lower)-alkoxy-, carbamoyl-(lower)-alkoxy-, halophenoxy-substituted lower alkoxy-, carbamoyl-substituted phenoxy-group; or R represents hydrolysable ester group; each X represents independently halogen atom; or its pharmaceutically acceptable salt wherein (-)-stereoisomer doesn't comprise conceptually (+)-stereoisomer. Also, invention relates to pharmaceutical compositions comprising (-)-stereoisomer of compound of the formula (I) and wherein compositions show significantly reduced inhibitory effect on activity of cytochrome P-450 2C9 as compared with racemic composition having 0% enantiomeric excess of (-)-stereoisomer.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition, improved preparing methods.

59 cl, 21 dwg, 8 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: preparation has autologic hemopoietic stem cells separated from peripheral patient blood enriched in cells containing CD34 antigen in final concentration of (40-100)x106 cells/ml. Blood enrichment is carried out by introducing granulocyte colony-stimulating factor like Neupogen in glucose solution in intermittent mode according to known scheme. Method involves applying the claimed preparation.

EFFECT: reduced tissue incompatibility and transplant rejection; enhanced effectiveness of treatment.

9 cl, 1 dwg, 2 tbl

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