Benzopyran derivatives substituted with secondary amines including tetrazol, process for the prepara

专利摘要:
PURPOSE: Benzopyran derivatives substituted with secondary amines including tetrazole, a preparation process thereof and pharmaceutical compositions containing the same compounds are provided, which compounds do not induce the decrease of blood pressure and inhibit the damage of nervous cells by oxidation stresses. CONSTITUTION: Benzopyran derivatives substituted with secondary amines including tetrazole represented by the formula 1, stereo isomers thereof or pharmaceutically acceptable salts thereof are provided, wherein R1 is H, F, Cl, Br, CF3, NO2, CN, ORa, OCORa, COORa, NH2, NHS(O)IRa, NHCORa or S(O)IRa; Ra is H, C1-C4 linear or branched chain alkyl or aryl; I is an integer of 0 to 2; R2 is CH2ORa, ORbORc or O(z)O; Rb and Rc are independently C1-C4 linear or branched chain alkyl; Z is C1-C5 linear or branched chain alkyl; R3 is OH, F, Cl, Br, ONO2 or COORa; R4 and R5 are independently H, F, Cl, Br, C1-C3 linear or branched chain alkyl, ORa, CF3, OCF3, NO2, CORa, OCORa, CCOORa or SO3Ra; R6 is hydrogen, C1-C3 linear or branched chain alkyl; n and m are independently an integer of 0 to 2; and * is chiral carbon.
公开号:KR20030081149A
申请号:KR1020030022746
申请日:2003-04-10
公开日:2003-10-17
发明作者:임홍；이동하；김선옥；최인영；유성은；이규양；이선경；서지희；김낙정；이병호；서호원；신화섭
申请人:동부한농화학 주식회사；
IPC主号:

专利说明:

Benzopyran derivatives substituted with secondary amines including tetrazole {BENZOPYRAN DERIVATIVES SUBSTITUTED WITH SECONDARY AMINES INCLUDING TETRAZOL, PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM}
[1] The present invention relates to a benzopyran derivative substituted with a secondary amine comprising tetrazole represented by the following formula (1), a method for preparing the same, and a pharmaceutical composition comprising the same.
[2]
[3] (Wherein
[4] R_OneIs H, F, Cl, Br, CF₃, NO₂, CN, OR^a,, COOR^a, NH₂, NHS (O)_lR^a,Or S (O)_lR^aWhere R^aH, C_One-C₄Is linear or pulverized alkyl or aryl of l is an integer of 0 to 2;
[5] R ₂ is CH ₂ OR ^a , or Is,
[6] Wherein R ^a is as defined above, R ^b and R ^c are each independently C ₁ -C ₄ straight or branched alkyl, Z is C ₁ -C ₅ straight or branched alkyl;
[7] R ₃ is OH, F, Cl, Br, ONO ₂ or Wherein R ^a is as defined above;
[8] R ⁴ and R ⁵ are each independently H, F, Cl, Br, C ₁ to C ₃ straight or branched alkyl, OR ^a , CF ₃ , OCF ₃ , NO ₂ , , , Or SO ₃ R ^a , wherein R ^a is as defined above;
[9] R ⁶ is hydrogen, C ₁ -C ₃ straight or pulverized alkyl;
[10] n and m are each independently an integer of 0 to 2;
[11] * Represents chiral carbon.)
[12] Nerve cells present in the mammal's CNS (central nervous system) are very sensitive to oxygen supply. It is known that transient critical reduction of oxygen in adjacent brains leads to various pathological phenomena and eventually fatal brain damage [K. Nieber, Pharmacol. Ther. 1999, 82 , 71]. The brain may lack oxygen through ischemia, or hypoxia in the blood due to cardiac arrest or clogging of blood vessels in the skull.
[13] Ischemic cell damage is impaired in electrophysiology, hemodynamics and energy metabolism [W. Paschen and B. Djuricic, J. Neurochem . 1995, 65 , 1692] and changes in synaptic neurotransmitters [HJ Luhmann, Prog. Neurobiol . 1996, 48 , 131] is known to occur by a complex interaction between a series of biochemical reactions, including. Disturbance of ion homeostasis with increased intracellular K ⁺ outflow and increased Na ⁺ and Ca ²⁺ influx may result in substantial extracellular acidosis, free radical formation, cell swelling, inhibition of protein synthesis and Ca-dependent or ATP-dependent K-channel and the like. As stated above, cellular changes due to ischemia do not occur through a single pathway, but are caused by a variety of pathways by complex interactions. Therefore, the development of neuroprotective agents requires a number of strategies and effective interventions that act at several key stages of the ischemic series of processes as effective therapeutics for cerebral ischemia. [De keyser et al. TrendsNeurosci. , 1999, 22, 535; Dirnagl et al., Trends Neurosci. , 1999, 22 , 391; Gladstone et al. Stroke, 2002, 33 , 2123].
[14] In addition, even after blood flow is restored, oxygen can promote biochemical reactions that generate free radicals, which can cause reperfusion injury. Acute / chronic damage of tissues and organs is known to be caused by endotoxins due to ischemic-reperfusion or bacterial infections. To prevent brain damage due to ischemic-reperfusion, the brain must be protected to avoid further damage and pathological cellular changes must be minimized.
[15] For this purpose, development of various neuronal cell protective agents such as excitatory amino acid antagonists, antioxidants, adenosine agonists, and K _ATP channel _openers is underway.
[16] Nerve cell damage or necrosis is known to be a major cause of neurological diseases, including stroke, head trauma, Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma, and diabetic neuropathy [GJ Zoppo et al., Drugs 1997, 54 , 9: I. Sziraki et al., Neurosci , 1998, 85 , 1101.
[17] Nerve damage is caused by a variety of factors including increasing iron concentrations in nerve cells, increasing active active oxygen, and increasing peroxides. MP Mattson et al., Methods Cell Biol . 1995, 46 , 187; Y. Goodman et al., Brain Res . 1996, 706 , 328.
[18] Excessive generation of free radicals due to oxidative stress promotes lipid peroxidation to increase and accumulate oxidants in cells, leading to changes in protein synthesis and changes in DNA. Since oxidative metabolism is essential for all cellular metabolism, over-generated free radicals are a wide variety of diseases [JM McCord, Am J. Med . 2000, 108 , 652, eg, arthritis; arteriosclerosis; Inflammatory diseases such as heart infarction and neurodegenerative diseases such as dementia, allergies, and cancer, as well as acute / chronic tissue and organ damage are the cause.
[19] Thus, there is a need for a therapeutic approach to inhibit lipid peroxidation, inhibit NO or free radical production by endotoxins, and further minimize neuronal damage or death. To date, antioxidants are known to improve nerve cell damage and death due to increased iron concentrations in nerve cells. Efforts have been made to develop drugs that can prevent neuronal cell damage caused by oxidative stress [Y. Zhang et al., J. Cereb. Bood Flow Metab . 1993, 13 , 378].
[20] The K _ATP opener induces antioxidant enzymes [S. Okubo et al., Mol. and cell Biochem. , 1999, 196 , 3] and reduced release of active amino acids [JL Moreau, G. Huber, Brain Res. , 1999, 31 , 65.
[21] Diazoxide, a K _ATP channel opener, is known to reversibly oxidize flavoproteins in mitochondria, inhibit the formation of oxygen free radicals, and protect cell damage from oxidative stress. AA Starkov, Biosci, Rep . 1997, 17 , 273; VP Skulachev, Q. Rev. Biophus . 1996, 29 , 169.
[22] Infants asyphyxia (IA), which are caused by a temporary lack of oxygen supply at delivery, are intracellular, including reduced energy production, damage to cell membranes by oxygen free radicals, release of excitatory neurotransmitters, calcium and zinc, etc. It is known to be caused by a change in ion concentration. IA is a worldwide disease because IA increases in mortality (nearly one third of all neonatal deaths). In addition, IA can cause long-term diseases including motor disorders, learning disabilities, epilepsy, mental retardation disorders, and convulsions [CF Loid et. al. Physiology and Behavior 2000, 68 , 263-269.
[23] Antioxidant enzymes, allopurinol, vitamin C, vitamin E, free radical scavengers, inhibitors of excitatory neurons, calcium channel blockers such as nimodipine or flulunarizine, NO production inhibitors, hyperglycemia and hypothermia therapy This may be useful for protecting brain damage, but has not yet been applied to clinical practice.
[24] Glaucoma, one of the main causes of visual impairment, is an optic nerve dilation that is associated with characteristic changes in the optic nerve. Human optic nerve consists of about one million axons, most of which are located in the ganglion and the rest of the inner core layer. The change of the optical nerve and damage of the optical nerve causes glaucoma, which is caused by the excavation of the optical nerve caused by neuronal death and loss of ganglion cells or axons, which is the main cause of blindness [NN Osborne, et. . Al. Survey of Ophthalmology 1999, 43 , suppl. S102-S128].
[25] Nerve cell protectors are those that protect the retinal nerves of glaucoma, especially ganglion cells, directly or indirectly. Therefore, various agents such as antagonists of N-Methyl-D-aspartate (NMDA) receptors, alpha-blockers, calcium antagonists, antioxidants and the like may be used to protect the death of optic nerve cells caused by ischemia and optic nerve cutting.
[26] Although the cause of diabetic neuropathy is not clearly identified, two major hypotheses have been proposed. One is abnormal metabolism, the other is a lack of blood flow in the epidermal nerve. Naka et al. Diabetes Research and Clinical Pratice , 1995, 30 , 153-162. Acetyl-L-carnitine (ALC) and prosaptide, which release neurotrophic factors, which promote the oxidation of lipids and improve the trauma-soluble response of damaged neurons, are in clinical trials. In addition, memantine, which has shown good efficacy in blood flow dementia through the regulation of NMDA receptors, is attempting clinical trials. Neuroprotective agents with various mechanisms of action have been developed to treat diabetic neuropathy.
[27] Ischemic heart disease is the result of myocardial ischemia, where the balance of oxygen demand and supply in the myocardium is unbalanced and the supply is significantly short of the demand [GJ Grover, Can. J. Physiol . 1997, 75 , 309; GD Lopaschuk et al. Science & Medicine 1997, 42]. Myocardial ischemia gradually causes intracellular pathological changes, ultimately leading to irreversible damage of the myocardium and necrosis of cells and tissues. In the early stages of reversibility, reperfusion can prevent such irreversible damage, but it has been reported that such reperfusion can cause damage [DJ Hearse, Medicographia 1996, 18 , 22].
[28] In order to delay ischemic damage and minimize reperfusion damage, adenosine agonists, Na ⁺ -K ⁺ exchange inhibitors, oxygen free radical scavengers, K _ATP (ATP), as well as an angiotensin converting enzyme (ACE) inhibitor and calcium antagonist Sensitive calcium channel) Opening agents and the like have been studied. In addition, overall ischemia occurs when the heart is stored at low temperatures for heart transplantation. Recently, the addition of a potassium channel opener to existing high potassium preservatives has been reported to improve the recovery of cardiac contractile function after normal or short-term hypothermic ischemia. D, J. Chambers, DJ Hearse, Ann. Thoar. Surg. 1999, 68 , 1960]. The use of compounds as long-term protective or therapeutic agents has been studied to be associated with ischemic-reperfusion injury such as retina and skeletal muscle in the heart and brain.
[29] As mentioned above, ischemic serial processes proceed by complex interactions, so it would be useful to develop compounds that can act at one or more target points in the ischemic serial process.
[30] K _ATP (ATP-sensitive potassium channel), which was first discovered in the myocardium, is widely distributed in various tissues and organs such as the beta cells of the pancreas, smooth muscle, kidney and central nervous system. Selective drug development involves difficulties.
[31] Unlike conventional K _ATP -sensitive potassium channel openers, the benzopyranyl cyanoguanidine compound represented by the following formula (4) (BMS-180448) and the benzopyranyl imidazole compound represented by the following formula (BMS) -191095) have excellent myocardial selectivity and are known to have adequate anti-ischemic efficacy. Although the compound represented by the formula (5) has all the desirable features that can serve as a leading substance, it still has vascular relaxation activity and hypotension activity [KS Atwal et al., J. Med. Chem. , 1995, 38 , 3236; KS Atwal et al., J. Med. Chem. , 1996, 40 , 24; KS Atwal et al., Current Pharmaceutical Design, 1996, 2 , 585. Thus, it is expected to develop cardiac selective compounds that can have cardioprotective efficacy without lowering blood pressure as new cardioprotectants.
[32]
[33]
[34] On the other hand, the proportion of cancer among human diseases is gradually increasing, and the formation of minute blood vessels, known as angiogenesis, is recognized as a key process of solid cancer proliferation and metastatic activity [Folkma, J. et al. , J. Biol. Chem . 1992, 267 , 10931-10934. Angiogenesis is regulated by the balance of angiogenesis inducers and inhibitors. When these factors are imbalanced, large numbers of neovascularization are formed. Angiogenesis is associated with a variety of physiological phenomena, including embryonic development, wound healing, chronic inflammation, hemangiomas, diabetic retinopathy, rheumatoid arthritis, psoriasis, and AIDS complications. And the growth and metastasis of malignancies. Forkman, J., Klagsbrun. M. Science 1987, 235 , 442-447.
[35] Angiogenesis involves a series of actions leading to the migration and proliferation of vascular endothelial cells and differentiation into vascular cells, which is known to be an important prerequisite for cancer growth and metastasis. In other words, the progressive growth of cancer requires angiogenesis from host cells, whereby angiogenesis promoters derived from tumors stimulate vascular endothelial cells to induce new angiogenesis into tumor masses. Since many malignant tumors are formed around the generated neovascularization, cancer cell metastasis also proceeds easily. Therefore, the inhibition of neovascularization can lead to the inhibition of cancer growth and metastasis, the discovery of neovascularization inducers, elucidating its mechanism of action, and finding factors that inhibit neovascularization are important for anticancer drug development. It is attracting attention as a research.
[36] Known angiogenesis inhibitors include proteins such as prostamine, tumor necrosis factor, factors derived from cartilage in tissues without blood vessels, and cortisone called angiostatic steroids. cortisone) and various types of steroid derivatives. Hydrocortisone is known to have anti-angiogenic effects when treated with heparin (Lee, A. et al., Science 1983, 221). , 1185-1187; Crum, R. et al., Science 1985, 230 , 1375-1378]. However, these substances have limitations as effective cancer therapeutic agents due to cytotoxicity.
[37] In view of the above problems, the present inventors have been trying to develop a compound capable of protecting a neuron having a pharmacological effect required, and benzopyran substituted with a secondary amine including a tetrazole represented by Chemical Formula 1 above. Derivatives were synthesized, and the compounds of the present invention exhibited a protective effect against ischemic heart, ischemic brain and retinal ganglion cells without decreasing blood pressure due to weak vascular relaxation effect, prevent cerebral ischemia-reperfusion and hypoxic brain injury, The present invention has been completed by identifying various pharmacological effects such as antioxidant activity, inhibition of lipid peroxidation and active oxygen inhibition, inhibition of NO production, protection against retinal cells, and inhibition of angiogenesis. .
[38] It is an object of the present invention to provide a benzopyran derivative substituted with a secondary amine comprising a tetrazole represented by formula (1) and a pharmaceutically acceptable salt thereof.
[39] Another object of the present invention is to provide a method for preparing a benzopyran derivative substituted with a secondary amine comprising tetrazole represented by the formula (1).
[40] Still another object of the present invention is to provide a pharmaceutical composition containing a benzopyran derivative substituted with a secondary amine and a pharmaceutically acceptable salt thereof as an active ingredient, including a new tetrazole represented by the formula (1).
[41] In order to achieve the above object, the present invention provides benzopyran derivatives and pharmaceutically acceptable salts substituted with secondary amines including tetrazole represented by the following general formula (1).
[42] <Formula 1>
[43]
[44] (Wherein
[45] R_OneIs H, F, Cl, Br, CF₃, NO₂, CN, OR^a,, COOR^a, NH₂, NHS (O)_lR^a,Or S (O)_lR^aWhere R^aH, C_One-C₄Is linear or pulverized alkyl or aryl of l is an integer of 0 to 2;
[46] R ₂ is CH ₂ OR ^a , or Is,
[47] Wherein R ^a is as defined above, R ^b and R ^c are each independently C ₁ -C ₄ straight or branched alkyl, Z is C ₁ -C ₅ straight or branched alkyl;
[48] R ₃ is OH, F, Cl, Br, ONO ₂ or Wherein R ^a is as defined above;
[49] R ₄ and R ₅ are each independently H, F, Cl, Br, C ₁ to C ₃ straight or branched alkyl, OR ^a , CF ₃ , OCF ₃ , NO ₂ , , , Or SO ₃ R ^a , wherein R ^a is as defined above;
[50] R ₆ is hydrogen, C ₁ -C ₃ straight or pulverized alkyl;
[51] n and m are each independently an integer of 0 to 2;
[52] * Represents chiral carbon.)
[53] More preferably in the compound of Formula 1
[54] R ₁ is NO ₂ , CN, or NH ₂ ;
[55] R ₂ is or Wherein R ^b and R ^c are each independently C ₁ -C ₃ linear or pulverized alkyl, and Z is C ₂ -C ₃ linear or pulverized alkyl;
[56] R ₃ is OH or Wherein R ^a is C ₁ to C ₃ linear or pulverized alkyl;
[57] R ₄ and R ₅ are each independently H, F, Cl, C ₁ to C ₃ linear or pulverized alkyl, OR ^a , CF ₃ , OCF ₃ or NO ₂ , wherein R ^a is C ₁ to C ₃ Straight chain or crushed alkyl;
[58] R ₆ is C ₁ to C ₃ linear or pulverized alkyl;
[59] n and m are the integers of 0-1 each independently.
[60] The present invention includes all of the benzopyran derivatives substituted with secondary amines including tetrazole represented by Formula 1, pharmaceutically acceptable salts thereof, as well as possible solvates and hydrates that can be prepared therefrom.
[61] In addition, the benzopyran derivative substituted with the secondary amine including the tetrazole represented by the formula (1) of the present invention is not only racemic mixture or stereoisomer mixture, but also at least one of positions 2, 3, and 4 is chiral. Includes all stereoisomers that are carbon.
[62] Preferred compounds among the compounds of Formula 1 are as follows.
[63] 1) (2S, 3S, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[64] 2) (2S, 3R, 4S) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[65] 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
[66] 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
[67] 5) (2S, 3S, 4R) -6-nitro-4- [N- (4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[68] 6) (2S, 3R, 4S) -6-nitro-4- [N- (4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[69] 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
[70] 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
[71] 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
[72] 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
[73] 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
[74] 12) (2S, 3S, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (1-methyl-1H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[75] 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
[76] 14) (2S, 3S, 4R) -6-nitro-4- [N- (4-fluorophenyl) -N- (1-methyl-1H-tetrazol-5-ylmethyl) amino] -3- Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[77] 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
[78] 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
[79] 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
[80] 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
[81] 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
[82] 20) (2S, 3S, 4R) -6-nitro-4- [N-benzyl-N- (1H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2-methyl-2-di Methoxymethyl-3,4-dihydro-2H-1-benzopyran
[83] 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
[84] 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
[85] 23) (2S, 3S, 4R) -6-nitro-4- [N-4-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy- 2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[86] 24) (2S, 3S, 4R) -6-amino-4- [N-4-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2 -Methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[87] 25) (2S, 3R, 4S) -6-nitro-4- [N- (3-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[88] 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
[89] 27) (2S, 3R, 4S) -6-nitro-4- [N- (4-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy -2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[90] 28) (2S, 3R, 4S) -6-Amino-4- [N- (4-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy- 2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[91] 29) (2S, 3R, 4S) -6-nitro-4- [N- (2-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[92] 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
[93] 31) (2S, 3R, 4S) -6-nitro-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[94] 32) (2S, 3R, 4S) -6-amino-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 -Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[95] 33) (2S, 3R, 4S) -6-nitro-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 -Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[96] 34) (2S, 3R, 4S) -6-Amino-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[97] 35) (2S, 3R, 4S) -6-nitro-4- [N- (3-acetylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[98] 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
[99] 37) (2S, 3R, 4S) -6-nitro-4- [N- (2-methyl-4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino ] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[100] 38) (2S, 3R, 4S) -6-Amino-4- [N- (2-methyl-4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[101] 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
[102] 40) (2S, 3R, 4S) -6-amino-4- [N- (4-methoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[103] 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
[104] 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
[105] 43) (2S, 3R, 4S) -6-nitro-4- [N- (2-methoxy-5-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[106] 44) (2S, 3R, 4S) -6-Amino-4- [N- (2-methoxy-5-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[107] 45) (2S, 3R, 4S) -6-nitro-4- [N- (2,4-dimethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 -Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[108] 46) (2S, 3R, 4S) -6-amino-4- [N- (2,4-dimethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[109] 47) (2S, 3R, 4S) -6-nitro-4- [N- (2,6-dimethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 -Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[110] 48) (2S, 3R, 4S) -6-amino-4- [N- (2,6-dimethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[111] 49) (2S, 3R, 4S) -6-nitro-4- [N- (2,3-dimethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 -Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[112] 50) (2S, 3R, 4S) -6-amino-4- [N-2,3-dimethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[113] 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
[114] 52) (2S, 3R, 4S) -6-amino-4- [N- (2-isopropylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[115] 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
[116] 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
[117] 55) (2S, 3R, 4S) -6-amino-4- [N- (2-methyl-2H-tetrazol-5-ylmethyl) phenylamino] -3-hydroxy-2-methyl-2-di Methoxymethyl-3,4-dihydro-2H-1-benzopyran
[118] 56) (2S, 3R, 4S) -6-Amino-4- [N- (4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[119] 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
[120] 58) (2S, 3R, 4S) -6-nitro-4- [N-[(3-methoxycarbonyl) phenyl] -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino ] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[121] 59) (2S, 3R, 4S) -6-amino-4- [N-[(3-methoxycarbonyl) phenyl] -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2-methyl-2-methoxymethyl-3,4-dihydro-2H-1-benzopyran
[122] 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
[123] 61) (2S, 3R, 4S) -6-amino-4- [N- (2-hydroxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[124] 62) (2S, 3R, 4S) -6-nitro-4- [N-[(2-methoxy-4-methoxycarbonyl) phenyl] -N- (2-methyl-2H-tetrazol-5 -Ylmethyl) amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[125] 63) (2S, 3R, 4S) -6-amino-4- [N-[(2-methoxy-4-methoxycarbonyl) phenyl] -N- (2-methyl-2H-tetrazol-5- Monomethyl) amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[126] 64) (2S, 3R, 4S) -6-nitro-4- [N-[(2-methyl-4-hydroxy) phenyl] -N- (2-methyl-2H-tetrazol-5-ylmethyl ) Amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[127] 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
[128] 66) (2S, 3R, 4S) -6-nitro-4- [N- (2-ethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[129] 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
[130] 68) (2S, 3R, 4S) -6-nitro-4- [N-[(2-methyl-5- (methoxycarbonyl) phenyl] -N- (2-methyl-2H-tetrazol-5 -Ylmethyl) amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[131] 69) (2S, 3R, 4S) -6-amino-4- [N-[(2-methyl-5- (methoxycarbonyl) phenyl] -N- (2-methyl-2H-tetrazol-5- Monomethyl) amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[132] 70) (2S, 3R, 4S) -6-nitro-4- [N- (2-hydroxy-5-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[133] 71) (2S, 3R, 4S) -6-Amino-4- [N- (2-hydroxy-5-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[134] 72) (2S, 3R, 4S) -6-nitro-4- [N- (2,4,6-trimethyl phenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[135] 73) (2S, 3R, 4S) -6-Amino-4- [N- (2, 4, 6-trimethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[136] 74) (2S, 3S, 4R) -6-nitro-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 -Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[137] 75) (2S, 3S, 4R) -6-Amino-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[138] 76) (2R, 3S, 4R) -6-nitro-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 -Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[139] 77) (2R, 3S, 4R) -6-amino-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[140] 78) (2R, 3R, 4S) -6-nitro-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 -Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[141] 79) (2R, 3R, 4S) -6-amino-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[142] 80) (2S, 3S, 4R) -6-nitro-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[143] 81) (2S, 3S, 4R) -6-amino-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 -Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[144] 82) (2R, 3R, 4S) -6-nitro-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[145] 83) (2R, 3R, 4S) -6-amino-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 -Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[146] 84) (2R, 3S, 4R) -6-nitro-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[147] 85) (2R, 3S, 4R) -6-amino-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 -Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[148] 86) (2S, 3S, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-acet Methoxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[149] 87) (2S, 3S, 4R) -6-acetamino-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-acet Methoxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[150] 88) (2S, 3S, 4R) -6-acetamino-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[151] 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
[152] 90) (2S, 3R, 4S) -6-Bromo-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[153] 91) (2R, 3R, 4S) -6-bromo-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[154] 92) (2S, 3R, 4S) -6-Bromo-4- [N-4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[155] 93) (2R, 3R, 4S) -6-bromo-4- [N-4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[156] 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
[157] 95) (2R, 3S, 4R) -6-methanesulfonyloxy-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 -Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[158] 96) (2S, 3S, 4R) -6-methanesulfonyloxy-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 -Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[159] 97) (2S, 3S, 4R) -6-hydroxy-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[160] 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
[161] 99) (2S, 3S, 4R) -6-nitro-4- [N- (4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Hydroxy-2-methyl-2-methoxymethyl-3,4-dihydro-2H-1-benzopyran
[162] 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
[163] 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
[164] 102) (2S, 3S, 4R) -6-hydroxy-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[165] 103) (2S, 3S, 4R) -8-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[166] 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
[167] 105) (2R, 3S, 4R) -8-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[168] 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
[169] 107) (2R, 3R, 4S) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[170] 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
[171] 109) (2R, 3S, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[172] 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
[173] 111) (2S, 3R, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[174] 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
[175] 113) (2S, 3S, 4S) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[176] 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
[177] 115) (2R, 3R, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[178] 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
[179] 117) (2R, 3S, 4S) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[180] 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.
[181] More preferable compounds of the compound of Formula 1 are as follows.
[182] 1) (2S, 3S, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Oxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
[183] 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;
[184] 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;
[185] 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;
[186] 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;
[187] 24) (2S, 3S, 4R) -6-Amino-4- [N- (4-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy- 2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
[188] 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;
[189] 28) (2S, 3R, 4S) -6-Amino-4- [N- (4-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy- 2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
[190] 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;
[191] 32) (2S, 3R, 4S) -6-amino-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 -Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
[192] 34) (2S, 3R, 4S) -6-Amino-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
[193] 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;
[194] 52) (2S, 3R, 4S) -6-amino-4- [N- (2-isopropylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Oxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
[195] 54) (2S, 3R, 4S) -6-amino-4- [N- [4- (ethoxycarbonyl) phenyl] -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
[196] 55) (2S, 3R, 4S) -6-amino-4- [N- (2-methyl-2H-tetrazol-5-ylmethyl) phenylamino] -3-hydroxy-2-methyl-2-di Methoxymethyl-3,4-dihydro-2H-1-benzopyran;
[197] 56) (2S, 3R, 4S) -6-Amino-4- [N- (4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Oxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
[198] 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;
[199] 59) (2S, 3R, 4S) -6-amino-4- [N-[(3-methoxycarbonyl) phenyl] -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2-methyl-2-methoxymethyl-3,4-dihydro-2H-1-benzopyran;
[200] 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;
[201] 61) (2S, 3R, 4S) -6-amino-4- [N- (2-hydroxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy Oxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
[202] 70) (2S, 3R, 4S) -6-nitro-4- [N- (2-hydroxy-5-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
[203] 75) (2S, 3S, 4R) -6-Amino-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
[204] 77) (2R, 3S, 4R) -6-amino-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
[205] 79) (2R, 3R, 4S) -6-amino-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
[206] 81) (2S, 3S, 4R) -6-amino-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 -Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
[207] 83) (2R, 3R, 4S) -6-amino-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 -Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
[208] 85) (2R, 3S, 4R) -6-amino-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 -Hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
[209] 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
[210] 107) (2R, 3R, 4S) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[211] 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
[212] 109) (2R, 3S, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[213] 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
[214] 111) (2S, 3R, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[215] 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
[216] 113) (2S, 3S, 4S) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[217] 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
[218] 115) (2R, 3R, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[219] 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
[220] 117) (2R, 3S, 4S) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Roxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[221] 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.
[222] In the present invention, the compound of formula 1 may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
[223] The pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid and phosphoric acid; And organic acids such as citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid, and the like. Can be prepared.
[224] Acid addition salts according to the invention are prepared by conventional methods, for example by dissolving a compound of formula 1 in an excess aqueous solution of an acid and precipitating by addition of a water miscible organic solvent selected from methanol, ethanol, acetone or acetonitrile. can do.
[225] In another method, an acid is added to the same amount of the compound of Formula 1 and a solvent selected from water or glycol monomethyl ether, followed by heating, followed by evaporation or drying of the mixed solution or suction filtration of the precipitated salt. can do.
[226] In addition, the form of the pharmaceutically acceptable salt of the present invention may be a pharmaceutically acceptable metal salt. The metal salt is an alkali metal salt or alkaline earth metal salt comprising the compound of formula 1, preferably the metal is selected from sodium, potassium or calcium.
[227] The metal salt of the present invention may be prepared by dissolving a compound of Formula 1 in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, and filtering the undissolved material in the above step and then evaporating or drying the filtrate. Corresponding silver salts can also be obtained by reacting alkali metal or alkaline earth metal salts with silver nitrate.
[228] The present invention provides a method for preparing a benzopyran compound substituted with a secondary amine comprising tetrazole of formula (1) represented by the following scheme 1.
[229] More specifically, the compound of formula 1a in which R ₃ is fixed with OH is reacted by reacting an epoxide compound of formula 2 with a secondary amine compound including a heterocycle of formula 3 in a solvent containing a metal salt.
[230] In addition, the present invention further includes a preparation step performed as in Scheme 2 on the compound of Formula 1a obtained above, and various substituents may be applied to R ₃ .
[231]
[232]
[233] (Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , n, m and * are as defined above.)
[234] The metal salt in Scheme 1 is selected from the group consisting of Mg (ClO ₄ ) ₂ , CoCl ₂ , LiClO ₄ , NaClO ₄ , CaCl ₂ , ZnCl ₂ , LiBF ₄ and Zn (Tf) ₂ .
[235] At this time, the solvent used is selected from the group consisting of acetonitrile, tetrahydrofuran and dimethylformamide, more preferably using acetonitrile.
[236] The reaction conditions may vary depending on the type of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ , which are structures of the compound of Formula 2, and the preparation methods, reaction reagents, and reaction conditions that may be performed accordingly. Typically, however, the reaction temperature is carried out at room temperature to the boiling point of the solvent used.
[237] In addition, through Scheme 2, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ may be changed according to the type of substituent, and in the case of Scheme 1, the stereochemistry of the carbon number 3 may be determined. Can be.
[238] Epoxide compounds of formula (2) can be prepared by known methods by the inventors [US Patent No. 5,236,935 and Korean Patent No. 094,546] (Scheme 3)
[239]
[240] (Wherein R ₁ and R ₂ are as defined above, (OZ) represents a leaving group and Hal is a halogen atom.)
[241] In addition, the olefin compound of Formula 2 may be prepared according to the method of Korean Patent No. 192,083 known by the present inventors, and the prepared olefin compound of Formula 2b is subjected to stereo chromatography or column crystallization by performing a conventional method. Can be obtained by separating the isomers.
[242] The epoxide compounds of the formulas (2a) to (2d) prepared in the separated reaction scheme can be separated separately, and as the compound to be used in the next reaction, the separated compound may be used or a non-separated compound may be used.
[243] In addition, according to the present invention, by using a mixture of stereoisomers, which are compounds of formula 2, which are synthetic intermediates, the compound of formula 1, which is a target compound, may be prepared as a mixture of stereoisomers.
[244] More specifically, by using an individual epoxide compound having a stereoisomer as a starting material, as shown in the general formulas (2a) to (2d) below, it is possible to obtain a target compound of the formula (1) in which the stereochemistry of the starting material is maintained as it is. .
[245]
[246]
[247]
[248]
[249] (Wherein R ₁ and R ₂ are as defined above).
[250] Another method for preparing the epoxide compound of Formula 2 is to prepare epoxide compounds having the properties of the respective stereoisomers from the olefin compounds using Mn (III) salen epoxidation catalysts [EN Jacobsen et al. al., Tetrahedron Lett . 1991, 38 , 5055.
[251] In Scheme 1, a secondary amine compound including tetrazole, which is a secondary amine compound including a heterocycle of Formula 3, which is another starting material, may be prepared by the following Scheme 4.
[252]
[253] (In the above scheme, n is 0, m is 1, R ₆ is methyl and R ₄ and R ₅ are as defined above.)
[254] The metal azide compound of step 1 is preferably selected from the group consisting of sodium azide, ammonium azide, trialkylammonium azide, trialkylsilyl azide and trialkyltin azide, more preferably sodium azide , Ammonium azide is to be used.
[255] The reaction solvent used is one selected from tetrahydrofuran, dimethylformamide, toluene or dimethoxyethane. The temperature is carried out within the boiling point of the solvent used at room temperature.
[256] The base used in step 3 is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydride, and sodium methoxide, wherein the solvent used is an ether solvent including tetrahydrofuran or dioxane; Ketone solvents such as acetone; Or dimethylformamide, and the reaction temperature is carried out at a temperature ranging from 0 ° C. to the boiling point of the solvent used.
[257] An example in which the target compound of Formula 1 is prepared according to the substituents of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ may be described as follows, but this is only one example, and thus It is not limited.
[258] (1) Introduction of Acetoxy Group to R ₃
[259] As shown in Scheme 2, the compound of Formula 1b obtained by introducing the acetoxy group at the R ₃ position may be obtained by reacting Formula 1a obtained in Scheme 1 with a base in the presence of a catalyst.
[260]
[261] (Wherein R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , n, m, and * are as defined above.)
[262] In Scheme 5, the acetyl group may be introduced using acetic anhydride (Ac ₂ O) or acetyl chloride (AcCl), where the base is both an organic base and an inorganic base, preferably the organic base Is selected from triethylamine, pyridine or N, N-diisopropylethylamine, and the inorganic base is selected from sodium carbonate, sodium hydroxide or calcium carbonate. At this time, it is preferable that 1-3 equivalents are used with respect to the compound of General formula (1a).
[263] The catalyst uses 4- (dimethylamino) pyridine, and the preferred amount is 0.05 to 0.5 equivalents based on the compound of formula 1a.
[264] The solvent used is selected from the group consisting of methylene chloride, chloroform, tetrahydrofuran, acetonitrile, and the reaction temperature is carried out at 0 to 40 ℃.
[265] (2) Introduction of R ₁ NH ₂
[266] Compound (1d) in which R ₁ is NH ₂ in the compound of Formula 1 may be prepared by reducing compound (1c) in which R ₁ is NO ₂ in the compound of Formula 1a.
[267]
[268] (Wherein R ₂ , R ₄ , R ₅ , R ₆ , n, m and * are as defined above.)
[269] The reduction is carried out using a hydrogenation reaction or a conventional reducing agent using a metal catalyst in a suitable solvent.
[270] The metal catalyst is selected from platinum, palladium-attached charcoal (Pd / C; palladium on carbon) or Raney-nickel, and the solvent used is alcohol selected from the group consisting of methanol, ethanol, and ethyl acetate. It is selected from the containing organic solvent.
[271] Another method is to reduce with a reducing agent of NaBH ₄ in the presence of CuSO ₄ , Cu (OAc) ₂ , CoCl ₂ , SnCl ₂ , or NiCl ₂ . At this time, the solvent used is preferably a mixed solvent of water and methanol.
[272] (3) to R ₁ Introduction of
[273] The compound of Formula 1d prepared by Scheme 6 may be reacted with an acyl chloride or an acid anhydride by adding a base to a solvent to prepare a compound of Formula 1e wherein R ₁ is NHC (O) R ^a .
[274] The base used at this time is selected from the group consisting of triethylamine, N, N-diisopropylethylamine, pyridine, 4- (dimethylamino) pyridine. In addition, the solvent is preferably selected from the group consisting of methylene chloride, chloroform, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and dioxane.
[275] (4) Introduction of -NHS (O) _l R ^a to R ₁
[276] The compound of Formula 1d prepared by Scheme 6 may be reacted with alkylsulfonylchloride or arylsulfonylchloride by adding a base to a solvent to prepare a compound of Formula 1f wherein R ₁ is NHS (O) _m R ^a . .
[277] In this case, the base is selected from the group consisting of triethylamine, N, N-diisopropylethylamine, pyridine, 4- (dimethylamino) pyridine. In addition, the solvent is preferably selected from the group consisting of methylene chloride, chloroform, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and dioxane.
[278] The present invention also provides a pharmaceutical composition containing a benzopyran derivative substituted with a secondary amine including a tetrazole represented by the formula (1) and a pharmaceutically acceptable salt thereof as an active ingredient.
[279] More specifically, a benzopyran derivative substituted with a secondary amine containing a tetrazole of the present invention, and a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutical composition for nerve cell protection, a pharmaceutical composition for brain injury protection, heart Protective pharmaceutical compositions, pharmaceutical compositions for protecting retinal ganglion cells, or pharmaceutical compositions that protect organs during cardiac hemorrhage surgery and organ transplantation, pharmaceutical compositions for antioxidants, pharmaceutical compositions that inhibit NO production, neovascularization ( Provided is a pharmaceutical composition that inhibits angiogenesis.
[280] It provides a protective agent for nerve cells containing a benzopyran derivative substituted with a secondary amine comprising a tetrazole of the present invention and a pharmaceutically acceptable salt thereof as an active ingredient.
[281] The pharmaceutical composition of the present invention has a neuronal protective effect of protecting nerve cells from oxidative stress caused by cell death by iron or hydrogen peroxide.
[282] The neuronal cell protection agent of the present invention is similar to the brain maturity of newborns, and since it is easy to obtain a sufficient amount of animals required for confirmation of the effect, it is currently used to determine the mechanism and treatment effect for neonatal hypoxia. In the most commonly used neonatal model, the ratio of Lipid / NAA (N-acetyl aspartate) and Lipid / Cr (creatine), which are important indicators in improving morphological analysis and survival as well as apoptosis, was significant. Thereby lowering ischemic-hypoxic and hypoxic brain damage. In addition, the compounds of the present invention exhibit neuroprotective effects by protecting truncated retinal ganglion cells and improving damaged retinal ganglion cells.
[283] In addition, the compounds of the present invention exhibit neuroprotective effects by improving impaired neurotransmission rates in diabetic neuropathy animal models. Thus, the compounds of the present invention can be used as nerve cell protective agents and can be used to prevent and treat neonatal hypoxia, glaucoma, diabetic neuropathy and head trauma caused by neuronal cell damage and necrosis.
[284] In addition, the compounds of the present invention inhibit lipid peroxidation induced by iron or copper, thereby inhibiting intracellular free radicals in A7r5 (Rat thoracic aorta smooth muscle cellline, ATCC) induced by H ₂ O ₂ . Thus, the compounds of the present invention can be used as antioxidants and effectively used for the medical treatment of degenerative neurological diseases caused by lipid peroxidation and the accumulation of free radicals in nerve cells, such as aging and senile dementia.
[285] In addition, the compounds of the invention inhibit the production of nitric oxide (NO) induced by endotoxins such as lipopolysaccharide (LPS) in a concentration dependent manner. Thus, the compounds of the present invention can be used as inhibitors of NO production and are caused by arthritis, cardiac infarction, atherosclerosis, and caused by damage to tissues or organs due to cellular damage or neuronal cell death due to the accumulation of NO in the cell, and It can also be used to treat inflammatory diseases such as dementia.
[286] In addition, the compounds of the present invention effectively protect the brain from ischemic-reperfusion injury. Ischemic diseases result from the complex effects of various types of neurotransmitters, ion channels and enzymes and the like. In addition, it has various pharmacological effects such as regulation of ion channels, protection of neurotoxicity caused by iron, hydrogen peroxide, etc., virtue of lipid peroxidation, and protection of brain damage, etc., thereby preventing and treating stroke caused by cerebral ischemia.
[287] The compounds of the present invention significantly delayed the time to contracture (TTC), an indicator of cardiac protection, in the ischemic heart model of Langendorf using the extracted heart of rats, and the cardiac function (left ventricular development pressure × heart rate) after reperfusion. LVDP × HR), and reduced the release of lactate dehydrogenase (LDH), an indicator of cellular damage, and showed a cardioprotective effect similar to that of the control drug (BMS-180448). In addition, in the ischemic myocardial model using anesthetized rats, the compounds of the present invention were observed to have an anti-ischemic effect similar to that of the control drug (BMS-180448). Furthermore, unlike the reference drug (BMS-180448), the compounds of the present invention have a significantly weaker vascular relaxation action, and thus, the cardiac selective anti-ischemic action was confirmed to have a better result.
[288] As described above, the benzopyran derivatives substituted with the secondary amines including the tetrazole of the present invention are weak in vascular relaxation, and thus do not lower blood pressure in vivo or in vitro . By exhibiting excellent anti-ischemic action in, it can be used as a cardioprotective agent for the prevention and treatment of myocardial infarction, heart failure, angina pectoris.
[289] In addition, benzopyran derivatives substituted with secondary amines including tetrazole of the present invention can be used as angiogenesis inhibitors by concentration-dependently inhibiting angiogenesis in vascular endothelial cells, resulting in rheumatic properties due to angiogenesis. It can be usefully used for the prevention and treatment of arthritis, psoriasis, AIDS complications, cancer, or diabetic retinopathy.
[290] A pharmaceutical composition comprising a benzopyran derivative substituted with a secondary amine including a tetrazole of the present invention and a pharmaceutically acceptable salt thereof as an active ingredient can be administered orally or parenterally during clinical administration, It can be used in the form.
[291] The benzopyran derivatives substituted with secondary amines comprising the tetrazole of the present invention and pharmaceutically acceptable salts thereof can be administered in effective amounts through various routes of administration. The use together contains a pharmaceutically acceptable carrier. More specifically, pharmaceutically acceptable carriers can be any standard pharmaceutical carrier that can be used in known formulations such as sterile solutions, tablets, coated tablets and capsules. Typically, the carrier may include excipients such as starch, milk, sugar, certain types of clays, gelatin, stearic acid, talc, vegetable oils or oils, gums, glycols, or other known excipients, and also flavors, color additives And other ingredients. Formulations for the administration of a composition containing the benzopyran derivatives substituted with secondary amines containing the tetrazole of the present invention and pharmaceutically acceptable salts thereof as an active ingredient within the above-mentioned ranges are oral, intravenous, Although it can administer by the method of intramuscular and transdermal administration, it is not limited to these methods. In actual clinical administration, it can be administered in a variety of oral and parenteral formulations, which are formulated using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like that are commonly used. Solid form preparations for oral administration include tablets, pills, powders, granules and capsules, and the like, and the solid form may include at least one excipient such as starch, calcium carbonate, It is prepared by mixing sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Oral liquid preparations include suspensions, liquid solutions, emulsions, syrups, and the like, and may include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents, water and liquid paraffin.
[292] In addition, the pharmaceutical compositions of the present invention can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection or intramuscular injection. To formulate into a parenteral formulation, a tetrabenzo-containing benzopyran derivative substituted with a secondary amine and a pharmaceutically acceptable salt thereof are mixed in water with a stabilizer or buffer to prepare a solution or suspension and Formulated in unit dosage forms of ampoules or vials.
[293] The dosage of the active ingredient according to the present invention is appropriately selected depending on the absorbance, inactivation rate, excretion rate, age, sex and condition of the patient and the severity of the disease to be treated in the body, but generally once a day It may be administered in three to three portions, and may be preferably formulated to be administered at a concentration of 1.0 to 20 mg / kg, more preferably 0.5 to 2.0 mg / kg. The exact amount, route of administration, and frequency of the agent can be readily determined according to the nature of the agent, the weight and condition of the subject to be administered, and the nature of the particular derivative to be used.
[294] In the present invention, the benzopyran derivatives substituted with secondary amines including tetrazole and pharmaceutically acceptable salts thereof are the result of acute toxicity test in experimental mice, and the minimum lethal dose (LD ₅₀ ) upon oral administration or intraperitoneal injection is It can be seen that the bio stability is very high by showing no toxic effect at least 2,000 mg / kg, and therefore the benzopyran derivatives substituted with secondary amines containing tetrazole of the present invention and pharmaceutically acceptable salts thereof Can be safely administered.
[295] Hereinafter, the present invention will be described in more detail with reference to Examples.
[296] However, the following examples are illustrative of the present invention, and the content of the present invention is not limited by the examples.
[297] The present invention is infrared spectroscopy, nuclear magnetic resonance spectrum. The molecular structure was confirmed by comparison between the mass spectrometry, the liquid chromatography method, the X-ray structure determination method, the photoluminescence measurement method, and the elemental analysis calculation and the measured value of a typical compound.
[298] Example 1 (2S, 3S, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[299] Step 1: Preparation of (2S, 3S, 4S) -6-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran
[300] 46.6 mL (22.8 mmol) of 0.55 M NaOCl aqueous solution at 0 ° C. was added 16.6 mL of 0.05 M Na ₂ HPO ₄ aqueous solution. 1.5 g (5.7 mmol) of (2S) -6-nitro-2-methyl-2-dimethoxymethyl-2H-1-benzopyran and (S, S) -Mn (III) developed by Jacobsen 155 mg (0.28 mmol) of a salen epoxidation catalyst was dissolved in 8.5 ml of dichloromethane and slowly added to the aqueous solution, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, the reaction solution was filtered to remove the epoxidation catalyst and the filtrate was extracted with 200 mL of dichloromethane. The dichloromethane layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed. The filtrate was purified by silica gel column chromatography under a solvent condition of a mixed solvent of n-hexane: ethyl acetate (4: 1) to obtain a compound of Formula 2 Phosphorous (2S, 3S, 4S) -6-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran 1.4 g (88%) Got.
[301] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.53 (s, 3H), 3.25 (s, 3H), 3.49 (s, 3H), 3.79 (d, 1H), 3.96 (d, 1H), 4.19 ( s, 1H), 6.82 (d, 1H), 8.09 (dd, 1H), 8.24 (d, 1H).
[302] Step 2: Preparation of N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine
[303] a. Preparation of 5-chloromethyl-1H-tetrazole
[304] 1.72 g (26.4 mmol) of sodium azide was added to 30 mL of THF, and 0.88 g (6.6 mmol) of aluminum chloride and 0.42 mL (6.6 mmol) of chloroacetonitrile were added at 0 ° C., and the mixture was heated under reflux for 48 hours. . After completion of the reaction, the reaction mixture was acidified with 3N HCl aqueous solution until pH 3 at 0 ° C. The reaction solution was extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed to obtain a white solid. The white solid was mixed with an ethyl acetate / nn-hexane solvent. 1: 4) to give 1.7 g (89% yield) of 5-chloromethyl-1H-tetrazole.
[305] ¹ H NMR (CD ₃ OD, 200 MHz): δ 4.86 (s, 2H), 5.10 (brs, 1H).
[306] b. Preparation of 5-chloromethyl-1-methyl-1H-tetrazole and 5-chloromethyl-2-methyl-2H-tetrazole
[307] 300 mg (2.53 mmol) of 5-chloromethyl-1H-tetrazole prepared above was dissolved in 10 ml of DMF, 455 mg (3.29 mmol) of K ₂ CO ₃ was added, and 0.16 ml (2.53 mmol) of MeI was slowly added dropwise. After stirring for 4 hours at room temperature. When the reaction was completed, 30 ml of water was added thereto, extracted with 50 ml of ether, the organic layer was washed with brine, dried over anhydrous MgSO ₄ , concentrated under reduced pressure, and the filtrate was a solvent of a mixed solvent of n-hexane: ethyl acetate (4: 1). Using silica gel column chromatography under conditions, 88.1 mg (26%) of 5-chloromethyl-1-methyl-1H-tetrazole and 184.2 mg (55%) of 5-chloromethyl-2-methyl-2H-tetrazole were obtained. Got it.
[308] 5-chloromethyl-2-methyl-2H-tetrazole; ¹ H NMR (CDCl ₃ , 200 MHz): δ 4.37 (s, 3H), 4.51 (s, 2H),
[309] 5-chloromethyl-1-methyl-1H-tetrazole; ¹ H NMR (CDCl ₃ , 200 MHz): δ 4.05 (s, 3H), 4.52 (s, 2H).
[310] c. Preparation of N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine
[311] 14 g (13.2 mmol) of p-chloroaniline was dissolved in 120 mL of DMF, 9.49 g (68.6 mmol) of K ₂ CO ₃ and 7 g of 5-chloromethyl-2-methyl-2H-tetrazole obtained in step 2 (34.4) were dissolved. mmol) and NaI 4.9 g (34.3 mmol) were added and reacted at 80 ° C for 4 hours. After the reaction was completed, 60 ml of water was added thereto, extracted with 20 ml of ether, the organic layer was washed with brine, dried with anhydrous MgSO ₄ , and concentrated. Purified by silica gel column chromatography under a solvent condition of a mixed solvent of n-hexane: ethyl acetate (4: 1), and a compound of Formula 3, N- (4-chlorophenyl) -N- (2-methyl-2H-tetra 3.9 g (61%) of sol-5-ylmethyl) amine were obtained.
[312] ¹ H NMR (CDCl ₃ , 200 MHz): δ 4.30 (s, 3H), 4.47 (brs, 1 H), 4.56 (s, 2H), 6.64 (d, 2H), 7.11 (d, 2H).
[313] Step 3: (2S, 3S, 4R) -6-Nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Preparation of hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[314] Dissolve 450 mg (1.6 mmol) of the compound prepared in Step 1 in 0.5 ml of acetonitrile, and 363 mg (1.6 mmol) of the secondary amine compound containing tetrazole prepared in Step 2 above and magnesium perchlorate ((MgClO ₄ ) ₂ ) 357 mg (1.6 mmol) was added. After stirring for 10 hours at room temperature, 20 ml of aqueous NaHCO ₃ solution was added and extracted with 30 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The obtained compound was purified by silica gel column chromatography under solvent conditions of a mixed solvent of n-hexane: ethyl acetate (2: 1) to obtain 435 mg (54%) of the title compound.
[315] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.62 (s, 3H), 3.49 (s, 3H), 3.59 (s, 3H), 3.95 (dd, 1H), 4.32 (d, 1H), 4.48 ( s, 3H), 4.72 (s, 1H), 4.83 (d, 1H), 5.60 (d, 1H), 6.82 (d, 2H), 6.95 (d, 1H), 7.16 (d, 2H), 7.99 (d , 1H), 8.06 (dd, 1H).
[316] Example 2 (2S, 3R, 4S) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[317] Step 1: Preparation of (2S, 3R, 4R) -6-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran
[318] 2.5 g (9.4 mmol) of (2S) -6-nitro-2-methyl-2-dimethoxymethyl-2H-1-benzopyran and (R, R) -Mn (III) salen epoxidation catalyst Performing the same method as in Step 1 of Example 1, the obtained compound was purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (4: 1), the target compound 2.1 g (80%) Got.
[319] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.28 (s, 3H), 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).
[320] Step 2: (2S, 3R, 4S) -6-Nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Preparation of hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[321] Except for using 250 mg (0.9 mmol) of the epoxide compound prepared in Step 1, was carried out in the same manner as in Step 3 of Example 1, a mixture of n-hexane: ethyl acetate (2: 1) Purification by silica gel column chromatography under conditions of a solvent gave 359 mg (87%) of the title compound.
[322] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.48 (s, 3H), 3.58 (s, 3H), 3.64 (s, 3H), 4.29 (s, 3H), 4.42 (dd, 1H), 4.42 ( d, 1H), 4.61 (s, 1H), 4.82 (d, 1H), 5.13 (d, 1H), 5.18 (d, 1H), 6.84 (d, 2H), 7.05 (d, 1H), 7.15 (d , 2H), 8.08 (dd, 1H), 8.10 (d, 1H).
[323] Example 3 (2S, 3S, 4R) -6-nitro-4- [N- (2-methyl-2H-tetrazol-5-ylmethyl) phenylamino] -3-hydroxy-2-methyl Preparation of 2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[324] Example 450 mg (1.6 mmol) of the epoxide compound prepared in Step 1 of Example 1 and 302 mg (1.6 mmol) of N- (2-methyl-2H-tetrazol-5-ylmethyl) phenylamine were used. It was carried out in the same manner as Step 3 of 1, and purified by silica gel column chromatography under the mixed solvent of n- hexane: ethyl acetate (2: 1) to give the title compound 484 mg (64%).
[325] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.49 (s, 3H), 3.57 (s, 3H), 3.64 (s, 3H), 4.31 (s, 3H), 4.32 (dd, 1H), 4.39 ( d, 1H), 4.82 (d, 1H), 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), 8.09 (s, 1H).
[326] Example 4 (2S, 3R, 4S) -6-nitro-4- [N- (2-methyl-2H-tetrazol-5-ylmethyl) phenylamino] -3-hydroxy-2-methyl Preparation of 2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[327] 225 mg (0.8 mmol) of the epoxide compound prepared in Step 1 of Example 2 and 151 mg (0.8 mmol) of N- (2-methyl-2H-tetrazol-5-ylmethyl) phenylamine were used. Purification was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under a mixed solvent of n-hexane: ethyl acetate (2: 1) to obtain 134 mg (56%) of the title compound.
[328] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.63 (s, 3H), 3.51 (s, 3H), 3.55 (s, 3H), 3.91 (dd, 1H), 4.29 (d, 1H), 4.33 ( s, 3H), 4.75 (s, 1H), 4.88 (d, 1H), 5.45 (d, 1H), 5.69 (d, 1H), 6.80-6.97 (m, 4H), 7.20 (d, 2H), 8.01 (d, 1 H), 8.07 (dd, 1 H).
[329] Example 5 (2S, 3S, 4R) -6-Nitro-4- [N- (4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] Preparation of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[330] 450 mg (1.6 mmol) of the epoxide compound prepared in Step 1 of Example 1 and 332 mg of N- (4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine 1.6 mmol) was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 1) to give 661 mg of the target compound ( 86%).
[331] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.62 (s, 3H), 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), 6.85-6.96 (m, 5H), 8.03 (s, 1H), 8.05 ( dd, 1 H).
[332] Example 6 (2S, 3R, 4S) -6-nitro-4- [N- (4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] Preparation of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[333] 450 mg (1.6 mmol) of the epoxide compound prepared in Step 1 of Example 2 and 332 mg of N- (4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine 1.6 mmol) was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 1) to give 528 mg of the target compound ( 69%).
[334] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.46 (s, 3H), 3.57 (s, 3H), 3.63 (s, 3H), 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 (d, 2H), 6.90 (d, 2H), 7.03 (d , 1H), 8.08 (dd, 1H), 8.14 (d, 1H).
[335] Example 7 (2S, 3S, 4R) -6-Nitro-4- [N-benzyl-N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy- Preparation of 2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[336] Using 300 mg (1.07 mmol) of the epoxide compound prepared in Step 1 of Example 1 and 217 mg (1.07 mmol) of N-benzyl-N- (2-methyl-2H-tetrazol-5-ylmethyl) amine It was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 2) to give the title compound 282 mg (55%).
[337] ¹ H NMR (CDCl ₃ , 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), 6.84 (d, 1H), 7.20-7.33 (m, 3H), 7.43 (d, 2H), 7.99 (dd, 1H), 8.74 (d, 1H)
[338] Example 8 (2S, 3R, 4S) -6-nitro-4- [N-benzyl-N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy- Preparation of 2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[339] Using 200 mg (0.71 mmol) of the epoxide compound prepared in Step 1 of Example 2 and 145 mg (0.71 mmol) of N-benzyl-N- (2-methyl-2H-tetrazol-5-ylmethyl) amine The purification was carried out in the same manner as in Step 3 of Example 1, and the residue was purified by silica gel column chromatography under a mixed solvent of n-hexane: ethyl acetate (1: 2) to obtain 165 mg (48%) of the title compound.
[340] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.58 (s, 3H), 3.30 (s, 3H), 3.34 (s, 3H), 3.89-4.12 (m, 6H), 4.27-4.33 (m, 5H ), 6.83 (d, 1H), 7.23-7.38 (m, 3H), 7.45 (d, 2H), 8.01 (dd, 1H), 8.73 (d, 1H).
[341] Example 9 (2S, 3S, 4R) -6-nitro-4- [N- (4-nitrophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] Preparation of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[342] 200 mg (0.71 mmol) of the epoxide compound prepared in Step 1 of Example 1 and 167 mg of N- (4-nitrophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine 0.71 mmol) was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 1) to give 162 mg of the target compound. 45%).
[343] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.59 (s, 3H), 3.65-3.49 (m, 7H), 4.32-4.40 (m, 4H), 4.62 (s, 1H), 4.86 (d, 1H ), 5.14 (d, 1H), 5.45 (d, 1H), 6.98 (d, 2H), 7.07 (d, 1H), 7.99-8.15 (m, 4H).
[344] Example 10 (2S, 3S, 4R) -6-Amino-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 Preparation of -hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[345] (2S, 3S, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] prepared in Example 1 Dissolve 100 mg (0.2 mmol) of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran in 2 mL of methanol and 0.38 aqueous solution of Cu (OAc) _2. ML (0.4 M aqueous solution, 0.15 mmol) was added. 113 mg (3.0 mmol) of sodium borohydride (NaBH ₄ ) was slowly added at room temperature over 30 minutes, then stirred for 1 hour, and 5 ml of ethyl acetate was added. As a result of the reaction, the precipitated black solid was removed by filtration, and 5 ml of saturated NaHCO ₃ aqueous solution was added to the filtrate, and extracted with 30 ml of ethyl acetate. The extracted solution was washed with brine, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and concentrated. The obtained compound was purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 3) to give 62 mg (67%) of the target compound wherein R ₁ was substituted with amino.
[346] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.34 (s, 3H), 3.51 (s, 3H), 3.61 (s, 3H), 4.02 (s, 3H), 4.10 (dd, 1H), 4.33 ( d, 1H), 4.47 (s, 1H), 4.68 (d, 1H), 4.80-4.97 (m, 2H), 6.35 (d, 1H), 6.54 (dd, 1H), 6.74 (d, 1H), 6.81 (d, 2H), 7.14 (d, 2H).
[347] Example 11 (2S, 3R, 4S) -6-Amino-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 Preparation of -hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[348] Silica gel column chromatography was carried out in the same manner as in Example 10, except that 150 mg (0.3 mmol) of the compound prepared in Example 2 was used, under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 3). Purification by chromatography gave 74 mg (52%) of the title compound.
[349] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.54 (s, 3H), 3.49 (s, 3H), 3.52 (s, 3H), 3.95 (dd, 1H), 4.30 (d, 1H), 4.32 ( s, 3H), 4.41-4.70 (m, 3H), 5.33 (d, 1H), 6.45 (s, 1H), 6.55 (dd, 1H), 6.68 (d, 1H), 6.82 (d, 2H), 7.13 (d, 2H).
[350] Example 12 (2S, 3S, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (1-methyl-1H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[351] Step 1: Preparation of N- (4-chlorophenyl) -N- (1-methyl-1H-tetrazol-5-ylmethyl) amine
[352] 5.8 g (45.3 mmol) of p-chloroaniline and 6 g (45.3 mmol) of 5-chloromethyl-1-methyl-1H-tetrazole were carried out in the same manner as in Step 2 of Example 1, and n-hexane: Purification by silica gel column chromatography under mixed solvent of ethyl acetate (2: 1) afforded the title compound (36%).
[353] Step 2: (2S, 3S, 4R) -6-Nitro-4- [N- (4-chlorophenyl) -N- (1-methyl-1H-tetrazol-5-ylmethyl) amino] -3- Preparation of hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[354] 150 mg (0.53 mmol) of the epoxide compound prepared in Step 1 of Example 1 and N- (4-chlorophenyl) -N- (1-methyl-1H-tetrazol-5-ylmethyl prepared in Step 1) 121 mg (0.53 mmol) of amine was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 1). 194 mg (72%) was obtained.
[355] ¹ H NMR (CDCl ₃ , 200 MHz): δ 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), 6.81 (d, 2H), 7.17 (d, 2H), 7.03 (d , 1H), 8.02 (d, 1H), 8.04 (dd, 1H).
[356] Example 13 (2S, 3S, 4R) -6-nitro-4- [N- (1-methyl-1H-tetrazol-5-ylmethyl) phenylamino] -3-hydroxy-2-methyl Preparation of 2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[357] Example 1 using 150 mg (0.53 mmol) of the epoxide compound prepared in step 1 of Example 1 and 101 mg (0.53 mmol) of N- (1-methyl-1H-tetrazol-5-ylmethyl) amine It was carried out in the same manner as Step 3, and purified by silica gel column chromatography under the mixed solvent of n- hexane: ethyl acetate (2: 1) to give the title compound 203 mg (81%).
[358] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.47 (s, 3H), 3.54 (s, 3H), 3.64 (s, 3H), 4.08 (s, 3H), 4.18 (dd, 1H), 4.37 ( d, 1H), 4.61 (s, 1H), 4.84 (d, 1H), 5.18 (d, 1H), 5.66 (d, 1H), 6.86-7.08 (m, 4H), 7.24 (d, 2H), 8.05 (s, 1 H), 8.10 (dd, 1 H).
[359] Example 14 (2S, 3S, 4R) -6-Nitro-4- [N- (4-fluorophenyl) -N- (1-methyl-1H-tetrazol-5-ylmethyl) amino] Preparation of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[360] 150 mg (0.53 mmol) of the epoxide compound prepared in Step 1 of Example 1 and 111 mg of N- (4-fluorophenyl) -N- (1-methyl-1H-tetrazol-5-ylmethyl) amine 0.53 mmol) was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 1) to give 198 mg (76) of the target compound. %) Was obtained.
[361] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.43 (s, 3H), 3.56 (s, 3H), 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), 5.47 (d, 1H), 7.03 (d, 1H), 7.94 (dd, 4H), 8.06 (dd , 1H), 8.09 (s, 1H).
[362] Example 15 (2S, 3S, 4R) -6-Nitro-4- [N-benzyl-N- (1-methyl-1H-tetrazol-5-ylmethyl) amino] -3-hydroxy- Preparation of 2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[363] Using 200 mg (0.71 mmol) of the epoxide compound prepared in Step 1 of Example 1 and 145 mg (0.71 mmol) of N-benzyl-N- (1-methyl-1H-tetrazol-5-ylmethyl) amine Purification was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under a mixed solvent of n-hexane: ethyl acetate (1: 2) to obtain 192 mg (56%) of the title compound.
[364] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.30 (s, 3H), 3.63 (s, 3H), 3.65 (s, 3H), 3.67 (s, 3H), 3.80-4.10 (m, 4H), 4.37-4.62 (m, 4H), 6.89 (d, 1H), 7.26-7.35 (m, 5H), 8.00 (dd, 1H), 8.57 (d, 1H).
[365] Example 16 (2S, 3R, 4S) -6-Nitro-4- [N-benzyl-N- (1-methyl-1H-tetrazol-5-ylmethyl) amino] -3-hydroxy- Preparation of 2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[366] Using 200 mg (0.71 mmol) of the epoxide compound prepared in Step 1 of Example 2 and 145 mg (0.71 mmol) of N-benzyl-N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Purification was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under a mixed solvent of n-hexane: ethyl acetate (1: 2) to obtain 70 mg (20%) of the title compound.
[367] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.60 (s, 3H), 3.39 (s, 3H), 3.41 (s, 3H), 3.56 (dd, 1H), 3.74-3.97 (m, 4H), 4.02-4.33 (m, 6H), 6.84 (d, 1H), 7.24-7.38 (m, 5H), 8.03 (dd, 1H), 8.52 (d, 1H).
[368] Example 17 (2S, 3S, 4R) -6-Amino-4- [N- (4-chlorophenyl) -N- (1-methyl-1H-tetrazol-5-ylmethyl) amino] -3 Preparation of -hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[369] 100 mg (0.2 mmol) of the compound prepared in Example 12, was used in the same manner as in Example 10, and purified by silica gel column chromatography under a mixed solvent of n-hexane: ethyl acetate (1: 4). 62 mg (67%) of the title compound were obtained.
[370] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.34 (s, 3H), 3.51 (s, 3H), 3.61 (s, 3H), 4.02 (s, 3H), 4.10 (dd, 1H), 4.33 ( d, 1H), 4.47 (s, 1H) 4.68 (d, 1H), 4.80-4.97 (m, 2H), 6.35 (d, 1H), 6.54 (dd, 1H), 6.74 (d, 1H), 6.81 ( d, 2H), 7.14 (d, 2H).
[371] Example 18 (2S, 3S, 4R) -6-Nitro-4- [N- (4-chlorophenyl) -N- (1H-tetrazol-5-ylmethyl) amino] -3-hydroxy Preparation of 2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[372] Step 1: (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
[373] 900 mg (3.2 mmol) of the epoxide compound prepared in Step 1 of Example 1 and N- (4-chlorophenyl) -N- [2- (1-ethoxyethyl) -2H-tetrazol-5-ylmethyl ] 900 mg (3.2 mmol) of amine were carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (2: 1), 566 mg (31%) of compound was obtained.
[374] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.12 (m, 3H), 1.48 (s, 3H), 1.82 (d, 3H), 3.26-3.34 (m, 1H), 3.49-3.59 (m, 1H ), 3.57 (s, 3H), 3.64 (s, 3H), 4.43-4.10 (m, 2H), 4.62 (s, 1H), 4.86 (d, 1H), 5.15 (d, 1H), 5.20 (d, 1H), 6.00 (q, 1H), 6.85 (d, 2H), 7.05 (d, 1H), 7.13 (d, 2H), 8.06 (dd, 1H), 8.10 (d, 1H).
[375] Step 2: (2S, 3S, 4R) -6-Nitro-4- [N- (4-chlorophenyl) -N- (1H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2 Preparation of -methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[376] 300 mg (0.53 mmol) of the compound obtained in step 1 was dissolved in 2 ml of methanol, and 1 ml of an aqueous 3% HCl solution was added. After reacting at room temperature for 12 hours, 20 ml of water was added and extracted with 30 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and then concentrated. The obtained compound was purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4) to obtain 160 mg (61%) of the target compound.
[377] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.49 (s, 3H), 3.63 (s, 6H), 4.60-4.40 (m, 3H), 5.20-4.95 (m, 3H), 6.78-6.50 (m , 3H), 7.00 (d, 1H), 7.10 (d, 2H), 7.99 (d, 1H), 8.10 (dd, 1H).
[378] Example 19 (2S, 3S, 4R) -6-nitro-4- [N- (1H-tetrazol-5-ylmethyl) phenylamino] -3-hydroxy-2-methyl-2-di Preparation of Methoxymethyl-3,4-dihydro-2H-1-benzopyran
[379] The tetrazol was protected in the same manner as in step 1 of Example 18, except that N- [2- (1-ethoxyethyl) -2H-tetrazol-5-ylmethyl] phenylamine was used. The compound was obtained. 272 mg (0.52 mmol) of the compound were used to carry out the same method as in Step 2 of Example 18. Purification by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4) gave 119 mg (50%) of the title compound.
[380] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.49 (s, 3H), 3.62 (s, 6H), 4.75-4.43 (m, 3H), 5.21-4.97 (m, 3H), 6.84-6.73 (m , 3H), 6.99 (d, 1H), 7.20-7.12 (m, 2H), 8.03 (d, 1H), 8.11 (dd, 1H)
[381] Example 20 (2S, 3S, 4R) -6-Nitro-4- [N-benzyl-N- (1H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2-methyl- Preparation of 2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[382] The step of Example 18 using the epoxide compound prepared in Step 1 of Example 1 and N-benzyl-N- [2- (1-ethoxyethyl) -2H-tetrazol-5-ylmethyl] amine Compound 254 mg (0.47 mmol) was obtained in the same manner as 1. Performed in the same manner as in Step 2 of Example 18 using the compound, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4), the target compound 107 mg (48%) Got.
[383] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.25 (s, 3H), 3.64 (s, 6H), 3.85 (m, 2H), 4.16 (d, 1H), 4.52-4.41 (m, 4H), 6.90 (d, 1H), 7.25-7.17 (m, 5H), 8.05 (dd, 1H), 8.41 (d, 1H)
[384] Example 21 (2S, 3S, 4R) -6-Nitro-4 [N- (3-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 Preparation of -hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[385] Using 150 mg (0.53 mmol) of epoxide compound prepared in Step 1 of Example 1 and N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Except that was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n- hexane: ethyl acetate (1: 1), 249 mg (9.3%) of the target compound. )
[386] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.50 (s, 3H), 4.10 (s, 3H), 4.41-4.34 (m, 4H), 4.62 (s, 1H), 4.81 (d, 1H), 5.20 (d, 2H), 6.80 (dd, 2H), 6.89 (s, 1H), 7.07 (m, 2H), 8.08 (m, 2H).
[387] Example 22 (2S, 3S, 4R) -6-Amino-4- [N- (3-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 Preparation of -hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[388] Except for using the compound 148 mg (0.3 mmol) prepared in Example 21, it was carried out in the same manner as in Example 10, the silica gel under the conditions of a mixed solvent of n- hexane: ethyl acetate (1: 4) Purification by column chromatography gave 106 mg (74%) of the title compound.
[389] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.41 (s, 3H), 3.55 (s, 3H), 3.61 (s, 3H), 4.20-4.40 (m, 6H), 4.57 (s, 1H), 4.68 (d, 1H), 5.09 (d, 1H), 6.40 (d, 1H), 6.54 (dd, 1H), 6.70-6.80 (m, 3H), 6.87 (s, 1H), 7.08 (t, 1H) .
[390] Example 23 (2S, 3S, 4R) -6-Nitro-4- [N-4-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Preparation of hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[391] Except using 300 mg (1.1 mmol) of epoxide compound prepared in Step 1 of Example 1 and N- (4-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Then, it was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (2: 1) to give the target compound 463 mg (69%). Got it.
[392] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.48 (s, 3H), 2.02 (s, 3H), 3.57 (s, 3H), 3.64 (s, 3H), 4.38-4.31 (m, 5H), 4.62 (s, 1H), 4.84 (d, 1H), 5.16 (s, 1H), 5.21 (s, 1H), 6.82 (d, 2H), 6.99-7.06 (m, 3H), 8.06 (dd, 1H) , 8.12 (s, 1H)
[393] Example 24 (2S, 3S, 4R) -6-amino-4- [N-4-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Preparation of oxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[394] Except for using 263 mg (0.54 mmol) of the compound prepared in Example 23, the same method as in Example 10, and was carried out under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4) silica gel Purification by column chromatography gave 176 mg (72%) of the title compound.
[395] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.41 (s, 3H), 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), 4.93 (s, 1H), 5.11 (d, 1H), 6.44 (d, 1H), 6.53 (dd, 1H), 6.79 (dd) , 3H), 7.00 (d, 2H)
[396] Example 25 (2S, 3R, 4S) -6-Nitro-4- [N- (3-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[397] Using 150 mg (0.53 mmol) of the epoxide compound prepared in Step 1 of Example 2 and N- (3-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Except for the same procedure as in Step 3 of Example 1, the mixture was purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 1) to give 124 mg (46%) of the title compound. Got.
[398] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.63 (s, 3H), 3.52 (s, 3H), 3.55 (s, 3H), 3.95 (q, 1H), 4.36 (m, 4H), 4.75 ( s, 1H), 4.85 (d, 1H), 5.47 (s, 1H), 5.70 (d, 2H), 6.78 (dd, 1H), 6.90 (s, 1H), 6.95 (d, 1H), 7.12 (t , 1H), 7.96 (s, 1H), 8.08 (dd. 1H)
[399] Example 26 (2S, 3R, 4S) -6-Amino-4- [N- (3-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 Preparation of -hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[400] The same procedure as in Example 10 was carried out, except that 180 mg (0.37 mmol) of the compound prepared in Example 25 was used, and the silica gel column was prepared under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4). Purification by chromatography gave 95 mg (54%) of the title compound.
[401] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.54 (s, 3H), 3.40 (s, 1H), 3.50 (s, 3H), 3.53 (s, 3H), 3.92 (q, 1H), 4.32- 4.50 (m, 4H), 4.64 (s, 1H), 4.63-4.73 (m, 2H), 5.41 (d, 1H), 6.42 (s, 1H), 6.56 (dd, 1H) 6.68-6.78 (m, 3H ), 6.91 (s, 1 H), 7.05 (t, 1 H)
[402] Example 27 (2S, 3R, 4S) -6-Nitro-4- [N- (4-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 Preparation of -hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[403] Except using 300 mg (1.1 mmol) of epoxide compound prepared in Step 1 of Example 2 and N- (4-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Then, it was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (2: 1) to give 388 mg (75%) of the target compound. Got it.
[404] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.62 (s, 3H), 2.24 (s, 3H), 3.49 (s, 3H), 3.55 (s, 3H), 3.92 (q, 1H), 4.26 ( m, 4H), 4.74 (s, 1H), 4.86 (d, 1H), 5.40 (d, 1H), 5.55 (d, 1H), 6.81 (d, 2H), 7.04-6.91 (m, 3H), 8.02 (s, 3 H), 8.06 (d, 1 H).
[405] Example 28 (2S, 3R, 4S) -6-Amino-4- [N- (4-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Preparation of hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[406] The same procedure as in Example 10 was carried out, except that 238 mg (0.49 mmol) of the compound prepared in Example 27 was used, and the silica gel column was prepared under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4). Purification by chromatography gave 168 mg (69%) of the title compound.
[407] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.53 (s, 3H), 2.23 (s, 3H), 3.48 (s, 3H), 3.52 (s, 3H), 3.92 (d, 1H), 4.30 ( s, 3H), 4.39 (d, 1H), 4.64 (s, 1H), 4.65-4.74 (m, 2H), 5.35 (d, 1H), 6.48 (d, 1H), 6.52 (d, 1H), 6.69 (d, 1H), 6.82 (d, 2H), 7.00 (d, 2H)
[408] Example 29 (2S, 3R, 4S) -6-nitro-4- [N- (2-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[409] 450 mg (1.6 mmol) of the epoxide compound prepared in Step 1 of Example 2 and using N- (2-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Except for this, the same procedure as in Example 3 was carried out in the same manner as in Example 3, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (2: 1), 118 mg (15%) of the target compound. )
[410] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.63 (s, 3H), 3.42 (s, 3H), 3.53 (m, 3H), 4.13 (d, 1H), 4.22 (s, 3H), 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), 7.67 (dd, 1H), 8.08 (dd, 1H), 9.12 (dd, 1H)
[411] Example 30 (2S, 3R, 4S) -6-Amino-4- [N- (2-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 Preparation of -hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[412] Except for using the compound 108 mg (0.21 mmol) prepared in Example 29, and was carried out in the same manner as in Example 10, the silica gel under the conditions of a mixed solvent of n- hexane: ethyl acetate (1: 4) Purification by column chromatography gave 78 mg (78%) of the title compound.
[413] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.49 (s, 3H), 3.16 (brs, 1H), 3.35 (s, 3H), 3.48 (s, 3H), 4.19 (s, 3H), 4.30 ( d, 1H), 4.50 (s, 1H), 4.82 (d, 1H), 4.94 (d, 1H), 6.58 (dd, 1H), 6.67 (d, 1H), 6.85 (t, 1H), 7.10 (t , 1H), 7.28 (d, 1H), 7.45 (d, 1H) 7.74 (d, 1H).
[414] Example 31 (2S, 3R, 4S) -6-nitro-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) Preparation of amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[415] 300 mg (1.07 mmol) of the epoxide compound prepared in Step 1 of Example 2 and N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Except for using the same method as in Step 3 of Example 1, the resultant was purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (2: 1) to give 248 mg of the target compound ( 42%).
[416] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.63 (s, 3H), 3.50 (s, 3H), 3.55 (s, 3H), 3.92 (q, 1H), 4.30 (brs, 1H), 4.35 ( s, 3H), 4.73 (s, 3H), 4.85 (d, 1H), 5.47 (s, 1H), 5.62 (d, 2H), 6.86 (d, 2H), 6.96 (d, 1H), 7.07 (d , 2H), 7.99 (s, 1H), 8.07 (dd, 1H).
[417] Example 32 (2S, 3R, 4S) -6-amino-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino ] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[418] Except for using 165 mg (0.30 mmol) of the compound prepared in Example 31, it was carried out in the same manner as in Example 10, and the silica gel under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4) Purification by column chromatography gave 117 mg (75%) of the title compound.
[419] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.54 (s, 3H), 3.48 (s, 3H), 3.52 (s, 3H), 3.95 (q, 1H), 4.32 (s, 1H), 4.41 ( d, 1H), 4.66-4.74 (m, 3H), 5.36 (d, 1H), 6.46 (s, 1H), 6.54 (dd, 1H), 6.70 (d, 1H), 6.86 (d, 2H), 7.03 (d, 2H).
[420] Example 33 (2S, 3R, 4S) -6-Nitro-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino ] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[421] 300 mg (1.07 mmol) of the epoxide compound prepared in Step 1 of Example 2 and N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine were used. Except that, the same procedure as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n- hexane: ethyl acetate (2: 1), the target compound 92 mg (16) %) Was obtained.
[422] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.63 (s, 3H), 3.51 (s, 3H), 3.54 (s, 3H), 3.98 (brs, 1H), 4.35 (m, 4H), 4.74 ( s, 1H), 4.92 (d, 1H), 5.80 (s, 1H), 6.72 (d, 1H), 6.96 (d, 2H), 7.40-7.47 (m, 2H), 7.95 (m, 1H), 8.06 (dd, 1H).
[423] Example 34 (2S, 3R, 4S) -6-Amino-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] Preparation of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[424] The same procedure as in Example 10 was carried out, except that 92 mg (0.17 mmol) of the compound prepared in Example 33 was used, and the silica gel was prepared under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4). Purification by column chromatography gave 26 mg (30%) of the title compound.
[425] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.55 (s, 3H), 3.50 (s, 3H), 3.53 (s, 3H), 3.99 (brs, 1H), 4.32-4.40 (m, 4H), 4.64-4.80 (m, 3H), 5.56 (s, 1H), 6.40 (s, 1H), 6.55 (dd, 1H), 6.71 (d, 1H), 6.95 (d, 2H), 7.42 (d, 2H)
[426] Example 35 (2S, 3R, 4S) -6-nitro-4- [N- (3-acetylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[427] Using 300 mg (1.07 mmol) of the epoxide compound prepared in Step 1 of Example 2 and N- (3-acetylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Except that was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the mixed solvent of n- hexane: ethyl acetate (1: 1), the target compound 232 mg (42%) Got.
[428] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.63 (s, 3H), 2.54 (s, 3H), 3.56 (s, 6H), 3.97 (s, 1H), 4.33 (m, 4H), 4.76 ( s, 1H), 4.92 (d, 1H), 5.43 (s, 1H), 5.80 (s, 1H), 6.96 (d, 1H), 7.04 (d, 1H), 7.24-7.38 (m, 2H), 7.60 (d, 1 H), 7.96 (d, 1 H).
[429] Example 36 (2S, 3R, 4S) -6-Amino-4- [N- [3- (1-hydroxyethyl) phenyl] -N- (2-methyl-2H-tetrazol-5-yl Methyl) amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[430] Except for using 151 mg (0.29 mmol) of the compound prepared in Example 35, it was carried out in the same manner as in Example 10, and the silica gel under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4) Purification by column chromatography gave 90 mg (64%) of the title compound.
[431] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.43 (dd, 3H), 1.54 (s, 3H), 3.51 (s, 3H), 3.54 (s, 3H), 3.97 (d, 1H), 4.30 -4.45 (m, 4H), 4.65-4.78 (m, 3H), 5.47 (d, 1H), 6.67-6.56 (m, 2H), 6.68-6.77 (m, 3H), 6.99 (d, 1H), 7.16 (t, 1H)
[432] Example 37 (2S, 3R, 4S) -6-nitro-4- [N- (2-methyl-4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-yl Methyl) amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[433] 450 mg (1.6 mmol) of the epoxide compound prepared in Step 1 of Example 2 and N-[(2-methyl-4-fluoro) phenyl] -N- (2-methyl-2H-tetrazol-5-yl Except for using methyl) amine, it was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (2: 1), the target compound 323 mg (40%) was obtained.
[434] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.63 (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), 6.75-6.85 (m, 2H), 7.55 (dd, 1H), 8.06 (dd, 1H), 9.02 (d, 1H).
[435] Example 38 (2S, 3R, 4S) -6-Amino-4- [N- (2-methyl-4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl ) Amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[436] Except for using 205 mg (0.41 mmol) of the epoxide compound prepared in Example 37, was carried out in the same manner as in Example 10, and the conditions of the mixed solvent of n-hexane: ethyl acetate (1: 4) Purified by silica gel column chromatography under the title compound to give 143 mg (74%) of the title compound.
[437] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.49 (s, 3H), 2.43 (s, 3H), 2..98 (d, 1H), 9.31 (s, 3H), 3.46 (s, 3H) , 4.19 (s, 3H), 4.23 (d, 1H), 4.37 (d, 1H), 4.43 (s, 3H), 4.81 (d, 1H), 6.58 (dd, 1H), 6.65-6.80 (m, 3H ), 7.40 (dd, 1H), 7.68 (d, 1H)
[438] Example 39 (2S, 3R, 4S) -6-nitro-4- [N- (4-methoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] Preparation of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[439] Using 300 mg (1.07 mmol) of the epoxide compound prepared in Step 1 of Example 2 and N- (4-methoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Except for the above, the same procedure as in Example 3, except that the mixture was purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (2: 1), 417 mg (78%) of the target compound. )
[440] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.62 (s, 3H), 3.48 (s, 3H), 3.54 (s, 3H), 3.74 (s, 3H), 3.93 (dd, 1H), 4.32 ( m, 4H), 4.72 (s, 1H), 4.83 (d, 1H), 5.34 (d, 1H), 5.46 (d, 2H), 6.76-6.95 (m, 3H), 8.03 (d, 1H), 8.08 (dd, 1H).
[441] Example 40 (2S, 3R, 4S) -6-Amino-4- [N- (4-methoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[442] Except for using 300 mg (0.6 mmol) of the compound prepared in Example 39, it was carried out in the same manner as in Example 10, the silica gel under the conditions of a mixed solvent of n- hexane: ethyl acetate (1: 4) Purification by column chromatography gave 270 mg (96%) of the title compound.
[443] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.53 (s, 3H), 3.39 (s, 2H), 3.48 (s, 3H), 3.51 (s, 3H), 3.73 (s, 3H), 3.93 ( dd, 1H), 4.30 (s, 3H), 4.44 (d, 1H), 4.61 (m, 1H), 4.67 (d, 1H), 5.17 (d, 1H), 6.54 (m, 1H), 6.69 (d , 1H), 6.77 (d, 2H), 6.89 (d, 2H)
[444] Example 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
[445] 450 mg (1.6 mmol) of the epoxide compound prepared in Step 1 of Example 2 and N-[(2-methyl-4-chlorophenyl)]-N- (2-methyl-2H-tetrazol-5-ylmethyl Except for using amine, it was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the mixed solvent of n- hexane: ethyl acetate (2: 1), the target compound 235 mg (28%) was obtained.
[446] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.63 (s, 3H), 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 (s, 1H), 4.67 (d, 1H), 4.87 (s, 1H), 6.90 (d, 1H), 7.01-7.09 (m, 2H) , 7.50 (d, 1 H), 8.07 (dd, 1 H), 8.99 (d, 1 H).
[447] Example 42 (2S, 3R, 4S) -6-Amino-4- [N- (2-methyl-4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) Preparation of amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[448] Except for using the compound 164 mg (0.31 mmol) prepared in Example 41, it was carried out in the same manner as in Example 10, the silica gel under the conditions of a mixed solvent of n- hexane: ethyl acetate (1: 4) Purification by column chromatography gave 86 mg (57%) of the title compound.
[449] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.50 (s, 3H), 2.42 (s, 3H), 2.99 (d, 1H), 3.32 (s, 3H), 3.46 (s, 3H), 4.03- 4.23 (m, 4H), 4.19 (s, 3H), 4.43 (s, 1H), 4.48 (d, 1H), 4.81 (d, 1H), 6.58 (dd, 1H), 6.68 (d, 1H), 6.96 -7.04 (m, 2 H), 7.34 (d, 1 H), 7.65 (d, 1 H).
[450] Example 43 (2S, 3R, 4S) -6-nitro-4- [N- (2-methoxy-5-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl ) Amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[451] 400 mg (1.4 mmol) of epoxide compound prepared in Step 1 of Example 2 and N-[(2-methoxy-5-methyl) phenyl] -N- (2-methyl-2H-tetrazol-5-yl Except for using methyl) amine, it was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (2: 1), 615 mg (85%) of compound was obtained.
[452] ¹ H NMR (CDCl ₃ , 200 MHz): δ 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 (s, 1H), 4.85 (d, 1H), 4.68 (s, 1H), 4.99 (d, 1H), 5.76 (d, 1H), 5.79 (d, 1H), 6.80 (s , 2H), 6.87 (d, 1H), 7.35 (s, 1H), 8.02 (dd, 1H), 8.83 (d, 1H).
[453] Example 44 (2S, 3R, 4S) -6-amino-4- [N- (2-methoxy-5-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) Preparation of amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[454] Except for using the compound 414 mg (0.8 mmol) prepared in Example 43, and was carried out in the same manner as in Example 10, the silica gel under the conditions of a mixed solvent of n- hexane: ethyl acetate (1: 4) Purification by column chromatography gave 285 mg (74%) of the title compound.
[455] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.53 (s, 3H), 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), 4.49 (d, 1H), 4.53 (s, 1H), 4.61 (d, 1H), 4.98 (d, 1H), 6.54 (dd, 1H), 6.64 -6.76 (m, 3H), 7.18 (s, 1H), 7.25 (s, 1H).
[456] Example 45 (2S, 3R, 4S) -6-Nitro-4- [N- (2,4-dimethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino ] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[457] 250 mg (0.89 mmol) of epoxide compound prepared in Step 1 of Example 2 and N- (2,4-dimethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine were used. Except that, the same process as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n- hexane: ethyl acetate (2: 1), 256 mg (57) of the target compound %) Was obtained.
[458] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.62 (s, 3H), 2.23 (s, 3H), 2.46 (s, 3H), 3.39 (s, 3H), 3.40 (s, 3H), 4.12- 4.16 (m, 2H), 4.22 (s, 3H), 4.40 (d, 1H), 4.51 (s, 1H), 4.64 (d, 1H), 4.89 (d, 1H), 6.87-6.94 (m, 3H) , 7.48 (d, 1 H), 8.05 (dd, 1 H), 8.99 (dd, 1 H).
[459] Example 46 (2S, 3R, 4S) -6-Amino-4- [N- (2,4-dimethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] Preparation of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[460] The same procedure as in Example 10 was carried out, except that 180 mg (0.36 mmol) of the compound prepared in Example 45 was used, and the silica gel was prepared under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4). Purification by column chromatography gave 155 mg (92%) of the title compound.
[461] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.49 (s, 3H), 2.20 (s, 3H), 2.42 (s, 3H), 3.10 (brs, 3H), 3.32 (s, 3H), 3.45 ( s, 3H), 4.12 (d, 1H), 4.16 (s, 3H), 4.20 (d, 1H), 4.45 (s, 1H), 4.49 (d, 1H), 4.82 (d, 1H), 6.56 (dd , 1H), 6.67 (d, 1H), 6.83 (s, 1H), 6.88 (s, 1H), 7.33 (d, 1H), 7.67 (d, 1H).
[462] Example 47 (2S, 3R, 4S) -6-nitro-4- [N- (3,6-dimethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino ] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[463] 300 mg (1.1 mmol) of epoxide compound prepared in Step 1 of Example 2 and N- (2,6-dimethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine were used. Except that, the same procedure as in Step 3 of Example 1, and was purified by silica gel column chromatography under the conditions of a mixed solvent of n- hexane: ethyl acetate (2: 1), 153 mg (29) of the target compound %) Was obtained.
[464] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.63 (s, 3H), 2.55 (brs, 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), 4.62 (d, 1H), 4.93 (d, 1H), 6.89-6.94 (m, 4H), 8.05 (dd, 1 H), 9.17 (d, 1 H).
[465] Example 48 (2S, 3R, 4S) -6-Amino-4- [N- (2,6-dimethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] Preparation of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[466] Except for using the compound 107 mg (0.21 mmol) prepared in Example 47, and was carried out in the same manner as in Example 10, the silica gel under the conditions of a mixed solvent of n- hexane: ethyl acetate (1: 4) Purification by column chromatography gave 78 mg (80%) of the title compound.
[467] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.51 (s, 3H), 2.53 (s, 6H), 2.91 (d, 1H), 3.28 (s, 3H), 3.45 (s, 3H), 3.54 ( s, 1H), 3.60 (d, 1H), 3.98-4.13 (m, 1H), 4.15 (s, 3H), 4.29 (d, 1H), 4.46 (s, 1H), 4.87 (d, 1H), 6.59 (d, 1H), 6.64 (d, 1H), 6.68-6.86 (m, 3H), 7.84 (s, 1H).
[468] Example 49 (2S, 3R, 4S) -6-nitro-4- [N- (2,3-dimethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino ] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[469] 300 mg (1.07 mmol) of the epoxide compound prepared in Step 1 of Example 2 and N- (2,3-dimethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine were used. Except for, the same process as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n- hexane: ethyl acetate (2: 1), the target compound 253 mg (47) %) Was obtained.
[470] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.63 (s, 3H), 2.26 (s, 3H), 2.40 (s, 3H), 3.38 (s, 3H), 3.39 (s, 3H), 4.04 ( d, 1H), 4.13 (d, 1H), 4.21 (s, 3H), 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), 8.06 (dd, 1H), 9.00 (d, 1H).
[471] Example 50 (2S, 3R, 4S) -6-Amino-4- [N-2, 3-dimethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[472] Except for using the compound 177 mg (0.35 mmol) prepared in Example 49, and was carried out in the same manner as in Example 10, the silica gel under the conditions of a mixed solvent of n- hexane: ethyl acetate (1: 4) Purification by column chromatography gave 131 mg (80%) of the title compound.
[473] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.48 (s, 3H), 2.23 (s, 3H), 2.35 (s, 3H), 2.90 (s, 1H), 3.30 (s, 3H), 3.45 ( s, 3H), 4.07-4.25 (m, 2H), 4.18 (s, 3H), 4.44 (s, 1H), 4.51 (d, 1H), 4.83 (d, 1H), 6.58 (dd, 1H), 6.68 (d, 1H), 6.78 (d, 1H), 6.96 (t, 1H), 7.31 (d, 1H), 7,71 (d, 1H).
[474] Example 51 (2S, 3R, 4S) -6-Nitro-4- [N- (2-isopropylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] Preparation of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[475] Using 300 mg (1.07 mmol) of the epoxide compound prepared in Step 1 of Example 2 and N- (2-isopropylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Except for the above, the same process as in Example 3 was carried out in the same manner as in Example 3, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (2: 1), the target compound 192 mg (35% )
[476] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.27 (d, 3H), 1.63 (s, 3H), 3.38 (s, 3H), 3.36 (s, 3H), 4.15 (d, 1H), 4.20 ( s, 3H), 4.31 (d, 1H), 4.45 (s, 1H), 4.75 (d, 1H), 4.82 (d, 1H), 6.90 (d, 1H), 7.02-7.12 (m, 2H), 7.23 (d, 1H), 7.60 (dd, 1H), 8.07 (dd, 1H), 9.02 (dd, 1H).
[477] Example 52 (2S, 3R, 4S) -6-Amino-4- [N- (2-isopropylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[478] The same procedure as in Example 10 was carried out, except that 140 mg (0.27 mmol) of the compound prepared in Example 51 was used, and the silica gel was prepared under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4). Purification by column chromatography gave 83 mg (64%) of the title compound.
[479] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.23 (d, 3H), 1.27 (d, 3H), 1.49 (s, 3H), 2.90 (brs, 1H), 3.27 (s, 3H), 3.44 ( s, 3H), 3.61 (m, 1H), 4.10-4.20 (m, 4H), 4.41 (s, 1H), 4.44 (d, 1H), 4.88 (d, 1H), 6.59 (dd, 1H), 6.68 (d, 1H), 6.95-7.06 (m, 2H), 7.19 (dd, 1H), 7.48 (dd, 1H), 7.65 (d, 1H).
[480] Example 53 (2S, 3R, 4S) -6-Nitro-4- [N- [4-ethoxycarbonyl) phenyl] -N- (2-methyl-2H-tetrazol-5-ylmethyl ) Amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[481] 400 mg (1.42 mmol) of epoxide compound prepared in Step 1 of Example 2 and N-[(4-ethoxycarbonyl) phenyl] -N- (2-methyl-2H-tetrazol-5-ylmethyl) Except for using an amine, it was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the mixed solvent of n- hexane: ethyl acetate (2: 1), the target compound 161 Mg (33%) was obtained.
[482] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.35 (t, 3H), 1.63 (s, 3H), 3.52 (s, 3H), 3.55 (s, 3H), 3.92 (s, 1H), 4.33 ( m, 6H), 4.51-4.75 (m, 2H), 4.91 (d, 1H), 5.49 (s, 1H), 5.81 (d, 1H), 6.89-6.99 (m, 3H), 7.87-8.10 (m, 4H).
[483] Example 54 (2S, 3R, 4S) -6-Amino-4- [N- [4- (ethoxycarbonyl) phenyl] -N- (2-methyl-2H-tetrazol-5-ylmethyl ) Amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[484] Except for using the compound 118 mg (0.22 mmol) prepared in Example 53, it was carried out in the same manner as in Example 10, the silica gel under the conditions of a mixed solvent of n- hexane: ethyl acetate (1: 4) Purification by column chromatography gave 49 mg (44%) of the title compound.
[485] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.33 (t, 3H), 1.54 (s, 3H), 3.25 (s, 1H), 3.49 (s, 3H), 3.52 (s, 3H), 3.99 ( s, 1H), 4.24-4.42 (m, 5H), 4.64-4.81 (m, 3H), 5.58 (s, 1H), 6.53 (dd, 1H), 6.70 (d, 1H), 6.89 (d, 2H) , 7.87 (d, 2 H).
[486] Example 55 (2S, 3R, 4S) -6-Amino-4- [N- (2-methyl-2H-tetrazol-5-ylmethyl) phenylamino] -3-hydroxy-2-methyl- Preparation of 2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[487] The same procedure as in Example 10 was carried out except that 217 mg (0.46 mmol) of the compound prepared in Example 4 was used, and the silica gel column was prepared under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4). Purification by chromatography gave 157 mg (77%) of the title compound.
[488] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.54 (s, 3H), 3.30 (s, 1H), 3.49 (s, 3H), 3.52 (s, 3H), 3.96 (d, 1H), 4.30 ( s, 3H), 4.45 (d, 1H), 4.64 (s, 1H), 4.71 (d, 1H), 5.43 (d, 1H), 6.46 (s, 1H), 6.52 (dd, 1H), 6.69 (d , 1H), 6.76 (d, 1H), 6.90 (d, 1H), 7.25 (t, 2H).
[489] Example 56 (2S, 3R, 4S) -6-Amino-4- [N- (4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[490] Except for using the compound prepared in Example 6 104 mg (0.21 mmol), it was carried out in the same manner as in Example 10, and the silica gel under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4) Purification by column chromatography gave 85 mg (88%) of the title compound.
[491] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.53 (s, 3H), 3.48 (s, 3H), 3.51 (s, 3H), 3.96 (d, 1H), 4.29 (s, 3H), 4.44 ( d, 1H), 4.61 (s, 1H), 4.67 (d, 1H), 5.26 (d, 1H), 6.53 (d, 2H), 6.69 (d, 1H), 6.85 (d, 2H), 6.88 (d , 2H).
[492] Example 57 (2S, 3R, 4S) -6-Amino-4 [N-benzyl-N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2- Preparation of Methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[493] The same procedure as in Example 10 was carried out, except that 75 mg (0.15 mmol) of the compound prepared in Example 8 was used, and the silica gel was prepared under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4). Purification by column chromatography gave 57 mg (87%) of the title compound.
[494] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.51 (s, 3H), 3.22 (s, 3H), 3.39 (s, 3H), 3.61 (d, 1H), 3.83 (d, 1H), 3.92 ( d, 1H), 4.02 (d, 1H), 4.12-4.27 (m, 3H), 4.31 (s, 3H), 6.52 (dd, 1H), 6.59 (d, 1H), 7.22-7.37 (m, 4H) , 7.48 (d, 2 H).
[495] Example 58 (2S, 3R, 4S) -6-amino-4- [N-[(3-methoxycarbonyl) phenyl] -N- (2-methyl-2H-tetrazol-5-ylmethyl ) Amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[496] 460 mg (1.65 mmol) of epoxide compound prepared in Step 1 of Example 2 and N-[(3-methoxycarbonyl) phenyl] -N- (2-methyl-2H-tetrazol-5-ylmethyl) Except for using amine, it was carried out in the same manner as in Step 3 of Example 1, purified by silica gel column chromatography under the mixed solvent of n- hexane: ethyl acetate (2: 1), the target compound 360 Mg (40%) was obtained.
[497] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.22 (s, 3H), 3.57 (s, 3H), 3.89 (s, 3H), 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), 7.96 (m, 1H), 8.07 (dd, 1H).
[498] Example 59 (2S, 3S, 4S) -6-amino-4- [N-[(3-methoxycarbonyl) phenyl] -N- (2-methyl-2H-tetrazol-5-ylmethyl ) Amino] -3-hydroxy-2-methyl-2-methoxymethyl-3,4-dihydro-2H-1-benzopyran
[499] Except for using the compound 520 mg (0.57 mmol) prepared in Example 58 was carried out in the same manner as in Example 10, and the silica gel column under the conditions of a mixed solvent of n- hexane: ethyl acetate (1: 2) Purification by chromatography gave 360 mg (40%) of the title compound.
[500] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.53 (s, 3H), 3.59 (d, 6H), 3.84 (s, 3H), 3.98 (m, 2H), 4.12 (s, 3H), 4.15 ( m, 1H), 4.78 (s, 1H), 5.55 (m, 1H), 6.66 (m, 2H), 6.71 (d, 1H), 7.01 (m, 1H), 7.17 (t, 1H), 7.38 (m , 1H), 7.68 (m, 1H).
[501] Example 60 (2S, 3R, 4S) -6-Nitro-4- [N- (2-hydroxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] Preparation of -3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran
[502] 370 mg (1.32 mmol) of the epoxide compound prepared in Step 1 of Example 2 using N- (2-hydroxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Except for the above, the same process as in Example 3 was performed, and the reaction mixture was purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 2) to obtain 140 mg (21%) of the target compound. )
[503] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.66 (s, 3H), 3.44 (d, 6H), 4.13 (m, 2H), 4.33 (s, 3H), 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).
[504] Example 61 (2S, 3R, 4S) -6-Amino-4- [N- (2-hydroxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[505] The same procedure as in Example 10 was carried out except that 210 mg (0.42 mmol) of the compound prepared in Example 60 was used, and the silica gel column was mixed under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4). Purification by chromatography gave 71 mg (37%) of the title compound.
[506] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.57 (s, 3H), 3.55 (d, 6H), 4.15 (m, 2H), 4.33 (s, 3H), 4.44 (s, 1H), 4.75 ( m, 1H), 4.84 (m, 1H), 6.86 (m, 6H) 7.49 (m, 1H).
[507] Example 62 (2S, 3R, 4S) -6-Nitro-4- [N-[(2-methoxy-4-methoxycarbonyl) phenyl] -N- (2-methyl-2H-tetra Preparation of sol-5-ylmethyl) amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[508] 380 mg (1.36 mmol) of the epoxide compound prepared in Step 1 of Example 2 and N-[(2-methoxy-4-methoxycarbonyl) phenyl] -N- (2-methyl-2H-tetrazol- Except for using 5-ylmethyl) amine, it was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under a mixed solvent of n-hexane: ethyl acetate (1: 3). Thus, 250 mg (48%) of the title compound were obtained.
[509] ¹ H NMR (CDCl ₃ , 200 MHz): δ 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), 8.74 (, m, 1H).
[510] Example 63 (2S, 3R, 4S) -6-Amino-4- [N-[(2-methoxy-3-methoxycarbonyl) phenyl] -N- (2-methyl-2H-tetrazole Preparation of -5-ylmethyl) amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[511] The same procedure as in Example 10 was carried out except for using the compound 200 mg (0.37 mmol) prepared in Example 62, and the silica gel column was prepared under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4). Purification by chromatography gave 90 mg (45%) of the title compound.
[512] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.52 (s, 3H), 3.42 (d, 6H), 3.58 (m, 1H), 3.75 (s, 3H), 3.77 (s, 3H), 3.98 ( m, 1H), 4.49 (s, 1H), 4.57 (m, 1H), 4.68 (m, 1H), 5.26 (d, 1H), 6.57 (m, 1H), 7.27 (m, 2H), 7.55 (m , 2H).
[513] Example 64 (2S, 3R, 4S) -6-nitro-4- [N-[(2-methyl-4-hydroxy) phenyl] -N- (2-methyl-2H-tetrazol-5 Preparation of -ylmethyl) amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[514] 350 mg (1.26 mmol) of the epoxide compound prepared in Step 1 of Example 2 and N-[(2-methyl-4-hydroxy) phenyl] -N- (2-methyl-2H-tetrazol-5-yl Except for using methyl) amine, it was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 2), Obtained 190 mg (30%) of compound.
[515] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.61 (s, 3H), 2.43 (s, 6H), 3.39 (d, 6H,) 3.64 (m, 1H), 3.96 (m, 1H), 4.16 ( s, 1H), 4.46 (s, 1H), 4.68 (m, 1H), 4.72 (m, 1H), 5.81 (brs, 1H), 6.59 (dd, 1H), 6.61 (m, 1H), 6.91 (d , 1H), 7.27 (d, 1H), 8.04 (dd, 1H), 9.05 (m, 1H).
[516] Example 65 (2S, 3R, 4S) -6-Amino-4- [N-[(2-methyl-4-hydroxy) phenyl] -N- (2-methyl-2H-tetrazol-5- Monomethyl) amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[517] The same procedure as in Example 10 was carried out, except that 140 mg (0.29 mmol) of the compound prepared in Example 64 was used, and the silica gel was mixed under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4). Purification by column chromatography gave 70 mg (53%) of the title compound.
[518] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.48 (s, 3H), 2.32 (s, 3H), 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).
[519] Example 66 (2S, 3R, 4S) -6-Nitro-4- [N- (2-ethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[520] Using 270 mg (0.98 mmol) of epoxide compound prepared in Step 1 of Example 2 and N- (2-ethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Except that was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 2), the target compound 100 mg (22%) Got.
[521] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.27 (t, 3H), 1.62 (s, 3H), 2.89 (t, 2H,) 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), 7.59 (dd, 1H), 8.08 (dd , 1H), 9.02 (m, 1H).
[522] Example 67 (2S, 3R, 4S) -6-Amino-4- [N- (2-ethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 Preparation of -hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[523] The same procedure as in Example 10 was carried out, except that 190 mg (0.39 mmol) of the compound prepared in Example 66 was used, and the silica gel was mixed under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4). Purification by column chromatography gave 30 mg (14%) of the title compound.
[524] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.24 (t, 3H), 1.49 (s, 3H), 2.65 (m, 1H,) 2.91 (m, 1H), 3.27 (d, 6H), 4.09 ( m, 2H), 4.14 (s, 3H), 4.42 (s, 1H), 4.45 (m, 1H), 4.92 (m, 1H), 6.70 (m, 2H), 7.05 (m, 3H), 7.45 (d , 1H), 7.67 (m, 1H).
[525] Example 68 (2S, 3R, 4S) -6-Nitro-4- [N-[(2-methyl-5- (methoxycarbonyl) phenyl] -N- (2-methyl-2H-tetra Preparation of sol-5-ylmethyl) amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[526] 420 mg (1.48 mmol) of the epoxide compound prepared in Step 1 of Example 2 and N- (2-methyl-5- (methoxycarbonyl) phenyl] -N- (2-methyl-2H-tetrazol-5 Except for using -ylmethyl) amine, it was carried out in the same manner as in Step 3 of Example 1, purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 2) 520 mg (51%) of the title compound were obtained.
[527] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.64 (s, 1H), 2.56 (s, 3H), 3.41 (d, 6H,) 3.87 (s, 3H), 4.07 (m, 2H), 4.10 ( s, 3H), 4.48 (s, 1H), 4.80 (d, 1H), 4.93 (d, 1H), 6.93 (d, 1H), 7.17 (d, 1H), 7.61 (m, 1H), 8.07 (dd) , 1H), 8.25 (m, 1H), 8.97 (m, 1H)
[528] Example 69 (2S, 3R, 4S) -6-amino-4- [N-[(2-methyl-5- (methoxycarbonyl) phenyl] -N- (2-methyl-2H-tetrazole Preparation of -5-ylmethyl) amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[529] Except for using the compound 220 mg (0.40 mmol) prepared in Example 68 was carried out in the same manner as in Example 10, and the silica gel under the conditions of a mixed solvent of n- hexane: ethyl acetate (1: 4) Purification by column chromatography gave 90 mg (44%) of the title compound.
[530] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.48 (s, 3H), 2.49 (s, 3H), 3.44 (d, 6H,) 3.72 (m, 1H), 3.83 (m, 1H), 4.05 ( s, 3H), 4.49 (s, 1H), 4.54 (d, 1H), 4.96 (d, 1H), 6.68 (m, 2H), 7.25 (d, 1H), 7.49 (m, 2H), 8.05 (m , 1H).
[531] Example 70 (2S, 3R, 4S) -6-nitro-4- [N- (2-hydroxy-5-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl ) Amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[532] 400 mg (1.43 mmol) of epoxide compound prepared in Step 1 of Example 2 and N- (2-hydroxy-5-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Except for using the same method as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 2), the target compound 280 mg (39%) was obtained.
[533] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.67 (s, 3H), 2.33 (s, 3H), 3.46 (d, 6H,) 4.07 (m, 2H), 4.25 (s, 3H), 4.87 ( s, 1H), 4.86 (d, 1H), 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).
[534] Example 71 (2S, 3R, 4S) -6-amino-4- [N- (2-hydroxy-5-methylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) Preparation of amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[535] The same procedure as in Example 10 was carried out, except that 140 mg (0.29 mmol) of the compound prepared in Example 70 was used, and the silica gel was prepared under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4). Purification by column chromatography gave 70 mg (53%) of the title compound.
[536] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.62 (s, 3H), 2.33 (s, 3H), 3.30 (d, 6H,) 3.62 (m, 1H), 3.74 (m, 1H), 3.78 ( s, 3H), 4.17 (m, 1H), 4.33 (s, 1H), 4.82 (d, 1H), 6.35 (m, 1H), 6.59 (m, 3H), 7.22 (m, 1H), 7.71 (m , 1H).
[537] Example 72 (2S, 3R, 4S) -6-nitro-4- [N- (2,4,6-trimethyl phenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl ) Amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[538] 400 mg (1.43 mmol) of epoxide compound prepared in Step 1 of Example 2 and N- (2,4,6-trimethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Except for using the same method as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 2), the target compound 260 mg (35%) was obtained.
[539] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.62 (s, 3H), 2.20 (s, 3H), 2.49 (m, 6H,) 3.30 (d, 6H), 3.68 (m, 2H), 4.10 ( m, 1H), 4.17 (s, 3H), 4.20 (s, 1H), 4.68 (m, 1H), 4.93 (m, 1H), 6.88 (m, 2H), 6.93 (d, 1H), 8.07 (dd) , 1H), 9.14 (m, 1H).
[540] Example 73 (2S, 3R, 4S) -6-amino-4- [N- (2,4,6-trimethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) Preparation of amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[541] Except for using the compound 190 mg (0.37 mmol) prepared in Example 72, and was carried out in the same manner as in Example 10, the silica gel under the conditions of a mixed solvent of n- hexane: ethyl acetate (1: 4) Purification by column chromatography gave 90 mg (52%) of the title compound.
[542] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.64 (s, 3H), 2.17 (s, 3H), 2.52 (m, 6H,) 3.31 (d, 6H), 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 (m, 3H), 7.84 (m, 1H).
[543] Example 74 (2S, 3S, 4R) -6-nitro-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino ] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[544] 340 mg (1.21 mmol) of epoxide compound prepared in Step 1 of Example 1 and N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine were used. Except for, the same procedure as in Step 3 of Example 1, and was purified by silica gel column chromatography under the conditions of a mixed solvent of n- hexane: ethyl acetate (2: 1), the target compound 522 mg (82 %) Was obtained.
[545] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.50 (s, 3H), 3.59 (s, 3H), 3.63 (s, 3H,) 4.38 (s, 5H), 4.60 (s, 1H), 4.90 ( m, 1H), 5.30 (m, 2H), 7.00 (m, 3H), 7.43 (m, 2H), 8.10 (m, 2H).
[546] Example 75 (2S, 3S, 4R) -6-amino-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] Preparation of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[547] Except for using the compound prepared in Example 74 200 mg (0.37 mmol), it was carried out in the same manner as in Example 10, and the silica gel under the conditions of a mixed solvent of n- hexane: ethyl acetate (1: 2) Purification by column chromatography gave 155 mg (81%) of the title compound.
[548] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.50 (s, 3H), 3.63 (s, 3H), 3.68 (s, 3H,) 4.40 (s, 5H), 4.63 (s, 1H), 4.80 ( m, 1H), 4.98 (m, 1H), 5.20 (m, 1H), 6.50 (m, 1H), 6.63 (m, 1H), 6.90 (d, 1H), 7.00 (m. 2H), 7.50 (m , 2H).
[549] Example 76 (2R, 3S, 4R) -6-nitro-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino ] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[550] Step 1: Preparation of (2R, 3S, 4S) -6-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran
[551] In the same manner as in step 1 of Example 1, except that 1.5 g (5.7 mmol) of (2R) -6-nitro-2-methyl-2-dimethoxymethyl-2H-1-benzopyran was used. The mixture was purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (4: 1) to obtain 1.3 g (82%) of the title compound.
[552] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.28 (s, 3H), 3.60 (s, 3H), 3.67 (s, 3H),
[553] 3.80 (d, 1H), 3.97 (d, 1H), 4.47 (s, 1H), 6.94 (d, 1H,) 8.15 (dd, 1H), 8.30 (d, 1H)
[554] Step 2: (2R, 3S, 4R) -6-Nitro-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[555] 426 mg (1.51 mmol) of the epoxide compound prepared in step 1 and 391 mg (1.51 mmol) of N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Was carried out in the same manner as in Step 3 of Example 1, except that n-hexane: ethyl acetate (2: 1) was purified by silica gel column chromatography under the conditions of a mixed solvent to give the title compound 111 Mg (14%) was obtained.
[556] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.63 (s, 3H), 3.50 (s, 3H), 3.55 (s, 3H,) 3.92 (q, 1H), 4.30 (brs, 1H), 4.35 ( s, 3H), 4.73 (s, 1H), 4.85 (d, 1H), 5.47 (s, 1H), 5.62 (d, 2H), 6.86 (d, 2H), 6.96 (d, 1H), 7.07 (d , 2H), 7.99 (s, 1H), 8.07 (dd, 1H).
[557] Example 77 (2R, 3S, 4R) -6-Amino-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] Preparation of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[558] The same procedure as in Example 10 was carried out, except that 93 mg (0.17 mmol) of the compound prepared in Example 76 was used, and the silica gel was prepared under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4). Purification by column chromatography gave 73 mg (84%) of the title compound.
[559] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.54 (s, 3H), 3.48 (s, 3H), 3.52 (s, 3H,) 3.95 (q, 1H), 4.32 (s, 1H), 4.41 ( d, 1H), 4.66-4.74 (m, 3H), 5.36 (d, 1H), 6.46 (s, 1H), 6.54 (dd, 1H), 6.70 (d, 1H), 6.86 (d, 2H), 7.03 (d, 2H).
[560] Example 78 (2R, 3R, 4S) -6-nitro-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino ] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[561] Step 1: Preparation of (2R, 3R, 4R) -6-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran
[562] Performed in the same manner as Step 1 of Example 2, except that 2.5 g (9.4 mmol) of (2R) -6-nitro-2-methyl-2-dimethoxymethyl-2H-1-benzopyran was used. Then, the resultant was purified by silica gel column chromatography under the condition of a mixed solvent of n-hexane: ethyl acetate (4: 1) to obtain 2.3 g (87%) of the title compound.
[563] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.56 (s, 3H), 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).
[564] Step 2: (2R, 3R, 4S) -6-nitro-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[565] 604 mg (2.15 mmol) of the epoxide compound prepared in step 1 and 555 mg (2.15 mmol) of N- (4-trifluoromethylphenyl) -N- (2-methyl-1H-tetrazol-5-ylmethyl) amine ) Was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (2: 1), the target compound 700 Mg (60%) was obtained.
[566] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.50 (s, 3H), 3.58 (s, 3H), 3.65 (s, 3H,) 4.38 (m, 5H), 4.60 (s, 1H), 4.90 ( m, 1H), 5.30 (m, 2H), 7.05 (d, 1H), 7.01 (m, 1H), 7.43 (d, 2H), 8.10 (dd, 1H).
[567] Example 79 (2R, 3R, 4S) -6-Amino-4- [N- (4-trifluoromethylphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] Preparation of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[568] Except for using the compound prepared in Example 78 376 mg (0.70 mmol), it was carried out in the same manner as in Example 10, and the silica gel under the conditions of a mixed solvent of n- hexane: ethyl acetate (1: 3) Purification by column chromatography gave 284 mg (80%) of the title compound.
[569] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.42 (s, 3H), 3.56 (s, 3H), 3.62 (s, 3H,) 4.40 (s, 5H), 4.63 (s, 1H), 4.80 ( m, 1H), 4.98 (m, 1H), 5.20 (m, 1H), 6.50 (m, 1H), 6.63 (m, 1H), 6.90 (d, 1H), 7.00 m, 2H), 7.50 (m, 2H).
[570] Example 80 (2S, 3S, 4R) -6-nitro-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) Preparation of amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[571] 293 mg (1.04 mmol) of the epoxide compound prepared in Step 1 of Example 1 and 285 mg of N- (4-trifluoromethoxyphenyl) -N- (2-methyl-1H-tetrazol-5-ylmethyl) amine (1.04 mmol) was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (2: 1), 433 mg (75%) of the title compound were obtained.
[572] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.45 (s, 3H), 3.59 (s, 3H), 3.63 (s, 3H,) 4.34 (s, 3H), 4.40 (m, 2H), 4.63 ( s, 1H), 4.83 (d, 1H), 5.19 (m, 2H), 6.87 (m, 2H), 7.04 (m, 3H), 8.08 (m, 2H).
[573] Example 81 (2S, 3S, 4R) -6-amino-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino ] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[574] Except for using the compound 240 mg (0.43 mmol) prepared in Example 80 was carried out in the same manner as in Example 10, the silica gel under the conditions of a mixed solvent of n- hexane: ethyl acetate (1: 4) Purification by column chromatography gave 189 mg (83%) of the title compound.
[575] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.43 (s, 3H), 3.60 (s, 3H), 3.63 (s, 3H,) 4.39 (s, 3H), 4.40 (m, 2H), 4.60 ( s, 1H), 4.76 (d, 2H), 4.90 (s, 1H), 5.16 (m, 1H), 6.43 (s, 1H), 6.59 (m, 1H), 6.88 (m, 3H), 7.18 (m , 2H).
[576] Example 82 (2R, 3R, 4S) -6-nitro-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) Preparation of amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[577] 260 mg (0.92 mmol) of epoxide compound prepared in Step 1 of Example 78 and N- (4-trifluoromethoxyphenyl) -N- (2-methyl-1H-tetrazol-5-ylmethyl) amine Except for using 253 mg (0.92 mmol), was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under a mixed solvent of n- hexane: ethyl acetate (2: 1) The desired compound 406 mg (80%) was obtained.
[578] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.45 (s, 3H), 3.59 (s, 3H), 3.63 (s, 3H,) 4.34 (d, 3H), 4.40 (m, 2H), 4.63 ( s, 1H), 4.83 (d, 1H), 5.19 (m, 2H), 6.87 (m, 2H), 7.04 (m, 3H), 8.08 (m, 2H).
[579] Example 83 (2R, 3R, 4S) -6-amino-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino ] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[580] Except for using the compound 240 mg (0.43 mmol) prepared in Example 82, and was carried out in the same manner as in Example 10, the silica gel under the conditions of a mixed solvent of n- hexane: ethyl acetate (1: 4) Purification by column chromatography gave 176 mg (78%) of the title compound.
[581] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.40 (s, 3H), 3.56 (s, 3H), 3.61 (s, 3H,) 4.37 (s, 3H), 4.40 (m, 2H), 4.60 ( s, 1H), 4.76 (d, 2H), 4.90 (s, 1H), 5.16 (m, 1H), 6.43 (s, 1H), 6.59 (m, 1H), 6.88 (m, 3H), 7.18 (m , 2H).
[582] Example 84 (2R, 3S, 4R) -6-nitro-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) Preparation of amino] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[583] 504 mg (1.79 mmol) of epoxide compound prepared in Step 1 of Example 76 and N- (4-trifluoromethoxyphenyl) -N- (2-methyl-1H-tetrazol-5-ylmethyl) amine Except for using 490 mg (1.79 mmol) was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (2: 1) 645 mg (65%) of the title compound were obtained.
[584] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.63 (s, 3H), 3.50 (s, 3H), 3.55 (s, 3H,) 3.92 (q, 1H), 4.30 (brs, 1H), 4.35 ( s, 3H), 4.73 (s, 1H), 4.85 (d, 1H), 5.47 (s, 1H), 5.62 (d, 2H), 6.86 (d, 2H), 6.96 (d, 1H), 7.07 (d , 2H), 7.99 (s, 1H), 8.09 (dd, 1H)
[585] Example 85 (2R, 3S, 4R) -6-amino-4- [N- (4-trifluoromethoxyphenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino ] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[586] Except for using the compound 295 mg (0.53 mmol) prepared in Example 84, it was carried out in the same manner as in Example 10, the silica gel under the conditions of a mixed solvent of n- hexane: ethyl acetate (1: 3) Purification by column chromatography gave 225 mg (81%) of the title compound.
[587] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.54 (s, 3H), 3.48 (s, 3H), 3.52 (s, 3H), 3.95 (q, 1H), 4.32 (s, 1H), 4.41 ( d, 1H), 4.66-4.74 (m, 3H), 5.36 (d, 1H), 6.46 (s, 1H), 6.54 (dd, 1H), 6.70 (d, 1H), 6.86 (d, 2H), 7.03 (d, 2H).
[588] Example 86 (2S, 3S, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-acetoxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[589] 700 mg (1.43 mmol) of the compound obtained in Example 21 was dissolved in 5 ml of dichloromethane, and 0.3 ml of triethylamine and 160 µl of acetic anhydride were added. 50 mg of 4-dimethylaminopyridine was added thereto, followed by stirring at room temperature for 5 hours. 30 mL of water was added to the reaction mixture, followed by extraction with 30 mL of ethyl acetate. The organic layer was washed with 20 ml brine, dried over anhydrous sodium sulfate and concentrated. Purification by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 1) gave 652 mg (83%) of the title compound.
[590] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.41 (s, 3H), 1.65 (d, 3H), 3.52 (s, 3H), 3.57 (s, 3H), 4.25 (s, 5H), 4.76 ( d, 1H), 5.24 (d, 1H), 5.71 (d, 1H), 6.90 (d, 2H), 7.00 (d, 1H), 7.15 (d, 2H), 8.08 (dd, 1H), 8.71 (d , 1H).
[591] Example 87 (2S, 3S, 4R) -6-acetamino-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-acetoxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[592] 150 mg (0.32 mmol) of the compound obtained in Example 10 was dissolved in 3 ml of dichloromethane, and 0.11 ml of triethylamine and 65 µl of acetic anhydride were added. 11 mg of 4-dimethylaminopyridine was added thereto, followed by stirring at room temperature for 12 hours. After adding 20 ml of water and extracting with 20 ml of ethyl acetate, the organic layer was washed with 20 ml of brine, dried over anhydrous sodium sulfate and concentrated. The obtained compound was purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 4) to give 158 mg (88%) of the target compound.
[593] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.32 (s, 3H), 1.65 (s, 3H), 2.08 (s, 3H), 3.47 (s, 3H), 3.56 (s, 3H), 4.33- 4.21 (brs, 5H), 4.68 (d, 1H), 5.13 (d, 1H), 5.62 (d, 1H), 6.86 (d, 3H), 7.11 (d, 2H), 7.39 (brs, 1H), 7.49 (s, 1 H), 7.63 (d, 1 H).
[594] Example 88 (2S, 3S, 4R) -6-acetamino-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[595] Except for using the compound prepared in Example 10 359 mg (0.76 mmol), it was carried out in the same manner as in Example 86, the silica gel under the conditions of a mixed solvent of n- hexane: ethyl acetate (1: 4) Purification by column chromatography gave 376 mg (96%) of the title compound.
[596] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.41 (s, 3H), 2.07 (s, 3H), 3.56 (s, 3H), 3.61 (s, 3H), 4.31 (brs, 4H), 4.57 ( s, 1H), 4.72 (d, 1H), 4.94 (brs, 1H), 5.06 (d, 1H), 6.83 (brs, 1H), 6.90 (d, 2H), 7.10 (d, 3H), 7.20 (brs , 1H), 7.38 (dd, 1H).
[597] Example 89 (2S, 3S, 4R) -6-Amino-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 Preparation of Acetoxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[598] The same procedure as in Example 10 was carried out, except that 150 mg (0.28 mmol) of the compound prepared in Example 86 was used, and the silica gel was mixed under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 3). Purification by column chromatography gave 102 mg (77%) of the title compound.
[599] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.30 (s, 3H), 1.62 (s, 3H), 3.45 (s, 3H), 3.56 (s, 3H), 4.18 (s, 1H), 4.23 ( s, 1H), 4.31 (d, 1H), 4.68 (d, 1H), 5.12 (d, 1H), 5.58 (d, 1H), 6.57 (dd, 1H), 6.72 (d, 1H), 6.87 (d , 2H), 7.03 (d, 1H), 7.11 (d, 2H).
[600] Example 90 (2S, 3R, 4S) -6-Bromo-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[601] 192 mg (0.61 mmol) of (2S, 3R, 4R) -6-bromo-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran and In the same manner as in Step 3 of Example 1, except that 136 mg (0.60 mmol) of N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5ylmethyl) amine was used. The mixture was purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 2) to obtain 55 mg (17%) of the title compound.
[602] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.26-1.31 (m, 3H), 1.57 (s, 3H), 3.48 (s, 3H), 3.52 (s, 3H), 3.96-3.91 (m, 1H ), 4.32 (s, 3H), 4.68 (d, 1H), 4.78 (d, 1H), 5.05 (brs, 1H), 5.49 (d, 1H), 6.88-6.74 (m, 3H), 7.27-7.12 ( m, 5H).
[603] Example 91 (2R, 3R, 4S) -6-Bromo-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[604] 232 mg (0.74 mmol) of (2R, 3R, 4R) -6-bromo-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran Same method as Step 3 of Example 1, except using 164 mg (0.74 mmol) of N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Purification was carried out by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (3: 1) to obtain 165 mg (41%) of the title compound.
[605] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.28-1.25 (m, 3H), 1.42 (s, 3H), 3.55 (s, 3H), 3.61 (s, 3H), 4.33-4.30 (brs, 5H ), 4.58 (s, 1H), 4.75 (d, 1H), 5.14-5.05 (brs, 1H), 6.87-6.82 (m, 3H), 7.12 (d, 2H), 7.28-7.23 (m, 2H).
[606] Example 92 (2S, 3R, 4S) -6-Bromo-4- [N-4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[607] 209 mg (0.66 mmol) of (2S, 3R, 4R) -6-bromo-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran and Same as step 3 of Example 1, except using 138 mg (0.66 mmol) of N- (4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine It was carried out by the method, and purified by silica gel column chromatography under the conditions of a mixed solvent of n- hexane: ethyl acetate (6: 1) to obtain the target compound 165 mg (51%).
[608] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.28-1.21 (m, 3H), 1.56 (s, 3H), 3.47 (d, 3H), 3.51 (s, 3H), 4.92 (d, 1H), 4.30 (d, 3H), 4.40 (s, 1H), 4.66 (d, 1H), 4.76 (d, 1H), 5.00 (brs, 1H), 5.41 (d, 1H), 6.94-6.72 (m, 5H) , 7.21-7. 26 (m, 2 H).
[609] Example 93 (2R, 3R, 4S) -6-Bromo-4- [N-4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[610] 198 mg (0.63 mmol) of (2R, 3R, 4R) -6-bromo-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran Same as step 3 of Example 1, except using 130 mg (0.63 mmol) of N- (4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine It was carried out by the method, and purified by silica gel column chromatography under the conditions of a mixed solvent of n- hexane: ethyl acetate (4: 1) to give the title compound 175 mg (53%).
[611] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.20-1.27 (m, 3H), 1.40 (s, 3H), 2.03 (d, 3H), 3.55 (s, 3H), 3.60 (s, 3H), 4.28-4.33 (m, 5H), 4.56 (s, 1H), 4.73 (d, 1H), 5.02 (d, 1H), 6.80-6.88 (m, 5H), 7.22-7.26 (m, 2H).
[612] Example 94 (2R, 3R, 4S) -6-Bromo-4- [N- (2-methyl-2H-tetrazol-5-ylmethyl) phenylamino] -3-hydroxy-2-methyl Preparation of 2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[613] 204 mg (0.65 mmol) of (2R, 3R, 4R) -6-bromo-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran and The same procedure as in Step 3 of Example 1 was conducted except that 123 mg (0.65 mmol) of N- (2-methyl-2H-tetrazol-5-ylmethyl) phenylamine was used. Purification by silica gel column chromatography under the conditions of a mixed solvent of ethyl acetate (3: 1) gave 196 mg (60%) of the title compound.
[614] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.27-1.39 (m, 3H), 1.60 (s, 3H), 3.50 (d, 3H), 3.53 (s, 3H), 3.91 (d, 1H), 4.30-4.50 (brs, 3H), 4.77 (d, 1H), 4.80 (d, 1H), 5.02 (brs, 1H), 5.40 (d, 1H), 6.62-6.89 (m, 5H), 7.10-7.40 ( m, 5H).
[615] Example 95 (2R, 3S, 4R) -6-Methanesulfonyloxy-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino ] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[616] 231 mg (0.70 mmol) of (3S, 4S) -6-methanesulfonyloxy-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran and Same method as Step 3 of Example 1, except using 187 mg (0.84 mmol) of N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Purification was carried out by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 1) to obtain 104 mg (27%) of the title compound.
[617] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.58 (s, 3H), 3.06 (s, 3H), 3.52 (d, 6H), 4.07 (m, 2H), 4.32 (s, 3H), 4.67 ( s, 1H), 5.10 (s, 1H), 5.50 (d, 1H), 6.78-7.15 (m, 7H).
[618] Example 96 (2S, 3S, 4R) -6-methanesulfonyloxy-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino ] -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[619] The same procedure as in Example 95 was carried out, and purification was performed by silica gel column chromatography under a mixed solvent of n-hexane: ethyl acetate (1: 1) to obtain 64 mg (17%) of the title compound.
[620] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.44 (s, 3H), 3.04 (s, 3H), 3.59 (d, 6H), 4.32 (s, 3H), 4.57 (s, 1H), 4.78 ( d, 1H), 5.10 (d, 1H), 6.94-7.14 (m, 7H).
[621] Example 97 (2S, 3S, 4R) -6-hydroxy-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[622] 50 mg (0.09 mmol) of the compound prepared in Example 96 was dissolved in 2 ml of ethyl alcohol, and 1 ml of 6N KOH was added. The reaction mixture was heated at reflux for 1 hour, and then 10 ml of 1N HCl was added, followed by extraction with 20 ml of ethyl acetate. The extracted solution was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by silica gel column chromatography under a mixed solvent of n-hexane: ethyl acetate (1: 1) to obtain 40 mg (93%) of the target compound. )
[623] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.38 (s, 3H), 3.56 (d, 3H), 4.28 (s, 3H), 4.55 (s, 1H), 4.90 (s, 1H), 5.10 ( d, 1H), 6.75-7.10 (m, 7H).
[624] Example 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
[625] 100 ml of (2S, 3S, 4S) -6-nitro-5-methyl-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran ( 0.34 mmol) was carried out in the same manner as in Step 3 of Example 1, and purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 1), 80 mg (45%) of compound was obtained.
[626] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.30 (s, 3H), 2.12 (s, 3H), 3.60 (d, 6H), 4.10 (s, 3H), 4.23 (s, 3H), 4.30 ( s, 2H), 4.62 (d, 1H), 5.08 (d, 1H), 6.80-7.80 (m, 6H).
[627] Example 99 (2S, 3S, 4R) -6-nitro-4- [N- (4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] Preparation of -3-hydroxy-2-methyl-2-methoxymethyl-3,4-dihydro-2H-1-benzopyran
[628] Conducted with 100 mg (0.40 mmol) of (2S, 3S, 4S) -6-nitro-2-methyl-2-methoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran 116 mg (0.52 mmol) of the amine compound prepared in Step 2 of Example 1 were carried out in the same manner as Step 3 of Example 1, and the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 1) Purified by silica gel column chromatography under the title compound to give 110 mg (58%) of the title compound.
[629] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.40 (s, 3H), 3.43 (s, 3H), 3.70 (dd, 2H), 4.28 (s, 2H), 4.90 (d, 1H), 5.12 ( d, 1H), 6.80-7.20 (m, 5H), 8.05 (m, 2H).
[630] Example 100 (3R, 4S) -6-Cyano-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Preparation of hydroxy-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran
[631] Example 2 Step 2 of Example 1 with 300 mg (1.49 mmol) of (3R, 4R) -6-cyano-2,2-dimethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran 270 mg (1.19 mmol) of the amine compound prepared in the above was carried out in the same manner as in Step 3 of Example 1, and by silica gel column chromatography under a mixed solvent of n-hexane: ethyl acetate (2: 1). Purification gave 109 mg (22%) of the title compound.
[632] ¹ H NMR (CDCl ₃ , 200 MHz): δ 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), 6.81-6.93 (m, 3H), 7.15 (d, 1H), 7.36 (s, 1H), 7.46 (dd, 1H).
[633] Example 101 (3R, 4S) -6-cyano-4- [N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2,2-dimethyl Preparation of -3,4-dihydro-2H-1-benzopyran
[634] (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 188 mg (0.99 mmol) of -2H-tetrazol-5-ylmethyl) phenylamine was carried out in the same manner as in Step 3 of Example 1, to obtain 299 mg (77%) of the title compound.
[635] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.43 (s, 3H), 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 (d, 2H), 7.40 (s, 1H), 7.45 (dd, 1H).
[636] Example 102 (2S, 3S, 4R) -6-hydroxy-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[637] 64 mg (0.1 mmol) of the compound prepared in Example 96 was dissolved in 2 ml of ethanol, and 1 ml of 6 N KOH was added, followed by stirring at room temperature for 1 hour. It was neutralized with 1N HCl and extracted with 20 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained compound was purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 2) to obtain 45 mg (82%) of the target compound.
[638] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.38 (s, 3H), 3.53 (s, 3H), 3.56 (s, 3H), 4.28 (s, 3H), 4.55 (s, 1H), 4.90 ( s, 1H), 5.10 (d, 1H), 6.75-7.10 (m, 7H).
[639] Example 103 (2S, 3S, 4R) -8-Nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[640] 752 mg (2.67 mmol) of (2S, 3S, 4S) -8-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran Same method as Step 3 of Example 1, except using 597 mg (2.67 mmol) of N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Purification by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (2: 1) afforded 691 mg (51%) of the title compound.
[641] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.41 (s, 3H), 3.49 (s, 3H), 3.53 (s, 3H), 4.24 (s, 3H), 4.46-4.72 (m, 4H), 5.06 (d, 1H), 6.79 (d, 1H), 6.91 (t, 1H), 7.04 (d, 2H), 7.45 (d, 1H), 7.67 (d, 1H).
[642] Example 104 (2S, 3S, 4R) -8-Amino-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 Preparation of -hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[643] Silica gel column was carried out in the same manner as in Example 10, except that 170 mg (0.34 mmol) of the compound prepared in Example 103 was used, and under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 2). Purification by chromatography gave 128 mg (80%) of the title compound.
[644] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.43 (s, 3H), 3.55 (s, 3H), 3.60 (s, 3H), 4.29 (s, 3H), 4.35 (d, 1H), 4.62 ( s, 2H), 4.89 (brs, 1H), 5.12 (d, 1H), 6.45 (d, 1H), 6.60-6.72 (m, 2H), 6.82 (d, 2H), 7.10 (d, 2H)
[645] Example 105 (2R, 3S, 4R) -8-Nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[646] 751 mg (2.67 mmol) of (2R, 3S, 4S) -8-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran Same method as Step 3 of Example 1, except using 597 mg (2.67 mmol) of N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amine Purification was carried out by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (2: 1) to obtain the title compound 200 mg (15%).
[647] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.63 (s, 3H), 3.46 (s, 6H), 4.00 (d, 1H), 4.31 (s, 3H), 4.76 (s, 2H), 5.30 ( brs, 1H), 5.59 (d, 1H), 6.78-6.94 (m, 3H), 7.13 (d, 2H), 7.23 (d, 1H), 7.66 (d, 1H).
[648] Example 106 (2R, 3S, 4R) -8-Amino-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 Preparation of -hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[649] The same procedure as in Example 10 was carried out, except that 100 mg (0.20 mmol) of the compound prepared in Example 105 was used, and the silica gel column was prepared under the conditions of a mixed solvent of n-hexane: ethyl acetate (1: 1). Purification by chromatography gave 70 mg (74%) of the title compound.
[650] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.60 (s, 3H), 3.48 (s, 3H), 3.53 (s, 3H), 4.00 (d, 1H), 4.30 (s, 3H), 4.42 ( brs, 1H), 4.63 (s, 2H), 5.40 (d, 1H), 6.45 (d, 1H), 6.61-6.70 (m, 2H), 6.83 (d, 2H), 7.11 (d, 2H).
[651] Example 107 (2R, 3R, 4S) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino]- Preparation of 3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[652] Except for using 250 mg (0.9 mmol) of the epoxide compound prepared in Step 1 of Example 2, and was carried out in the same manner as Step 3 of Example 1, n-hexane: ethyl acetate (2: 1 Purification by silica gel column chromatography under the mixed solvent) afforded 340 mg (82%) of the title compound.
[653] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.62 (s, 3H), 3.49 (s, 3H), 3.59 (s, 3H), 3.95 (dd, 1H), 4.32 (d, 1H), 4.48 ( s, 3H), 4.83 (d, 1H), 4.72 (s, 1H), 5.60 (d, 1H), 6.82 (d, 2H), 6.95 (d, 1H), 7.16 (d, 2H), 7.99 (d , 1H), 8.06 (dd, 1H).
[654] Example 108 (2R, 3R, 4S) -6-Amino-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3 Preparation of -hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[655] (2R, 3R, 4S) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] prepared in Example 107] Dissolve 100 mg (0.2 mmol) of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran in 2 mL of methanol and 0.38 aqueous solution of Cu (OAc) _2. ML (0.4 M aqueous solution, 0.15 mmol) was added. 113 mg (3.0 mmol) of sodium borohydride (NaBH ₄ ) was slowly added at room temperature over 30 minutes, then stirred for 1 hour, and 5 ml of ethyl acetate was added. As a result of the reaction, the precipitated black solid was removed by filtration, and 5 ml of saturated NaHCO ₃ aqueous solution was added to the filtered solution and extracted with 30 ml of ethyl acetate. The organic layer was washed with brine and the extracted solution was dried over anhydrous sodium sulfate and removal of solvent, n- hexane: ethyl acetate (1: 3) under the conditions of a mixed solvent purified by silica gel column chromatography, and, R ₁ is amino 60 mg (63%) of the title compound was obtained.
[656] ¹ H NMR (CDCl ₃ , 200 MHz): δ1.34 (s, 3H), 3.51 (s, 3H), 3.61 (s, 3H), 4.02 (s, 3H), 4.10 (dd, 1H), 4.33 ( d, 1H), 4.47 (s, 1H), 4.68 (d, 1H), 4.80-4.97 (m, 2H), 6.35 (d, 1H), 6.54 (dd, 1H), 6.74 (d, 1H), 6.81 (d, 2H), 7.14 (d, 2H).
[657] <Example 109> (2R, 3S, 4R) -6-Nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy- Preparation of 2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[658] 450 mg (1.6 mmol) of the epoxide compound prepared in Step 1 of Example 1 was dissolved in 0.5 ml of acetonitrile. As the solution, 363 mg (1.6 mmol) of the secondary amine compound containing tetrazole prepared in Example 1 Step 2 and 357 mg (1.6 mmol) of magnesium perchlorate ((MgClO ₄ ) ₂ ) were added. After stirring for 10 hours at room temperature, 20 ml of aqueous NaHCO ₃ solution was added and extracted with 30 ml of ethyl acetate. The extracted solution was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed. The filtrate was purified by silica gel column chromatography under the conditions of a mixed solvent of n-hexane: ethyl acetate (2: 1) to obtain 480 mg (60%) of the title compound.
[659] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.48 (s, 3H), 3.58 (s, 3H), 3.64 (s, 3H), 4.29 (s, 3H), 4.42 (dd, 1H), 4.42 ( d, 1H), 4.61 (s, 1H), 4.82 (d, 1H), 5.13 (d, 1H), 5.18 (d, 1H), 6.84 (d, 2H), 7.05 (d, 1H), 7.15 (d , 2H), 8.08 (dd, 1H), 8.10 (d, 1H).
[660] <Example 110> (2R, 3S, 4R) -6-amino-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2 Preparation of -methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[661] (2R, 3S, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] prepared in Example 109] Dissolve 100 mg (0.2 mmol) of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran in 2 mL of methanol and 0.38 aqueous solution of Cu (OAc) _2. ML (0.4 M aqueous solution, 0.15 mmol) was added. 113 mg (3.0 mmol) of sodium borohydride (NaBH ₄ ) was slowly added at room temperature over 30 minutes, then stirred for 1 hour, and 5 ml of ethyl acetate was added. As a result of the reaction, the precipitated black solid was removed by filtration, and 5 ml of saturated NaHCO ₃ aqueous solution was added to the filtered solution and extracted with 30 ml of ethyl acetate. The organic layer was washed with brine and the extracted solution was dried over anhydrous sodium sulfate and removal of solvent, n- hexane: ethyl acetate (1: 3) under the conditions of a mixed solvent purified by silica gel column chromatography, and, R ₁ is amino 58 mg (62%) of the title compound was obtained.
[662] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.54 (s, 3H), 3.49 (s, 3H), 3.52 (s, 3H), 3.95 (dd, 1H), 4.30 (d, 1H), 4.32 ( s, 3H), 4.41-4.70 (m, 3H), 5.33 (d, 1H), 6.45 (s, 1H), 6.65 (dd, 1H), 6.68 (d, 1H), 6.82 (d, 2H), 7.13 (d, 2H).
[663] <Example 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
[664] (2S, 3S, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] prepared in Example 1 100 mg (0.20 mmol) of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran was dissolved in toluene / tetrahydrofuran (1/1) 3.8 Dissolve in mL, add 268 mg (0.99 mmol) of triphenylphosphine, 149 mg (0.87 mmol) of 4-nitrobenzoic acid at 0 ^o C dropwise into solution, and 156 mL (0.99 mmol) of diethyl azocarboxylate Was slowly added to the solution with a syringe and reacted at room temperature for 3 days. The solvent was removed under reduced pressure to give a compound. The obtained compound was purified by short silica gel column chromatography. No further purification. The obtained compound was dissolved in 1.4 ml of dichloromethane solvent, and slowly added dropwise with 1.4 ml (1 M in hexane, 1.36 mmol) of DIBAL-H while maintaining the reaction temperature at -20 ^° C., and reacting for 20 hours. To complete the reaction, brine was added to the reaction mixture. The organic layer was separated, the solvent was removed under reduced pressure, and the filtrate was purified by silica gel column chromatography under the conditions of a mixed solvent of hexane: ethyl acetate (1: 2) to obtain 18 mg (19%) of the title compound.
[665] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.52 (s, 3H), 3.63 (s, 3H), 3.69 (s, 3H), 4.32 (s, 3H), 4.48 (d, 1H), 4.53 ( m, 2H), 4.74 (m, 1H), 5.32 (d, 1H), 5.45 (d, 1H), 6.85 (d, 2H), 7.03 (d, 1H), 7.16 (d, 2H), 8.09 (d , 1H), 8.11 (dd, 1H).
[666] <Example 112> (2S, 3R, 4R) -6-amino-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2 Preparation of -methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[667] (2S, 3R, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] prepared in Example 111 100 mg (0.2 mmol) of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran was reacted under the same conditions as in Example 110 to give the target compound 62. Mg (67%) was obtained.
[668] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.48 (s, 3H), 3.52 (s, 3H), 3.56 (s, 3H), 4.01 (s, 3H), 4.13 (m, 1H), 4.48 ( d, 1H), 4.75 (m, 1H), 4.90 (m, 3H), 6.42 (d, 1H), 6.62 (dd, 1H), 6.82 (d, 1H), 6.94 (d, 2H), 7.18 (d , 2H).
[669] <Example 113> (2S, 3S, 4S) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy- Preparation of 2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[670] (2S, 3R, 4S) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] prepared in Example 2] 14 mg of the target compound was reacted with 100 mg (0.20 mmol) of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran under the same conditions as in Example 111. (14%) was obtained.
[671] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.57 (s, 3H), 3.53 (s, 3H), 3.62 (s, 3H), 4.34 (s, 3H), 4.52 (d, 1H), 4.67 ( m, 2H), 4.82 (m, 1H), 5.41 (d, 1H), 5.47 (d, 1H), 6.86 (d, 2H), 7.12 (d, 1H), 7.18 (d, 2H), 8.12 (d , 1H), 8.14 (dd, 1H).
[672] Example 114 (2S, 3S, 4S) -6-amino-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2 Preparation of -methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[673] (2S, 3S, 4S) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] prepared in Example 113 100 mg (0.2 mmol) of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran was reacted under the same conditions as in Example 110 to obtain the target compound 55 MG (57%) was obtained.
[674] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.48 (s, 3H), 3.53 (s, 3H), 3.58 (s, 3H), 4.02 (dd, 3H), 4.35 (m, 1H), 4.38 ( d, 1H), 4.92 (m, 2H), 5.35 (m, 2H), 6.42 (d, 1H), 6.59 (dd, 1H), 6.73 (d, 1H), 6.92 (d, 2H), 7.19 (d , 2H).
[675] <Example 115> (2R, 3R, 4R) -6-Nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy- Preparation of 2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[676] (2R, 3S, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] prepared in Example 2] 100 mg (0.20 mmol) of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran was reacted under the same conditions as in Example 111 to obtain 11 mg of the target compound. (11%) was obtained.
[677] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.57 (s, 3H), 3.53 (s, 3H), 3.62 (s, 3H), 4.34 (s, 3H), 4.52 (d, 1H), 4.67 ( m, 2H), 4.82 (m, 1H), 5.41 (d, 1H), 5.47 (d, 1H), 6.86 (d, 2H), 7.12 (d, 1H), 7.18 (d, 2H), 8.12 (d , 1H), 8.14 (dd, 1H).
[678] <Example 116> (2R, 3R, 4R) -6-amino-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2 Preparation of -methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[679] (2R, 3R, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] prepared in Example 115] 100 mg (0.2 mmol) of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran was reacted under the same conditions as in Example 110 to obtain the target compound 51. Mg (55%) was obtained.
[680] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.48 (s, 3H), 3.53 (s, 3H), 3.58 (s, 3H), 4.02 (dd, 3H), 4.35 (m, 1H), 4.38 ( d, 1H), 4.92 (m, 2H), 5.35 (m, 2H), 6.42 (d, 1H), 6.59 (dd, 1H), 6.73 (d, 1H), 6.92 (d, 2H), 7.19 (d , 2H).
[681] <Example 117> (2R, 3S, 4S) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy- Preparation of 2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[682] (2R, 3R, 4S) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] prepared in Example 107] 100 mg (0.20 mmol) of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran was reacted under the same conditions as in Example 111 to obtain 13 mg of the target compound. (13%) was obtained.
[683] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.52 (s, 3H), 3.63 (s, 3H), 3.69 (s, 3H), 4.32 (s, 3H), 4.48 (d, 1H), 4.53 ( m, 2H), 4.74 (m, 1H), 5.32 (d, 1H), 5.45 (d, 1H), 6.85 (d, 2H), 7.03 (d, 1H), 7.16 (d, 2H), 8.09 (d , 1H), 8.11 (dd, 1H).
[684] Example 118 (2R, 3S, 4S) -6-amino-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy-2 Preparation of -methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran
[685] (2R, 3S, 4S) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] prepared in Example 117] 100 mg (0.2 mmol) of -3-hydroxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran was reacted under the same conditions as in Example 110 to obtain the target compound 55 Mg (59%) was obtained.
[686] ¹ H NMR (CDCl ₃ , 200 MHz): δ 1.48 (s, 3H), 3.52 (s, 3H), 3.56 (s, 3H), 4.01 (s, 3H), 4.13 (m, 1H), 4.48 ( d, 1H), 4.75 (m, 1H), 4.90 (m, 3H), 6.42 (d, 1H), 6.62 (dd, 1H), 6.82 (d, 1H), 6.94 (d, 2H), 7.18 (d , 2H).
[687] The compounds of the present invention prepared in the above examples are shown in Table 1 below.
[688]
[689]
[690]
[691] Various pharmacological actions were investigated by performing the following experiments on the compounds of Formula 1 according to the present invention.
[692] Experimental Example 1 Relaxation of Rat Blood Vessels
[693] In order to find out whether the compounds of Formula 1 according to the present invention to relax the blood vessels, the following experiment.
[694] The head of the rat (350-450 g, Korea Research Institute of Chemistry) was struck and stunned. The blood was passed through the carotid artery, and the chest was dissected. The thoracic aorta was quickly removed to remove adipose tissue and a 3 mm long aortic ring. To remove the endothelium, the aorta was lightly rubbed into the vessel wall with a cotton bat moistened with physiological fluid (Krebs Henseleit buffer). Under the vascular tissue in a physiological fluid containing a water bath (organ bath) was a still tension (resting tension) of 2 g, with from 37 ℃ supplying a _{95% O 2 ~ 5% CO} 2 gas mixture (carbogen) for about one hour Stabilized by maintaining the state. After the stabilization, 10 ⁻⁵ M phenylephrine was added to constrict the vascular tissue and wash twice with physiological fluids twice so that the contraction relaxation response of vascular smooth muscle was reproducibly induced.
[695] On the other hand, vascular smooth muscle was strongly contracted by the addition of 3 × 10 ^-6 M methoxamine (Methoxamine). When the vascular contraction response by methoxamine reaches its peak and the state is maintained, it is controlled to accumulate the test substance and the control substance in each tank at concentrations of 1, 3, 10, and 30 μM. Induced relaxation of blood vessels. At this time, the control material used was Chromakalim, a first generation KATP opener having a large vascular relaxation action, BMS-180448 (compound of Formula 4) and BMS-191095 (compound of Formula 5) of BMS.
[696] Concentration-relaxation response curves were calculated by calculating the rate of change of maximal contractile force by methoxamine before drug administration, and IC ₅₀ , a 50% relaxation concentration by drug administration, was calculated by the least linear regression analysis. These results are shown in Table 2 below.
[697] Vascular Relaxation of Compounds of Formula 1 compoundMetoxamine Contraction Inhibitory Concentration in the Rat Aorta (IC ₅₀ , μM) 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
[698] As shown in Table 2, the chroma Kalim with a strong vasodilator effect is yieoteuna IC ₅₀ are 0.067 μM for the rat aortic contraction by methoxy samin 3 μM, BMS-180448 and BMS-191095 is the IC _50, respectively Observed at 1.38 μM and 2.14 μM, vascular relaxation was about 20-30 times weaker than the chromacalim.
[699] On the other hand, the compounds of the present invention showed a high IC ₅₀ value in the range of 5.59 μM to 30 μM or more, showing significantly lower vascular relaxation than the control chromachrom, BMS-180448, and BMS-191095.
[700] When the compounds of the present invention act on K _ATP in the heart, they play a role in protecting the heart. On the other hand, K _ATP openers acting on the K _ATP in vascular smooth muscle may be to expand the blood vessels, lowering the blood pressure. The hypotensive action inhibits the long-term protective effect of lowering coronary perfusion pressure, thus limiting its use in treating myocardial ischemia. Therefore, the compound of the present invention can be optimally used as a long-term protective agent because of its low vascular relaxation effect.
[701] Experimental Example 2 Neuronal Protective Effect Against Iron
[702] In order to determine whether the compounds of Formula 1 of the present invention inhibit neuronal damage and necrosis by iron, the following experiment was performed.
[703] Cortical neurons were isolated from the brains of 17-18 day-old fetuses and cultured at 37 ° C. for 7-9 days in a 5% CO ₂ incubator. The nerve cells were washed twice with MEM (Minimum essential medium) medium to lower the serum concentration to 0.2%, and serial dilution of the test material four times, resulting in 30, 7.5, It was added to 1.875 and 0.469 μM and pretreated for 30 minutes. At this time, the test material was dissolved in DMSO and diluted in the medium used, the final concentration of DMSO was adjusted not to exceed 0.1%. As a control, only solvent was used.
[704] After the pretreatment, FeSO ₄ was added to a final concentration of 50 μM and incubated for 24 hours in a CO ₂ incubator. The amount of lactate dehydrogenase (LDH) was increased by iron in the culture process, and the amount of lactate dehydrogenase liberated in the medium was measured to evaluate the degree of cell death by oxidative toxicity of iron. The neuronal protective effect of the test substance was evaluated by calculating the rate of reduction of LDH in the treated group. Concentration-neuroprotective effect curves were obtained and, through least linear regression analysis, IC ₅₀ , the drug concentration that produced 50% of the highest effect, was calculated. The results are shown in Table 3 below.
[705] Protective effect of nerve cell damage induced by iron compoundNeuroprotective effect against iron Inhibition rate (%, 30 μM compound added)IC ₅₀ (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 76525.7 Example 771111.9 Example 78694.4 Example 791071.7 Example 80955.0 Example 811201.5 Example 82691.3 Example 83803.7 Example 84485.6 Example 851191.8 Example 988510.5 Example 996920.8
[706] As shown in the results of Table 3, the compounds of the present invention showed a protective effect against neuronal damage caused by iron. Preferably the compounds of Examples 11, 17, 31, 32, 54,59, 61, 70, 75, 77, 79, 81, 82 and 85 have an IC ₅₀ of 2 μM or less, more preferably Example 60 And in the case of the compound of Example 71, by showing an IC ₅₀ of 1 μM or less, the effect of strongly inhibiting the neuronal damage caused by iron was confirmed.
[707] Therefore, the benzopyran derivatives substituted with secondary amines including tetrazole of the present invention show excellent protective effect of neurons against neurotoxicity caused by iron, resulting in stroke or dementia caused by neuronal damage or necrosis. S. Miranda et al. The role of oxidative stress in the toxicity induced by amyloid β-peptide as well as degenerative neurological disorders in patients with arthritis, inflammatory diseases such as arthritis, myocardial infarction and acute tissue damage. in Alzheimer's disease Progress in Neurobiology, 2000, 62 , 633-648; SA Cook, PH 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; JM McCord, The Evolution of Free Radicals and Oxidative Stress.Am J Med , 2000, 108 , 652-659).
[708] Experimental Example 3 Protective Effect of Neurons on Hydrogen Peroxide
[709] In order to determine whether the compounds of Formula 1 according to the present invention inhibit neuronal cell damage and necrosis caused by hydrogen peroxide, the following experiment was performed.
[710] The concentration of the test substance was added to 30 μM, except that hydrogen peroxide was added to the final concentration of 30 μM instead of FeSO ₄ in Experimental Example 2, was carried out in the same manner as in Experimental Example 2, the results It is shown in Table 4 below.
[711] Protective effect of nerve cell damage by hydrogen peroxide compoundAddition amount (μM)Inhibition Rate (%) Experimental Example 113096 BMS-18044830-5 BMS-1910953027 Propyl gallate1094 Promethazine597
[712] As shown in the results, the compound of formula 5 (BMS-191095) used as a control shows a 27% protective effect at a concentration of 30 μM, whereas the compound of Experimental Example 11 of the present invention has a high inhibition rate of 96% Seemed.
[713] Therefore, the benzopyran derivatives substituted with the secondary amine containing tetrazole of the present invention show similar results to the protective effect of the antioxidants Propyl gallate and Promethazine. Strongly inhibit neurotoxicity caused by oxidative stress, preventing inflammatory diseases such as arthritis, myocardial infarction, as well as nervous system damage or necrosis caused by hydrogen peroxide such as stroke and dementia, and preventive or chronic tissue damage or S. Miranda et al. The role of oxidative stressin the toxicity induced by amyloid β-peptide in Alzheimer's disease Progress in Neurobiology, 2000, 62 , 633-648; SA Cook, PH 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; JM McCord, The Evolution of Free Radicals and Oxidative Stress.Am J Med, 2000, 108 , 652-659).
[714] Experimental Example 4 Inhibition Effect of Lipid Peroxidation Induced by Iron
[715] In order to determine the effect of inhibiting lipid peroxidation induced by iron, the compounds of Formula 1 of the present invention, the following experiment was performed.
[716] Brains of rats were treated with Krebs buffer (15 mM HEPES, 10 mM glucose, 140 mM NaCl, 3.6 mM KCl, 1.5 mM CaCl ₂ , 1.4 mM KH ₂ PO ₄ , 0.7 mM MgCl ₂ , PH 7.4) After homogenization, the mixture was centrifuged at 12,000 rpm for 10 minutes to use a brain homogenate as a supernatant as a raw material of lipids. FeCl ₂ was added so that the final concentration of the brain homogenate was 400 μM and left at 37 ° C. for 30 minutes to promote oxidation. At this time, 100 μM of test substance was added, and only the solvent was added as a control.
[717] When iron is added to the brain homogenate, oxidation is promoted, and the amount of lipid peroxidation product, malonaldehyde (malonaldehyde, MDA) is increased, and the amount of lipid peroxidation was determined using an MDA quantitative method. The lipid peroxidation inhibitory effect of the test substance was calculated to the extent that the amount of MDA was reduced based on the amount of MDA of the control group.
[718] On the other hand, the MDA quantitative method is generally used to measure the absorbance at 530 nm by reacting the sample with 2-thiobarbituric acid (TBA), but it is not suitable for processing a large volume of samples because of the boiling step. Therefore, in the present invention, N-methyl-2-phenylindole, which is a coloring reagent, was used instead of TBA. In this case, two molecules of N-methyl-2-phenylindole react with each molecule of malonaldehyde (MDA) to form a chromosome, which exhibits a maximum absorbance at 586 nm, and a separate boiling process can be omitted. (Bioxytech Absorbance measurement with LPO-586 Kit). The experimental results are shown in Table 5 below.
[719] Inhibitory Effect of Iron on Lipid Peroxidation compoundInhibition rate of lipid peroxidation effect by iron (%, 100 μM) Example 1090 Example 1191 Example 1787 Example 22108 Example 2494 Example 26101 Example 2883 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
[720] As shown in the above results, the compounds of Examples 10, 11, 22, 24, 26, 34, 57, 70, 71, 83 85 and 108 showed more than 90% inhibitory effect on the lipid peroxidation inhibition by iron. . In addition, the compounds of Examples 11, 17, 32, 54, 59, 60, 61, 70, 71, 81, and 85 have a protective effect on nerve cell damage by oxidative stress induced by iron or copper (Table 3 and Table 3). 4) and simultaneously inhibit lipid lipid peroxidation, which promotes lipid peroxidation, leading to accumulation of oxidation products in neurons, as well as degenerative neurological diseases such as stroke and dementia, as well as inflammatory diseases such as arthritis, myocardial infarction and acute tissue damage. (Chul Lee, Antioxidant ability of caffein and its metabolites based on the study of oxygengen radical absorbing capacity and inhibition of LDL peroxidation. Clinica Chimica Acta, 2000, 295 , 141-154; PE. Chabrier et al FBN 80933, a dual inhibitor of neuronal nitric oxide synthase and lipid peroxidation L A promising neuroprotective strategy.Pro. Natl. Acad Sci USA, 1999, 96 , 10824-10829).
[721] Experimental Example 5 Inhibition Effect of Lipid Peroxidation Induced by Copper
[722] In order to investigate the inhibitory effect on the oxidation of low density lipoprotein (LDL) induced by copper of the compounds of Formula 1, the following experiment was performed.
[723] Human low-density lipoprotein (human LDL, sigma) was dissolved in distilled water at a final concentration of 1 mg / ml and dialyzed for 18 hours in 4 ° C phosphate buffer to remove ethylenediamine tetraacetate (EDTA), with three replacements of buffer. It was performed by. Phosphate buffer was added to the EDTA-free LDL (100 μg LDL protein / ml), CuSO ₄ 10 μM was added as oxidant, and the final concentrations of tocopherols in the test and control were 10 ⁻⁹ , 10 ⁻ , respectively. ⁷ and ^10-5 M. The group without addition of CuSO ₄ was used as a blank test group, and CuSO ₄ was added and a group in which a solvent was added instead of a test material was used as a control. The mixture was incubated at 37 ° C. for 18 hours and the oxidation reaction was terminated by adding 200 μM EDTA at 4 ° C.
[724] In the same manner as in Experiment 4, the amount of lipid peroxidation was determined by the MDA quantitative method performed by increasing the amount of malonaldehyde (Malonaldehyde, MDA), an oxide of LDL, by an oxidation reaction by Cu ⁺² . In the MDA assay, the sample was reacted with 2-thiobarbituric acid (TBA) to measure absorbance at 530 nm. Sigma's 1,1,3,3-tetramethoxypropane was used as a standard. The lipid peroxidation inhibitory effect of the test substance was calculated by calculating the amount of nmol of MDA per mg of protein and reducing the amount of MDA based on the amount of MDA of the control group, and the experimental results are shown in Table 6 below.
[725] Inhibitory Effect of Copper on Lipid PeroxidationInhibition Rate (%) Addition amount (m)Example 11TocopherolProbucol 10 ^-7 27.321.333.7 10 ^-6 54.9 58.7 10 ^-5 63.929.766.7
[726] As shown in the results of Table 6, the compound of Example 11 of the present invention significantly inhibited the concentration of copper-induced lipid peroxidation, more than twice as good at 10 ^-5 M than tocopherol (control) Inhibitory effect was shown, similar to probucol.
[727] Therefore, the benzopyran derivatives substituted with the secondary amine including the tetrazole of the present invention are excellent in inhibiting the lipid peroxidation induced by copper, thereby promoting stroke and dementia caused by accumulation of oxidation products in nerve cells by promoting lipid peroxidation. (Chul Lee, Antioxidant ability of caffein and its metabolites based on the study of oxygen radical absorbing capacity and inhibition, 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; PE. 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).
[728] Experimental Example 6 Inhibitory Effect by Accumulation of Free radicals in Cells Induced by Hydrogen Peroxide
[729] In order to determine the effect of the compounds of formula 1 of the present invention to inhibit the active oxygen in the cell induced by hydrogen peroxide, the following experiment was performed.
[730] In order to measure reactive oxygen species in cells, H ₂ DCFDA (2 ', 7'-dichlorodihydrofluorescein diacetate, Molecular Probes, Eugene, OR, USA) was used. Non-polar H ₂ DCFDA is converted into membrane impermeable H ₂ DCF (2 ', 7'-dichlorodihydrofluorescein) by intracellular esterases through the cell membrane. H ₂ DCF is low fluorescence, intracellular oxygen peroxide, or It is converted into a solid fluorescent DCF (2 ', 7'-dichlorofluorescein) by hydroxy radicals. H ₂ DCFDA 10 mM solution dissolved in DMSO was prepared immediately before use. Rath thoracic aorta smooth muscle cell line (ATCC), a vascular smooth muscle cell, was cultured in 48-well plates using Dulbecco's Modified Eagle's Medium (DMEM) medium containing 10% fetal bovine serum (FBS). It was replaced with a serum-free DMEM and used for the experiment after 24 hours of incubation. Washing and treatment of cell monolayers were carried out in Craps-Ringer buffer (Krebs-Ringer (KR), 99.01 mM NaCl, 4.69 mM KCl, 1.87 mM CaCl ₂ , 1.2 mM MgSO ₄ , 1.03 mM K ₂ HPO ₄ , 25 mM NaHCO). ₃ , 20 mM Hepes, 11.1 mM D-glucose, pH 7.4) was used. The medium of the cell monolayer was removed, 0.2 ml of each test substance was added, pretreated at 37 ° C. for 15 minutes, adjusted to a final concentration of 50 μM, and treated with hydrogen peroxide for 30 minutes. After the solution was removed and washed once, 20 μM of H ₂ DCFDA was added for 30 minutes, and after 2 washes, the degree of oxidation of H ₂ DCFDA was measured by a fluorescence reader (FL600, Biotek Instruments) (485 nm excitation, 530 nm emission), the results are shown in Table 7 below.
[731] Inhibitory Effect on Intracellular Oxygen Accumulation compoundAddition amount (μM)Inhibition Rate (%) Experimental Example 1130124108236 Propyl gallate301081094357
[732] When hydrogen peroxide was added to A7r5 cells, DCF fluorescence was increased due to cell damage caused by free radicals, and the increased DCF fluorescence due to hydrogen peroxide was inhibited in a concentration-dependent manner by pretreating the compound of Experimental Example 11 of the present invention. Most preferably completely inhibited at a concentration of 30 μM. Therefore, the compound of Experimental Example 11 of the present invention has a strong effect of inhibiting intracellular free radicals induced by hydrogen peroxide, thereby promoting degenerative nervous system such as stroke, dementia, etc., which promotes lipid peroxidation and causes accumulation of oxidizing substances in neurons. It can be useful as a preventive or therapeutic agent for diseases, arthritis, inflammatory diseases such as myocardial infarction, myocardial infarction and acute tissue damage (GJ Gross, JR Kersten, DC Warltier Mechanism of post ischemic contractile dysfunction Ann Thoar Sur 68, 1999, 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, JAJoseph, Neurobehavioral aspects of antioxidants in aging Int J. Neuroscience, 2000, 18 , 267-381).
[733] Experimental Example 7 Protective Effect of Brain Injury by Cerebral Ischemia-Reperfusion
[734] In order to determine the effect of the compounds of formula 1 according to the present invention to protect brain damage caused by cerebral ischemia-reperfusion, the following experiment was performed.
[735] Male rats (Sprague-Dawley Rat, 350-450 g, three meats) were injected by injecting pentovalbital sodium 40 mg / Kg, followed by insertion of a tubule (PE-19 tubing) into the femoral vein and artery and exposing the left carotid artery. I was. Five minutes prior to surgery, 20 μg of heparin sulfate was injected intraperitoneally. A blood pressure measurement device was inserted into the femoral artery to continuously measure arterial pressure. About 10 ml of blood was withdrawn into the femoral vein and the blood pressure dropped to 30 mmHg. If the blood pressure does not fall below 100 mmHg until the blood collection is about 7 ml, it may be determined that the sympathetic tone is too high. In this case, even if the blood pressure can not drop to 30 mmHg or successful, the mortality of the rat after surgery is high, so it was excluded from the experiment.
[736] Ischemia was caused by closing the left carotid artery for 20 minutes with an aneurysm clamp while maintaining blood pressure at 30 mmHg, and reperfusion was performed with drawn blood and 5 ml of 0.84% aqueous bicarbonate saline solution. During the ischemia, the rats were kept at a constant temperature of 37.5 ° C using a thermal blanket and incandescent lamps. Transferred to the thread. The animal observation room was kept at a temperature of 27 ° C., 60% humidity and light cycle (12-12 hours).
[737] 24 hours after the operation, the rats were sacrificed with the head and the brains were removed within 3 minutes. The extracted brain was cut at 2 mm intervals using a brain matrix on ice to obtain 6 coronal sections. The cut pieces were stained with 2% 2,3,5-triphenyltetrazolium chloride solution at 37 ° C. for 30 minutes. The stained sections were photographed, developed, and printed, and then expressed as a percentage of necrosis area relative to the area of the entire brain using an image analyzer.
[738] On the other hand, the test substance was injected intraperitoneally four times at a dose of 30 mg / Kg, 30 minutes before surgery and 2, 4, and 16 hours after carotid artery occlusion, respectively. In the control group, only a vehicle was used instead of the test substance. In the comparative group, 5R, 10 (S)-(+)-5-, which is a noncompetitive N-methyl-D-aspartate antagonist, was used. Methyl-10,11-dihydro-5H-dibenzo- [a, d] cyclohepten-5,10-imine hydrogen maleate (MK 801) was used.
[739] The effect of protecting the brain injury due to cerebral ischemia-reperfusion of the test substance was calculated by the reduction of the necrosis area based on the% necrosis area of the brain in the control group, and the results are shown in Table 8 below.
[740] Cerebral Injury Protection Effect by Cerebral Ischemia-Reperfusion Test substanceDose (mg / Kg)n numberInfarct degree Average (%)Reduction Rate (%) Control 1340.3 ± 5.5Comparative bacteria (MK80)301129.8 ± 4.925.9 Compound of Example 11301421.5 ± 2.646.3
[741] As shown in Table 8, infarct volume (infarct volume) was 29.8% in the MK 801 30 mg / Kg treated group compared to the control group was reduced by 24.8% compared to the control group.
[742] On the other hand, when the same amount of the compound of Example 11 of the present invention was treated with an infarct region of 21.5%, the infarct region was reduced by 46.3% compared to the control group, thereby protecting brain injury by cerebral ischemia-reperfusion than the control substance MK 801. The effect was confirmed to be 2 times better.
[743] In addition, in the MK 801 treatment group compared to the side effects such as a decrease in motility of the rat was observed, the administration of the compound of Example 11 of the present invention did not show any behavioral changes, including motility. These results confirmed that the compounds of the present invention, as shown in Table 2, has a weak vascular relaxation action (IC ₅₀ > 30 μM), which can significantly reduce the side effects caused by perfusion decrease during ischemia-reperfusion.
[744] Therefore, the benzopyran derivatives substituted with secondary amines including the tetrazole of the present invention are excellent in protecting brain damage caused by cerebral ischemia-reperfusion, and thus can be usefully used in diseases caused by brain damage such as stroke and dementia. (EV Golanov, JD Christensen, DJ Reis, Role of potassium channels in the central neurogenic neuroprotection elicited by cerebellar stimulation in rat. Brain Research, 1999, 842 , 496-500)
[745] Experimental Example 8 Protective Effects of Neonatal Rats on Ischemic-hypoxic Brain Injury
[746] In order to investigate the effects of the compounds of Formula 1 of the present invention on the protection of ischemic-hypoxic brain injury and hypoxic brain injury in the neonatal white paper, experiments were performed using magnetic resonance spectrum (MRS) as follows. .
[747] The protective effect of hypoxic brain injury in vivo was determined using a study showing that there was a significant correlation between histologic findings and changes in magnetic resonance spectroscopy in the ischemic-hypoxia model of neonatal white paper [Van der A Toorn et al. Magnetic Resonance in Medicine , 1996, 36 , 914-922. When brain cells are damaged by ischemia, lipid concentrations increase in the magnetic resonance spectrum due to the destruction of brain cell membranes, including the blood-brain barrier, and there is a correlation between increased lipid concentrations and apoptosis. [A. Bizzi et al., Magnetic Resonance Imaging , 1996, 14 , 581-592. Therefore, Lipid / NAA and Lipid / Cr values compared to lipids and N-acetylaspartate (NAA) and creatine (Cr), which are markers for neurons, were used for brain injury caused by ischemia. Correlations with morphological changes and apoptosis are known.
[748] In the ischemic-hypoxic and hypoxic models of neonatal rats weighing 10-15 g of body weight, the left carotid artery was ligated to induce unilateral ischemia for 3 hours, followed by intraperitoneal administration of the drug, and 1 hour after drug administration. Hypoxia was induced for 2 hours. The left eye with ligation of the carotid artery was set as an ischemic-hypoxic model, and the non-ligation right eye with a hypoxic model, and hydrogen magnetic resonance spectroscopy was obtained immediately before histologic examination on day 1 after injury. Lipid / Cr ratio was measured, and Morphologic score was also calculated by visual inspection of survival and cerebral infarct size. The results are shown in Table 9 below.
[749] Protective effect against hypoxic brain injuryControlExample 11 (50 mg / Kg) Ischemic to hypoxicHypoxicIschemic to hypoxicHypoxic Lip / NAA11.554.635.431.69 Lip / Cr13.904.115.161.55 Survival rate13/26 (50%)19/24 (79%) Morpholgicscore3.01.4
[750] As can be seen from the results of Table 9, the results of hydrogen magnetic resonance spectroscopy in an ischemic-hypoxic or hypoxic neoplastic model showed that the compounds of Example 11 of the present invention with respect to the ratio of Lip / NAA and Lip / Cr Was shown to be 2 times lower than the ischemic-hypoxia model of the control group and 3 times or more in the hypoxic model, thereby confirming the brain protective effect against brain injury. In the comparison of survival rate, the compound of Example 11 was significantly higher than that of the control group of 50% (79%), and the morphological score determined by visual inspection of cerebral infarction was 2 times lower. In addition, the size of cerebral infarction was also significantly reduced.
[751] Therefore, benzopyran derivatives substituted with secondary amines including tetrazole of the present invention can be usefully used as a preventive and therapeutic agent for neonatal hypoxia by confirming the brain protective effect against ischemic-hypoxia and hypoxia induced brain damage. (CC Huang et al Measurement of the urinary lactate: 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)
[752] Experimental Example 9 Neuronal Protective Effects on Axotomy
[753] In order to determine the protective effect of the neurons against the cell damage that occurs after the optic nerve cutting compound of the formula 1, the following experiment was carried out.
[754] The test substance was dissolved in DMSO to prepare a 100 mM stock solution, diluted to a concentration of 20 μM with physiological saline, and 10 μl of the standard solution was injected into the eye.
[755] Adult rats were anesthetized with chloral hydrate (400 mg / Kg), and the optic nerve was exposed through the conjunctiva, and 0.5 mm and 3 mm corresponding sites were cut from the eye. Alternatively, a skin incision was made through the upper eyelid, and a part of the tear glands was removed, and the superior rectus muscle was incised in the direction of muscle progression over the eye to expose the optic nerve, and cut about 5 mm from the eye. After avoiding damage of the retinal blood vessels that supply blood to the retina, the retinal vessel status was confirmed by a fundscope. One-half of the test groups received fluorogold (Fluorochrome Inc. 5% in PBS (phosphate buffered solution)) as retrograde after optic nerve cleavage, and observed the ganglion cell death after cutting. Eyes were removed at 3 days, 1 week, 2 weeks, 4 weeks, 2 months, 4 months, and 6 months, and then the retinas were separated and examined by transmission electron microscopy. It was observed by chemical staining or by a fluorescence microscope with a filter of 530 to 560 nm. The experimental results are shown in Table 10 .
[756] Protective effect of nerve cell damage on optic nerve cuttingGanglion cell survival rate (%) Control22% Experimental Example 11 (20 μM)43%
[757] As can be seen from the results of Table 10, the survival rate of ganglion cells was significantly increased to 43% when 20 μM of the compound of Experimental Example 11 was administered, compared to 22% of the retinal ganglion cells in the control group after optic nerve cutting.
[758] Accordingly, the benzopyran derivatives substituted with secondary amines comprising tetrazole of the present invention can be used in the prevention and treatment of glaucoma caused by ganglion cell damage by identifying the lingual department that protects the death of retinal ganglion cells against optic nerve cutting. P. Hardy et al. Oxidant, nitric oxide and prostanoids in the developing ocular vasculature: a basis for ischemic retinopathy Car diovascular Research, 2000, 47 , 489-509.
[759] Experimental Example 10 Improvement of Neuroconduction Speed in Diabetic Rats
[760] In order to determine the effect of the compounds of the formula (1) of the present invention to improve the damaged nerve conduction rate in diabetic rats, the following experiment was performed.
[761] Diabetes was induced by injecting streptozotocin (65 mg / kg) into the abdominal cavity of rats, and the test substance was dissolved in 2 ml of a mixed solution of physiological saline: ethanol: twin 80 (8: 1: 1), 1 day 1 The dose was administered orally. The stimulus-induced activating voltage causes the diabetic rat to be anesthetized with pentotal, exposing the spinal nerve, plugging the two stimulating electrodes into the proximal and distal ends of the nerve, and measuring electrodes at the hind limbs. Measured by inserting into the toe muscle. The motor Nerve Conduction Velocity (MNCV) over the distance between the two stimulation electrodes was calculated as the difference in latency from each stimulus to the active voltage. The recovery rate of the nerve conduction rate of the compound of the present invention was compared using a group administered with 100 mg / Kg of lipoic acid (lipoic acid) known as a nerve conduction rate improving agent damaged by diabetes. The recovery rate of the nerve conduction rate damaged by diabetes was calculated as in Equation 1 below, the results are shown in Table 11 below.
[762] Recovery rate of nerve conduction (%) = (MNCV of drug administration group-MNCV of diabetes group) / (of normal group)
[763] MNCV-MNCV of the diabetic) X 100
[764] Restoration Effect of Nerve Conductivity in Diabetic RatsMNCV (msec)Recovery rate (%) Normal59.78100 Diabetes49.03- Example 11 (50 mg / Kg)53.9545.8
[765] According to the results of Table 11, the diabetic group has a significantly reduced nerve conduction rate compared to the normal group, while the nerve conduction rate delayed by diabetes when the compound of Example 11 is administered at 50 mg / Kg and Significantly recovered.
[766] From the above results, the benzopyran derivatives substituted with the secondary amine containing the tetrazole of the present invention can be used as a prophylactic or therapeutic agent for diabetic neuropathy or diabetic peripheral neuropathy by improving nerve conduction rate in diabetic mice ( K. Naka et al. Effects of cilostazol on development of experimental diabetic neuropathy: functional and structural studies, and Na ⁺ -K ⁺ -ATPase acidity in peripheral nerve in rats with streptozocin-induced diabetes.Diabetes Res. And Clinical Practice, 1995, 30 , 153 to 162).
[767] Experimental Example 11 Effect of Inhibiting NO Production
[768] In order to investigate the inhibitory effect of the compounds of Formula 1 according to the present invention on nitric oxide (NO), the following experiment was performed.
[769] Using a RPMI1640 medium containing 10% FBS (fetal bovine serum), RAW264.7 cells (American Type Culture Collection, USA), a murine macrophage cell line, were maintained in a 5% CO ₂ incubator at 37 ° C. I was. The concentration of the RAW264.7 cells was adjusted to 5 × 10 ⁵ cells / ml using RPMI1640 medium containing 0.5% FBS, and inoculated (5 × 10 ⁴ cells) in a 96 well plate to 20 in a CO ₂ incubator. Incubated for hours. Thereafter, the medium was removed, and the medium containing the test substance was added to 30 M and pretreated for 1 hour. At this time, the test substance was dissolved in DMSO and diluted to each concentration using a medium, and the concentration of DMSO was 0.1% or less so that DMSO contained in each well did not affect the production of nitrogen monoxide in RAW264.7 cells. It was set as.
[770] After 1 hour of pretreatment was completed, the cells were activated by adding lipopolysaccharide (Lipopolysaccharide, E. coli serotype 055: B5) to a final concentration of 1 μg / ml and incubated for 24 hours in a CO ₂ incubator. NO was produced by this reaction, and NO liberated in the medium was quantified using a Greis reagent in the form of nitrite ions (NO ₂ ⁻ ). As a control, one treated with the same amount of vehicle was used instead of the test drug. Investigations using the nitrite standard showed that the test drug itself did not interfere with the quantification of NO.
[771] The NO production inhibitory effect of the test substance was calculated to the extent that the amount of NO was reduced based on the amount of NO increased by LPS in the control group. The results are shown in Table 12 below.
[772] NO production inhibitory effect compoundAddition amount (μM)% Inhibition rate Example 113027 Example 293079 Example 453075 Example 473062 Example 513096 Example 533096 Example 583076 Example 603086 Example 683064 Example 703075
[773] As can be seen in Table 12, the benzopyran derivatives substituted with secondary amines including tetrazole of the present invention inhibited the production of NO by endotoxins such as LPS. Preferably, the compounds of Examples 29, 45, 58, 60 and 70 showed a high inhibition rate of at least 75% at a concentration of 30 μM, most preferably the compounds of Examples 51 and 53 were at least 90% at the same concentration Inhibition rate was shown.
[774] Therefore, it was confirmed that benzopyran derivatives substituted with secondary amines including tetrazole of the present invention strongly inhibited NO production, and inflammatory diseases such as arthritis, as well as neurological diseases such as stroke and dementia caused by the high production of NO. , JF Kerwin Jr. Nitric Oxide: A New Paradigm for second Messengers J. Med. Chem 1995, 3 8 , 4343-4362).
[775] Experimental Example 12 Cardioprotective Effect on the Isolated Ischemic Heart of Rats
[776] In order to determine the effect of the compounds of Formula 1 according to the present invention to protect the ischemic heart in the extraction heart, the anti-ischemic effect on the rat was investigated through the extraction heart experiment as follows.
[777] Male rats (300-450 g, Korea Research Institute of Chemical Technology) were anesthetized with intraperitoneal injection of 100 mg / kg of phenobalbital sodium salt (Sodium pentobarbital), and heparin 1000 U / kg was administered intravenously and the heart was extracted. It was. Specifically, the cannula (PE 240) is inserted into the trachea, and artificial respiration is performed using a rodent ventilator. In this state, the aortic cannula is inserted into the aorta, and the heart is extracted under retrograde perfusion. (Langendorff Apparatus) quickly hung and removed unnecessary tissues attached to the heart, and then modified Krebs-Henseleit bicarbonate buffer (composed <mM) saturated with 95% O ₂ /5% CO ₂ under 85 mmHg of constant pressure perfusion. / L>: 116 NaCl, 4.7 KCl, 1.1 MgSO ₄ , 1.17 KH ₂ PO ₄ , 24.9 NaHCO ₃ , 2.52 CaCl ₂ , 8.32 Glucose, 2.0 Pyruvate), mixed with ethanol and distilled water (1: 1 v / v) A metal cannula connected with a latex balloon was inserted into the left ventricle through the pulmonary vein, and the left ventricular pressure delivered to the balloon was treated with an isovolumetric expander (Plugsys bridge amplifier) through a pressure transducer. group Recorded on a roc system (Linearcorder mark 8 WR 3500) After the heart had stabilized for 15 minutes the left ventricular enddiastolic pressure was 5 mmHg and the balloon volume was maintained for the entire experimental period.
[778] Baseline cardiac contractile function, heart rate (HR) and coronary flow (CF) were measured. Left ventricular developed pressure (LVDP), an indicator of cardiac contractile function, is the difference between left ventricular peak systolic pressure (LVSP) and left ventricular end diastolic ptrssure (LVEDP). Calculated. Unlike the in vivo heart, the heart rate-pressure product (Double product RPP), an important indicator of cardiac performance indirectly in the Langendorff heart, where cardiac output cannot be measured. rate-pressure product) was calculated by multiplying heart rate (HR) by left ventricular ventricular pressure (LVDP). Total coronary blood flow was measured with an electromagnetic flowmeter using a coronary flow probe (1.0 mm diameter) fixed on an aortic cannula. The temperature of the heart was kept constant by soaking the heart in a physiological fluid at 37 ° C. continuously supplied with 95% O ₂ /5% CO ₂ over the entire period of the experiment. After stabilization, the heart was perfused for 10 minutes with a solvent (0.04% dimethylsulfoxide) or a solution containing a certain concentration of the compound according to the present invention and a control drug, followed by cardiac contractile function, heart rate (HR) and coronary blood flow (CF). After repeated measurements, perfusion solution was completely blocked to induce global ischemia for 30 minutes. During the global ischemia, left ventricular diastolic pressure (LVEDP) until the 5 mmHg rise (min) was calculated as time to contracture (TTC). Each indicator (LVDP, HR, and CF) was then repeatedly measured after perfusion was completely reperfused for 30 minutes. After 30 minutes of reperfusion, lactate dehydrogenase (LDH) concentration in total reperfusion was measured using a kit and used as an index of ischemic myocardial injury. The results are shown in Table 13 below.
[779] Cardioprotective Effect on Extracted Ischemic Heart in Rats Test drugCardioprotective effect on rat isolated ischemic heart (10 μM) LVDP × HR (%)EDP (mmHg)TTC (minutes)LDH (u / g) menstruum23.043.420.329.9 BMS-18044867.616.527.817.2 Example 146.829.324.815.2 Example 1124.847.619.916.5 Example 3264.717.027.915.7 Example 6152.723.020.022.4 Example 7031.937.022.018.4
[780] As shown in Table 13, in the extraction ischemia heart experiment using the extraction heart of the rat, in the solvent-administered group, the product of two indices that better reflect the contractile function of the heart in consideration of the LV ventricular pressure (LVDP) and the heart rate ( The double product parameter (LVDP × HR) was significantly lowered to 23.0% before drug administration after reperfusion, and the reperfusion diastolic pressure (EDP), another indicator of anti-ischemic action (heart protection), was significant from 5 mmHg to 43.4 mmHg. Increased, and contraction induction time (TTC) was 20.3 minutes. The free amount upon reperfusion of lactate dehydrogenase (LDH), an indicator of cell damage, was 29.9 u / g.
[781] In addition, the administration group of BMS-180448, a known compound, significantly increased myocardial contractile function (LVDP × HR) after reperfusion to 67.6% before drug administration and the diastolic end pressure (EDP) was 16.5 mmHg, which was significantly higher than that of the solvent group. TTC was extended to 27.8 minutes, and the LDH release amount at reperfusion decreased to 17.2 u / g, showing a clear protective effect of ischemic heart significantly compared to the solvent group at all indicators.
[782] On the other hand, the benzopyran derivatives substituted with secondary amines including tetrazole of the present invention are similar to the known compounds BMS-180448 as a result of comparing the cardiac protective effect parameters of cardiac contractile function, EDP, TTC, and LDH. Or more. Specifically, most preferably, the compound of Example 32 has a 20-fold lower vascular relaxation activity than that of BMS-180448 (IC ₅₀ > 30 × HM), but myocardial contraction function (LVDP × HR) is 64.7% before the drug administration, and EDP. Was 17.0 mmHg, TTC was 27.9 minutes, and LDH glass was 15.7 u / g at reperfusion, showing excellent protective effect in all indicators, indicating that cardiac selectivity against vascular relaxation was much better than that of BMS-180448. In addition, the compounds of Examples 1, 11, and 32 significantly reduced the free amount of LDH, suggesting a protective effect of cell damage by ischemia-reperfusion.
[783] Therefore, the benzopyran derivatives substituted with secondary amines including the tetrazole of the present invention showed superior or better effects than the known compounds BMS-180448 in the cardioprotective effect on ischemic heart, more preferably. Unlike the BMS-180448, the vasorelaxation effect is remarkably weak, so that the cardiac selective anti-ischemic effect is excellent, and thus it can be used as a cardioprotective agent for the prevention and treatment of myocardial infarction, heart failure and angina pectoris (T. Miura et al. Roles of Mitochondrial ATP-sensitive K Channels and PKC in Anti-Infarct Tolerance afforded by Adenosine A1 receptor Activation.J Am Coll Cardiol , 1999, 35 , 238-45; DJ Chambers, DJ Hearse Developments in Cardioprotection: "Polarized" Arrest as an Alternative to "Depolarized" Arrest Ann. Thorc. Surg, 1999, 68 , 1960-6).
[784] Experimental Example 13 Inhibition of Tubular Formation in HUVEC Cells
[785] In order to measure the neovascularization inhibitory activity of the test substances at the cellular stage, the following experiment was conducted.
[786] Human Umbilical Vein Endothelial Cells (HUVEC), the vascular endothelial cells of the human umbilical cord, are cultured to induce tube formation of capillary-like structures on the Matrigel, and the effect of each compound on the formation of the solvent Inhibition of neovascularization was indirectly confirmed in vivo ( invitro ) by comparison with the control group treated only. The results are shown in Table 14 below.
[787] Inhibitory effect on tube formation in HUVEC cellsTube forming Control10 μM100 μM Example 2+++ Example 28+/-+ -No effect, +/-; Minor inhibitory effect +; Moderate inhibitory effect, ++; Strong inhibitory effect
[788] As shown in Table 14, the compound of Example 2 of the present invention was confirmed that the inhibitory effect on the formation of the tube formation at a concentration of 10 μM and showed a strong inhibitory effect of increasing the tube formation concentration-dependently at a concentration of 100 μM. In addition, the compound of Example 28 also exhibited an inhibitory effect on the formation of angiogenesis at a concentration of 100 μM showed an neovascularization inhibitory effect.
[789] Therefore, the benzopyran derivatives substituted with secondary amines including tetrazole of the present invention have an excellent effect of inhibiting the formation of neovascularization, thereby causing rheumatoid arthritis, psoriasis, AIDS complications, cancer, and diabetes. It can be useful for the treatment of various diseases of retinopathy (PA Burke, SJ DeNardo Antiangiogenic agents and their promising potential in combined therapy. Critical Reviews in Oncology / Hematology, 2001, 39 , 155-171)
[790] Experimental Example 14 Oral Acute Toxicity in Rats
[791] In order to determine the acute toxicity of the compound of Formula 1 of the present invention, the following experiment was performed.
[792] Six-week-old SPF SD rats were used and two animals per group were used in Examples 1, 7, 11, 17, 22, 24, 26, 28, 30, 32, 34, 42, 52, Compounds obtained from 54, 55, 56, 57, 59, 60, 61, 70, 75, 77, 79, 81, 83, 85, and 89 were suspended in 0.5% methylcellulose solution to give 1 g / kg / 15 ml Single oral doses were administered. After administration of the test substance, mortality, clinical symptoms, and changes in body weight were observed. Hematological and hematological examinations were performed. Necropsy was performed to observe abdominal and thoracic organ abnormalities. As a result, there were no clinical symptoms or deaths in all animals treated with the test substance, and no toxicity change was observed in weight change, blood test, blood biochemistry test, autopsy findings, etc. As a result, all of the tested compounds did not show toxic changes up to 2 g / kg in rats, and the minimum lethal dose (LD ₅₀ ) was determined to be a safe substance of 2 g / kg or more.
[793] As described above, the benzopyran derivatives substituted with secondary amines containing tetrazole represented by the general formula (1) according to the present invention are reacted with a secondary amine compound including an epoxide compound and a heterocycle in the presence of a metal salt in a solvent. Compounds of the present invention show a protective effect against ischemic heart, ischemic brain and retinal ganglion cells without reducing blood pressure due to weak vascular relaxation, prevent nerve cell damage caused by oxidative stress and inhibit lipid peroxidation In addition, it exhibits various pharmacological effects by showing the effect of inhibiting the formation of neovascularization. Accordingly, pharmaceutical compositions containing benzopyran derivatives substituted with secondary amines, including tetrazole of the present invention, stereoisomers thereof and pharmaceutically acceptable salts thereof as active ingredients include neonatal hypoxia, glaucoma, diabetic neurosis and brain. Neuronal cell protective agents for the treatment and prevention of trauma; Brain injury protectors for the prevention and treatment of strokes; Antioxidants for the prevention and treatment of degenerative neurological diseases such as aging, dementia and atherosclerosis; NO production inhibitors; Cardioprotectants for the prevention and treatment of heart attack, myocardial infarction, heart failure and angina pectoris; Angiogenesis inhibitors for the prevention and treatment of cancer, diabetic retinopathy; It can be useful for organs for storage of kidneys, heart, tissue, etc. and for organ protection in cardiovascular surgery.

权利要求:
Claims (16)
[1" claim-type="Currently amended] Benzopyran derivatives substituted with secondary amines including tetrazole represented by the following formula (1), stereoisomers thereof or pharmaceutically acceptable salts thereof.
Formula 1

(Wherein
R_OneIs H, F, Cl, Br, CF₃, NO₂, CN, OR^a,, COOR^a, NH₂, NHS (O)_lR^a,Or S (O)_lR^aWhere R^aH, C_One-C₄Is linear or pulverized alkyl or aryl of l is an integer of 0 to 2;
R ₂ is CH ₂ OR ^a , or Is,
Wherein R ^a is as defined above, R ^b and R ^c are each independently C ₁ -C ₄ straight or branched alkyl, Z is C ₁ -C ₅ straight or branched alkyl;
R ₃ is OH, F, Cl, Br, ONO ₂ or Wherein R ^a is as defined above;
R ₄ and R ₅ are each independently H, F, Cl, Br, C ₁ to C ₃ straight or branched alkyl, OR ^a , CF ₃ , OCF ₃ , NO ₂ , , , Or SO ₃ R ^a , wherein R ^a is as defined above;
R ₆ is hydrogen, C ₁ -C ₃ straight or pulverized alkyl;
n and m are each independently an integer of 0 to 2;
* Represents chiral carbon.)
[2" claim-type="Currently amended] The compound of claim 1, wherein R ₁ is NO ₂ , CN, or NH ₂ ; R ₂ is or Wherein R ^b and R ^c are each independently C ₁ to C ₃ straight or branched alkyl, and Z is C ₂ to C ₃ straight or branched alkyl; R ₃ is OH or Wherein R ^a is C ₁ to C ₃ linear or pulverized alkyl; R ₄ and R ₅ are each independently H, F, Cl, C ₁ to C ₃ linear or pulverized alkyl, OR ^a , CF ₃ , OCF ₃ or NO ₂ , wherein R ^a is C ₁ to C ₃ Straight chain or crushed alkyl; R ⁶ is C ₁ -C ₃ straight or branched alkyl; n and m are each independently an integer of 0 to 1, benzopyran derivatives, stereoisomers thereof or pharmaceutically acceptable salts thereof.
[3" claim-type="Currently amended] The compound of claim 1 wherein
1) (2S, 3S, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Oxy-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-hydro Oxy-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-fluorophenyl) -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-fluorophenyl) -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-dihydro-2H-1-benzopyran;
12) (2S, 3S, 4R) -6-nitro-4- [N- (4-chlorophenyl) -N- (1-methyl-1H-tetrazol-5-ylmethyl) amino] -3-hydro Oxy-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-fluorophenyl) -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-di Methoxymethyl-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-hydro Oxy-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-methylphenyl) -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-methylphenyl) -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-hydro Oxy-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-methylphenyl) -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-methylphenyl) -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-hydro Oxy-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-trifluoromethoxyphenyl) -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-trifluoromethoxyphenyl) -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-trifluoromethylphenyl) -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-trifluoromethylphenyl) -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-hydro Oxy-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-fluorophenyl) -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-fluorophenyl) -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-hydro Oxy-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-methylphenyl) -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-methylphenyl) -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-dimethylphenyl) -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-dimethylphenyl) -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-dimethylphenyl) -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-dimethylphenyl) -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-dimethylphenyl) -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-dimethylphenyl) -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-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-hydro Oxy-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-di Methoxymethyl-3,4-dihydro-2H-1-benzopyran;
56) (2S, 3R, 4S) -6-Amino-4- [N- (4-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Oxy-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-methoxycarbonylphenyl) -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-methoxycarbonylphenyl) -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 Oxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
62) (2S, 3R, 4S) -6-nitro-4- [N-[(2-methoxy-4-methoxycarbonyl) phenyl] -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-methoxycarbonylphenyl) -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-hydro Oxy-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-methoxycarbonylphenyl) -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-methoxycarbonylphenyl) -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-methylphenyl) -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-methylphenyl) -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-trimethylphenyl) -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-trimethylphenyl) -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-trifluoromethylphenyl) -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-trifluoromethylphenyl) -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-trifluoromethylphenyl) -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-trifluoromethylphenyl) -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-trifluoromethylphenyl) -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-trifluoromethylphenyl) -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-trifluoromethoxyphenyl) -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-trifluoromethoxyphenyl) -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-trifluoromethoxyphenyl) -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-trifluoromethoxyphenyl) -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-trifluoromethoxyphenyl) -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-trifluoromethoxyphenyl) -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-acet Methoxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
87) (2S, 3S, 4R) -6-acetamino-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-acet Methoxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
88) (2S, 3S, 4R) -6-acetamino-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydro Oxy-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-hydro Oxy-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-hydro Oxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran;
92) (2S, 3R, 4S) -6-Bromo-4- [N- (4-fluorophenyl) -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-fluorophenyl) -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, 3S, 4R) -6-methanesulfonyloxy-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-methanesulfonyloxy-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 Oxy-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-fluorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3- Hydroxy-2-methyl-2-methoxymethyl-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 Oxy-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-hydro Oxy-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-hydro Oxy-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-hydro Oxy-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-hydro Oxy-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-hydro Oxy-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-hydro Oxy-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-hydro Oxy-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-hydro Oxy-2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran; or
118) (2R, 3S, 4S) -6-amino-4- [N- (4-chlorophenyl) -N- (2-methyl-2H-tetrazol-5-ylmethyl) amino] -3-hydroxy Benzopyran derivatives, their stereoisomers or pharmaceutically acceptable salts thereof, characterized in that they are 2-methyl-2-dimethoxymethyl-3,4-dihydro-2H-1-benzopyran.
[4" claim-type="Currently amended] A method for preparing the benzopyran derivative according to claim 1, wherein the compound of formula 1a is prepared by reacting an epoxide compound of formula 2 with a secondary amine compound comprising a heterocycle of formula 3 in the presence of a metal salt.
Scheme 1

(Wherein R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , n, m, and * are as defined in claim 1.)
[5" claim-type="Currently amended] The method according to claim 4, further comprising the step of preparing the compound of Formula 1 by introducing various substituents into R ³ by the compound of Formula 1a.
Scheme 2

(Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , n, m, and * are as defined in claim 1.)
[6" claim-type="Currently amended] The method of claim 4, wherein the metal salt is selected from the group consisting of Mg (ClO ₄ ) ₂ , CoCl ₂ , LiClO ₄ , NaClO ₄ , CaCl ₂ , ZnCl ₂ , LiBF ₄ and Zn (Tf) ₂ . .
[7" claim-type="Currently amended] The method for preparing a benzopyran derivative according to claim 4, wherein the compound of Formula 1c is prepared by reducing the compound of Formula 1c, wherein R ₁ is a derivative fixed with NO ₂ in a compound of Formula 1a in a reaction solvent.
Scheme 6

Wherein R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , n and m are as defined in claim 1.
[8" claim-type="Currently amended] The method of claim 7, wherein the reduction is a metal catalyst selected from platinum, palladium attached charcoal (Pd / C; palladium on carbon) or Raney-nickel; CuSO ₄ ; Cu (OAc) ₂ ; CoCl ₂ ; SnCl ₂ ; or NiCl _{2 in} the presence of a reducing method using a reducing agent of NaBH ₄ .
[9" claim-type="Currently amended] The process according to claim 7, wherein the reaction solvent is methanol, alcohols such as ethanol and ethyl acetate.
[10" claim-type="Currently amended] Pharmaceutical protection for neuronal cells for the prevention and treatment of neonatal hypoxia, glaucoma, diabetic neuropathy, head trauma, spinal cord injury, containing the benzopyran derivative of claim 1, its stereoisomer or pharmaceutically acceptable salt thereof as an active ingredient. Composition.
[11" claim-type="Currently amended] Claim 1 benzopyran derivatives, stereoisomers thereof or pharmaceutically acceptable salts thereof containing as an active ingredient, a brain composition for the protection of brain damage for the prevention and treatment of stroke.
[12" claim-type="Currently amended] A benzopyran derivative according to claim 1, a stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient, anti-aging pharmaceutical composition for the prevention and treatment of degenerative neurological diseases, including dementia and atherosclerosis.
[13" claim-type="Currently amended] A pharmaceutical composition for inhibiting NO production for the prevention and treatment of arthritis, arteriosclerosis, myocardial infarction, stroke, and dementia, comprising the benzopyran derivative of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
[14" claim-type="Currently amended] A benzopyran derivative of claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as an active ingredient, heart protection pharmaceutical composition for the prevention and treatment of myocardial infarction, heart attack, angina pectoris, congestive heart failure.
[15" claim-type="Currently amended] A benzopyran derivative according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, the pharmaceutical composition for inhibiting neovascular production for the prevention and treatment of cancer and diabetic retinopathy.
[16" claim-type="Currently amended] A benzopyran derivative according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, the organ for the storage of the heart, kidneys, liver and tissues, and a pharmaceutical composition for long-term protection during cardiovascular surgery.

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同族专利:

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公开号 | 公开日

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EP1499610A4|2006-05-24|

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CA2481707C|2010-09-28|

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KR100526119B1|2005-11-08|

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AT421513T|2009-02-15|

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MXPA04009747A|2004-12-13|

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BR0309239A|2005-02-15|

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WO2003084464A3|2003-11-27|

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AU2003218824A1|2003-10-20|

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DE60325956D1|2009-03-12|

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US20060035948A1|2006-02-16|

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JP2005529863A|2005-10-06|

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PT1499610E|2009-04-29|

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RU2004132869A|2005-06-10|

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HK1074048A1|2010-03-26|

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ES2318118T3|2009-05-01|

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RS27803A|2007-02-05|

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CA2481707A1|2003-10-16|

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AU2003218824A8|2003-10-20|

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EP1499610B1|2009-01-21|

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AR039283A1|2005-02-16|

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RS50905B|2010-08-31|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2002-04-10|Priority to KR1020020019460

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2002-04-10|Priority to KR20020019460

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2003-04-10|Application filed by 동부한농화학 주식회사

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2003-10-17|Publication of KR20030081149A

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2005-11-08|Application granted

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2005-11-08|Publication of KR100526119B1

优先权:

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申请号 | 申请日 | 专利标题

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KR1020020019460|2002-04-10|

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KR20020019460|2002-04-10|