Benzopyranyl guanidine derivatives, process for preparation thereof, and pharmaceutical compositions containing them

The present invention relates to novel benzopyranyl guanidine derivatives of the formula 1, process for preparation therof and pharmaceutical use of the benzopyranyl guanidine derivatives. The benzopyranyl guanidine derivatives of the present invention can be used for protecting heart, neuronal cell or brain damage, preserving organs, and also the benzopyranyl guanidine derivatives are pharmacologically useful for inhibiting NO generation, and for suppressing lipid peroxidation, angiogenesis or restenosis. ##STR1## Wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, n and * are each defined in specification.

BACKGROUND OF THE INVENTION
 1. Field of the Invention
 The present invention relates to novel benzopyranyl guanidine derivatives
 of formula 1. IL also relates to process for preparing the novel compounds
 and pharmaceutical formulations comprising one or more of the compounds as
 an active ingredient.
 The present invention also relates to pharmaceutical use of the
 benzopyranyl guanidine derivatives. In particular, the present invention
 is pharmacologically useful in the protection of heart, neurconsonal cell
 or brain injury, or preserving organs, and also pharmacologically useful
 for inhibition of NO generation, lipid peroxidation, angiogenesis or
 restenosis.
 ##STR2##
 Wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, n and * are
 each defined in specification.
 2. Description of the Prior Art
 Ischemic heart diseases usually occur as a result of myocardial ischemia,
 when the oxygen supply is significantly decreased compared to the oxygen
 demand due to the imbalance between them. In most cases, a coronary artery
 disorder was found to be a main reason of the ischemic heart diseases. If
 the inner diameter of coronary artery becomes narrow, the blood supply,
 resulting in oxygen supply, becomes insufficient, which can cause angina
 pectoris, myocardial infarction, acute cardioplegia, arrhythmia, and so on
 (G. J. Grover, Can. J. Physiol. 75, 309 (1997); G. D. Lopaschuk et al.,
 Science & Medicine 42 (1997)). Because ischemic heart diseases are also
 caused by other complex factors besides coronary artery disorders, drug
 therapy as well as operational method such as perculaneous transluminal
 coronary angioplasty (PTCA) is required for its treatment. For that
 purpose, several drugs are being used, including anti-thrombotic agents,
 arteriosclerosis curatives, especially by beta blockers, nitrate, calcium
 antagonists such as nifedipin, thromobolytics, aspirin, and angiotensin
 converting enzyme (ACE) inhibitors.
 Differently from conventional potassium channel openers, the pyranyl
 guanidine compound (BMS-180448) represented by the following formula 2,
 has been reported to act selectively on ATP-sensitive potassium channels
 (K.sub.ATP) located in the heart (K. S. Atwal et al. , J. Mde. Chem. 36,
 3971 (1993); K. S. Atwal et al., J. Me. Chem. 38, 1966 (1995)). The BMS
 180448 compound was found to protect ischemic hearts without a significant
 lowering of blood pressure, which gives the prospects for novel drug
 development as a cardionprotectant.
 ##STR3##
 Both global and focal ischemia initiate progressive cellular changes, which
 lead to ischemic brain injury (M. D. Ginsburg, Neuros Scientist 1, 95
 (1995)). Even after blood flow is restored, oxygen can enhance the
 biochemical reactions that generate free radicals, which can lead to a
 potential for "reperconsfusion injury" to occur. In order to prevent the
 brain injury caused by ischemia-reperfusion, the brain must be protected
 during ischemic period to avoid additional injury and pathological
 progressive cellular to changes have to be minimized. For that purpose,
 neuroproteconstives such as excitatory amino acid antagonists and
 anti-oxidants are being used.
 Damage or death of neurons is known to be a main cause for various
 neurological disorders such as stroke, head trauma, Alzheimer's disease,
 Parkinson's disease, infant asphyxia, glaucoma and daiabetic neuropathy,
 etc. (G. J. Zoppo et al., Drugs 54, 9(1997); I. Sziraki et al., Neurosci.
 85, 110(1998)). Neurons are damaged by various consfactors and typically
 by increase in iron concentration, reactive oxygen species, and
 peroconsxidants within neurons (M. P. Mattson et al. , Methods Cell Biol.
 46, 187 (1995); Y. Goodman et al., Brain Res. 706, 328 (1996)).
 An increase of iron concentration in neuronal cells induces the formation
 of highly reactive hydroxyl radicals. An excess of oxygen free radicals
 facilitates lipid peroxidation, so that peroxidants are accumulated in
 neurons. The reactive free radicals accumulated in cells are known o be
 responsible for inflammatory diseases such as arthritis; atherosclerosis;
 cardiac infarction; and neurodegenerative disease such as dementia as well
 as acute and chronic injury of tissues and organs caused by
 ischemia-reperfusion or by endotoxins via bacterial infection.
 Therefore, therapeutic approaches to minimize the damage or death of
 neurons have been pursued, including the inhibition of lipid peroxidation,
 NO formation, and reactive oxygen species induced by endotoxins. To date,
 anti-oxidants are reported to ameliorate the neuronal damage and death
 caused by an increase of iron concentration within neurons. Much effort
 has been continued to develop pharmaceutical drugs which are able to
 prevent neuronal damage by oxidative stress (Y. Zhang et al., J. Cereb.
 Blood Flow Metab. 13, 378 (1993)).
 Infant asphyxia (IA), triggered by transient deficiency of oxygen supply
 during delivery, was reported to be caused by the reduction of energy
 production, damage of cell membrane due to oxygen free radical, release of
 excitatory neurotransmitters, change of intracellular ion concentrations
 including calcium, zinc, etc. IA is a major worldwide problem, because if
 IA is severe, the chances of mortality are high (around 1/3 of the cases)
 [C. F. Loid et. al. Physiology and Behavior 68; 263-269 (2000)]. In
 addition, it can produce long term sequela such as movement disorders,
 learning disabilities, epilepsy, dystonia, mental retardation, and
 spasticity.
 Antioxidant enzymes, allopurinol, Vitamine C & E, free radical scavengers,
 inhibitors of excitatory neurotransmitters, calcium channel blockers such
 as nimodipinconsa and flunarizine, inhibitors of NO formation,
 hyperglycemic and hypothermic therapy may be beneficial for the protection
 of brain injury, but their clinical application is still limited. Thus
 more intensive research is required to treat infant asphyxia properly.
 Glaucoma, one of the leading causes of blindness, is defined as an optic
 neuropathy associated with characteristic changes in optic nerve. In
 humans, the optic nerve consists of 1 million axons from neurons whose
 perikarya reside primarily in the ganglion cell layer and, to a less
 extent, in the inner part of the inner nuclear layer. The excavated
 appearance of the optic nerve head in glaucoma is thought to be caused by
 the death and subsequent loss of ganglion cells and their axons [N. N.
 Osborne, et. Al. Survey of Ophthalmology, 43; suppl. S102-s128 (1999)].
 Neuroprotective agents in glaucoma may protect death of retinal neurons,
 in particular the ganglion cells, either directly or indirectly. A variety
 agents such as NMDA receptor antagonist, .beta.-blockers, calcium
 antagonists, and antioxidants can be used to protect the death of retinal
 neurons induced by ischemia.
 Although the pathogenesis of diabetic neuropathy has not been clearly
 established, two main hypotheses have been proposed for it. One is
 metabolic abnormalities, and the other is blood flow deficits in
 peripheral nerve [K. Naka et. Al. Diabetes Research and Clinical Practice,
 30: 153-162 (1995)]. Acetyl-L-carnitine (ALC) by stimulating metabolism of
 lipid and improving impaired nociceptive responses of neurons, and
 Prosaptide by releasing neutrophic factors are in clinical trials. In
 addition, memantime showing good effects on vascular dementia through the
 regulation of NMDA receptor, is pursuing clinical trial. Then,
 neuroprotective agents having a variety of mechanisms of action may be
 developed to treat diabetic neuropathy.
 The ratio of cancer in human diseases is being gradually increased.
 Angiogenesis, formation of new blood vessels, is recognized as the core
 process for growth and metastasis of solid tumors (Folkma, J. et al., J.
 Biol. Chem. 267: 10931-10934 (1992)). Angiogenesis is controlled by
 inducers and inhibitors of angiogenesis. When the balance between them is
 broken, that is, when angiogenesis inducers prevail over angiogenesis
 inhibitors, a large quantity of new blood vessels are formed. Angiogenesis
 is closely related to various physiological phenomena, such as embryonic
 development, wound healing, chronic inflammation, hemangiomas, diabetic
 retinopathy, rheumatoid arthritis, psoriasis, AIDS complications, and the
 growth and metastasis of malignant tumors (Forkman, J., Klagsbrun. M.
 Science 235: 442-447 (1987)). Angiogenesis includes a series of processes
 such as the migration, proliferation and differentiation of endothelial
 cells, and is an important prerequisite for the growth and metastasis of
 cancers. Tn detail, because the growing tumor cells require the formation
 of blood vessels from host cells, angiogenesis promotors derived from
 tumors stimulate to induce the angiogenesis into the consumor mass.
 Afterwards, the blood vessels formed around the malignant tumors
 facilitate to metastasize the tumor cells to other sites. Therefore, the
 inhibition of angiogenesis leads to the prevention of the growth and
 metastasis of cancers. As one of the important research areas for the
 developing of anti-cancer drugs, extensive attention is paid to the
 finding of angiogenesis inducers and angiogenesis inhibitors and the
 revealing of their working mechanisms.
 Thus far, proteins such as prostamine and tumor necrotic factors, factors
 derived from cartilage tissues, and cortisone called angiostatic steroids
 and various steroid derivatives, have been found to be able to play roles
 as angiogenesis inhibitors. In particular, hydrocortisone exhibits
 anti-angiogenetic activity by cotreatment with heparin (Lee, A. et al.,
 Science 221: 1185-1187 (1983); Crum, R. et al., Science 230: 1375-1378
 (1985)). However, these compounds have a potential problem to treat
 cancers effectively owing to their cytotoxicity.
 Percutaneous coronary interventions (PCI) play an important role in the
 management of coronary artery stenosis, narrowing of the lumen as a result
 of growth of an atherosclerotic plaque in the intima (Inner coat) of the
 vessel, with success rate of more than 95%, but these are complicated by
 significant renarrowing of the artery (restenosis) in 20-50% of patients
 with 6 months after the intervention (Bult, H. Tips, 21; 274-279 (2000)).
 The biology of restenosis is not completely understood, but the
 predominant cellular mechanisms that contribute to restenosis include
 thrombosis, vascular smooth muscle cell migration and proliferation, and
 adventitious scarring. Different form atherosclerosis, restenosis is not
 dependent on the concentration or composition of atherogenic plasma
 lipids.
 Finding effective therapies for restenosis has been difficult because of
 incomplete understanding of biology of restenosis and the lack of suitable
 animal models. Some drug classes, glycoprotein IIb/IIIa antagonist,
 antioxidant probucol, have recently demonstrated potential benefits in
 clinical trials (Bult, H. Tips, 21; 274-279 (2000)). Since angiogenesis
 restenosis is characterized by intensive proliferative activity, then
 development of drugs to reduce vascular smooth muscle cell proliferation
 are being pursued.
 The intensive research on the development of compounds with the
 above-mentioned pharmacological efficacies by the inventors, found that
 the benzopyranyl guanidine derivatives represented by the formula 1 have
 superior cardioprotective and neuroprotective activity from
 ischemia-reperfusion and hypoxic damage. The compounds also exhibit
 various pharmacological efficacies, including protection of neurons,
 prevention of lipid peroxidation and reactive oxygen species formation,
 protection of ischemic retina, improvement of impaired nociceptive
 responses in diabetic rats, inhibition of NO formation, and suppression of
 angiogenesis and restenosis. Thus the compound of the present invention
 can be useful in the prevention and treatment of various diseases related
 to cardiovascular system such as cardiac infarction and congestive heart
 failure; stroke; neuronal damage such as infant asphyxia, glaucoma,
 diabetic neuropathy and head trauma; oxygen free radical-related disease
 such as neurodegenerative diseases and atherosclerosis; angiogenesis such
 as cancers and diabetic retinopathy, or restenosis, and also can be used
 in protecting preserving organs such as heart, kidney, liver, and tissues
 and protecting organs in major cardiovascular surgery.
 SUMMARY OF THE INVENTION
 One of the objectives of the present invention is to provide novel
 benzopyranyl guanidine derivatives of formula
 Another objective of the present invention is to provide process for the
 preparation of the benzopyranyl guanidine derivatives.
 Further objective of the present invention is to provide pharmaceutical use
 of the benzopyranyl guanidine derivatives. In particular, the present
 invention provides the use of the benzopyranyl guanidine derivatives for
 the protection of heart and brain from ischemic and hypoxia injury,
 neuroprotection, inhibition of NO formation, lipid peroxidation and
 reactive oxygen species generation, or suppression of and suppression of
 angiogenesis and restenosis.
 DETAILED DESCRIPTION OF THE INVENTION
 The present invention provides benzopyranyl guanidine derivatives
 represented by the following formula 1 and their pharmaceutically
 acceptable salts.
 ##STR4##
 Wherein
 R.sub.1 R represents H, halogen, CF.sub.3, NO.sub.2, CN, Or.sup.a,
 O(C.dbd.O)R.sup.a, COOR.sup.a, NH.sub.2, NHS(O).sub.m R.sup.a,
 NH(C.dbd.O)R.sup.a or S(O).sub.m R.sup.a ; R.sup.a represents straight or
 branched alkyl group of C.sub.1 -C.sub.4 or aryl group; and m is an
 integer of 0-2,
 R.sub.2 represents straight or branched alkyl group of C.sub.1 -C.sub.4,
 R.sub.3 represents CH.sub.2 OR.sup.a,
 ##STR5##
 R.sup.a is defined as above; R.sup.b and R.sup.c are independent each other
 and represent straight or branched alkyl group of C.sub.1 -C.sub.4,
 respectively; and Z represents straight or branched alkyl group of C.sub.1
 -C.sub.5 ;
 R.sub.4 represents OH, H, halogen, ONO.sub.2, or O(C.dbd.O)R.sup.a ; and
 R.sup.a is defined as above; R.sub.5 and R.sub.6 are independent each
 other and represent H, halogen, straight or branched alkyl group of
 C.sub.1 -C.sub.3, OR.sup.a, CX.sub.3, NO.sub.2, CO.sub.2 R.sup.a,
 --(C.dbd.O)R.sup.a or SO.sub.3 R.sup.a ; R.sup.a is defined above; and X
 represents halogen, and
 n is an integer of 0-2.
 And * represents the chiral center.
 In the formula 1, more preferably
 R.sub.1 represents NO.sub.2, CN, NH.sub.2 or S(O).sub.m R.sup.a ; R.sup.a
 represents straight or branched alkyl group of C.sub.1 -C.sub.2, or aryl
 group; and m is an integer of 0-2,
 R.sub.2 represents CH.sub.3,
 R.sub.3 represents
 ##STR6##
 R.sup.b and R.sup.c are independent each other and represent straight or
 branched alkyl group of C.sub.1 -C.sub.3, respectively; and Z represents
 straight or branched alkyl group of C.sub.1 -C.sub.5,
 R.sub.4 represents OH, H or O(C.dbd.O)R.sup.a ; and R.sup.a represents
 straight or branched alkyl group of C.sub.1 -C.sub.3 ;
 R.sub.5 and R.sub.6 are independent each other and represent H, halogen,
 straight or branched alkyl group of C.sub.1 -C.sub.3, OR.sup.a, CX.sub.3
 or NO.sub.2 ;R.sup.a represents straight or branched alkyl group of
 C.sub.1 -C.sub.3 ; and X represents halogen, and
 n is an integer of 0-2.
 The present invention includes all the solvates and hydrates which can be
 prepared from benzopyranyl guanidine derivatives of formula 1 in addition
 to benzopyranyl guanidine derivatives of formula 1 and their
 pharmaceutically acceptable salts.
 The present invention includes all the separate stereochemical isomers, i.
 e. diastereomerically pure or enantiomerically pure compounds which have
 one or more chiral centers at 2, 3 and 4-positions, in addition to the
 racemic mixtures or diastereomer mixtures of benzopyranyl guanidine
 derivatives of formula 1.
 In case of having three chiral centers at 2, 3 and 4-positions, the
 3,4-dihydro benzopyran derivatives according to the present invention are
 represented by the optical isomers such as (I.sub.1), (I.sub.2), (I.sub.3)
 and (I.sub.4) (See the following formula 3).
 ##STR7##
 Wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and n are
 defined as above.
 In particular, the preferable compounds of the present invention are:
 1)
 (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4yl)-N'-(4-chlorophenyl)guanidine;
 2)
 (2R,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine;
 3)
 (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-chlorophenyl)guanidine;
 4)
 (2R,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-chlorophenyl)guanidine;
 5)
 (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-nitrophenyl)guanidine;
 6)
 (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-trifluoromethylphenyl)guanidine;
 7)
 (2R,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-trifluoromethylphenyl)guanidine;
 8)
 (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-methoxyphenyl)guanidine;
 9)
 (2R,3S,4R)-N"-cyano-N"-6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4yl)-N'-(4-methoxyphenyl)guanidine;
 10)
 (2S,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine;
 11)
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine;
 12)
 (2S,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-chlorophenyl)guanidine;
 13)
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-chlorophenyl)guanidine;
 14)
 (2S,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-trifluoromethylphenyl)guanidine;
 15)
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-trifluoromethylphenyl)guanidine;
 16)
 (2S,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-methoxyphenyl)quanidine;
 17) (2S,3S,4R-N"-cyano-N-(6-nitro-3,4dihydro-N'-(4-methoxyphenyl)guanidine;
 18)
 (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-methylphenyl)guanidine;
 19)
 (2R,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-methylphenyl)guanidine;
 20)
 (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-methoxybenzyl)guanidine;)
 21)
 (2R,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-methoxybenzyl)guanidine;
 22)
 (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine;
 23)
 (2R,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine;
 24)
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine;
 25)
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4yl)-benzylguanidine;
 26)
 (2R,3R,4S)-N"-cyano-N-(3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H
 -benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine;
 27)
 (2R,3S,4R)-N"-cyano-N-(3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H
 -benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine;
 28)
 (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-hydroxymet
 hyl-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine;
 29)
 (2R,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-hydroxymet
 hyl-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine;
 30)
 (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-methoxymet
 hyl-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)quanidine;
 31)
 (2R,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-methoxymet
 hyl-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine;
 32)
 (2S,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(2-chlorophenyl)guanidine;
 33)
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4dihydro-3-hydroxy-2-dimethoxymethyl-2H-b
 enzopyran-4-yl)-N'-(2-chlorophenyl)guanidine;
 34)
 (2S,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(2-trifluoromethylphenyl)guanidine;
 35)
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(2-trifluoromethylphenyl)guanidine;
 36)
 (2S,3S,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(2-chlorobenzyl)guanidine;
 37) (2S, 3S,
 4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2
 H-benzopyran-4-yl)-N'-(2-chlorobenzyl)guanidine;
 38)
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-acetoxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine;
 39) (2S)-N"-cyano-N-(6-nitro-2-methyl-2-dimethoxymethyl
 -2-H-benzopyran-4-yl)-N'-benzylguanidine;
 40)
 (2S,3S,4P)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N"-benzylguanidine;
 41)
 (2S,3S,4R)-N"-cyano)-N-(6-acetoxyamino-3,4-dihydro-3-hydroxy-2-methyl-2-di
 methoxymethyl-2H-benzopyran -4-yl)-N'-benzylguanidine;
 42) (2S,3S,4R)-N"-cyano-N-(6-methanesulfonylamino
 -3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H
 -benzopyran-4-yl)-N'-benzylguanidine;
 43)
 (2S,3S,4R)-N"-cyano-N-(6-cyano-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)guandine;
 44)
 (2S,3R,4S)-N"-cyano-N-(6-cyano-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine;
 45)
 (2S,3S,4R)-N"-cyano-N-(6-cyano-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine;
 46)
 (2S,3R,4S)-N"-cyano-N-(6-cyano-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine;
 47)
 (2S,3S,4R)-N"-cyano-N-(6-bromo-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine;
 48)
 (2S,3S,4R)-N"-c-yano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-(dimethox
 ymethyl-2H-benzopyran-4-yl)-N'-(3,4-dimethoxybenzyl)guanidine;
 49)
 (2S,3S,4R)-N"-cyao-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-(dimethoxym
 ethyl-21-benzopyran-4-yl)-N'-(3,4-dimethoxylbenzyl)guanidine;
 50)
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-methoxybenzyl)guanidine;
 51)
 (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-methoxybenzyl)guanidine;
 52)
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-nitrobenzyl)guanidine;
 53)
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-trifluoromethylbenzyl)guanidine;
 54)
 2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxyme
 thyl-2H-benzopyran-4-yl)-N'-(3-trifluoromethylbenzyl)guanidine;
 55) (2S,3S,4R)-N"-cyano-N-(6-methanesulfonyloxy
 -3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran
 -4-yl)-N'-benzylguanidine;
 56) (2R,3S,4R)-N"-cyano-N-(6-methanesulfonyloxy
 -3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran
 -4-yl)-N'-benzylguanidine;
 57)
 (2S,3R,4S)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2!!-benzopyran-4-yl)-N'-benzylguanidine;
 58)
 (2R,3R,4S)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine;
 59)
 (2R,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine;
 60)
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-([1,3]diox
 olan-2-yl)-2H-benzopyran-4-yl)-N'-benzylguanidine;
 61)
 (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-([1,3]diox
 olan-2-yl)-2H-benzopyran-4-yl)-N'-benzylguanidine;
 62)
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-([1,3]diox
 an-2-yl)-2H-benzopyran-4-yl)-N'-benzylguanidine;
 63)
 (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-([1,3]diox
 an-2-yl)-2H-benzopyran-4-yl)-N'-benzylguanidine;
 64)
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-([1,3]-5,5
 -dimethyldioxan-2-yl)-2H-benzopyran -4-yl)-N'-benzylguanidine;
 65)
 (2S,3S,4R)-N"-cyano-N-(6-amino)-3,4-dihydro-3-hydroxy-2-methyl-2-([1,3]-5,
 5-dimethyldioxan-2-yl)-2H-benzopyran -4-y)-N'-benzylguanidine;
 66)
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-diethoxyme
 thyl-2H-benzopyran-4-yl)-N'-benzylguanidine;
 67)
 (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-diethoxyme
 thyl-2H-benzopyran-4-yl)-N'-benzylguanidine;
 68) (2S,3S,4R)-N"-cyano-N-(6-methoxycarbonyl
 -3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran
 -4-yl)-N'-benzylguanidine;
 69)
 (2R,3S,4R)-N"-cyano-N-(6-methoxycarbonyl-3,4-dihydro-3-hydroxy-2-methyl-2-
 dimethoxymethyl-2H-benzopyran -4-yl)-N'-benzylguanidine;
 70)
 (3S,4R)-N"-cyano-N-(8-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymeth
 yl-2H-benzopyran-4-yl)-N'-benzylguanidine;
 71)
 (2S,3S,4R)-N"-cyano-N-(8-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine; and
 72)
 (2R,3S,4R)-N"-cyano-N-(8-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine.
 The more, preferable compounds of the present invention are:
 (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxyme
 thyl-2H-benzopyran-4-yl)-N'-benzylguanidine;
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxyme
 thyl-2H-benzopyran-4-yl)-N'-benzylguanidine; and
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-acetoxy-2-methyl-2-dimethoxyme
 thyl-2H-benzopyran-4-yl)-N'-benzylguanidine.
 The compounds of formula 1 may be used as pharmaceutically acceptable salts
 derived from pharmaceutically or physiologically acceptable free acids.
 These salts include but are not limited to the following: angiogenesis
 salts with inorganic acids such as hydrochloric acid, hydrobromic acid,
 sulfuric acid, sulfonic acid, phosphoric acid, stannic acid, etc. and
 organic acids such as citric acid, acetic acid, lactic acid, maleic acid,
 fumaric acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic
 acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic
 acid, glutamic acid, aspartic acid, etc.
 The acid salts of the compounds according to the present invention can he
 prepared in the customary manner, for example by dissolving the compound
 of formula 1 in excess aqueous acid and precipitating the salt with a
 water-miscible organic solvent, such as methanol, ethanol, acetone or
 acetonitrile. It is also possible to prepare by heating equivalent amounts
 of the compound of formula 1 and an acid in water or an alcohol, such as
 glycol monomethyl ether, and then evaporating the mixture to dryness or
 filtering off the precipitated salt with suction.
 Also the compounds of formula 1 may be in the form of pharmaceutically
 acceptable ammonium, alkali metals or alkaline earth metals salts. The
 alkali metal or alkaline earth metal salts of the compound of formula 1
 can be obtained, for example, by dissolving the compound of formula 1 in
 equimolar amount of alkali metal or alkaline earth metal hydroxide
 solution, filtering from the undissolved materials and evaporating the
 filtrate to dryness. Sodium, potassium or calcium salts are
 pharmaceutically suitable. The corresponding silver salts are obtained by
 the reaction of an alkali metal or alkaline earth metal salt with a
 suitable silver salt, such as silver nitrate.
 In addition, the present invention provides processes for preparing of the
 benzopyranyl guanidine derivatives of formula 1.
 In particular, the present invention provides processes for preparing of
 the benzopyranyl guanidine derivatives of formula 1, represented by the
 following scheme 1 (Preparation Method T).
 ##STR8##
 Wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and n are each
 defined as above.
 The present invention also provides processes for preparing of the
 benzopyranyl guanidine derivatives of formula 1, represented by the
 following scheme 2 (Preparation Method II).
 ##STR9##
 Wherein R.sub.1, R.sub.2 R.sub.3, R.sub.4, R.sub.5, R.sub.6 and n are each
 defined as above.
 In addition, the present invention provides processes for preparing of the
 benzopyranyl guanidine derivatives of formula 1 by using the compound (I')
 prepared in the scheme 1 or scheme 2, represented by the following scheme
 3.
 ##STR10##
 Wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and n are each
 defined as to above.
 The substituents of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and
 R.sub.6 can be modified or 3,4-double bond can be formed via the reaction
 represented by the above scheme 3.
 The derivatives of formula 1 can be prepared separately as an optically
 active isomer by using the corresponding optical isomer as a starting
 material.
 In case of using a racemic mixture as a starting material, the derivatives
 of formula 1 are prepared as a racemic mixture, and then the racemic
 mixture is separated into each optical isomers. The optical isomers can be
 separated by common chiral column chromatography or recrystallization.
 The compounds of formula 1 can be synthesized using the reactions and
 techniques described herein below. The reactions are performed in a
 solvent appropriate to the reagents and materials employed and suitable
 for the transformation being effected.
 I. Preparation of Starting Materials
 Aminoalcohol compounds (III) which were used as a starting material in
 scheme I or scheme 2, can be prepared by the reaction represented by the
 following scheme 4.
 ##STR11##
 Wherein R.sub.1, R.sub.2 and R.sub.3 are each defined as above, (OZ)
 represents a leaving group and Hal represents a halogen atom.
 The method for the preparation of the epoxide compound (II) represented by
 the above scheme 4 is described in U.S. Pat. No. 5,236,935 and KR Pat. No.
 096,546 which were acquired by the present inventors, in detail.
 Also, the epoxide compound (II) can be prepared from propazylether
 derivatives (J. Med. Chem. 26, 1582 (1983)).
 (1) Preparation of Olefin Compounds (VIII)
 Olefin compounds (VIII) exist as enantiomers (VIII.sub.1 and VIII.sub.2)
 such as formula 4.
 ##STR12##
 Wherein R.sub.1, R.sub.2 and R.sub.3 are each defined as above.
 Olefin compounds (VIII) can be obtained separately as an optically active
 olefin compound (VIII.sub.1) and olefin compound (VIII.sub.2) of formula
 4, respectively. The olefin compound (VIII) can be prepared by the method
 disclosed in KR Pat. Appln. No. 96-7399 according to the present
 inventors.
 The following scheme 5 shows the detail process for the preparation of the
 olefin compound (VIII) from an alcohol compound (VII).
 ##STR13##
 Wherein R.sub.1, R.sub.2 and R.sub.3 are each defined as above.
 (2) Preparation of Epoxide Compounds (II)
 Epoxide compounds (II.sub.1) and epoxide compounds (II.sub.2) can be
 prepared from the compound (VIII.sub.1) and epoxide compounds (II.sub.3)
 and epoxide compounds (II.sub.4) can be prepared from the compound
 (VIII.sub.2) as represented by the following scheme 6, by using the
 compound (VIII.sub.1) and the compound (VIII.sub.2) prepared in scheme 5
 as a starting material, respectively.
 ##STR14##
 Wherein R.sub.1, R.sub.2 and R.sub.3 are each defined as above.
 The epoxide compounds (II.sub.1) and (II.sub.2) can be separated to each
 optical isomer, and all the separated epoxide compounds or the mixture
 thereof an be used in the next: step. Also the epoxido compounds
 (II.sub.3) and (II.sub.4) can be separated, and all the separated epoxide
 compounds or the mixture thereof can be used in the next step.
 Epoxide compounds (II.sub.1) and (II.sub.2) and epoxide compounds
 (II.sub.3) and (II.sub.4) can be prepared from olefin compounds
 (VIII.sub.1) and (VIII.sub.2), respectively, by the preparation method
 disclosed in U.S. Pat. No. 5,236,935 and KR Pat. No. 096,546 which were
 acquired by the present inventors.
 It is also possible to prepare optical isomers (II.sub.1), (II.sub.2),
 (II.sub.3) and (II.sub.4) of epoxide compounds, respectively, from olefin
 compounds (VIII.sub.1) or (VIII.sub.3), by using Mn(III) salen epoxidation
 catalysts (E. N. Jacobsen et al., Tetrahedron Lett., 38, 5055 (1991)). In
 case of using (R, R)--Mn(III) salen catalyst, epoxide compounds (II.sub.1)
 can be prepared from olefin compounds (VIII.sub.1) and epoxide compounds
 (II.sub.3) from the olefin compounds (VIII.sub.2). In case of using (S,
 S)--Mn(III) salen catalyst, epoxide compounds (II.sub.2) can be prepared
 from the olefin compounds (VIII.sub.1) and epoxide compounds (II.sub.4)
 from the olefin compounds (VIII.sub.2). This epoxidation reaction is
 performed in mixture of methylene chloride and water by using NaOCl as an
 oxidizing agent.
 (3) Preparation of Aminoalcohol Comopunds (III)
 Aminoalcohol compounds (III) are prepared by the reaction of the epoxide
 compound (II) with ammonia gas (NH.sub.3) or ammonium hydroxide (NH.sub.4
 OH) in the presence of a suitable solvent, in the above scheme 4.
 Preferred solvent are alcohols such as methanol, ethanol, isopropanol,
 etc. The reaction temperature may range from 5.degree. C. to the boiling
 point of the solvent employed.
 In case of using each epoxide compound (II.sub.1), (II.sub.2), (II.sub.3)
 and (II.sub.4) as a starting material, aminoalcohol compounds (III.sub.1),
 (III.sub.2), (III.sub.3) and (III.sub.4) can be obtained, respectively. In
 case of using a mixture of epoxy compound (II.sub.1) and (II.sub.2) as a
 starting material, a mixture of aminoalcohol compounds (III.sub.1) and
 (III.sub.2) is obtained. And in case of using a mixture of epoxide
 compound (II.sub.3) and (II.sub.4) as a starting material, a mixture of
 aminoalcohol compounds (III.sub.3) and (III.sub.4) is obtained.
 ##STR15##
 Wherein R.sub.1, R.sub.2 and R.sub.3 are each defined as above.
 ##STR16##
 Wherein R.sub.1, R.sub.2 and R.sub.3 are each defined as above.
 II. Preparation Method I
 The method for the preparation of the compounds formula 1 comprises the
 step of reacting an aminoalcohol compound (III) and a thiourea compound
 (IV) in the presence of a suitable condensing agent and a suitable
 solvent. The compound (I'), which is a compound of formula 1 with the
 R.sub.4 =OH, is prepared by this reaction.
 Examples of such condensing agents include carbodiimide-type condensing
 agents such as 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
 hydrochloride, and N,N'-dicyclohexylcarbodiimide, etc. More preferably
 water-soluble carbodiimide-type condensing agents are employed.
 One to three equivalents of the condensing agent is preferable, to that of
 the aminoalcohol compound (III). Also one to two equivalent of thiourea
 compound (IV) is preferable, to that of the aminoalcohol compound (III).
 Preferable solvents are methylene chloride, chloroform, dimethylformamide,
 dimethylsulfoxide, tetrahydrofuran, 1,2-dichloroethane, dioxane, etc.
 Reaction temperature may range from 5.degree. C. to 40.degree. C.
 In case of using each stereoisomer of the aminoalcohol compound (III) as a
 starting material, the product with the same configuration to that of the
 starting material is obtained, respectively. That is, the compounds
 (I.sub.1), (I.sub.2), (I.sub.3) and (I.sub.4) of formula 1 can be prepared
 from aminoalcohol compounds (III.sub.1), (III.sub.2), (III.sub.3) and
 (III.sub.4), respectively. In case of using a mixture of aminoalcohol
 compounds (III.sub.1) and (III.sub.2) as a starting material, a mixture of
 compounds (I.sub.1) and (I.sub.2) is obtained. And in case of using a
 mixture of aminoalcohol compounds (III.sub.3) and (III.sub.4) as a
 starting material, a mixture of compounds (I.sub.3) and (I.sub.4) is
 obtained. A mixture of the compounds of formula 1 can be separated to
 afford the separated optical isomers. The optical isomers can be separated
 by common column chromatography or recrystallization.
 The thiourea compound (IV) used in the above reaction can be prepared by
 the reaction of an isocyanate compound (IX) with sodium cyanamide (NaHNCN)
 in ethanol as represented by the following scheme 7.
 ##STR17##
 Wherein R.sub.5, R.sub.6 and n are each defined as above.
 III. Preparation Method II
 Another method for the preparation of the compounds of formula 1 comprises
 1) reacting an aminoalcohol compound (III) with diphenyl cyanocarbonimidate
 (X) in the presence of a base to prepare the compound (V) (step 1); and
 2) reacting the compound (V) with an appropriate amine compound (VI) in a
 suitable solvent to prepare the compound (I') (step 2).
 The compound (I') which is a compound of formula with R.sub.4 =CH, is
 prepared by this reaction.
 In step 1, various inorganic and organic bases can be employed. Examples of
 such inorganic bases include CaCO.sub.3, NaOH, KOH, Na.sub.2 O.sub.3,
 NaHCO.sub.3, etc. Examples of such organic bases include metal salts of
 alcohols such as sodium methoxide (CH.sub.3 ONa), sodium ethoxide
 (CH.sub.3 CH.sub.2 ONa) etc.; sodium acetate (CH.sub.3 COONa); metal salts
 of ammonia; bicyclic amines such as 1,8-diazabicyclo[5.4.0]undec-7-ene
 (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), etc.; triethylainine;
 N,N-diisoprocylethylamine; pyridine; lutidine; N,N-dimethylaniline;
 4-(dimethylamino)-pyridine; 1,4-diazabicyclo[2.2.2]octane (DABCO), etc.
 More prefereablly tertiary amines are employed such as triethylamine,
 N,N-diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-6-ene,
 4-(dimethylamino)pyridine, etc.
 One to three equivalent of the base is preferable, to that of the
 aminoalcohol compound (III). And one to two equivalent of diphenyl
 cyanocarbonimidate (X) is preferable, to that of the aminoalcohol compound
 (III).
 Preferred solvents are alcohols such as ethanol, isopropanol, etc.,
 dimethylformamide (DMF), dimethylsulfoxide (DMSO), chloroform, etc.
 Reaction temperature is preferably maintained from 5.degree. C. to the
 boiling point of solvent employed.
 In step 2, one to five equivalent of the amine compound (VI) is preferable,
 to that of the aminoalcohol compound (III).
 Examples of the reaction solvent are alcohols such as ethanol,
 Lsopropariol, etc., dimethylformamide, dimethylsulfoxide, chloroform,
 methylene chloride, tetrahydrofuran (THe), etc.
 Reaction temperature is preferably maintained from 5.degree. C. to the
 boiling point of solvent employed.
 In addition, the reaction of step 2 can be carried out in the presence of a
 base. Examples of such bases are mentioned as above.
 In case of using each optical isomer of aminoalcohol compound (III) as a
 starting material, the product (I') with the same configuration of the
 starting material is obtained, respectively. Tn case of using a mixture of
 aminoalcohol compounds (II.sub.1) and (III.sub.2) as a starting material,
 a mixture of compounds (I.sub.1) and (I.sub.2) is obtained. In case of
 using a mixture of aminoalcohol compounds (III.sub.3) and (III.sub.4) as a
 starting material, a mixture of compounds (I.sub.3) and (I.sub.4) is
 obtained. A mixture of optical isomers can be separated to afford the
 separated optical isomers of compounds (I'). The optical isomers can be
 separated by common column chromatography or recrystallization.
 IV. Preparation of Compounds (I) from Compounds (I')
 The substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 or R.sub.6 can
 be modified to other functional groups, and a double bond can be formed at
 3,4-position by the reaction of scheme 3. In this reaction, the compounds
 (I') are used as a starting material, which has been prepared by the above
 scheme 1 or scheme 2.
 A starting material, reactants and the reaction condition are determined
 according to the structure of product, that is what are the substituents
 R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 and whether there
 is a double bond at 3,4-position. Therefore the present invention includes
 all the reaction types, reactants and reaction condition by which it is
 possible to prepare the compound of formula 1.
 Several processes for the preparation of the compounds of formula 1
 according to scheme 3 are described below in detail. However, the
 description of the process should not be understood to limit the present
 invention.
 (1) Introduction of Acethoxy Group at R.sub.4
 Acetoxy group can be introduced at R.sub.4 by reacting the compound (I')
 with acetic anhydride in suitable solvent in the presence of a suitable
 catalyst as represented in the below scheme 8.
 ##STR18##
 Wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and n are each
 defined as above.
 Preferred bases are mentioned as above. More preferably triethylamine,
 pyridine or N,N-diisopropylethylamine is employed.
 Preferred catalyst is 4-(dimethylamino)pyridine. One to three equivalent of
 the base is preferable, to that of the compound (I'). And 0.05-0.5
 equivalent of the catalyst is preferable, to that of the compound (I').
 Preferred solvents are methylene chloride, chloroform, tetrahydrofuran,
 acetonitrile, etc. The reaction 10 temperature is preferably 0-40.degree.
 C.
 (2) Introduction of Double Bond at 3,4-position
 R.sub.4 is substituted with hydrogen atom and a double bond is formed at
 3,4-position by reacting the acetate compound (I.sub.a) prepared in the
 above scheme 8 with suitable base in suitable solvent as represented in
 the below scheme 9.
 ##STR19##
 Wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and n arc each
 defined as above.
 Preferred bases are mentioned as above. More preferably
 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene or
 1,4-diazabicyclo[2.2.2]octane is employed.
 One to three equivalents of the base is preferable, to that of compound
 (I.sub.a).
 Preferred solvents are toluene, benzene, xylene, dioxane, etc. The reaction
 temperature is preferably from 5.degree. C. to the boiling point of
 solvent.
 (3) Introduction of NH.sub.3 Group at R.sub.1 p The compound (I.sub.d) of
 formula 1 whose R.sub.1 is NH.sub.2 can be prepared by the reduction of
 the compound (I.sub.c) with R.sub.1 =NO.sub.2 as represented in the below
 scheme 10.
 ##STR20##
 Wherein R.sub.2, R.sub.3, R.sub.5, R.sub.6 and n are each defined as above.
 The NO.sub.2 group can be reduced to NH.sub.2 group by hydrogenation using
 metal catalysts such as platinum, palladium, palladium on carbon (Pd/C),
 Paney-nickel, etc. in a suitable solvent. Preferred solvents are alcohols
 such D as methanol, ethanol, etc., and ethyl acetate.
 In addition, the reduction of NO.sub.2 group to NH.sub.2 group can be
 carried out by using a reducing agent such as NaBH.sub.4 in the presence
 of CuSO.sub.4, Cu(OAc).sub.2, CoCl, SnCl.sub.2 or NiCl.sub.2. At this
 time, preferred solvent is a mixture of water and methanol and room
 temperature for reaction temperature is preferred.
 (4) Introduction of NH(C.dbd.O)R.sup.a at R.sub.1
 The compound of formula 1 with R.sup.1 =NH(C.dbd.O)R.sup.a can be prepared
 by the reaction of the compound (I.sub.d) prepared in the above scheme 10
 with acylchloride or acid anhydride in the presence of a base.
 Preferred bases are mentioned as above. More preferably bases are employed
 such as triethylamine, N,N-diisopropylethylamine, pyridine or
 4-(dimethylamino)pyridine. Preferred solvents are methylene chloride,
 chloroform, dimethylsulfoxide, dimethylformamide, tetrahydrofuran and
 dioxane.
 (5) Introduction of --NHS(O).sub.m R.sup.a at R.sub.1
 The compound of formula 1 with R.sub.1 =--NHS(O).sub.m R.sup.a can be
 prepared by the reaction of the compound (Id) prepared in the above scheme
 10 with alkylsulfonyl chloride or arylsulfonyl chloride in the presence of
 a base.
 Preferred bases are mentioned as above. More preferably bases are employed
 such as triethylamine, N,N-diisopropylethylamine, pyridine and
 4-(dimethyLamino)pyridine. Preferred solvents are methylene chloride,
 chloroform, dimethylsulfoxide, dimethylformamide, tetrahydroturan and
 dioxane.
 In addition, the present invention provides pharmaceutical compositions
 which contain the benzopyranyl guanidine derivatives of claim 1 or their
 pharmaceutically acceptable salts as an active ingredient. In particular,
 the present invention provides pharmaceutical compositions for protecting
 heart, protecting neuronal cells or protecting of brain injury, or
 protecting preserving organs, inhibiting NO generation and lipid
 peroxidation or suppressing angiogenesis and restenosis.
 In the experiments using isolated rat aorta, the compounds of the present
 invention showed remarkably low vasorelaxant activity compared to the
 reference K.sub.ATP openers such as Cromakalim and BMS-180448. While the
 KAY openers have cardioprotective properties by exerting their effects on
 heart, those have vasorelaxant properties by acting on the K.sub.ATP
 located in smooth muscle. The vasodilation effect is unnecessary, probably
 contraindicated for ischemia, due to under perfusion of the tissue already
 at risk. In other words, the vasorelaxant effect of these compounds would
 limit their utility in treating myocardial ischemia. As mentioned above,
 the compounds of the present invention are nearly devoid of vasorelaxant
 activity, thus their cardiac selectivity might offer a higher margin of
 safety as cardioprotectants.
 Accordingly, the compounds of the present invention are confirmed their
 antiischemic activity with significant improvement in cardiac selectivity.
 In the ischemic myocardium injury models of anesthetized rats, the
 compounds of the present invention exhibited equal or superior
 antiischemic activity compared to that of BMS-180448. Further, in contrast
 to BMS-180448, the compounds of the present invention have noticeably low
 vasorelaxant activity and thus, they are far superior to the conventional
 drugs as cardiac selective cardioproteclants. In addition, in the ischemic
 myocardium unjury models of anesthetized beagle dogs, the compounds of the
 present invention considerably reduced the size of infarct zone as a
 percentage of area at risk (%IZ/AAR), which was superior to the reference
 BMS180448.
 As described above, the compounds of the present invention show almost no
 vasodilatation activity, but exert excellent anti-ischemic activity on
 various animals, so that they can be used for the prevention or treatment
 of the diseases related to myocardial ischemia, such as postischemic
 contractile dysfunction as well as a cardiprotective in myocardial
 infarction, angina pectoris and congestive heart failure.
 In addition, the compounds of the present invention have an ability to
 protect neurons. In detail, the compounds of the present invention protect
 neurons from oxidative injury by iron dose-dependently. Also, the
 compounds of the present invention protect retinal cell death from
 ischemic damage dose-dependently, and represent neuroprotective effects by
 improving impaired MNCV (motor nerve conduction velocity) and nociceptive
 responses using hot plates in diabetic rats. And the compounds of the
 present invention protect hypoxic brain injury in newborn rats by,
 decreasing the value of lipid/NAA (N-aetyl aspartate) and (lipid)/Cr
 (creatine) in proton PRS (magnetic resonance spectroscopy). Therefore, the
 compounds of the present invention can be used as a neuroprotectives and
 can also be applied for the treatment of neurodegenerative disorders
 caused by the apoptosis or necrosis of neurons, such as stroke, cerebral
 dementia, infant asphyxia, glaucoma, diabetic neuropathy, and head trauma.
 Further, the compounds of the present invention inhibit the lipid
 peroxidation induced by iron or copper and LDL (low density lipoprotein)
 oxidation in A7r5 (rat aortic smooth muscle cell), whose antioxidant
 effect was more significant when H.sub.2 O.sub.2 was added. In addition,
 the compounds of the present invention inhibit ROS (reactive oxygen
 species) induced by H.sub.2 O.sub.2 both in A7r5 and HUVEC cells, and
 remove oxygen radicals in ORAC (oxygen radical absorbance capacity) test
 using AAPH (2.2'-azobis(2-aminopropane)dihydrodichloride) as a radical
 generator. Hence, the compounds of the present invention can be used as an
 antioxidant against lipid peroxidation and can be effectively applied for
 the medical treatment of the neurological disorders caused by the
 accumulation of free radical species within neurons, such as
 neurodegenerative diseases (stroke and dementia), atherosclerosis and
 inflammation.
 Furthermore, the compounds of the present invention inhibit No (nitric
 oxide) formation induced by endotoxins such as lipopolysaccharide (LPS),
 dose-dependently. Therefore, the compounds of the present invention can be
 used as inhibitors against NO production and can be effectively applied
 for the treatment of inflammatory diseases such as arthritis, cardiac
 infarction, arteriosclerosis, and dementia, which are caused by the injury
 of tissues or organs as a result of the apoptoic or necroptic cell death
 due to accumulation of NO within the cells.
 Moreover, the compounds of the present invention effectively protect the
 brain from ischemia-reperfusion injury. The compounds of the present
 invention have advantage over the reference MK801. While the MK
 801-treated rats showed decreased motility as a side effect, rats treated
 with the compounds of the present invention did not show any significant
 side effects such as behavioral change. Hence, the compounds of the
 present invention can be used as a neuroprotective agent against brain
 ischemia-reperfusion damage and can be effectively applied for the
 treatment of various diseases caused by brain ischemic injury such as
 ischemic cerebral vascular occlusion induced by thrombi.
 In the experiment of the formation of new blood vessels induced by
 antiotensin II, the compounds of the present invention effectively inhibit
 the angiogenesis. In particular the compounds of the present invention are
 able to almost completely prevent the formation of new blood vessels in a
 dose-dependent manner. Therefore, the compounds of the present invention
 can be used as an angiogenesis inhibitor and can be usefully applied for
 the medical treatment of various diseases induced by angiogenesis, such as
 rheumatoid arthritis, psoriasis, AIDS complications, and cancers.
 Also, the compounds of the present invention significantly suppress
 vascular smooth muscle cell proliferation by inhibition of DNA synthesis
 in [.sup.3 H]-thymidine incorporation experiments. Hence, the compounds of
 the present invention can be used for the prevention and treatment of
 restenosis, frequently occurred after percutaneous coronary intervention.
 Also, the compounds of the present invention can be used for protection of
 preserving organs such as heart, kidney, liver, and tissues and for the
 protection of organs in major cardiovascular surgery.
 The present invention includes pharmaceutical formulations which contain,
 in addition to non-toxic, inert pharmaceutically suitable additives, one
 or more than one active ingredients according to the present invention and
 processes for the preparation of these formulations.
 The present invention also includes pharmaceutical formulations in dosage
 units. The dosage unit of each formulations, for example tablets, coated
 tablets, capsules, pills, suppositories and ampules, contain the more than
 one active ingredients corresponding to a fraction or a multiple of an
 individual dose. For example the dosage units can contain 1, 2, 3 or 4
 times or 1/2, 1/3 or 1/4 active ingredients of an individual dose. A
 dosage unit preferably contains the amount of active ingredients which is
 administered in one application or which usually corresponds to a whole,
 one half, one third or a quarter of a daily dose.
 Non-toxic inert pharmaceutically suitable vehicle includes as solid,
 semi-solid or liquid diluents, fillers and formulation additives of all
 types.
 Preferred pharmaceutical formulations are tablets, coated tablets,
 capsules, pills, granules, suppositories, solutions, suspensions and
 emulsions, pastes, ointments, gels, reams, lotions, dusting powders and
 sprays.
 Tablets, coated tablets, capsules, pills and granules can contain more than
 one additives in addition to the active ingredient or ingredients, such as
 (a) fillers and diluents, for example starches, lactose, sucrose, glucose,
 mannitol and silicic acid, (b) binders, for example
 carboxymethylcellulose, alginates, gelatine and polyvinylpyrrolidone, (c)
 humectants, for example glycerol, (d) disintegrants, for example agar,
 calcium carbonate and sodium carbonate, (e) solution retarders, for
 example paraffin, and (f) absorption accelerators, for example quaternary
 ammonium compounds, (g) wetting agents, for example cetyl alcohol and
 glycerol monostearate, (h) adsorbents, for example kaolin and bentonite,
 and (i) lubricants, for example talc, calcium stearate, magnesium
 stearate, and solid polyethylene glycols, or mixtures of the substances
 listed under (a) to (i).
 The tablets, coated tablets, capsules, pills and granules can be provided
 with the customary coatings and shells, optionally containing opacifying
 agents, and can also be of a composition such that they release the active
 ingredient or ingredients only or preferentially in a certain part of the
 intestinal tract, if appropriate in a delayed manner, examples of
 embedding compositions which can be used being polymeric substances and
 waxes.
 If appropriate, the active ingredient or ingredients can also be present in
 microencapsulated form with one or more of the above mentioned excipients.
 Suppositories can contain, in addition to the active ingredient or
 ingredients, the customary water-soluble or water-insoluble excipients,
 for example polyethylene glycols, fats, for example cacao fat, and higher
 esters (for example, C.sub.14 -alcohol with C.sub.16 -fatty acid) or
 mixtures of these substances.
 Ointments, pastes, creams and gels can contain, in addition to the active
 ingredient or ingredients, the customary oxcipients, for example animal
 and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose
 derivatives, polyethylene glycols, silicones, bentonites, silicic acid,
 talc and zinc oxide, or mixtures of these substances.
 Dusting powders and sprays can contain, in addition to the active
 ingredient or ingredients, the customary excipients, for example lactose,
 talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide
 powder, or mixtures of these substances. Sprays can additionally contain
 the customary propellants, for example chlorofluorohydrocarbons.
 Solutions and emulsions can contain, in addition to the active ingredient
 or ingredients, the customary excipients, such as solvents, solubilizing
 agents and emulsifiers, for example water, ethyl alcohol, isopropyl
 alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
 propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in
 particular cottonseed oil, groundnut oil, corn germ oil, olive oil, castor
 oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuyl alcohol,
 polyethylene glycols and fatty acid esters of sorbitan, or mixtures of
 these substances.
 For parenteral. administration, the solutions and emulsions are also be in
 a sterile form which is isotonic with blood.
 Suspensions can contain, in addition to the active ingredient or
 ingredients, the customary excipients, such as liquid diluents, for
 example water, ethyl alcohol and propylene glycol, and suspending agents,
 for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and
 sorbitan esters, microcrystalline cellulose, aluminum metahydroxide,
 bentonite, agar-agar and tragacanth, or mixtures of these substances.
 The formulation forms mentioned can also contain coloring agents,
 preservatives and additives which improve the smell and taste, for example
 peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.
 The therapeutically active ingredients should preferably be present in the
 abovementioned pharmaceutical formuLations in a concentration of about 0.1
 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.
 The abovementioned pharmaceutical formulation can also contain other
 pharmaceutical active compounds in addition to the compounds according to
 the present invention.
 The abovementioned pharmaceutical formulations are prepared in the
 customary manner by known methods, for example by mixing the active
 ingredient or ingredients with vehicles.
 The formulations mentioned can be used on humans and animals either orally,
 rectally, parenterally (intravenously, intramuscularly or subcutaneously),
 intracisternally, intravaginally, intraperitoneally or locally (dusting,
 powder, ointment, drops) and for the therapy of infections in hollow
 spaces and body cavities. Possible suitable formulations are injection
 solutions, solutions and suspensions for oral therapy and gels, infusion
 formulations, emulsions, ointments or drops, ophthalmological and
 dermatological formulations, silver salts and other salts, eardrops, eye
 ointments, dusting powders or solutions can be used for local therapy. In
 the case Of animals, intake can also be in suitable formulations via the
 feed or drinking water.
 Gels, powders, dusting powders, tablets, delayed release tablets, premixes,
 concentrates, granules, pellets, boli, capsules, aerosols, sprays and
 inhalants can further more be used on humans and animals. The compounds
 according to the present invention can moreover be incorporated into other
 carrier materials, such as for example, plastics (chain of plastic for
 local therapy), collagen or bone cement.
 D In general, it has proved advantageous in human medicine to administer
 the active ingredient or ingredients according to the present invention in
 total amounts of about 0.1 to about 100, preferably 0.1 to 20 mg/kg of
 body weight every 24 hours, if appropriate in the form of several
 individual doses, to achieve the desired results. However, it may be
 necessary to deviate from the dosages mentioned, and in particular to do
 so as a function of the nature and body weight of the object to be
 treated, the nature and severity of the disease, the nature of the
 formulation and of the administration of the medicament and the period or
 interval within which administration takes place.
 Thus in some cases it can suffice to manage with less than the
 abovementioned amount of active ingredient, while in other cases the
 abovementioned amount of active ingredient must be exceeded. The
 particular optimum dosage and mode of administration required for the
 active ingredient can be determined by any expert on the basis of his
 expert knowledge.
 The molecular structure of the compounds according to the present invention
 was identified by IR spectroscopy, UV spectroscopy, NMR spectroscopy, mass
 spectroscopy, liquid chromatography, X-ray diffraction, optical rotation
 analysis and elemental analysis.

PREATION EXAMPLES
 The starting materials (III) of scheme 1 or scheme 2 were prepared by the
 following preparation examples.
 Preparation Example 1
 Preparation of
 (2R,3R,4S)-6-nitro-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydr
 o-2H-1-benzopyran and
 (2R,3S,4R)-6-nitro-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydr
 o-2H-1-benzopyran
 (Step 1) Preparation of
 (2R)-6-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopy
 ran
 To a solution of 75 g (0.28 mol) of
 (2R)-6-nitro-2-methyl-2-dimethoxymethyl-2H-1-benzopyran in 1 L of acetone
 was added 1 L of water. To the mixture was added 84 g (0.99 mol) of sodium
 hydrogen carbonate and the mixture was stirred for 10 min. To the mIxture
 was added 174 g (0.28 mol) of oxone and the mixture was strongly stoed.
 Sodium hydrogencarbonate and oxone were added to the mixture three times
 more every 15 min. The reaction mixture was filtered, acetone was removed
 under reduced pressure and the residue was extracted with ethyl acetate
 (500 ml.times.2). The organic layer was dried over anhydrous magnesium
 sulfate, filtered, concentrated and purified by silica gel column
 chromatography (n-hexane:ethyl acetate=4:1) to afford 76 g (yield: 95%) of
 the desired compound as a white solid.
 (Step 2) Preparation of
 (2R,3R,4S)-6-nitro-2-methyl-2-dimetshoxymethyl-3-hydroxy-4-amino-3,4-dihyd
 ro-2H-1-benzopyran and
 (2R,3S,4R)-6-nitro-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydr
 o-2H-1-benzopyran
 8.8 g of the epoxide compound prepared in the step 1 was dissolved in 250
 ml of the saturated ammonia ethanol and the reaction mixture was stirred
 for 7 days at room temperature. The solvent was removed and the residue
 was purified by silica gel column chromatography (n-hexane:ethyl ethyl
 acetate=1:4) to recover 2.58 g of the starting material and to afford 5.6
 g (yield: 60%) of the desired compound as a racemic mixture.
 Preparation Example 2
 Preparation of
 (2S,3R,4S)-6-nitro-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydr
 o-2H-1-benzopyran and
 (2S,3S,4R)-6-nitro-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydr
 o-2H-1-benzopyran
 (Step 1) Preparation of
 (2S)-6-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopy
 ran
 To a solution of 5 g (19 mmol) of
 (2R)-6-nitro-2-methyl-2-dimethoxymethyl-2H-1-benzopyran in 100 ml of
 acetone was added 100 ml of water. To the mixture was added 5.6 g (66
 mmol) of sodium hydrogen carbonate and the mixture was stirred for 10 min.
 To the mixture was added 11.6 g (19 mmol) of oxone and the mixture was
 strongly stirred. Sodium hydrogencarbonate and oxone were added to the
 mixture three times more every 15 min. The reaction mixture was filtered,
 acetone was removed under reduced pressure and the residue was extracted
 with ethyl acetate (100 ml.times.2). The organic layer was dried over
 anhydrous magnesium sulfate, filtered, concentrated under reduced pressure
 and purified by silica gel column chromatography (n-hexane:ethyl
 acetate=4:1) to afford 5.1 g (yield: 97%) of the desired compound, a white
 solid as a racemic mixture.
 (Step 2) Preparation of
 (2S,3R,4S)-6-nitro-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydr
 o-4-amino-3,4-dihydro-2H-1-benzopyran and
 (2S,3S,4R)-6-nitro-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydr
 o-4-amino-3,4-dihydro-2H-1-benzopyran
 5.1 g of the epoxide compound prepared in the step 1 was dissolved in 100
 ml of the saturated ammonia ethanol and the reaction mixture was stirred
 for 7 days at room temperature. The solvent was removed and the residue
 was purified by silica gel column chromatography (n-hexane:ethyl
 acetate=1:4) to afford 4.4 g (yield: 80%) of the desired compound as a
 racemic mixture.
 Preparation Example 3
 Preparation of
 (2R,3R,4S)-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydro-2H-1-b
 enzopyran and
 (2R,3S,4R)-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydro-2H-1-b
 enzopyran
 (Step 1) Preparation of
 (2R)-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran
 To a solution of 400 mg (1.82 mmol) of
 (2R)-2-methyl-2-dimethoxymethyl-2H-1-benzopyran dissolved in 1 ml of DMSO
 was added 82 ul of distilled water. The reaction mixture was allowed to
 cool to 0.degree. C., and to the mixture was added 647 mg of
 N-bromosuccinimide slowly. After 30 min, 1 ml of water was added to the
 mixture and the mixture was extracted with ethyl acetate. The organic
 layer was dried over anhydrous magnesium sulfate, filtered and
 concentrated under reduced pressure. The residue was dissolved in 1 ml of
 dioxane-water (3:1) and 146 mg of NaOH was added to the mixture. The
 reaction mixture was stirred for 24 min at room temperature and extracted
 with ethyl acetate. The organic layer was dried over anhydrous magnesium
 sulfate, filtered and concentrated under reduced pressure. The residue was
 purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1)
 to afford 358 mg (yield: 83%) of the desired compound as a racemic
 mixture.
 (Step 2) Preparation of
 (2R,3R,4S)-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydro-2H-1-b
 enzopyran and
 (2R,3S,4R)-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydro-2H-1-b
 enzopyran
 560 mg (2.37 mmol) of the epoxide compound prepared in the step was
 dissolved in 20 ml of the saturated ammonia ethanol and the reaction
 mixture was stirred for 7 days at room temperature. The solvent was
 removed and the residue was purified by silica gel column chromatography
 (n-hexane:ethyl acetate=1:2) to afford 340 mg (yield: 57%) of the desired
 compound as a racemic mixture.
 Preparation Example 4
 Preparation of
 (2R,3R,4S)-6-nitro-2-methyl-2-hydroxymethyl-3-hydroxy-4-amino-3,4-dihydro-
 2H-1-benzopyran and
 (2R,3S,4R)-2-methyl-2-hydroxymethyl-3-hydroxy-4-amino-3,4-dihydro-2H-1-ben
 zopyran
 (Step 1) Preparation of
 (2R)-6-nitro-2-methyl-2-hydroxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyra
 n
 The reaction with 708 mg (3.20 mol) of
 (2R)-6-nitro-2-methyl-2-hydroxymethyl-2H-1-benzopyran in place of
 (2R)-6-nitro-2-methyl-2-dimethoxymethyl-2H-1-benzopyran as a starting
 material, was performed by the same method to the step 1 of preparation
 example 1. The residue was purified by silica gel column chromatography
 (n-hexane:ethyl acetate=2:1) to afford 625 mg (yield: 82%) of the desired
 compound as a racemic mixture.
 (Step 2) Preparation of
 (2R,3R,4S)-6-nitro-2-methyl-2-hydroxymethyl-3-hydroxy-4-amino-3,4-dihydro-
 2H-1-benzopyran and
 (2R,3S,4R)-2-methyl-2-hydroxymethyl-3-hydroxy-4-amino-3,4-dihydro-2H-1-hen
 zopyran
 625 mg (2.63 mmol) of the epoxide compound prepared in the step 1 was
 dissolved in 10 ml of the saturated ammonia ethanol and the reaction
 mixture was stirred for 7 days at room temperature. The solvent was
 removed and the residue was purified by silica gel column chromatography
 (n-hexane:ethyl acetate=1:5) to afford 328 mg (yield: 49%) of the desired
 compound as a racemic mixture.
 Preparation Example 5
 Preparation of
 (2R,3R,4S)-6-nitro-2-methyl-2-methoxymethyl-3-hydroxy-4-amino-3,4-dihydro-
 2H-1-benzopyran and
 (2R,3S,4R)-2-methyl-2-methoxymethyl-3-hydroxy-4-amino-3,4-dihydro-2H-1-ben
 zopyran
 (Step 1) Preparation of
 (2R)-6-nitro-2-methyl-2-methoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyra
 n
 The reaction with 580 ml g (2.47 mmol) of
 (2R)-6-nitro-2-methyl-2-methoxymethyl-2H-1-benzopyran in place of
 (2R)-6-nitro-2-methyl-2-dimethoxymethyl-2H-1-benzopyran as a starting
 material, was performed by the same method to the step 1 of preparation
 example 1. The residue was purified by silica gel column chromatography
 (n-hexane:ethyl acetate=2:1) to afford 328 mg (yield: ethyl 98% of the
 desired compound as a racemic mixture.
 Step 2) Preparation of
 2R,3R,4S)-6-nitro-2-methyl-2-methoxymethyl-3-hydroxy-4-amino-3,4-dihydro-2
 H-1-benzopyran and
 (2R,3S,4R)-2-methyl-2-methoxymethyl-3-hydroxy-4-amino-3,4-dihydro-2H-1-ben
 zopyran
 607 mg (2.42 mmol) of the epoxide compound prepared in the step 1 was
 dissolved in 10 ml of the saturated ammonia ethanol and the reaction
 mixture was stirred for 7 days at room temperature. The solvent was
 removed and the residue was purified by silica gel column chromatography
 (n-hexane:ethyl acetate=1:4) to afford 345 mg (yield: 53%) of the desired
 compound as a racemic mixture.
 Preparation Example 6
 Preparation of
 (2S,3S,4R)-6-cyano-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydr
 o-2H-1-benzopyran
 The reaction with 1.2 g (4.90 mmol) of
 (2S)-6-cyano-2-methyl-2-dimethoxymethyl-2H-1-benzopyran in place of
 (2R)-6-nitro-2-methyl-2-dimethoxymethyl-2H-1-benzopyran as a starting
 material, was performed by the same method to the step and step 2 of
 preparation example 1. The residue was purified by silica gel column
 chromatography (n-hexane:ethyl acetate=4:1) to afford 0.65 g (yield: 48%)
 of the desired compound of (2S,3S,4R) stereochemistry.
 Preparation Example 7
 Preparation of
 (2S,3R,4S)-6-cyano-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydr
 o-2H-1-benzopyran
 The reaction was performed by the same method to the preparation example 6.
 The residue was purified by silica gel column chromatography
 (n-hexane:ethyl acetate 4:1) to afford 0.30 g (yield: 22%) of the desired
 compound of (2S,3R,4S) stereochemistry.
 Preparation Example 8
 Preparation of
 (2S,3S,4R)-6-bromo-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydr
 o-2H-1-benzopyran
 The reaction with 1.6 g (5.35 mmol) of
 (2S)-6-bromo-2-methyl-2-dimethoxymethyl-2H-1-benzopyran in place of
 (2R)-6-nitro-2-methyl-2-dimethoxymethyl-2H-1-benzopyran as a starting
 material, was performed by the same method to the step 1 and step 2 of
 preparation example 1. The residue was purified by silica gel column
 chromatography (n-hexane:ethyl acetate=1:4) to afford 1.28 g (yield: 72%)
 of the desired compound of (2S,3S, 4R) stereochemistry.
 Preparation Example 9
 Preparation of
 (2S,3S,4R)-4-amino-6-methanesulfonyloxy-4-dihydro-3-hydroxy-2-methyl-2-dim
 ethoxymethyl -2H-1-benzopyran
 The reaction with 2.52 g (8.45 mmol) of
 (2S)-6-methanesulfonyloxy-2-methyl-2-dimethoxymethyl-2H-1-benzopyran in
 place of (2R)-6-nitro-2-methyl-2-dimethoxymethyl-2H-1-benzopyran as a
 starting material, was performed by the same method to the step 1 and step
 2 of preparation example 1. The residue was purified by silica gel column
 chromatography (n-hexane:ethyl acetate 1:5) to afford 1.74 g (yield: 62%)
 of the desired compound of (2S,3S,4R) stereochemistry.
 Preparation Example 10
 Preparation of
 (2R,3S,4R)-4-amino-6-methanesulfonyloxy-3,4-dihydro-3-hydroxy-2-methyl-2-d
 imethoxymethyl-2H-1-benzopyran
 The reaction with 0.79 g (2.65 mmol) of
 (2R)-6-methanesulfonyloxy-2-methyl-2-dimethoxymethyl-2H-1-benzopyran in
 place of (2R)-6-nitro-2-methyl-2-dimethoxymethyl-2H-1-benzopyran as a
 starting material, was performed by the same method to the step 1 and step
 2 of preparation example 1. The residue was purified by silica gel column
 chromatography (n-hexane:ethyl acetate=1:5) to afford 0.60 g (yield: 68%)
 of the desired compound of (2R,3S,4R) stereochemistry.
 Preparation Example 11
 Preparation of
 (2S,3S,4R)-2-methyl-2-([,3]dioxolan-2-yl)-6-nitro-3-hydroxy-4-amino-3,4-di
 hydro-2H-1-benzopyran
 (Step 1) Preparation of
 (2S)-2-methyl-2-([1,3]dioxolan-2-yl)-6-nitro-2H-1-benzopyran
 1 g (3.77 mmol) of (2S)-2-methyl-2-dimethoxymethyl-6-nitro-2H-1-benzopyran,
 0.63 ml (11.31 mmol) of ethylene glycol and 71.7 mg (0.377 mol) of
 p-toluenesulfonic acid were dissolved in 20 ml of toluene, and the
 reaction mixture was refluxed for 5 hours. The reaction mixture was washed
 with saturated aqueous NaHCO solution and extracted with water and ethyl
 acetate. The organic layer was dried over anhydrous magnesium sulfate,
 filtered and concentrated under reduced pressure. The residue was purified
 by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to afford
 0.93 g (yield: 93%) of the desired compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.6 1.48(s, 3H), 3.91-3.97(m, 4H),
 4.95(s, 1H), 5.73(d, 1H), 6.49(d, 1H), 6.83(d, 1H), 7.86(d, 1H), 8.01(dd,
 1H)
 (Step 2) Preparation of
 (2S,3S,4R)-2-methyl-2-([1,3]dioxolan-2-yl)-6-nitro-3-3,1-epoxy-3,4-dihydro
 -2H-1-benzopyran
 Into 100 ml one-neck flask was pouted 25.6 (14.08 mmol) of 0.55M aqueous
 NaOCl solution and 9.6 ml of 0.05M Na.sub.2 HPO.sub.4, and the mixture was
 allowed to cool to 0.degree. C. To the mixture were added 0.93 g (3.52
 mmol) of the compound prepared in the step 1 and 96.22 mg (0.176 mmol) of
 Jacobsen's catalyst (S, S) in 7 ml of methylene chloride.
 The reaction mixture was stirred for 8 hours at room temperature and
 filtered on cellite pad to remove Jacobsen's catalyst. The methylene
 chloride layer was washed with brine, dried over Na.sub.2 SO.sub.4,
 filtered and concentrated under reduced pressure. The residue was purified
 by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to afford
 470 mg (yield: 48%) of the desired compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) 67 1.57(s, 3H), 3.73(d, 1H),
 3.80-3.90(m, 4H), 4.02(d, 1H), 4.96(s, 1H), 6.88(d, 1H), 8.13(dd, 1H),
 8.29(d, 1H)
 (Step 3) Preparation of
 (2S,3S,4R)-2-methyl-2-([1,3]dioxolan-2-yl)-6-nitro-3-hydroxy-4-amino-3,4-d
 ihydro-2H-1-benzopyran
 To a solution of 40 mg (1.68 mmol) of the compound prepared in the step 2
 dissolved in 15 ml of ethanol was added 2.3 ml (16.3 mmol) of 25% NH.sub.4
 OH solution, and the reaction mixture was stirred for 5 (days at
 25.degree. C. Ethanol was removed under reduced pressure. The residue was
 extracted with ethyl acetate, washed with brine, dried over Na.sub.2
 SO.sub.4, filtered and concentrated under reduced pressure. The residue
 was purified by silica gel column chromatography (n-hexane:ethyl
 acetate=1:3) to afford 440 mg (yield: 80%) of the desired compound.
 Preparation Example 12
 Preparation of
 (2S,3S,4R)-2-methyl-2-([1,3]dioxan-2-yl)-6-nitro-3-hydroxy-4-amino-3,4-dih
 ydro-2H-1-benzopyran
 (Step 1) Preparation of
 (2S)-2-methyl-2-([1,3]dioxan-2-yl)-6-nitro-2H-1-benzopyran -
 The reaction of 1 g (3.77 mmol) of
 (2S)-2-methyl-2-dimethoxymethyl-6-nitro-2H-1-benzopyran with 2.73 ml of
 1,3-propanediol, was performed by the same method to the step 1 of
 preparation example 11. The residue was purified by silica gel column
 chromatography (n-hexane:ethyl acetate=6:1) to afford 1 g (yield: 96%) of
 the desired compound.
 (Step 2) Preparation of
 (2S,3S,4S)-2-methyl-2-([1,3]dioxan-2-yl)-6-nitro-3,4-epoxy-3,4-dihydro-2H-
 1-benzopyran
 The reaction was performed by the same method of the step 2 of preparation
 example 11 except using the compound prepared in the above step 1 as a
 starting material. The residue was purified by silica gel column
 chromatography (n-hexane:ethyl acetate=4:1) to afford 0.57 g (yield: 54%)
 of the desired compound.
 (Step 3) Preparation of
 (2S,3S,4R)-2-methyl-2-([1,3]dioxan-2-yl)-6-nitro-3-hydroxy-4-amino-3,4-dih
 ydro-2H-1-benzopyran
 The reaction was performed by the same method of the step 3 of preparation
 exmaple 11 except using the compound prepared in the above step 2 as a
 starting material. The residue was purified by silica gel column
 chromatography (n-hexane:ethyl acetate=1:3) to afford 0.46 g (yield: 76%)
 of the desired compound.
 Preparation Example 13
 Preparation of
 (2S,3S,4R)-2-methyl-2-([1,3]-5,5-dimethyldioxan-2-yl)-6-nitro-3-hydroxy-4-
 amino-3,4-dihydro-2H-1-benzopyran
 (Step 1) Preparation of
 (2S)-2-methyl-2-([1,3]-5,5-dimethyldioxan-2-yl)-6-nitro-2H-1-benzopyran
 The reaction was performed by the same method to the step 1 of preparation
 example 11 except using 1 g (3.77 mmol) of
 (2S)-2-methyl-2-dimethoxymethyl-6-nitro-2H-1-benzopyran and 2,80 ml of
 2,2-dimethyl-1,3-propanediol as a starting material. The residue was
 purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1)
 to afford 1.01 g (yield: 88%) of the desired compound.
 (Step 2) Preparation of
 (2S,3S,4S)-2-methyl-2-([3]-5,5-dimethyldioxan-2-yl)-6-nitro-3,4-epoxy-3,4-
 dihydro-2H-1-benzopyran
 The reaction was performed by the same method of the step 2 of preparation
 exmaple 11 except using the compound prepared in the above step 1 as a
 starting material. The residue was purified by silica gel column
 chromatography (n-hexane:ethyl acetate=4:1) to afford 0.62 g (yield: 58%)
 of the desired compound.
 (Step 3) Preparation of
 (2S,3S,4R)-2-methyl-2-([1,3]-5,5-dimethyldioxan-2-yl)-6-nitro-3-hydroxy-4-
 amino-3,4-dihydro-2H-1-benzopyran
 The reaction was performed by the same method of the step 3 of preparation
 example 11 except using the compound prepared in the above step 2 as a
 starting material. The residue was purified by silica gel column
 chromatography (n-hexane:ethyl acetate=1:3) to afford 0.53 g (yield: 82%)
 of the desired compound.
 Preparation Example 14
 Preparation of
 (2S,3S,4R)-2-methyl-2-diethoxymethyl-6-nitro-3-hydroxy-4-amino-3,4-dihydro
 -2H-1-benzopyran
 (Step 1) Preparation of
 (2S)-2-methyl-2-diethoxymethyl-6-nitro-2H-1-benzopyran
 The reaction was performed by the same method to the step 1 of preparation
 example 11 except using 1 g (3.77 mmol) of
 (2S)-2-methyl-2-dimethoxymethyl-6-nitro-2H-1-benzopyran and 3.0 ml of
 ethanol as a starting material. The residue was purified by silica gel
 column chromatography (n-hexane:ethyl acetate=6:1) to afford 1.01 g
 (yield: 91%) of the desired compound.
 (Step 2) Preparation of
 (2S,3S,4S)-2-methyl-2-diethoxymethyl-6-nitro-3,4-epoxy-3,4-dihydro-2H-1-be
 nzopyran
 The reaction was performed by the same method of the step 2 of preparation
 example 11 except using the compound prepared in the above step 1 as a
 starting material. The residue was purified by silica gel column
 chromatography (n-hexane:ethyl acetate=4:1) to afford 0.71 g (yield: 67.)
 of the desired compound.
 (Step 3) Preparation of
 (2S,3S,4R)-2methy-2-diethoxymethyl-6-nitro-3-hydroxy-4-amino-3,4-dihydro-2
 H-1-benzopyran
 The reaction was performed by the same method of the step 3 of preparation
 example 11 except using the compound prepared in the above step 2 as a
 starting material. The residue was purified by silica gel column
 chromatography (n-hexane:ethyl acetate=1:3) to afford 0.65 g (yield: 86%)
 of the desired compound.
 Preparation Example 15
 Preparation of
 (2S,3S,4R)-2-methyl-2-dimethoxymethyl-6-methoxycarbonyl-3-hydroxy-4-amino-
 3,4-dihydro-2H-1-benzopyran
 The reaction was performed by the same method to the step 1 and step 2 of
 preparation example 1 except using 1.41 g (5.32 mmol) of
 (2S)-2-methyl-2-dimethoxy methyl-6-methoxycarbonyl-2H-1-benzopyran as a
 starting material. The residue was purified by silica gel column
 chromatography (n-hexane:ethyl acetate=1:4) to afford 0.86 g (yield: 52%)
 of the desired compound.
 Preparation Example 16
 Preparation of
 (2R,3S,4R)-2-methyl-2-dimethoxymethyl-6-methoxycarbonyl-3-hydroxy-4-amino-
 3,4-dihydro-2H-1-benzopyran
 The reaction was Performed by the same method to the step 1 and step 2 of
 preparation example 1 except using 1.27 g (4.79 mmol) of
 (2R)-2-methyl-2-dimethoxy methyl-6-methoxycarbonyl-2H-1-benzopyran as a
 starting material. The residue was purified by silica gel column
 chromatography (n-hexane:ethyl acetate=1:4) to afford 0.85 g (yield: 57%)
 of the desired compound.
 Preparation Example 17
 Preparation of
 (3S,4R)-2-methyl-2-dimethoxymethyl-8-nitro-3-hydroxy-4-amino-3,4-dihydro-2
 H-1-benzopyran
 The reaction was performed by the same method to the step 1 and step 2 of
 preparation example 1 except using 1.82 g (6.86 mmol) of
 (2S)-2-methyl-2-dimethoxy methyl-8-nitro-2H-1-benzopyran as a starting
 material. The residue was purified by silica gel column chromatography
 (n-hexane:ethyl acetate=1:4) to afford 1.31 g (yield: 64%) of the desired
 compound.
 EXAMPLES
 The compounds of formula 1 were prepared by the following examples.
 Example 1
 Preparation of
 (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine
 To a solution of 508 mg of N-cayno-N'-(4-chlorophenyl)thiourea sodium salt
 and 500 mg (1.68 mmol) of the aminoalcohol compound prepared in the
 preparation example 1 dissolved in 5 ml of DMF was added 418 mg of
 1-[3-(dimethylamino)propyl]-2-ethylcarbodiimide hydrochloride. The
 reaction mixture was stirred for 5 hours at room temperature, and
 extracted with ethyl acetate (30 ml.times.2) after acidifying the mixture
 by adding 10 ml of 1N HCl. The organic layer was washed with water and
 brine, dried over anhydrous magnesium sulfate and concentrated under
 reduced pressure. The residue was purified by silica gel column
 chromatography (n-hexane:ethyl acetate=1:1) to afford 260 mg (yield: 339')
 of the desired compound of (2R,3R,4S) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.35(s, 3H), 3.36(d, 6H),
 3.85(t, 1H, 4.59(s, 1H), 5.10(t, 1H), 5.97(s, 1H), 6.3(d, 1H), 7.35(dd,
 4H), 7.62(d, 1H), 8.01(d, 2H), 9.44(s, 1H).
 Example 2
 Preparation of
 (2R,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine
 The reaction was performed by the same method to the example 1. The residue
 was purified by silica gel column chromatography (n-hexane:ethyl
 acetate=1:4) to afford 200 mg (yield: 25%) of the desired compound of
 (2R,3S, 4R) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) 67 1.23(s, 3H), 3.42(d, 6H), 4.07(t,
 1H), 4.48(s, 1H), 4.99(t, 1H), 5.80(s, 1H), 6.96(d, 1H), 7.36(dd, 4H),
 7.76(s, 1H), 8.03(s, 2H), 9.48(s, 1H)
 Example 3
 Preparation of
 (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-chlorophenyl)guanidine
 To a solution of 508 mg of N-cyano-N'-(4-chlorophenyl)thiourea sodium salt
 and 500 mg of the aminoalcohol compound prepared in the preparation
 example 1 dissolved in 5 ml of DMF was added 418 mg of
 1-[3-(dimethylamino)propyl]-2-ethylcarbodiimide hydrochloride. The
 reaction mixture was stirred for 6 hours at room temperature, and
 extracted with ethyl acetate (30 ml.times.2) after acidifying the mixture
 by adding 10 ml of 1N HCl. The organic layer was washed with water and
 brine, dried over anhydrous magnesium sulfate and concentrated under
 reduced pressure. The residue was purified by silica gel column
 chromatography (n-hexane:ethyl acetate=1:1) to afford 230 mg (yield: 29%)
 of the desired compound of (2R,3R,4S) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.35(s, 3H), 3.38(d, 6H),
 3.88(s, 3H), 4.59(s, 1H), 5.11(s, 1H), 5.97(s, 1H), 6.94(d, 1H), 7.28(m,
 4H), 7.79(d, 1H), 8.04(m, 2H), 9.49(s, 1H)
 Example 4
 Preparation of
 (2R,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-chlorophenyl)guanidine
 The reaction was performed by the same method to the example 3. The residue
 was purified by silica gel column chromatography (n-hexane:ethyl
 acetate=1:4) to afford 200 mg (yield: 25%) of the desired compound of
 (2R,3S, 4R) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.23(s, 3H), 3.42(d, 5H),
 4.08(t, 1H), 4.49(s, 1H), 4.99(t, 1H), 6.98(d, 1H), 7.30(m, 4H), 7.91(d,
 1H), 8.04(d, 2H), 9.6(s, 1H)
 Example 5
 Preparation of
 (2R,3R,4S)-N"-cyano-1-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-nitrophenyyl)guanidine
 To a solution of 532 mg of N-cyano-N'-(4-nitrophenyl)thiourea sodium salt
 and 500 mg of the aminoalcohol compound prepared in the preparation
 example 1 dissolved in 5 ml of DMF was added 418 mg of
 1-[3-(dimethylamino)propyl-2-ethylcarbodiimide hydrochloride. The reaction
 mixture was stirred for 6 hours at room temperature, and extracted with
 ethyl acetate (30 ml.times.2) after acidifying the mixture by adding 10 ml
 of 1N HCl. The organic layer was washed with water and brine, to dried
 over anhydrous magnesium sulfate and concentrated under reduced pressure.
 The residue was purified by silica gel column chromatography
 (n-hexane:ethyl acetate=1:1) to afford 210 mg (yield: 26%) of the desired
 compound of (2R,3R,4S) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.36(s, 3H), 3.38(d, 6H),
 3.88(t, 1H), 4.60(s, 1H), 5.12(t, 1H) 6.2(s, 1H), 6.97(d, 1H), 7.48(d,
 1H), 8.04(dd, 1H), 8.11(s, 1H), 8.20(d, 2H), 8.33(d, 1H), 10.07(s, 1H)
 Example 6
 Preparation of
 (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl )-N'-(3-trifluoromethylphenyl)guandine
 To a solution of 500 mg of N-cyano-N'-(4-tri-fluoromethylphenyl)thiourea
 sodium salt and 500 mg of the aminoalcohol compound prepared in the
 preparation example 1 dissolved in 5 ml of DMF was added 418 mg of
 1-[3-(dimethylamino))propyl]-2-ethylcarbodiimide hydrochloride. The
 reaction mixture was stirred for 5 hours at room temperature, and
 extracted with ethyl acetate (30 ml.times.2) after acidifying the mixture
 by adding 10 ml of 1N HCl. The organic layer was washed with water and
 brine, dried over anhydrous magnesium sulfate and concentrated under
 reduced pressure. The residue was purified by silica gel column
 chromatography (n-hexane:ethyl acetate=1:1) to afford 250 mg,(yield: 29%)
 of the desired compound of (2R,3R,4S) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.34(s, 3H), 3.38(d, 6H),
 3.38(t, 1H), 4.59(s, 1H), 5.10(t, 1H), 6.0(s, 1H), 6.94(d, 1H), 7.52(d,
 1H), 7.57(m, 3H), 7.86(d, 1H), 8.02(dd, 1H), 8.09(s, 1H)
 Example 7
 (2R,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxyme
 thyl-2H-benzopyran-4-yl)-N'-(3-trifluoromethylphenyl)guanidine
 The reaction was performed by the same method to the example 6. The residue
 was purified by silica gel column chromtography (n-hexane:ethyl acetate=1)
 to afford 200 mg (yield: 23%) of the desired compound of (2R,3S, 4R)
 stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.23(s, 3H), 3.43(d, 6H),
 4.08(t, 1H), 4.49(s, 1H), 5.01(t, 1H), 5.85(s, 1H), 6.98(d, 1H), 7.49(d,
 1H), 7.60(m, 3H), 8.03(m, 3H), 9.7(s, 1H)
 Example 8
 Preparation of
 (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-methoxyphenyl)guanidine
 To a solution of 500 mg of N-cyano-N'-(4-methoxyphenyl)thiourea sodium salt
 and 500 mg of the aminoalcohol compound prepared in the preparation
 example 1 dissolved in 5 ml of DMF was added 418 mg of
 1-[3-(dimethylamino)propyl]-2-ethylcarbodiimide hydrochloride. The
 reaction mixture was stirred for 5 hours at room temperature, and
 extracted with ethyl acetate (30 ml.times.2) after acidifying the mixture
 by adding 10 ml of 1N HCl. The organic layer was washed with water and
 brine, dried over anhydrous magnesium sulfate and concentrated under
 reduced pressure. The residue was purified by silica gel chromatography
 (n-hexane:ethyl acetate=1:1) to afford 49 mg (yield: 6%) of the desired
 compound of (2R,3R,4S) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz), .delta.1.24(s, 3H), 3.35(d, 6H),
 compound of (2R,2R,4S) stereochemistry.
 .sup.1 H NMR (DMSO-.sub.6, 300 MHz) .delta.1.24(s, 3H), 3.55(d, 6H),
 3.70(s, 3H), 4.08(t, 1H), 4.45(s, 1H), 5.64(d, 1H), 5.78(t, 1H), 6.93 (m,
 3H), 7.24(d, 2H), 8.02(d, 2H), 8.17(s, 1H), 9.59(s, 1H)
 Example 9
 Preparation of
 (2R,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-methoxyphenyl)guanidine
 The reaction was performed by the same method to the example 8. The residue
 was performed by silica gel chromatography (n-hexane:ethyl acetate=1:1) to
 afford 190 mg (yield: 24%) of the desired compound of (2R,3S, 4R)
 stereochemistry.
 .sup.1 H NMR (DMSO-.sub.6, 300 MHz) .delta.1.33(s, 3H), 3.38(d, 6H),
 3.72(s, 3H), 3.78(t, 1H), 4.58(s, 1H), 5.10(t, 1H), 5.88(s, 1H), 6.19(d,
 3H), 7.20(d, 3H), 7.20(d, 3H), 7.97(s, 1H), 9.14(s, 1H)
 Example 10
 Preparation of
 (2S,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine
 To a solution of 508 mg of N-cyano-N'-(4-chlorophenyl)thiourea sodium salt
 and 500 mg of the aminoalcohol compound prepared in the preparation
 example hydrochloride. The reaction mixture was stirred for 5 hours at
 room temperature, and extracted with ethyl acetate (30 ml.times.2) after
 acidifying the mixture by adding 10 ml of 1N HCl. The organic layer was
 washed with water and brine, dried over anhydrous magnesium sulfate and
 concentrated under reduced pressure. The residue was purified by silica
 gel chromatography (n-hexane:ethyl acetate=1:1) to afford 260 mg (yield:
 33%) of the desired compound of (2S, 3R,4S) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.35(s, 3H), 3.37(d, 6H),
 3.85(t, 1H), 4.59(s, 1H), 5.11(t, 1H), 5.91(s, 1H), 6.93(d, 1H), 7.35(dd,
 4H), 7.63(d, 1H), 8.01(d, 2H), 9.44(s, 1H)
 Example 11
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine
 The reaction was performed by the same method to the example 10. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 200 mg (yield: 25%) of the desired compound of
 (2S,3S,4R) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.23(s, 3H), 3.43(d, 6H),
 4.05(t, 1H), 4.48(s, 1H), 4.99(t, 1H), 5.81(s, 1H), 6.97(d, 1H), 7.37(dd,
 4H), 7.76(s, 1H), 8.03(s, 2H), 9.49(s, 1H)
 Example 12
 Preparation of
 (2S,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-chlorophenyl)guanidine
 The reaction was performed by the same method to the example 10. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 188 mg (yield: 24%) of the desired compound of
 (2S,3R, 4S) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.35(s, 3H), 3.43(d, 6H)
 3.88(t, 1H), 4.60(s, 1H), 5.11(t, 1H), 5.97(s, 1H), 6.95(d, 1H), 7.17(d,
 1H), 7.25(d, 1H), 7.34(d, 2H), 7.79(d, 1H), 8.03(m, 2H), 9.49(s, 1H)
 Example 13
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-chlorophenyl)guanidine
 The reaction was performed by the same method to the example, 12. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 270 mg (yield: 34%) of the desired compound of
 (2S,3S,4R) streochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.18(s, 3H), 3.43(d, 6H),
 4.09(t, 1H), 4.49(s, 1H), 5.00(t, 1H), 5.85(s, 1H), 6.98(d, 1H), 7.29(d,
 1H), 7.37(d, 1H), 7.40(m, 2H), 7.91(d, 1H), 8.05(m, 2H)
 Example 14
 Preparation of
 (2S,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-trifluoromethylphenyl)guanidine
 The reaction was performed by the same method to the example 10 except
 using 582 mg of N-cyano-N'-(3-trifluoromethylphenyl)thiourea sodium salt
 and 500 mg of the aminoalcohol compound prepared in the preparation
 example 2. The residue was purified by silica gel chromatography
 (n-hexane:ethyl acetate=1:1) to afford 220 mg (yield: 26%) of the desired
 compound of (2S,3R, 4S) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.34(s, 3H), 3.43(d, 6H),
 3.88(t, 1H), 4.60(s, 1H), 5.11(t, 1H), 5.95(s, 1H), 6.95(d, 1H), 7.45(d,
 1H), 7.57(m, 3H), 7.88(d, 1H), 8.03(dd, 1H), 8.10(s, 1H), 9.62(s, 1H)
 Example 15
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-trifluoromothyl phenyl)guanidine
 The reaction was performed by the same method to the example 14. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 320 mg (yield: 37%) of the desired compound of
 (2S,3S, 4R) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.24(s,3 H), 3.43(d, 6H),
 4.08(t, 1H), 4.49(s, 1H), 5.01(t, 1H), 5.82(s, 1H), 6.98(d, 1H), 7.47 (d,
 1H), 7.57 (m, 3H), 7.98(d, 1H), 8.03 (m, 2H), 9.67(s, 1H)
 Example 16
 Preparation of
 (2S,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2-benzopyran-4-yl)-N'-(4-methoxyphenyl)guanidine
 The reaction was performed by the same method to the example 10 except
 using 500 mg of N-cyano-N'-(4-methoxyphenyl)thiourea sodium salt and 500
 mg of the aminoalcohol compound prepared in the preparation example 2. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 170 mg (yield: 21%) of the desired compound of
 (2S,3R, 4S) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.33(s, 3H), 3.36(d, 6H),
 3.72(s, 3H), 3.86(t, 1H), 4.58(s, 1H), 5.09(t, 1H), 5.88(s, 1H), 6.91(d,
 3H), 7.20(d, 3H), 7.97(s, 1H), 8.00(d, 1H)
 Example 17
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-methoxyphenyl)guanidine
 The reaction was performed by the same method to the example 16. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 270 mg (yield: 34%) of the desired compound of
 (2S,3S,4R) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.22(s, 3H), 3.38(d, 6H),
 3.72(s, 3H), 4.06(t, 1H), 4.45(s, 1H), 4.99(t, 1H), 5.75(s, 1H), 6.93(t,
 3H), 7.20(d, 2H), 7.35(s, 1H), 8.01(s, 1H), 8.03(d, 1H), 9.19(s, 1H)
 Example 18
 Preparation of
 (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-methylphenyl)guanidine
 The reaction was performed by the same method to the example 1 except using
 465 mg of N-cyano-N'-(4-methylphenyl)thiourea sodium salt and 500 mg of
 the aminoalcohol compound prepared in the preparation example 2. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 158 mg (yield: 21%) of the desired compound of
 (2R,3R,4S) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.34(s, 3H), 2.26(s, 3H),
 3.37(d, 6H), 3.87(s, 1H), 4.59(s, 1H), 5.11(t, 1H), 5.93(s, 1H), 6.92(d,
 1H), 7.16(s, 3H), 7.38(d, 1H), 8.00 (1H, 2H), 9.24(s, 1H)
 Example 19
 Preparation of
 (2R,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-methylphenyl)guanidine
 The reaction was performed by the same method to the example 18. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 250 mg (yield: 33%) of the desired compound of
 (2R,3S,4R) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.22(s, 3H), 2.26(s, 3H),
 3.38(d, 6H), 4.06(t, 1H), 4.46(s, 1H), 4.99(t, 1H), 5.74(s, 1H), 6.95(d,
 1H), 7.16(s, 3H), 7.53(s, 1H), 8.02(d, 2H), 9.28(s, 1H)
 Example 20
 Preparation of
 (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-methoxybenzyl)quanidine
 The reaction was performed by the same method to the example 1 except using
 530 mg of N-cyano-N'-4-methoxybenzyl)thiourea sodium salt and 500 mg of
 the aminoalcohol compound prepared in the preparation example 1. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 134 mg (yield: 16%) of the desired compound of
 (2R,3R,4S) stereochemistry.
 .sup.1 H NMR (CDCl.sub.3, 300 MHz) .delta.1.47(s, 3H), 3.51(d, 6H), 3.77(s,
 3H), 3.80(d, 2H), 4.44(t, 1H), 4.56(s, 1H), 5.32(m, 1H), 6.06(s, 1H),
 6.40(d, 1H), 6.90(m, 3H), 7.12(m, 2H), 7.30(d, 1H), 8.00(dd, 1H), 8.03(s,
 1H)
 Example 21
 Preparation of
 (2R,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-methoxybenzyl)guanidine
 The reaction was performed by the same method to the example 20. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 140 mg (yield: 17%) of the desired compound of
 (2R,3S,4R) stereochemistry.
 .sup.1 H NMR (CDCl.sub.3, 300 MHz) .delta..SIGMA.1.32(s, 3H), 3.49(s, 6H),
 3.58(t, 1H), 3.77(s, 3H), 4.04(d, 1H), 4.41(s, 1H), 4.65(s, 2H), 6.35(s,
 1H), 6.88(dd, 4H), 7.26(d, 2H), 8.04(dd, 1H), 8.08(s, 1H)
 Example 22
 Preparation of (2R,3R,
 4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2
 H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the example except using
 465 mg of N-cyano-N'-benzylthiourea sodium salt and 500 mg of the
 aminoalcohol compound prepared in the preparation example 1. The residue
 was purified by silica gel chromatography (n-hexane:ethyl acetare=1:1) to
 afford 260 mg (yield: 34%) of the desired compound of (2R,3R,4S)
 stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.24(s, 3H), 3.41(m, 1H),
 3.44(d, 6H), 4.04(m, 1H), 4.51(s, 1H), 4.76(s, 2H), 5.70(s, 1H), 6.98(d,
 1H), 7.32 (m, 4H), 8.03(m, 2H), 8.16(s, 1H)
 Example 23
 Preparation of
 (2R,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the example 22. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 200 mg (yield: 26%) of the desired compound of
 (2R,3S,4R) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.26(s, 3H), 3.36(d, 6H),
 3.44(d, 1H), 3.87(t, 1H)), 4.44(d, 21), 4.56(s, 2H), 5.02(t, 1H), 5.86(s,
 1H), 6.94(d, 1H), 1.29(m, 4H), 7.75(t, 1H), 7.93(s, 1H), 7.99(dd, 1H)
 Example 24
 Preparation of
 (2S,3R,4S)-N'-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-cenzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the example 10 except
 using 508 mg of N-cyano-N'-benzylthiourea sodium salt and 500 mg of the
 aminoalcohol compound prepared in the preparation example 2. The residue
 was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1) to
 afford 170 mg (yield: 22%) of the desired compound of (2S,3R,4S)
 stereochemistry.
 .sup.1 H NMR (CDCl.sub.3, 300 MHz) .delta.1.27(s, 3H), 3.48(d, 6H), 3.5(m,
 1H), 4.02(d, 1H), 4.48(s, 1H), 4.75(s, 2H), 6.0(s, 1H), 6.72(s, 1H),
 6.87(d, 1H), 7.30(m, 5H), 8.0(d, 1H), 8.02(s, 1H)
 Example 25
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the example 24. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 190 mg (yield: 25%) of the desired compound of
 (2S,3S,4R) stereochemistry.
 .sup.1 H NMR (CDCl.sub.3, 300 MHz) .delta.1.31(s, 3H), 3.44(d, 6H), 3.5(m,
 1H), 3.71(d, 1H), 4.47(s, 1H), 5.14(m, 2H), 5.69(s, 1H), 6.70(s, 1H),
 6.58(d, 1H), 7.25(m, 5H), 8.0(d, 1H) 8.02(s, 1H)
 Example 26
 Preparation of
 (2R,3R,4S)-N"-cyano-N-(3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H
 -benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine
 The reaction was performed by the same method to the example 1 except using
 500 mg of N-cyano-N'-(4-chlorophenyl)thiourea sodium salt and 500 mg of
 the aminoalcohoL compound prepared in the preparation example 3. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 170 mg (yield: 23%) of the desired compound of
 (2R,3R,4S) stereochemistry.
 .sup.1 H NMR (DMISO-d.sub.6, 300 MHz) .delta.1.25(s, 3H), 3.37(d, 6H),
 3.82(t, 1H), 4.52(s, 1H), 5.00(t, 1H), 5.45(s, 1H), 6.71(d, 1H), 6.90(t,
 1H), 7.10(m, 2H), 7.24(d, 2H), 7.38(d, 2H) 7.54(d, 1H), 9.24(s, 1H)
 Example 27
 Preparation of
 (2R,3S,4R)-N"-cyano-N-(3,4-dihydro-3-dydroxy-2-methyl-2-dimethoxymethal-2H
 -benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine
 The reaction was performed by the same method to the example 26. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 190 mg (yield: 26%) of the desired compound of
 (2R,3S,4R) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.16(s, 3H), 3.40(d, 6H),
 4.01(t, 1H), 4.43(s, 1H), 4.92(t, 1H), 5.48(s, 1H), 6.72(d, 1H), 6.90(t,
 1H), 7.15(m, 3H), 7.31(m, 4H), 7.67(s, 1H), 9.29(s, 1H)
 Example 28
 Preparation of
 (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-hydroxymet
 hyl-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine
 The reaction was performed by the same method to the example except using
 289 mg of N-cyano-N'-(4-chlorophenyl)thiourea sodium salt and 210 mg of
 the aminoalcohol compound prepared in the preparation example 4. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 40 mg (yield: 11%) of the desired compound Of
 (2R,3R,4S) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.35 s, 3), 3.5 (m, 1H),
 3.75(m, 1H), 4.95(t, 1H), 5.2(t, 1H), 6.0(s, 1H), 6.97(d, 1H), 7.4(m, 4),
 7.7(d, 1H), 8.0(m, 2H), 9.51(s, 1H)
 Example 29
 Preparation of
 (2R,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-hydroxymet
 hyl-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine
 The reaction was performed by the same method to the example 28. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 40 mg (yield: 11%) of the desired compound of
 (2R,3S,4R) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.2(s, 3H), 3.65 (m, 2H)
 4.11(t, 1H), 5.08(t, 1H), 5.85(s, 1H), 7.01(d, 1H), 7.4(m, 4H), 7.9(d,
 1H), 8.1(d, 2H), 9.58(s, 1H)
 Example 30
 Preparation of
 (2R,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-methoxymet
 hy-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine
 The reaction was performed by the same method to the example 1 except using
 800 mg of N-cyano-N'-(4-chlorophenyl)thiourea sodium salt and 200 mg of
 the aminoalcohol compound prepared in the preparation example 5. The
 residue was purified by silica gel chromatography (n-hexane ethyl
 acetate=1:1) to afford 108 mg (yield: 32 32%) of the desire compound of
 (2R,3R,4S) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.4(s, 3H), 3.15(s, 3H),
 3.45(d, 1H), 3.64(d, 1H), 3.8(t, 1H), 5.08(t, 1H), 6.09(s, H), 6.94(d,
 1H), 7.34(dd, 4H), 7.64(s, 1H), 8.01(d, 2H), 9.5(s, 1H)
 Example 31
 Preparation of
 (2R,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-methoxymet
 hyl-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine
 The reaction was performed by the same method to the example 30. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 107 mg (yield: 32%) of the desired compound of
 (2R,3S,4R) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.15(s, 3H), 3.3(s, 3H),
 3.45(d, 1H), 3.6(d, 1H), 4.06(t, 1H), 5.00(t, 1H), 5.9(s, 1H), 6.96(d,
 1H), 1.34(dd, 4H), 7.8(s, 1H), 8.0(m, 2H), 7.48(s, 1H)
 Example 32
 Preparation of
 (2S,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(2-chlorophenyl)guanidine
 The reaction was performed by the same method to the example 10 except
 using 508 mg of N-cyano-N-40 -(2-chlorophenyl)thiourea sodium salt and 500
 mg of the aminoalcohol compound prepared in the preparation example 2. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 188 mg (yield: 24%) of the desired compound of
 (2S,3R,4S) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.35(s, 3H), 3.43(d, 6H),
 3.88(t, 1H), 4.60(s, 1H), 5.11(t, 1H), 5.97(s, 1H), 6.95(d, 1H), 7.17(d,
 1H) 7.25(d, 1H), 7.34(d, 2H), 7.19(d, 1H), 8.03(m, 2H), 9.49(s, 1H)
 Example 33
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(2-chlorophenyl)guanidine
 The reaction was performed by the same method to the example 32. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 270 mg (yield: 34%) of the desired compound of
 (2S,3S,4R) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.24(s, 3H), 3.43(d, 6H),
 4.10(t, 1H, 4.49(s, 1H), 5.00(s, 1H), 5.85(s, 1H), 6.98(d, 1H), 7.19(d,
 1H), 7.28(d, 1H), 7.35(m, 2H), 7.10(d, 1H), 8.05(d, 1H), 9.53(s, 1H)
 Example 34
 Preparation of
 (2S,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(2-trifluoromethylphenyl)guanidine
 The reaction was performed by the same method to the example 10 except
 using 582 mg of N-cyano-N'-(2-trifluoromethylphenyl)thiourea sodium salt
 and 500 mg of the aminoalcohol compound prepared in the preparation
 example 2. The residue was purified by silica gel chromatography
 (n-hexane:ethyl acetate=1:1) to afford 220 mg (yield: 26%) of the desired
 compound of (2S,3R,4S) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.34(s, 3H), 3.43(d, 6H),
 3.88(t, 1H), 4.60(s, 1H), 5.11(t, 1H), 5.97(s, 1H), 6.95(d, 1H), 7.45(d,
 1H), 7.60(m, 3H), 7.87(d, 1H), 8.03(dd, 1H), 8.10(s, 1H), 9.62(s, 1H)
 Example 35
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(2-trifluoromethylphenyl,)guanidine
 The reaction was performed by the same method to the example 34. The
 residue was purified by silica gel chromography (n-hexane:ethyl
 acetate=1:1) to afford 320 mg (yield: 37%) of the desired compound of
 (2S,3S, 4R) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.24(s, 3H), 3.43(d, 6H),
 4.08(t, 1H), 4.49(s, 1H), 5.00(s, 1H), 5.82(s, 1H), 6.98(d, 1H), 7.47(d,
 1H), 7.61(dd, 3H), 8.03(m, 3H), 9.67(s, 1H)
 Example 36
 Preparation of
 (2S,3R,4S)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl
 -2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-(2-chlorobenzyl)guanidine
 The reaction was performed by the same method to the example 10 except
 using 540 mg of N-cyano-N'-(2-chlorobenzyl)thiourea sodium salt and 500 mg
 of the aminoalcohol compound prepared in the preparation example 2. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 73 mg (yield: 9%) of the desired compound of
 (2S,3R,4S) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.36(s, 3H), 3.47(d, 6H),
 3.68(s, 1H), 4.13 (m, 1H), 4.39(s, 1H), 4.52(s, 2H), 5.57(s, 1), 6.6(s,
 1H), 6.88 (m, 1H), 7.25 (m, 6H), 8.01(d, 1H), 8.16(s, 1H)
 Example 37
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(2-chlorobenzyl)guanidine
 The reaction was performed by the same method to the example 36. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 100 mg (yield: 12%) of the desired compound of
 (2S,3S, 4R) stereochemistry.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.28(s, 3H), 3.5(d, 6H), 3.6(s,
 1H), 3.98(d, 1H), 4.53(m, 3H), 5.61(d, 1H), 5.89(t, 1H), 6.88(d, 1H), 7.25
 (m, 3H), 7.40(d, 1H), 8.02(m, 2H), 8.14(s, H)
 Example 38
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-acetoxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 To a solution of 68 mg (0.15 mmol) of the compound prepared in the example
 25 dissolved in 3 ml of methylene chloride were added 21 ul of acetic
 anhydride, 42 ul of triethylamine and 2 mg of DMAP
 (4-(dimethylamino)pyridine). The reaction mixture was stirred for 5 hours
 at room temperature and extracted with ethyl acetate (10 ml.times.2) after
 adding 5 ml of water. The organic layer was washed with water and brine,
 dried over anhydrous magnesium sulfate, filtered and concentrated under
 reduced pressure. The residue was purified by silica gel chromatography
 (n-hexane:ethyl acetate=1:1) to afford 67 mg (yield: 90%) of the desired
 compound.
 .sup.1 H NMR (DLSO-d.sub.6, 300 MHz) .delta.1.3(s, 3H), 1.25(s, 1H), 2.1(s,
 1H), 3.3(s, 3H), 3.5(s, 3H), 4.35(s, 1H), 4.52(s, 2H), 5.25(m, 1H) 5.32(s,
 1H), 6.98(d, 2H), 7.38(s, 5H), 8.15(d, 2H)
 Example 39
 Preparation of
 (2S)-N"-cyano-N-(6-nitro-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'
 -benzylguanidine
 To a solution of 54 mg (0.11 mmol) of the compound prepared in the example
 38 dissolved in 2 ml of toluene was added 24 ul (0.1628 mol) of DBU. The
 reaction mixture was stirred for 24 hours at room temperature and
 extracted with ethyl acetate. The organic layer was dried over anhydrous
 magnesium sulfate, filtered and concentrated under reduced pressure. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:1) to afford 31 mg (yield: 64%) of the desired compound.
 .sup.1 H NMR (DMSO-d.sub.6, 300 MHz) .delta.1.43(s, 3H), 3.29(s, 3H),
 3.39(s, 3H), 4.21(s, 1H), 4.59(d, 2H), 5.45(s, 1H), 7.02(d, 1H), 7.36(m,
 5H), 8.29(dd, 2H), 8.82(d, 1H)
 Example 40
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 To a solution of 1.11 g of the compound prepared in the example 24
 dissolved in 20 ml of methanol was added 10 ml of the saturated cupric
 acetate solution. To this mixture was added 276 mg of sodium borohydride
 slowly. The reaction mixture was stirred for 3 hours at room temperature
 and extracted with 100 ml of ethyl acetate after adding 50 ml of water.
 The organic layer was dried over anhydrous magnesium sulfate, filtered and
 concentrated under reduced pressure. The residue was purified by silica
 gel chromatography (n-hexane:ethyl acetate=1:3) to afford 576 mg (yield:
 56%) of the desired compound.
 .sup.1 H NMR (CDCl.sub.3, 300 MHz) .delta.1.21(s, 3H), 3.58(s, 3H), 3.59(s,
 3H), 4.14(d, 1H), 4.30(s, 1H), 4.45(d, 1H), 4.47(d, 1H), 5.46(d, 1H),
 6.60-6.66((m, 3H), 7.32-7.36(m, 5H)
 Example 41
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-acetoxyamino-3,4-dihydro-3-hydroxy-2-methyl-2-dim
 ethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 To a solution of 50 mg of the compound prepared in the example, 40
 dissolved in 2 ml of methylene chloride were added 25 ul of triethylamino
 and 10 ul of acetyl chloride.
 The reaction mixture was stirred for 1 hour at room temperature and
 extracted with 10 ml of water and 20 ml of ethyl acetate. The organic
 layer was dried over anhydrous magnesium sulfate, filtered and
 concentrated under reduced pressure. The residue was purified by silica
 gel chromatography (n-hexane:ethyl acetate=1:2) to afford 51 mg (yield:
 92%) of the desired compound.
 .sup.1 H NMR (DMSO-d.sub.6, 200 MHz) .delta.1.15(s, 3H), 1.96(s, 3H),
 3.38(s, 3H), 3.51(s, 3H), 3.98(m, 2H), 4.30(s, 1H), 4.38-4.49(m, 2H),
 5.22(br s, 1H), 5.48(br s, 1H), 6.64(d, 1H), 7.31(br s, 5H), 7.61(br s,
 1H), 7.94(s, 1H), 9.76(s, 1H)
 Example 42
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-methanesulfonylamino-3,4-dihydro-3-hydroxy-2-meth
 yl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 To a solution of 91 mg of the compound prepared in the example 40 dissolved
 in 2 ml of methylone chloride were added 45 ul of triethylamine and 20 ul
 of methanesulfonyl chloride. The reaction mixture was stirred for 2 hours
 at room temperature and extracted with 10 ml of water and 20 ml of ethyl
 acetate. The organic layer was dried over anhydrus magnesium sulfate,
 filtered and concentrated under reduced pressure. The residue was purified
 by silica gel chromatography (n-hexane:ethyl acetate=1:2) to afford 90 mg
 (yield: 85%) of the desired compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.25(s, 3H), 2.90(s, 3H), 3.57(s,
 6)H), 4.10(d, 1H), 4.25(d, 1H), 4.34(s, 1H), 4.43(d, 1H), 4.50(d, 1H),
 4.61(t, 1H), 5.83(d, 1H), 6.78(d, 1H), 7.20-7.38(m, 7H), 8.18(br s, 1H)
 Example 43
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-cyano-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine
 To a solution of 100 mg of
 (2S,3S,4R)-6-cyano-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydr
 o-2H-1-benzopyran prepared in the preparation example 6 is dissolved in 3
 ml of DMF, were added 92 mg of N-cyano-N'-(4-chlorophenyl)thiourea sodium
 salt and 89 mg of 1-[3-(dimethylamino)propyl]-2-ethylcarbodiimide
 hydrochloride. The reaction mixture was stirred for 6 hours at room
 temperature, and extracted with 30 ml of ethyl acetate after acidifying
 the mixture by adding 5 ml of 1N HCl. The organic Layer was dried over
 anhydrous magnesium sulfate and concentrated under reduced pressure. The
 residue was purified by siLica gel chromatography (n-hexane:ethyl
 acetate=1:1 to afford 70 mg (yield: 43%) of the desired compound Of
 (2S,3R,4S) stereochemistry.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.36(s, 3H), 3.49(s, 3H), 3.53(s,
 3H), 3.58(t, 1H), 4.34(s, 1H), 4.99(t, 1H), 5.62(s, 1H), 6.86(d, 1H),
 7.25-7.55(m, 5H), 7.69(s, 1H)
 Example 44
 Preparation of
 (2S,3R,4S)-N"-cyano-N-(6-cyano-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-chlorophenyl)guanidine
 The reaction was performed by the same method to the example 43 except
 using 99 mg (0.35 mmol) of
 (2S,3R,4S)-6-cyano-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydr
 o-2H-1-benzopyran prepared in the preparation example 7 as a starting
 material. The residue was purified by silica gel chromatography
 (n-hexane:ethyl acetate=1:1) to afford 68 mg (yield: 42%) of the desired
 compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.50(s, 3H), 3.44(s, 3H), 3.48(s,
 3H), 3.66(t, 1H), 4.43(s, 1H), 5.24(d, 2H), 6.84(d, 1H), 7.27-7.44(m, 4H),
 7.55(s, 1H), 8.53(s, 1H)
 Example 45
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-cyano-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 (Step 1) Preparation of
 (2S,3S,4R)-4-[[(cyanoimino)phenoxymethyl]amino]-3,4-dihydro-3-hydroxy-2-me
 thyl-2-dimethoxymethyl-2H-benzopyran-6-carbonitrile
 To a solution of 150 mg of
 (2S,3S,4R)-6-cyano-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydr
 o-2H-1-benzopyran prepared in the preparation example 6 dissolved in 3 ml
 of isopropanol-DMF (2:1), were added 141 mg of diphenyl cyanocarbonimidate
 and 97 ul of triethylamine. The reaction mixture was stirred for 18 hours
 at room temperature, and extracted with 10 ml of water and 30 ml of ethyl
 acetate. The organic layer was dried aver anhydrous magnesium sulfate,
 filtered and concentrated under reduced pressure. The residue was purified
 by silica gel chromatography (n-hexane:ethyl acetate=1:2) to afford 182 mg
 (yield: 80%) of the desired compound.
 (Step 2) Preparation of
 (2S,3S,4R)-N-cyano-N-(6-cyano-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxyme
 thyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 To a solution of 182 mg of the compound prepared in the above step 1
 dissolved in 2 ml of DMF was added 0.42 ml of benzylamine. The reaction
 mixture was stirred for 12 hours at room temperature and extracted with 20
 ml of water and 50 ml of ethyl acetate. The organic layer was dried over
 anhydrous magnesium sulfate, fiLtered and concentrated under reduced
 pressure. The residue was purified by silica gel chromatography
 (n-hexane:ethyl acetate=1:2) to afford 163 mg (yield: 68%) of the desired
 compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.29(s, 3H), 3.45(s, 3H), 3.52(s,
 3H), 4.09(t, 1H), 4.35(s, 2H), 4.43(d, 1H), 4.81(t, 1H), 5.94(s, 1H),
 6.83(d, 1H), 7.28-7.40(m, 7H)
 Example 46
 Preparation of
 (2S,3R,4S)-N"-cyano-N-(6-cyano-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the step 1 and step 2 of
 example 45 except using 150 mg of (2S,
 3R,4S)-6-cyano-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydro-2H
 -1-benzopyran prepared in the preparation example 7 as a starting material.
 The residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:2) to afford 160 mg (yield: 69%) of the desired compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.35(s, 3H), 3.43(s, 3H), 3.44(s,
 3H), 3.75(t, 1H) 3.82(s, 2H), 4.47(s, 1H) 5.05(t, 1H), 5.60(s, 1H),
 6.81(d, 1H), 7.20-7.40(m, 7H)
 Example 47
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-bromo-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl 2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the step 1 and step 2 of
 example 45 except using 98 mg of (2S,
 3S,4R)-6-bromo-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydro-2H
 -1-benzopyran prepared in the preparation example 8 as a starting material.
 The residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:2) to afford 86 mg (yield: 83%) of the desired compound.
 .sup.1 H NMR (CDCl.sub.3) .delta.1.21(s, 3H), 3.39(s, 3H), 3.42(s, 3H),
 4.10(d, 1H), 4.29(s, 1H), 4.42(dd, 2H), 4.65(m, 2H), 5.61(d, 1H),
 7.20-1.40(m, 4H)
 Example 48
 Preparation of (2S, 3S,
 4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2
 -H-benzopyran-4-yl)-n'-(3,4-dimethoxybenzyl)guanidine
 (Step 1) Preparation of
 (2S,3S,4R)-4-[[(cyanoimino)phenoxymethyl]amino]-6-nitro-3,4-dihydro-3-hydr
 oxy-2-methyl-2-dimethoxymethyl-2H-benzopyran
 The compound prepared in the preparation example 2 was separated by silica
 gel chromotography (n-hexane:ethyl
 4R)-6-nitro-2-methyl-2-dimethoxymethyl-2H-benzopyran.
 To a solution of 400 mg (1.34 mmol) of (2S,3S,
 4R)-6-nitro-2-methyl-2-dimethoxymethyl-2H-benzopyran dissolved in 3 ml of
 DMF, were added 352 mg (1.48 mmol) of diphenyl cyanocarbonimidate and 243
 ul (1.74 mmol) of triethylamine. The reaction mixture was stirred for 12
 hours at room temperature and extracted with 20 ml of water and 30 ml of
 ethyl acetate. The organic layer was dried over anhydrous magnesium
 sulfate, filtered and concentrated under reduced pressure. The residue was
 purified by silica gel chromatography (n-hexane:ethyl acetate=1:2) to
 afford 498 mg (yield: 84%) of the desired compound.
 (Step 2) Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3,4-dimethoxybenzyl)guanidine
 To a solution of 327 mg (0.74 mmol) of the compound prepared in the above
 step 1 dissolved in 3 ml of DMF was added 371 mg (2.22 mmol, 3 eq) of
 (3,4-dimethoxybenzyl)amine. The reaction mixture was stirred for 12 hours
 at room temperature and extracted with 20 ml of water and 30 ml of ethyl
 acetate. The organic layer was dried over anhydrous magnesium sulfate,
 filtered and concentrated under reduced pressure. The residue was purified
 by silica gel chromatography (n-hexane:ethyl acetate=1:2) to afford 338 mg
 (yield: 89%) of the desired compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.33(s, 3H), 3.53(s, 3H), 3.57(s,
 3H), 3.86(s, 3H), 3.87(s, 3H), 4.14(d, H), 4.38(s, 1H), 4.24-4.50(m, 2H),
 4.82(br t, 1H), 6.15(s, 1H), 6.61(t, 1H), 6.84 (m, 3H), 6.92(d, 1H),
 8.08(dd, 1H), 8.35(s, 1H)
 Example 49
 Preparation of
 (2S,3S,4R)-N'-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl -2H-benzopyran-4-yl)-N'-(3,4-dimethoxybenzyl)guanidine
 To a solution of 209 mg (0.41 mmol) of the compound prepared in the example
 48 dissolved in 5 ml of methanol was added 0.5 ml (0.2 mmol, 0.5 eq) of
 0.4M aqueous Cu(OAc).sub.2 solution. To this mixture was added 155 mg (4.1
 mmol, 10 eq) of sodium borohydride slowly for 30 min. The reaction mixture
 was stirred for 1 hour aL room temperature, extracted with 10 ml of ethyl
 acetate and filtered to remove a precipitated black solid. The filtered
 solution was extracted with 30 ml of ethyl acetate after adding 10 ml of
 the saturated aqueous NaHCO.sub.3 solution. The organic layer was washed
 with brine, dried over anhydrous magnesium sulfate, filtered and
 concentrated under reduced pressure. The residue was purified by silica
 gel chromatography (n-hexane:ethyl acetate=9:1) to afford 169 mg (yield:
 85%) of the desired compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.20(s, 3H), 3.57(s, 6H), 3.87(s,
 6H), 4.29(s, 1H), 4.04-4.12(m, 2H), 4.32-4.58(m, 2H), 5.46(d, 1H),
 6.50-6.69(m, 3H), 6.84(m, 3H), 7.26(br s, 1H)
 Example 50
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-methoxybenzyl)guanidine
 The reaction was performed by the same method to the step 2 of example 48
 except using 360 mg of the compound prepared in the step 1 of example 48
 as a starting material and 333 mg (2.43 mmol) of 4-methoxybenzylamine in
 place of (3,4-dimethoxybenzyl)amine. The residue was purified by silica
 gel chromatography (n-hexane:ethyl acetate=1:2) to to afford 343 mg
 (yield: 87%) of the desired compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.20(s, 3H), 3.51(d, 6H), 3.77(s,
 3H), 3.80(d, 2H), 4.44(t, 1H), 4.56(s, 1H), 5.32(m, 1H), 6.06(s, 1H),
 6.40(d, 1H), 6.90(m, 3H), 7.12(m, 2H), 7.30(d, 1H), 8.00(dd, 1H), 8.03(s,
 1H)
 Example 51
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(4-methoxybenzyl)guanidine
 The reaction was performed by the same method to the example 49 except
 using 304 mg (0.62 mmol) of the compound prepared in the example 50 as a
 starting material. The residue was purified by silica gel chromatography
 (n-hexane:ethyl acetate=1:4) to afford 241 mg (yield: 85%) of the desired
 compound.
 .sup.1 H NMR (CDC.sub.3, 200 MHz) .delta.1.21(s, 3H), 3.58(s, 6H), 3.81(s,
 3H), 4.15(d, 1H), 4.17(d, 1H), 4.30(s, 1H), 4.36-4.54(m, 3H), 5.48(d, 1H),
 6.52-6.71(m, 3H), 6.88(d, 2H), 7.09(br s, 1H), 7.24(d, 2H)
 Example 52
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-nitrobenzyl)guanidine
 The reaction was performed by the same method to the step 2 of example 48
 except using 358 mg (0.81 mmol) of the compound prepared in the step 1 of
 example 48 as a starting material and 458 mg (2.43 mmol) of
 3-nitro)bernzylamine HCl salt in place of (3,4-dimethoxybenzyl)amine. The
 residue was purified by silica gel chrotography (n-hexane:ethyl
 acetate=1:2 to afford 302 mg (yield: 74%) of the desired compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.18(s, 3H), 3.43(d, 6H), 4.09(t,
 1H), 4.49(s, 1H), 5.00(t, 1H), 5.85(s, 1H), 6.98(d, 1H), 7.29(d, 1H),
 7.37(d, 1H), 7.40(m, 2H), 7.91(d, 1H), 8.05(m, 2H)
 Example 53
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-trifluoromethylbenzyl)guanidine
 The reaction was performed by the same method to the step 2 of example 48
 except using 443 mg (1.0 mmol) of the compound prepared in the step 1 of
 example 48 as a starting material and 525 mg (3.0 mmol) of
 (3-trifluoromethyl)benzylamine in place of (3,4-dimethoxyenzyl)amine. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:2) to afford 497 mg (yield: 95%) of the desired compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.33(s, 3H), 3.55(s, 3H), 3.59(s,
 3H), 4.19(d, 1H), 4.38(s, 1H), 4.40 (m, 1H), 4.54(d, 1H), 4.78 (m, 1H),
 6.48 (br s, 1H), 6.84 (br s, 1H), 6.94(d, 1H), 7.53(m, 5H), 8.09(dd, 1H),
 8.56(s, 1H)
 Example 54
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-(3-trifluoromethylbenzyl)quanidine
 The reaction was performed by the same method to the example 49 except
 using 278 mg (0.53 mmol) of the compound prepared in the example 53 as a
 starting material. The residue was purified by silica gel chromatography
 (n-hexane:ethyl acetate=1:4) to afford 192 mg (yield: 73%) of the desired
 compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.23(s, 3H), 3.59(s, 6H), 4.16(d,
 1H), 4.31(s, 1H), 4.40-4.67(m, 3H), 5.53(d, 1H), 6.57-6.14(m, 3H), 7.31(br
 t, 1H), 7.46-7.59(m, 5H)
 Example 55
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-methanesulfonyloxy-3,4-dihydro-3-hydroxy-2-methyl
 -2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 (Step 1) Preparation of
 (2S,3S,4R)-4-[[(cyanoimino)phenoxymethyl]amino]-6-methanesulfonyloxy-3,4-d
 ihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-1-benzopyran
 The reaction was performed by the same method to the step 1 of example 48
 except using 58 mg (0.18 mmol) of the compound prepared in the preparation
 example 9 as a starting material. The residue was purified silica gel
 chromatography (n-hexane:ethyl acetate=1:2) to afford 64 mg (yield: 74%)
 of the desired compound.
 (Step 2) Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-methanesulfonyloxy-3,4-dihydro-3-hydroxy-2-methyl
 -2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the step 2 of example 48
 except using 64 mg (0.13 mmol) of the compound prepared in the above step
 1 and 28 ul (0.26 mmol). The residue was purified by silica gel
 chromatography (n-hexane:ethyl acetate=1:1) to afford 32 mg (yield: 49%)
 of the desired compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.28(s, 1H), 3.21(s, 3H), 3.58(s,
 3H), 3.59 (s, 3H), 4.15(m, 1H), 4.35(s, 1H), 4.52(m, 1H), 4.63(m, 1H),
 5.45(d, 1H), 6.87(d, 1H), 6.92(br s, 1H), 7.20-7.42(m, 6H)
 Example 56
 Preparation of
 (2R,3S,4R)-N"-cyano-N-(6-methanesulfonyloxy-3,4-dihydro-3-hydroxy-2-methyl
 -2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzy]guanidine
 (Step 1) Preparation of
 (2R,3S,4R)-4-[[(cyanoimino)phenoxymethyl]amino]-6-methanesulfonyloxy-3,4-d
 ihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-1-benzyopyran
 The reaction was performed by the same method to the step 1 of example 55
 except using 63 mg (0.19 mmol) of the compound prepared in the preparation
 example 10 as a starting material. The residue was purified by silica gel
 chromatography (n-hexane:ethyl acetate=1:2) to afford 75 mg (yield: 79%)
 of the desired compound.
 (Step 2) Preparation of
 (2R,3S,4R)-N"-cyano-N-(6-methanesulfonyloxy-3,4-dihydro-3-hydroxy-2-methyl
 -2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the step 2 of example 55
 except using 75 mg (0.15 mmol) of the compound prepared in the above step
 1 and 28 ul (0.26 mmol). The residue was purified by silica gel
 chromatography (n-hexane:ethyl acetate=1:2) to afford 57 mg (yield: 74%)
 of the desired compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.26(s, 3H), 3.16(s, 3H), 3.41(s,
 3H), 3.47(s, 3H), 3.72(d, 1H), 4.43(s, 1H), 4.46(d, 1H), 5.02(t, 1H),
 5.25(d, 1H), 6.59(t, 1H), 6.84(d, 1H), 7.02-7.20(m, 2H), 7.22-7.40(m, 4H)
 Example 57
 Preparation of
 (2S,3R,4S)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the example 49 except
 using 884 mg (1.94 mmol) of the compound prepared in the example 24 as a
 starting material. The residue was purified by silica gel chromatography
 (n-hexane:ethyl acetate=1:3) to afford 313 mg (yield: 38%) of the desired
 compound.
 .sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta.1.41(s, 3H), 1.75(br s, 1H),
 3.39(s, 3H), 3.45(s, 3H), 3.46(d, 1H), 3.72(d, 1H), 4.40(s, 1H), 4.46(d,
 2H), 4.78(d, 1H), 5.22(m, 1H), 6.41(m, 1H), 6.50(m, 1H), 6.59(d, 1H),
 6.73(m, 1H), 7.30-7.37 (m, 4H)
 Example 58
 Preparation of (2R,3R,
 4S)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2
 H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the example 49 except
 using 1.2 g (2.7 mmol) of the compound prepared in the example 22 as a
 starting material. The residue was purified by silica gel chromatography
 (n-hexane:ethyl ethyl acetate=1:3) to afford 547 mg (yield: 48%) of the
 desired compound.
 .sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta.1.21(s, 3H), 1.80(br s, 2H),
 3.57(s, 3H), 3.58(s, 3H), 4.10-4.13(m, 1H), 4.20-4.38(m, 1H), 4.31(s, 1H),
 4.98(dd, 1H), 4.50(dd, 1H), 5.60(s, 1H), 6.58-6.79(m, 2H), 7.28-7.37(m,
 6H)
 Example 59
 Preparation of
 (2R,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the example 49 except
 using 1.07 g (2.3 mmol) of the compound prepared in the example 23 as a
 starting material. The residue was purified by silica gel chromatography
 (n-hexane:ethyl acetate=1:2) to afford 589 mg (yield: 60.degree.) of the
 desired compound.
 .sup.1 H NMR (CDCl.sub.3, 500 MHz) .delta.1.41(s, 3H), 1.75(br s, 1H),
 3.39(s, 3H), 3.45(s,3H), 3.46(d, 1H), 3.72(d, 1H), 4.40(s, 1H), 4.46(d,
 2H), 4.78(d, 1H), 5.22(m, 1H), 6.41(m, 1H), 6.50(m, 1H), 6.59(d, 1H),
 6.73(m, 1H), 7.30-7.37(m, 4H)
 Example 60
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-([1,3]diox
 olan-2-yl)-2H-benzopyran-4-yl)-N'-benzylguanidine
 (Step 1) Preparation of
 (2S,3S,4R)-4-[[(cyanoimino)phenoxymethyl]amino]-6-nitro-3,4-dihydro-3-hydr
 oxy-2-methyl-2-([1,3]dioxolan-2-yl)-2H-1-benzopyran
 The reaction was performed by the same method to the step 1 of example 48
 except using 400 mg (1.35 mmol) of the compound prepared n the preparation
 example 11 as a starting material. The residue was purified by silica gel
 chromatography (n-hexane:ethyl acetate=1:3) to afford 400 mg (yield: 67%)
 of the desired compound.
 1H NMR (CDCl.sub.3, 200 MHz) .delta.1.40(s, 3H), 3.2(d, 1H), 3.81-3.9(m,
 4H), 4.69(sr 1H), 5.15(t, 1H), 6.98(d, 1H), 7.15-7.42(m, 5H), 8.12(dd,
 1H), 8.30(d,1H)
 (Step 2) Preparation of
 (2S,3S,4R,)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-([1,3]dio
 xolan-2-yl)-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the step 2 of example 48
 except using 400 mg (0.1 mmol) of the compound prepared in the above step
 1 as a starting material and 0.3 ml (2.7 mmol) of benzylamine in place of
 (3,4-dimethoxybenzyl)amine. The residue was purified by silica gel
 chromatography (n-hexane:ethyl acetate=1:2) to afford 350 mg (yield: 85%)
 of the desired compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.35(s, 3H), 3.95-4.15(m, 4H),
 4.49(dd, 2H), 4.91(t, 1H), 5.05(s, 1H), 5.62(s, 1H), 6.61(t, 1H), 6.95(d,
 1H), 7.29-7.41(m, 5H), 8.12(dd, 1H), 8.21(d, 1H)
 Example 61
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-([1,3]diox
 olan-2-yl)-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the example 49 except
 using 200 mg (0.44 mmol) of the compound prepared in the example 60 as a
 starting material. The residue was purified by silica gel chromatography
 (n-hexane:ethyl acetate=1:3) to afford 90 mg (yield: 48%) of the desired
 compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.24(s, 3H), 3.92-4.14(m, 4H),
 4.45(dd, 2H), 4.97(s, 1H), 5.51(d, 1H), 6.45-6.80(m, 3H), 7.12(s, 1H),
 7.25-7.42(m, 3H)
 Example 62
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-([1,3]diox
 an-2-yl)-2H-benzopyran-4-yl)-N'-benzylguanidine
 (Step 1) Preparation of
 (2S,3S,4R)-4-[[(cyanoimino)phenoxymethyl]amino]-6-nitro-3,4-dihydro-3-hydr
 oxy-2-methyl-2-([1,3]dioxan-2-yl)-2H-1-benzopyran
 The reaction was performed by the same method to the step 1 of example 60
 except using 700 mg (2.26 mmol) of the compound prepared in the
 preparation example 12 as a starting material. The residue was purified by
 silica gel chromatography (n-hexane:ethyl acetate=1:1) to afford 840 mg
 (yield: 83%) of the desired compound.
 (Step 2) Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-([1,31
 ]dioxan-2-yl)-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the step 2 of example 48
 except using 840 mg (1.85 mmol) of the compound prepared in the above step
 1 as a starting material and 0.61 ml (5.56 mmol) of benzylamine in place
 of (3,4-dimethoxybenzyl)amine. The residue was purified by silica gel
 chromatography (n-hexane:ethyl acetate=1:2) to afford 750 mg (yield: 87%)
 of the desired compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.31(s, 3H), 1.4-1.52(m, 1H),
 2.13-2.26(m, 1H), 3.80-3.98(m, 2H), 4.18-4.31(m, 3H), 4.45(d, 2H), 4.75(s,
 1H), 4.81(t, 1H), 5.81(s, 1H), 6.75(t, 1H), 6.96(d, 1H), 7.28-7.40(m, 5H),
 8.1(dd, 1H), 8.35(d, 1H)
 Example 63
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-([1,3]diox
 an-2-yl)-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method of the example 49 except
 using 350 mg (0.75 mmol) of the compound prepared in the example 62 as a
 starting material. The residue was purified by silica gel chromatography
 (n-hexane:ethyl acetate=1:2) to afford 278 mg (yield: 85%) of the desired
 compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.23(s, 3H), 1.40-1.50(m, 1H),
 2.12-2.22(m, 1H), 3.8-3.96(m, 2H), 4.15-4.32(m, 3H), 4.48(dd, 2H), 4.70(s,
 1H), 5.41(d, 1H), 6.52-6.71(m, 3H), 7.15(s, 1H), 7.30-7.39(m, 5H)
 Example 64
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-([,3]-5,5-
 dimethyldioxan-2-yl)-2H-benzopyran-4-yl)-N'-benzylguanidine
 (Step 1) Preparation of
 (2S,3S,4R)-4-[[(cyanoimino)phenoxymethyl]amino]-6-nitro-3,4-dihydro-3-hydr
 oxy-2-methyl-2-([1,3]-5,5-dimethyldioxan-2-yl)-2H-1-benzopyran
 The reaction was performed by the same method to the step 1 of example 60
 except using 1.1 g (3.60 mmol) of the compound prepared in the preparation
 example 13 as a starting material. The residue was purified by silica gel
 chromatography (n-hexane:ethyl acetate 1:2) to afford 1 g (yield: 86%) of
 the desired compound. (step 2) Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-([1,31-5,5
 -dimethyldioxan-2-yl)-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the step 2 of example 48
 except using 1 g (2.1 mmol) of the compound prepared in the above step 1
 as a starting material. The residue was purified by silica gel
 chromatography (n-hexane:ethyl acetate=1:2) to afford 900 mg (yield: 87%)
 of the desired compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.0.78(s, 3H), 1.21(s, 3H), 1.34(s,
 3H), 3.54(dd, 2H), 3.76(d, 2H), 4.20(d, 2H), 4.44(dd, 2H), 4.65(s, 1H),
 4.81(t, 1H), 5.82(s, 1H), 6.72(t, 1H), 6.96(d, 1H), 7.29-7.41(m, 5H),
 8.11(dd, 1H), 8.38(d, 1H)
 Example 65
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-([1,3]-5,5
 -dimethyldioxan-2-yl)-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the example 49 except
 using 400 mg (0.81 mmol) of the compound prepared in the example 64 as a
 starting material. The residue was purified by silica gel chromatography
 (n-hexane:ethyl acetate=1:3) to afford 350 mg (yield: 93%) of the desired
 compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.0.79(s, 3H), 1.21(s, 3H), 1.27(s,
 3H), 3.51(dd, 2H), 3.74(d, 2H), 4.2(d, 1H), 4.35(d, 1H), 4.51(dd, 2H),
 4.61(s, 1H), 4.73(s, 1H), 5.44 (dd, 1H), 6.52-6.75(m, 3H), 7.16(s, 1H),
 7.28-7.41 (m, 5H)
 Example 66
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 (Step 1) Preparation of
 (2S,3S,4R)-4-(cyanoimino)phenoxymethyl]amino]-6-nitro-3,4-dihydro-3-hydrox
 y-2-methyl-2-dimethoxymethyl-2H-1-benzopyran
 The reaction was performed by the same method to the step 1 of example 48
 except using 234 mg (0.72 mmol) of the compound prepared in the
 preparation example 14 as a starting material. The residue was purified by
 silica gel chromatography (n-hexane:ethyl acetate=1:2) to afford 237 mg
 (yield: 70%) of the desired compound.
 (Step 2) Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the step 2 of example 48
 except using 217 mg (0.46 mmol) of the compound prepared in the above step
 1 as a starting material. The residue was purified by silica gel
 chromatography (n-hexane:ethyl acetate=1:2) to afford 200 mg (yield: 90%
 of the desired compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.29(m, 9H), 3.74 (m, 5H),
 4.20(d, 1H), 4.50 (m, 3H), 4.83(br s, 1H), 5.92(m, 1H), 6.52(m, 1H),
 6.90(d, 1H), 7.34(m, 5H), 8.11(dd, 1H), 8.30(s, 1H)
 Example 67
 Preparation of
 (2S,3S,4R)-N'-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the example 49 except
 using 122 mg (0.25 mmol) of the compound prepared in the example 66 as a
 starting material. The residue was purified by silica gel chromatography
 (n-hexane:ethyl acetate=1:3) to afford 91 mg (yield: 80%) of the desired
 compound. .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.25(m, 9H), 3.78(m,
 4H), 4.18(d, 1H), 4.30(m, 4H), 5.53(d, 1H), 6.68(m, 3H), 7.18(br, 1H),
 7.36(m, 5H)
 Example 68
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-methoxycarbonyl-3,4-dihydro-3-hydroxy-2-methyl-2-
 dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 (Step 1) Preparation of
 (2S,3S,4R)-4-[[(cyanoamin)phenoxymethyl]amino]-6-methoxycarbonyl-3,4-dihyd
 ro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-1-benzopyran
 The reaction was performed by the same method to the step 1 of example 48
 except using 399 mg (1.28 mmol) of the compound prepared in the
 preparation example 15 as a starting material. The residue was purified by
 silica gel chromatography (n-hexane:ethyl acetate=1:2) to afford 397 mg
 (yield: 68%) of the desired compound.
 (Step 2) Preparation of
 (2S,3S,4R)-N"-cyano-N-(6-methoxycarbonyl-3,4--dihydro-3-hydroxy-2-methyl-2
 -dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the step 2 of example 48
 except using 397 mg (0.93 mmol) of the compound prepared in the above step
 1 and 0.21 ml (1.98 mmol) of benzylamine as a starting material. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:2) to afford 270 mg (yield: 67%) of the desired compound.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.21(s, 3H), 3.55(d, 6H), 3.86(s,
 3H), 4.13(d, 1H), 4.17(s, 1H), 4.48(m, 2H), 5.77(d, 1H), 6.83(m, 1H),
 6.85(d, H), 7.33(m, 4H), 7.93(dd, 1H), 7.99(s, 1H)
 Example 69
 Preparation of
 (2R,3S,4R)-N"-cyano-N-(6-methoxycarbonyl-3,4-dihydro-3-hydroxy-2-methyl-2-
 dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 (Step 1) Preparation of
 (2R,3S,4R)-4-[[(cyanoimino)phenoxymethyl]amino]-6-methoxycarbonyl-3,4-didh
 ydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-1-benzopyran
 The reaction was performed by the same method to the step 1 of example 48
 except using 121 mg (0.39 mmol) of the compound prepared in the
 preparation example 16 as a starting material. The residue was purified by
 silica gel chromatography (n-hexane:ethyl acetate=1:2) to afford 131 mg
 (yield: 74%) of the desired compound.
 (Step 2) Preparation of (2R,
 3S,4R)-N"-cyano-N-(6-methoxycarbonyl-3,4-dihydro-3-hydroxy-2-methyl-2-dime
 thoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the step 2 of example 48
 except using 131 mg (0.31 mmol) of the compound prepared in the above step
 1 and 60 ul (0.61 mmol) of benzylamine as a starting material. The residue
 was purified by silica gel chromatography (n-hexane:ethyl acetate=1:2) to
 afford 107 mg (yield 79%) of the desired compound.
 .sup.1 N HMR (CDCl.sub.3, 200 MHz) .delta.1.26(s, 3H), 3.43(d, 6H), 3.82(d,
 1H), 3.77(s, 3H), 4.45(s, 1H), 4.48 (m, 2H), 5.64(d, 1H), 6.81(m, 1H),
 6.83(d, 1H), 7.29(m, 4H), 7.80(dd, 1H), 7.84(s, 1H)
 Example 70
 Preparation of
 (3S,4R)-N"-cyano-N-(8-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymeth
 yl-2H-benzopyran-4-yl)-N'-benzylguanidine
 (Step 1) Preparation of
 (3S,4R)-4-[[(cyanoimino)phenoxymethyl]amino]-8-nitro-3,4-dihydro-3-hydroxy
 -2-methyl-2-dimethoxymethyl-2H-1-benzopyran
 The reaction was performed by the same method to the step 1 of example 48
 except using 0.97 g (3.24 mmol) of the compound prepared in the
 preparation example 17 as a starting material. The residue was purified by
 silica gel chromatography (n-hexane:ethyl acetate=1:2) to afford 1.16 g
 (yield: 81%) of the desired compound.
 (Stop 2) Preparation of
 (3S,4R)-N"-cyano-N-(8-nitro-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymeth
 yl-2H -benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the step 2 of example 48
 except using 1.16 g (2.6 mmol) of the compound prepared in the above step
 1 and 0.85 ml (7.8 mmol) of benzylamine as a starting material. The
 residue was purified by silica gel chromatography (n-hexane:ethyl
 acetate=1:2) to afford 0.94g (yield: 79%) of the desired compound as a
 racemic mixture of (2S,3S,4R- and (2R,3S, 4R)-stereochemistry.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.23(s, 3H), 1.32(s, 3H),
 3.37-3.40(s, 3H), 3.48(s, 3H), 3.84-3.87(d, 1H), 4.17-4.21(d, 1H),
 4.36-4.38(d, 1H), 4.41-4.45(d, 1H), 4.8(t, 1H), 5.04(t, 1H), 5.82(d, 1H),
 6.09(d, 1H), 6.82-6.96(m, 2H), 1.27(s, 5H), 7.57-7.69(q, 1H)
 Example 71
 Preparation of
 (2S,3S,4R)-N"-cyano-N-(8-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the example 49 except
 using 298 mg (0.66 mmol) of the racemic mixture prepared in the example 70
 as a starting material. The residue was purified by silica gel
 chromatography (n-hexane:ethyl acetate=1:4) to afford 117 mg (yield: 42%)
 f the desired compound of (2S,3S,4R) stereochemistry.
 .sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta.1.25(s, 3H), 3.58(s, 3H), 3.8(s,
 1), 4.39-4.47 (m, 4H),5.62(d, 1H), 6.58-6.61(d, 1H), 6.74-6.78(d, 1H),
 7.12(s, H), 7.27-7.34(m, 5H)
 Example 72
 Preparation of
 (2R,3S,4R)-N"-cyano-N-(8-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxym
 ethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
 The reaction was performed by the same method to the example 49 except
 using 298 mg (0.66 mmol) of the racemic mixture prepared in the example 70
 as a starting material. The residue was purified by silica gel
 chromatography (n-hexane:ethyl acetate=1:4) to afford 106 mg (yield: 38%)
 of the desired compound of (2R,3S,4R) stereochemistry.
 .sup.1 H NMR (CDC.sub.6, 200 MHz) .delta.1.46(s, 3H), 3.41(s, 3H), 3.46(s,
 3H), 3.73-3.81(m, 2H), 4.44(s, 1H), 4.46(s, 1H), 4.87(m, 1H), 5.2(m, 1H),
 6.59-6.60(d, 1H), 6.63-6.76(t, 2H), 7.26-7.36(m, 5H)
 The compounds prepared in the-above examples were listed in Table 1.
 TABLE 1
 R.sub.1 R.sub.5 R.sub.6
 Stereo
 No S.sup.a P.sup.c R.sub.1 R.sub.3 R.sub.4 S P S P
 n chemistry
 1 2 3 4 5 NO.sub.2 NO.sub.2 NO.sub.2 NO.sub.2 NO.sub.2 6 6 6 6 6 CH.sub.3
 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 ##STR21## OH OH OH OH OH Cl Cl Cl
 #Cl NO.sub.2 4 4 3 3 4 H H H H H -- -- -- -- -- 0 0 0 0 0 2R, 3R, 4S 2R,
 3S, 4R 2R, 3R, 4S 2R, 3S, 4R 2R, 3R, 4S
 6 NO.sub.2 6 CH.sub.3 OH CF.sub.3 3 H --
 0 2R, 3R, 4S
 7 NO.sub.2 6 CH.sub.3 OH CF.sub.3 3 H --
 0 2R, 3S, 4R
 8 NO.sub.2 6 CH.sub.3 OH OCH.sub.3 4 H --
 0 2R, 3R, 4S
 9 NO.sub.2 6 CH.sub.3 OH OCH.sub.3 4 H --
 0 2R, 3S, 4R
 10 NO.sub.2 6 CH.sub.3 OH Cl 4 H --
 0 2S, 3R, 4S
 11 NO.sub.2 6 CH.sub.3 OH Cl 4 H --
 0 2S, 3S, 4R
 12 NO.sub.2 6 CH.sub.3 OH Cl 3 H --
 0 2S, 3R, 4S
 13 NO.sub.2 5 CH.sub.3 OH Cl 3 H --
 0 2S, 3S, 4R
 14 NO.sub.2 6 CH.sub.3 OH CF.sub.3 3 H --
 0 2S, 3R, 4S
 15 NO.sub.2 6 CH.sub.3 OH CF.sub.3 3 H --
 0 2S, 3S, 4R
 16 NO.sub.2 6 CH.sub.3 OH OCH.sub.3 4 H --
 0 2S, 3R, 4S
 17 NO.sub.2 6 CH.sub.3 OH OCH.sub.3 4 H --
 0 2S, 3S, 4R
 18 NO.sub.2 6 CH.sub.3 OH CH.sub.3 4 H --
 0 2R, 3R, 4S
 19 NO.sub.2 6 CH.sub.3 OH CH.sub.3 4 H --
 0 2R, 3S, 4R
 20 NO.sub.2 6 CH.sub.3 OH OCH.sub.3 4 H --
 1 2R, 3R, 4S
 21 NO.sub.2 6 CH.sub.3 OH OCH.sub.3 4 H --
 1 2R, 3S, 4R
 22 NO.sub.2 6 CH.sub.3 OH H -- H --
 1 2R, 3R, 4S
 23 NO.sub.2 6 CH.sub.3 OH H -- H --
 1 2R, 3S, 4R
 24 NO.sub.2 6 CH.sub.3 OH H -- H --
 1 2S, 3R, 4S
 25 NO.sub.2 6 CH.sub.3 OH H -- H --
 1 2S, 3S, 4R
 26 H 6 CH.sub.3 OH Cl 4 H --
 0 2R, 3R, 4S
 27 H 6 CH.sub.3 OH Cl 4 H --
 0 2R, 3S, 4R
 28 NO.sub.2 6 CH.sub.3 CH.sub.2 OH OH Cl 4 H --
 0 2R, 3R, 4S
 29 NO.sub.2 6 CH.sub.3 CH.sub.2 OH OH Cl 4 H --
 0 2R, 3S, 4R
 30 NO.sub.2 6 CH.sub.3 CH.sub.2 OCH.sub.3 OH Cl 4 H
 -- 0 2R, 3R, 4S
 31 NO.sub.2 6 CH.sub.3 CH.sub.2 OCH.sub.3 OH Cl 4 H
 -- 0 2R, 3S, 4R
 32 33 34 35 36 NO.sub.2 NO.sub.2 NO.sub.2 NO.sub.2 NO.sub.2 6 6 6 6 6
 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 ##STR22## OH OH OH OH OH
 Cl Cl CF.sub.3
 #CF.sub.3 Cl 2 2 2 2 2 H H H H H -- -- -- -- -- 0 0 0 0 0 2S, 3R, 4S 2S,
 3S, 4R 2S, 3R, 4S 2S, 3S, 4R 2S, 3R, 4S
 37 NO.sub.2 6 CH.sub.3 OH Cl 2 H --
 1 2S, 3S, 4R
 38 NO.sub.2 6 CH.sub.3 OAc H -- H --
 1 2S, 3S, 4R
 39 NO.sub.2 6 CH.sub.3 OH H -- H --
 1 2S
 R.sub.1 R.sub.5 R.sub.6
 Stereo
 No S P R.sub.2 R.sub.3 R.sub.4 S P S
 P n chemistry
 40 41 42 43 44 NH.sub.2 NHCOCH.sub.3 NHSO.sub.2 CH.sub.3 CN CN 6 6 6 6 6
 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 ##STR23## OH OH OH
 OH OH H H H Cl
 #Cl -- -- -- 4 4 H H H H H -- -- 1 1 1 0 0 2S, 3S, 4R 2S,
 3S, 4R 2S, 3S, 4R 2S, 3S, 4R 2S, 3R, 4S
 45 CN 6 CH.sub.3 OH H -- H
 -- 1 2S, 3S, 4R
 46 CN 6 CH.sub.3 OH H -- H
 -- 1 2S, 3R, 4S
 47 Br 6 CH.sub.3 OH H -- H
 -- 1 2S, 3S, 4R
 48 NO.sub.2 6 CH.sub.3 OH OCH.sub.3 4
 OCH.sub.3 3 1 2S, 3S, 4R
 49 NH.sub.2 6 CH.sub.3 OH OCH.sub.3 4
 OCH.sub.3 3 1 2S, 3S, 4R
 50 NO.sub.2 6 CH.sub.3 OH OCH.sub.3 4 H
 -- 1 2S, 3S, 4R
 51 NH.sub.2 6 CH.sub.3 OH OCH.sub.3 4 H
 -- 1 2S, 3S, 4R
 52 NO.sub.2 6 CH.sub.3 OH NO.sub.2 3 H
 -- 1 2S, 3S, 4R
 53 NO.sub.2 6 CH.sub.3 OH CF.sub.3 3 H
 -- 1 2S, 3S, 4R
 54 NH.sub.2 6 CH.sub.3 OH CF.sub.3 3 H
 -- 1 2S, 3S, 4R
 55 SO.sub.2 CH.sub.3 6 CH.sub.3 OH H --
 H -- 1 2S, 3S, 4R
 56 SO.sub.2 CH.sub.3 6 CH.sub.3 OH H --
 H -- 1 2R, 3S, 4R
 57 NH.sub.2 6 CH.sub.3 OH H -- H
 -- 1 2S, 3R, 4S
 58 NH.sub.2 6 CH.sub.3 OH H -- H
 -- 1 2S, 3R, 4S
 59 NH.sub.2 6 CH.sub.3 OH H -- H
 -- 1 2R, 3S, 4R
 60 61 NO.sub.2 NH.sub.2 6 6 CH.sub.3 CH.sub.3 ##STR24## OH OH
 H H -- -- H H -- -- 1 1 2S, 3S, 4R 2S, 3S, 4R
 62 63 BO.sub.2 NH.sub.2 6 6 CH.sub.3 CH.sub.3 ##STR25## OH OH
 H H -- -- H H -- -- 1 2S, 3S, 4R 2S, 3S, 4R
 64 65 NO.sub.2 NH.sub.2 6 6 CH.sub.3 CH.sub.3 ##STR26## OH OH
 H H -- -- H H -- -- 1 2S, 3S, 4R 2S, 3S, 4R
 66 67 NO.sub.2 NH.sub.2 6 6 CH.sub.3 CH.sub.3 ##STR27## OH OH
 H -- -- H H -- -- 1 1 2S, 3S, 4R 2S, 3S, 4R
 68 69 70 71 72 CO.sub.2 CH.sub.3 CO.sub.2 CH.sub.3 NO.sub.2 NH.sub.2
 NH.sub.2 6 6 8 8 8 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 CH ##STR28##
 OH OH OH OH OH H H H
 #H H -- -- -- -- -- H H H H H -- -- -- -- -- 1 1 1 1 1 2S, 3S, 4R
 2R, 3S, 4R 3S, 4R 2S, 3S, 4R 2R, 3S, 4R
 a: S represents substituent.
 b: P represents position.
 *The compound of No. 39 has a double bond at 3,4-position.
 EXPERIMENTAL EXAMPLES
 The following experiments were made on the compounds of the formula 1 to
 investigate their pharmacological actions.
 Experimental Example 1
 Vasodilation Effects on Isolated Blood Vessels of Rats
 The following experiment was conducted to examine whether the compounds of
 the formula 1 dilate blood vessels.
 Male Sprague-Dawly rats (350-450 g, obtained from the Experimental Animal
 Team of the Korea Research Institute of Chemical Technology) were knocked
 uncious by hitting the occipital region, sacrificed by cervical
 dislocation, and underwent thoracotomy. After being quickly removed, the
 thoracic aorta was deprived of the adipose tissue and cut into aortic
 rings of 3 mm width. The aorta was lightly rubbed with a modified Krebs
 Henseleit buffer (Physiological Salt Solution, PSS) soaked cotton club to
 remove the inner epithelial layer therefrom. While being suspended in an
 organ bath containing a physiological buffer, the vascular tissue was
 allowed to equilibrate under a resting tension of 2 g and then, stand for
 1 hour at 37.degree. C. for stabilization with a supply of a carbogen
 consisting of 95% O.sub.2 -5% CO.sub.2.
 Thereafter, the vascular tissue was constricted with 10.sup.-5 M
 phenylephrine and washed several times with PSS and this procedure was
 repeated again to ensure the stable reacivity of vascular smooth muscle to
 repetitive triction/dilatation.
 In addition, 3.times.10.sup.-6 M methoxamine was used to induce an
 intensive triction in the vascular smooth muscle. When the
 vasoconstriction induced by the methoxamine reached and maintained a
 maximum, test compounds and controls were cumulatively added to the organ
 baths in concentrations of 1, 3, 10 and 30 uM so as to induce
 vasodilatation. As for the controls, they were Cromakalim and BMS-180448
 (the compounds of the chemical formula 2), both known to be the first
 generation K.,, activator with potent vasodilatation and cardioprotection
 effects.
 Following the addition of the drugs, the change in the maximal triction
 induced by methoxamine was calculated to plot a concentration-dilation
 response curve. Through a linear regression analysis, IC.sub.50, the drug
 concentration at which the vascular tissue is 50% dilated, was obtained
 for each drug. The results are given in Table 2, below.
 TABLE 2
 Vasodilation and Anti-Ischemic Effect (Cardioprotective
 Effect) of Compounds of Formula 1
 Experimental Experimental
 Example 2 Example 3
 Experimental Anti-ischemic Anti-ischemic
 Example 1 Activity Activity
 Vasodilation (in vivo, rats) (in vivo, dogs)
 Activity (0.3 mg/kg (2 mg/kg/40
 (in Vitro, rat i.v.) min, i.v.)
 Test aorta) AAR/LV IZ/AAR AAR/LV IZ/AAR
 Drugs (IC.sub.50, uM) (%) (%) (%) (%)
 Vehicle -- 39.75 60.78 37.61 52.39
 Cromakalim 0.067
 BMS-180448 1.38 38.83 39.14 37.73 38.02
 Exmp. 15 14.07
 Exmp. 24 9.78 37.92 48.48 35.33 28.03
 Exmp. 25 &gt;30 36.88 48.55
 Exmp. 32 3.57 42.49 44.72
 Exmp. 38 24.48 38.26 51.13
 Exmp. 41 &gt;30 33.59 30.25
 Exmp. 41 &gt;30
 Cromakalim had an IC.sub.50 of 0.067 uM and showed a potent dilation effect
 on the isolated rat aorta constricted with methoxamine (3 uM) while
 BMS-180448 was 1.38 uM in IC.sub.50, showing a vasodilatation activity
 twenty times as weak as Cromakalim. On the other hand, the compounds of
 the present invention ranged, in IC.sub.50, from 9.78 uM to greater than
 30 uM, so that their vasodilatation effects were, very little, even
 smaller than those of the controls, Cromakalim and BMS-180448.
 When exerting their actions on the KIT present in the heart, the compounds
 according to the present invention play a role in protecting the heart. On
 the other hand, the benzopyranyl guanidine derivatives acting on the
 K.sub.ATP present in peripheral blood vessels dilate the blood vessels,
 decreasing the blood pressure. Therefore, the compounds of the present
 invention have more efficient cardioprotective effects by virtue of their
 low vasodilatation activity.
 As illustrated above, the compounds of the present invention are so low in
 the activity of dilating the blood vessels that they are improved in the
 selectivity for heart protective function.
 Experiment Example 2
 Heart Protective Activity in Ischemic Heart Models of Rats
 In order to determine whether the compounds of the formula 1 are protective
 for ischemic hearts, experiments determining the anti-ischemic effects of
 the compounds on rats were conducted as follows.
 Male rats (350-450 g, obtained from the Experimental Animal Team of the
 Korea Research Institute of Chemical Technology) were anesthetized by the
 intraperitoneal injection of pentobarbital at a dose of 75 mg/kg. After
 trachetomy, the rats were rendered to respire artificially at a rate of
 60/min with a stroke volume of 10 ml/kg.
 Cannulars were inserted into the fermoral vein and the fermorat artery and
 used for drug administration and blood pressure measurement, respectively.
 In the ischemic myocardium damage models, the body temperature has an
 important influence on the results. To avoid the change in the body
 temperature, a body temperature measuring probe was inserted into the
 rectum of each rat and the body temperature was tantly kept at 37.degree.
 C. with the aid of a homeothermic blanket control unit.
 Afterwards, during testing, a continuous measurement was made of the mean
 arterial blood pressures and heart rates from the rats. For the
 measurement of the blood pressure, a pressure transducer, such as that
 manufactured by Grass Ins., MA, U.S.A., identified as Model Statham P23XL,
 was used. The heart rate was measured by a tachometer, such as that
 manufactured by Gould Inc., OH, U.S.A., identified as Biotachometer. in
 addition, all of the changes occuring were continuously recorded through
 the Gould 2000 chart recorder, manufactured by Gould Inc.
 The left coronary artery was occluded according to the Selye H. method as
 follows. The rats underwent a left thoracotomy operation for partial
 opening of the chest and the right-side chest was pressurized by the
 middle finger of the left hand to push the heart out. Immediately after
 the left anterior descending coronary artery hereinafter referred to as
 (LAD) was carefully stitched using a suture needle with 5-0 silk ligature,
 the heart was then repositioned in the thoracic cavity while both ends of
 the ligature were situated outside. The opposite ligature ends were passed
 through a PE tube (PE100, 2.5 cm) and allowed to stand loose for 20 min
 for stabilization. Via the cannula inserted into the femoral vein,
 vehicles or drugs were administered into the rats which were rendered to
 stand for 30 min in order to sufficiently elicit the efficacies of the
 drugs. BMS-180448 was used as a control drug and the i.v. administration
 dose was 0.3 mg/kg for all test drugs of interest and the control drug.
 Next, the PE tube which had the doubled strands of the ligature passed
 therethrough was pushed toward the heart and then, set upright by tightly
 pulling end regions of the ligature wits a hemostatic pincette while
 pressing the coronary artery. The PE tube was allowed to stand or 45 min
 for the occlusion of the coronary artery, followed by the removal of the
 hemostatic pincette and then, by the reperfusion for 90 min.
 After the reocclusion of the coronary artery in accordance with the above
 procedure, the rats were administered with 2 ml of 1% Evans blue through
 an intravenous route. Subsequently, an excess of pentobarbital was
 intravenously injected to kill the rats, after which the heart was removed
 and then, deprived of the right ventricle and both atria. The left
 ventricle was cut horizontally to the heart apex into 5 or 6 slices which
 were weighed. From the surface of each slice, images were input with the
 aid of a Hi-scope into a computer installed with an image analyzing
 program (Image Pro Plus). From the images input into the computer, the
 area of the normal blood stream tissue region which appeared blue in a
 computer monitor and the area which appeared colorless were measured. The
 percentage of the colorless area to the total area of each slice was
 calculated and multiplied by the weight of each slice to determine the
 area at risk (AAR) of each slice. The AAR obtained from each slice was
 summed for all slices and the total AAR was divided by the total weight of
 the left ventricle to yield h AAR, as shown in the following mathematical
 formula 1:
 [Mathematical Formula 1]
 ##EQU1##
 In addition, the heart slices were incubated for 15 min in
 2,3,5-triphenyltetrazolium chloride (TTC) phosphate buffer (pH 7.4) at
 37.degree. C. and fixed for 20-24 hours in a 10% formalin solution. During
 this fixation, 2,3,5-triphenyltetrazolium chloride was reduced into
 formazan dye by the myocardial dehydrogenase and its cofactor NADH, so
 that the normal regions of the tissue were colored brick-red. In contrast,
 the infarct zones of the tissue were deficient in the dehydrogenase and
 its cofactor, so that no reduction occurred on the
 2,3,5-triphenyltetrazolium, allowing the color to remain unchanged.
 According to whether the tissue regions were colored by
 2,3,5-triphenyltetrazolium, a measurement was made of the areas of the
 normal and infarct zones in each ventricle slice. The infarct zone area of
 each slice was summed for all slices and the resulting summed infarct zone
 area was divided by total AAR weight or total left ventricle weight to
 yield% IZ as shown in the following mathematical formula 2:
 [Mathematical Formula 2]
 ##EQU2##
 In this experimental model, some of the test drugs were determined as being
 of more potent anti-ischemic activity as the % IZ was smaller. The results
 are given in Table 2, above.
 In the ischemic myocardium damage model of anesthetized rats, as seen in
 Table 2, the vehicle-administered group showed a myocardial infarction
 rate to area at risk (IZ/AAR) of 60.78%, which indicates a serious damage
 in the myocardial muscle. Being measured to be 39.14% in myocardial
 infarction rate, BMS-180448 showed noticeable anti-ischemic activity. When
 compared only in myocardial infarction rate, the compounds of the present
 invention were similar to or superior to BMS-180448. However, because the
 compounds of the present invention are remarkably lower in vasodilatation
 activity than is BMS-180448, they are far superior to the conventional
 drug in heart-selective anti-ischemic activity. Especially, the compound
 of Example 40 was of very Slow vasodilatation activity (IC.sub.50 &gt;30
 uM) with a myocardial infarction rate of as low as 30.25%, so it shows
 much better heart selectivity upon vasodilatation than is BMS-180448.
 Further, the compounds of the present invention did not act to reduce the
 blood pressure. Consequently, the compounds of the present invention can
 be used as an agent for the treatment of ischemic heart diseases by virtue
 of their excellent protective activity against ischemic cardiovascular
 diseases.
 Experimental Example 3
 Heart Protective Activity in Ischemic Heart Models of Beagle Dogs
 In order to determine whether the compounds of the formula are protective
 for the ischemic hearts of larger animals, experiments determining the
 anti-ischemic effects of the compounds on beagle dogs were conducted as
 follows. The experiments on beagle dogs followed the method of Grover et
 al.' (G. J. Grover et al., J. Cardiovasc. Pharmacol. 25, 40 (1995)).
 After being anesthetized by an intravenous injection of pentobarbital at a
 dose of 35 mg/kg, male beagle dogs (8-12 kg) were further infused with
 pentobarbital sodium at a dose of 3-4 mg/kg through the right cephalic
 vein throughout the experiments, so as to keep the anesthesia constant.
 For the maintenance of breathing during the experiment, a tracheal
 catheter was inserted into the respiratory tract of each beagle dog, after
 which they were allowed to respire with the aid of a respirator, such as
 that manufactured by CWE Inc., PA, U.S.A., identified as Model SAR-830,
 while the pCO.sub.2 was maintained at 30-35 mmHg by use of room air and
 supplied oxygen. 0.5 ml of blood was taken through a catheter inserted
 into the femoral artery each hour and used to measure the oxygen level in
 blood with the aid of an apparatus, such as that manufactured by
 Ciba-Corning, MA, U.S.A., identified as Blood Cas Analyzer 280. While
 monitoring the temperature obtained at the recta, the body temperature of
 the experimental animals was maintained constantly (38.degree. C.) by
 controlling the temperature of the laboratory tables on which the animals
 were laid. With the aim of measuring the blood pressure and the heart
 rate, a heparinized catheter was inserted into the right femoral artery.
 In this regard, a pressure transducer, such as that manufactured by Grass
 Ins., MA, U.S.A., identified as Model Statham P23XL, was used to measure
 the blood pressure. The heart rate was measured by a tachometer, such as
 that manufactured by Gould Inc., OH, U.S.A., identified as Biotachometer.
 In addition, all of the changes occurring during the experiment were
 continuously recorded through the Gould 2000 chart recorder, manufactured
 by Gould Inc.
 The fifth intercostal space was incised to open the thorax and the TAD was
 separated from its surrounding tissues. A silk ligature was hung around
 the LAD to occlude the LAD, later. The LAD part upstream of the silk
 ligature was isolated from adjacent tissues and the blood flow was
 measured quantitatively. In this regard, a chart recorder, such as that
 manufactured by MFE Ins., MA, U.S.A., identified as 1400 Thermal Chart
 Recorder was used. Using polygraph such as Grass Model 7E, the
 electrocardiogram was measured and read (Lead II). For infusing the beagle
 dogs with the drugs of interest, a catheter was inserted into the left
 cephalic vein and fixed. After the operation, when all parameters were
 maintained stable, test compounds and vehicles were administered
 intravenously.
 Before the occlusion of the LAD, the experimental animals were divided into
 a control group (PEG 400) and a test drug-administered group (KR-31372, 50
 ug/kg/min). Ten minutes before the occlusion of the LAD, test drugs began
 to be infused through an intravenous route. The infusion of the test drugs
 and the vehicle lasted for 40 min. (total dose 2 mg/kg, total PEG400
 volume 4 ml or less). Ten min. after the beginning of the infusion, the
 LAD was completely occluded and after a lapse of 90 min, reperfusion was
 conducted to maintain coronary flow for five hours. After 5 hours, the LAD
 was cannulated for perfusion with a Ringer's solution at the same pressure
 as the blood pressure.
 A blue violet dye solution (1 mg/kg, 10 mg/ml) was injected into the left
 atrium, after which the heart was endered to get an electric shock and
 removed. After removal of both atria, the ventricles were transversely cut
 t an interval of 0.5 cm. Photographs were taken of the transverse sections
 of the resulting ventricle slices by a digital camera. For the measurement
 of the IZ, the tissue slices were incubated at 37.degree. C. for 30 min in
 a 1% 2,3,5-triphenyltetrazolium chloride phosphate buffer, followed by
 taking photographs of the transverse sections with the digital camera.
 Using an image analyzing program (Image-Pro Plus ver. 3.0.1, Media
 Cybernetics, Maryland, U.S.A.), the AAR and the IZ were measured and
 analyzed. The IZ was expressed as a percentage to the AAR (refer to the
 mathematical formula 2). Lower IZ values mean more potent effects of the
 test drugs on this beagle dog model. The results are given in Table 2,
 above.
 In the ischemic myocardium damage models of anesthetized beagle dogs, as
 indicated in Table 2, the compounds of the present invention also showed
 iderably decreased values for the myocardial infarction rate in the area
 at risk(AAR). In detail, the solvent group showed a myocardial infarction
 rate to area at risu (IZ/AAR) of 52.39%, which indicates a serious damage
 in the myocardial muscle. Being measured to be 38.02% in myocardial
 infarction rate, BMS-180448 showed a good anti-ischemic activity. On the
 other hand, when the compounds of the present invention were administered,
 the myocardial infarction rate was decreased down to as low as 28.03%
 (compound of Example 24). Of course, no significant reduction in the blood
 pressure was found upon the administration of the compounds of the present
 invention.
 As described above, the compounds of the present invention exert excellent
 anti-ischemic action on beagle dog with superiority in anti-ischemic
 activity to the control BMS-180448. Therefore, the compounds of the
 present invention can be used as preventive or curative agents against the
 diseases related to ischemic heart disease.
 Experimental Example 4
 Protective Activity for Neurons
 In order to examine whether the compounds of the formula 1 suppress the
 iron-induced neuronal death, experiments were conducted as follows.
 From the brains of 17-18 day-old rat embryos, cerebra. cortical neurons
 were isolated and then, cultured at 37.degree. C. for 7-9 days in a 5%
 CO.sub.2 incubator. The cortical cell cultures were washed twice with a
 minimum essential medium (MEM) to reduce tiLe serum concentration to 0.2%
 and pre-treated for 30 min with 10 uM and 30 uM of each of test compounds.
 For the experiments, the test compounds were dissolved in DMSO and diluted
 in a medium. At this time, the final concentration of DMSO was not allowed
 to exceed For a control group, only vehicle was applied.
 After the pre-treatment with test compounds or vehicle, FeSO.sub.4, was
 added to a final concentration of 50 uM, and the cultures were maintained
 for 24 hours in a CO.sub.2 incubator. During incubation, lactate
 dehydrogenase (LDH) was released into the medium upon neuronal death by
 the oxidative toxicity of iron. The extent of neuronal damage was assessed
 by measuring the amount of LDH secreted into the media. The protective
 effect of the compounds of interest on neurons was evaluated beg
 calculating the LDH reduction rate of treatment group compared with that
 of the control group. The results are given in Table 3, below.
 TABLE 3
 Protective Effect of Compounds of Formula 1 on Neurons
 Compounds Concentration (uM) % Protection
 Example 24 30 47
 10 29
 Example 25 30 69
 10
 Example 38 30 78
 10 56
 Example 40 30 97
 10 45
 As seen in Table 3, the compounds of the present invention protected
 neurons from being damaged by iron in a dose-dependent manner. The
 compound of Example 38 protected the neuronal death by as high as 56% even
 at 10 uM. In addition, the compound of Example 40 showed a protection rate
 of as high as 97%, which demonstrates that the compound has very potent
 protective activity against the iron-included damage to neurons.
 Since the compounds of the present invention showed an excellent protective
 effects on neurons, they can be used as preventive or curative agents for
 the medical treatment of the neurological disorders caused by the (damage
 or death of neurons, such as cerebral stroke and dementia as well as for
 the medical treatment of inflammatory diseases such as arthritis, cardiac
 infarction, and acute/chronic tissue damage.
 Experimental Example 5
 Inhibitory Activity Against Lipid Peroxidation
 (1) Inhibitory Effect on Iron-induced Lipid Peroxidation
 In order to examine whether the compounds of the formula 1 suppress the
 iron-induced lipid peroxidation, experiments were conducted as follows.
 The rat brain was homogenized in a Krebs buffer (15 mM HEPES, ID mM
 glucose, 140 mM NaCl, 3.6 mM KCl, 1.5 mM CaCl.sub.2, 1.4 mM KH.sub.2
 PO.sub.4, 0.7 mM MgCl.sub.2, pH 7.4) and the supernatant separated by
 centrifugation at 12,000 rpm for 10 min. was used for further experiments.
 FeCl.sub.2 was added to a final concentration of 400 uM in the brain
 homogenate which was then allowed to stand at 37.degree. C. for 30 min.
 for the facilitation of oxidation. Each of the test compounds was added at
 a concentration of 100 uM and vehicle was used as a control.
 Iron facilitates the oxidation of the brain homogenate to produce
 malondialdehydo (MDA), a lipid peroxidation product. Thus, the lipid
 peroxidarion was determinne by MDA quartification. The inhibitory effect
 of the test compounds against the lipid peroxidation was evaluated by
 calculating MDA reduction rate of the test compounds compared with that of
 the control group.
 Typically, the MDA quantification is achieved by reacting samples with
 2-thiobarbituric acid (TBA) and measuring the absorbance at 530 nm.
 However, this method is unsuitable to treat samples on a large scale
 because of a boiling step. Thus, in this experiment,
 N-methyl-2-phenylindole was used instead of TBA. In this case, one
 molecule of MDA reacts with two molecules of N-methyl-2-phenylindole to
 form a chromogen which shows a maximal absorbance at 586 nm and requires
 no boiling steps. Bioxytech.sup.R LPO-586 Kit was used for MDA
 quantification. The results are given in Table 4a, below.
 TABLE 4a
 Inhibitory Effect of Compounds of Formula 1 on Lipid
 Peroxidation by iron
 Concentration
 Compounds (uM) % Inhibition
 Example 7 100 70
 Example 24 100 12
 Example 25 100 2
 Example 32 100 86
 Example 38 100 4
 Example 40 100 79
 As seen in Table 4a, the compounds of the present invention suppress the
 iron-induced lipid peroxidation. In particular, the compounds of Examples
 7, 32 and 40 showed very potent inhibitory activity against the
 iron-induced lipid peroxidation with inhibitory effects of 70%, 86% and
 79%, respectively.
 (2) Inhibitory Effect on Copper-induced LDL Oxidation
 In order to examine whether the compounds of the formula 1 suppress the
 oxidation of LDL (low density lipoprotein) induced by copper, experiments
 were conducted as follows.
 ID Human LDL (sigma) was dissolved in distilled water at a concentration of
 1 mg/ml. LDL was dialyzed against three changes of phosphate-buffered
 solution before oxidation to remove EDTA (ethylenediamine tetraacetate) at
 4.degree. C. for 18 hr. EDTA-free LDL (100 ug LDL protein/ml) was
 incubated in EDTA-free phosphate-buffered solution at 37.degree. C. for 18
 hr in the presence of CuSO.sub.4 (10 uM) under pretreatment with the test
 compounds or tochopherol of which final concentrations were 10.sup.-9,
 10.sup.-7, and 10.sup.-5 M. Blank was incubated without CuSO, and vehicle
 was used as a solvent group. Oxidation was stopped at 4.degree. C. by
 addition of EDTA (200 uM).
 Copper (Cu.sup.+2) facilitates the oxidation of LDL to produce
 malondialdehyde (MDA), thus the lipid peroxidation was determined by MDA
 quantification same as the above example 5 (1). The MDA quantification was
 estimated by reacting samples with 2-thiobarbituric acid (TBA) and
 measuring the absorbance at 530 nm. 1,1,3,3-Tetramethoxy propane (Sigma)
 was used as a standard agent, and calculated the quantity of MDA as nmol
 of MDA equivalents per mg protein. The inhibitory effect of the test
 compounds against the lipid peroxidation was evaluated by calculating MDA
 reduction rate of the test compounds compared with that of the control
 group. The results are given in Table 4b, below.
 TABLE 4b
 Inhibitory Effect of Compounds of Formula 1 on Lipid
 Peroxidation induced by copper
 Compounds Concentration (M) % Inhibition
 Example 40 10.sup.-9 7.6
 10.sup.-7 24.3
 10.sup.-5 27.6
 Tocopherol 10.sup.-9 18.5
 10.sup.-7 21.3
 10.sup.-5 29.7
 As seen in Table 4b, the compound of example 40 significantLy suppress the
 copper-induced LDL oxidation at concentration of 10.sup.-7 and 10.sup.-5
 M, which was similar to that of tocopherol.
 (3) Inhibitory Effect on A7r5 Mediated LDL Oxidation
 In order to examine whether the compounds of the formula 1 suppress the
 A7r5 mediated oxidation of LDL (low density lipoprotein), experiments were
 conducted as follows.
 A7r5 (ATCC CAL-1444, smooth muscles, thoracic aorta, BDIX rat) cells were
 cultured in 24 well plates, using the medium of DMEM (Dulbecco's modified
 Eagle's Medium) supplemented with 10% heat-inactivated FBS (fetal bovine
 serum) and 1% antibiotics. Confluent A7r5 from plates were washed with
 phosphate-buffered solution, and DMEM with 10% FBS and 1% antibiotics was
 added in a total volume of 0.5 ml/well. Cells (2.times.10.sup.5 cells/ml)
 were preincubated without and with either test compounds (10.sup.-6
 -10.sup.-4 M) or Tocopherel (10.sup.-6 -10.sup.-4 M) at 37.degree. C. for
 30 min. Then, A7r5 alone or A7r5 plus H.sub.2 O.sub.2 (10.sup.-7 M) were
 exposed to LDL (100 ug/ml) for 24 hr.
 The inhibitory effect of the test compounds against the lipid peroxidation
 was evaluated by calculating MDA reduction rate of the test compounds
 compared with that of the control group same as the above example 5 (2).
 The results are given in Table 4c, below.
 TABLE 4c
 Inhibitory Effect of Compounds of Formula 1 on A7r5
 mediated LDL oxidation
 % Inhibition
 Concentration LDL + H.sub.2 O.sub.2
 Compounds (M) LDL (10.sup.-7 M)
 Example 40 10.sup.-6 40.9 49.7
 10.sup.-5 51.4 62.5
 10.sup.-4 57.5 64.3
 Tocopherol 10.sup.-6 41.1 43.2
 10.sup.-5 57.0 53.0
 10.sup.-4 73.7 63.9
 As seen in Table 4c, the compound of example 40 and Tocopherol
 significantly suppress the A7r5 mediated LDL oxidation at all
 concentrations tested. Especially, the compound of example 40 represented
 more significant inhibition of LDL oxidation when H.sub.2 O.sub.2 was
 added.
 With excellent inhibitory activity against lipid peroxidation as seen in
 the above experimental example 5 (1), (2), and 3), the compounds of the
 present invention can be used for the prevention and treatment of
 neurodegenerative diseases such as cerebral stroke and dementia,
 inflammatory diseases such as arthritis, cardiac infarction, and
 acute/chronic tissue damage, which may be caused by the lipid peroxidation
 and its accumulation in tissues.
 Experimental Example 6
 Inhibitory Effect on NO Production
 In order to examine whether the compounds of the formula 1 inhibit the
 formation of nitric oxide (NO), experiments were conducted as follows.
 Using RPMI1640 media supplemented with 10% fetal bovine serum (EBS), RAW
 264.7 cells (obtained from American Type Culture Collection), a murine
 macrophage cell line, were cultured at 37.degree. C. in a 5% CO.sub.2
 incubator. The RAW264.7 cells were harvested and cell density was adjusted
 to 5.times.10.sup.5 /ml with a RPMI medium supplemented with 0.5% FBS and
 plated at 5.times.10.sup.4 cells/well to 96-well plates, which were then
 cultured for 20 hr in a CO.sub.2 incubator. After removal of the media,
 the cells were pre-treated for 1 hour with fresh media containing 33 uM
 and 100 uM of test compounds. The test compounds were dissolved in DMSO
 and diluted to respective concentration in the media. In order to
 minimimize DMSO effect on the nitric oxide formation by the RAW264.7 cells
 in the wells, the media were allowed to contain DMSO at a concentration of
 0.1% or less.
 After completion of one hour pre-treatment, lipopolysaccharide (LPS, E.
 coli serotype 055:B5) was added to activate the cells, which were, then,
 maintained for 24 hours in a CO.sub.2 incubator. As a result of the
 activation of RAW264.7 cells with LPS, NO was formed. The NO released into
 the media was in a form of nitrite NO.sub.2.sup.- and quantitatively
 measured using the Griess reagent. A control was treated only with vehicle
 instead of test compounds. Using the nitrite standard it was shown that
 the test drugs themselves do not hinder the quantification of NO.
 The inhibitory effects of the test compounds against NO production were
 determined as the reduction of NO quantity compared with that of the
 control group. The results are given in Table 5, below.
 TABLE 5
 Inhibitory Effect of Compounds of Formula 1 on NO
 Production
 Compounds Concentration (uM) % Inhibition
 Example 7 100 88
 Example 24 100 48
 33 16
 Example 25 100 54
 33 39
 Example 32 100 83
 Example 38 100 85
 33 56
 Example 40 100 26
 As indicated in Table 5, the compounds of the present invention exhibited a
 dose-dependent behavior in inhibiting the induction of NO production by
 endotoxins such as LPS. In particular, the compound of Example 38
 inhibited the NO production by as high as 56% even at as low as 33 uM. In
 addition, 100 uM of the compounds of Examples 7 and 32 had inhibition
 rates of as high as 88% and 83%, respectively, showing that the compounds
 of the present invention exert very potent inhibitory activity against the
 NO production induced by LPS.
 With good inhibitory activity against NO production, the compounds of the
 present invention can be used as preventive or curative agents for the
 medical treatment of neurological disorders such as cerebral stroke and
 dementia, which may be caused by the neuronal damage or death due to a
 large amount of NO released as well as for the medical treatment of
 inflammatroy diseases such as arthritis, cardiac infarction, and
 acute/chronic tissue damage.
 Experimental Example 7
 Preventive Effect on the Brain Damaged Induced by Brain
 Ischemia-Reperfusion
 in order to examine whether the compounds of the formula 1 are protective
 against the brain damage by brain ischemia-reperfusion, experiments were
 conducted as follows.
 Male Sprague-Dawley rats (350.+-.50 g, SamYook Experimental Animals Co.,
 Korea) were anesthetized by the injection of pentobarbital sodium at a
 dose of 40 mg/kg, after which the femoral vein and the artery were
 cannulated with PE-10 while the left carotid artery was exposed. Five min.
 before the operation, 20 ug/kg of heparin sulfate was injected into the
 peritoneal cavity. For the continuous measurement of arterial pressure,
 with a insertion of a blood pressure measuring device into the femoral
 artery. About 10 ml of blood was taken from the femoral vein to reduce the
 blood pressure down to 30 mmHg. If the blood pressure is not reduced to
 less than 100 mmHg with a withdrawal of 7 ml of blood, the rats are
 considered to have high sympathetic tone. In such a case, those rats were
 excluded from the experiments because the blood pressure cannot be reduced
 to 30 mmHg or even after success in reducing the blood pressure, the rats
 showed high mortality after the operation.
 While the blood pressure was maintained at 30 mmHg, the exposed left
 carotid artery was occluded for 20 min by an aneurysm clamp to cause
 cerebral ischemia. Then, the carotid clamps were removed and the extracted
 blood was reinfused. To minimize the systemic acidosis, the rats were
 reinfused with 5 ml of saline containing 0.84% bicarbonate sodium
 (bicarbonate saline). During operation and restoration period, body
 temperature was maintained at 37.+-.0.5.degree. C. with the aid of a
 thermal blanket and incandescent light bulbs. During their restoration
 from the operation, the body temperature was kept tant for 2 hours or
 more. After being completely recovered, the rats were transferred to an
 animal observatory, which was under a homeostatic condition for
 temperature (27.degree. C.), humidity (60%) and light cycle (12-12 hours).
 24 hours after the operation, the rats were sacrificed with a scaffold and
 the brain was removed rapidly (3 min). On ice, the removed brain was
 sliced into six 2-mm coronal sections with the aid of a brain matrix. The
 sections were stained in a 2% 2,3,5-triphenyltetrazolium chloride solution
 at 37.degree. C. for 30 min. After photographs were taken of the stained
 sections, developed and printed, the percentages of the infarcted brain
 areas to the total brain were measured and analyzed using an image
 analyzing program (Image-Pro Plus ver. 3.0.1).
 At 30 min before the operation and at 2, 4 and 16 hours after the carotid
 artery occlusion, the test compounds were peritoneally injected into the
 rats to a dose of 30 mg/kg. For the control, vehicle was injected. For the
 reference compound, MK801 (RBI, (SR,10S)-(+)-5-methyl-10,
 11-dihydro-5H-dibenzo[a,d]cyclo-heptene-5,10-imine hydrogen maleate) was
 administered at 3 mg/kg with the same intervals.
 The protective effects of the test compounds on the brain damage caused by
 brain ischemia-reperfusion were expressed as a reduction percentages of
 infarcted brain areas compared with those of the control group. The
 results are given in Table 6, below.
 TABLE 6
 Protective Effect of Compounds of Formula 1 on Brain
 Damage Induced by Brain Ischemia-Reperfusion
 Test Dose Infarction Area
 Drug (mg/kg) Mean .+-. SD (%) Reduction (%) No.
 Vehicle 0 39.7 .+-. 1.6 10
 NK801 3 29.8 .+-. 1.5 24.8* 7
 Example 40 30 23.0 .+-. 3.3 42.0* 11
 P &lt; 0.01 compared with the control group administered with only vehicle
 The comparative group, in which rats were administered with MK801 at a dose
 of 3 mg/kg, had an infarct area of 29.8%, which was reduced by 24.8%
 compared with that of the control group. On the other hand, in the group
 treated with the compound of Example 40, the infarct area was measured to
 be 23.0%, which was reduced by 42.0% compared with that of the control
 group. Therefore, the compound of Example 42 was twice as effective in the
 protective activity against the brain damage cause by brain
 ischemia-reperfusion as the conventional compound MK801.
 In the MK801-treuted group, the rats showed a side effect of low motility
 whereas when being administered with the compound of Example 40, the rats
 did not suffer from any side effects including behavorial change such as
 motility.
 With excellent protective activity against brain damage induced by
 ischemia-reperfusion, the compounds of the present invention can be used
 as preventive or curative agents for the medical treatment of the
 neurological disorders such as cerebral stroke and dementia, which may be
 caused by the brain damage such as cerebral vascular occlusion induced by
 thrombi.
 Experimental Example 8
 Suppressive Effect Against Angiogenesis
 In order to examine whether the compounds of the formula 1 had inhibitory
 effect on the formation of new blood vessels, experiments were conducted
 as follows.
 (1) Effect on .sup.99m Tc-DTPA Clearance
 A polyester sponge with a size dimension of 5 mm.times.diameter 12 mm was
 used as a matrix for the growth of blood vessels. Inside each sponge, a
 polyethylene tube with a length of 5 mm was fixed by a thread.
 Sprague-Dawley rats were anesthetized by the intraperitoneal injection of
 chloral hydrate at a dose of 300 mg/kg. The rat's hair in the region
 between the neck and the dorsi was shaved and the hare regions were
 incised at a length of 10 mm to secure a hypodermic space large enough to
 accommodate the sponge. After being inserted to the hypodermic space, the
 sponge was secured for the tube not to rock. Except for when the drugs
 were administered, the tube hole was kept closed in order to prevent
 contamination.
 In order to induce angiogenesis, Angiotensin II was employed. For use,
 Angiotensin II was dissolved in a phosphate buffered saline (PBS). 50 ul
 of a 100 nmol solution was injected. As for the compounds of the present
 invention, they were dissolved in PBS and injected at doses of 0.1, 0.3,
 and 1.0 mg/kg through the tube. In control groups, the vehicle PBS or
 Angiotensin II alone was injected at the same doses. The suppressive
 effect of the test compounds against angiogenesis was measured 7 days
 after the injection.
 The extent of angiogenesis in transplanted sponge was examined for blood
 stream by the measurement of .sup.99m Tc-DTPA
 (technetium-dimethylenetriamine pentaacetic acid) clearance. Seven days
 after the injection of the test compounds, the rats were again
 anesthetized by the intraperitoneal injection of chloral hydrate at a dose
 of 30 mg/kg, followed by careful injection of 50 ul of a solution of
 .sup.99m Tc-DTPA (0.5 ) in sterilized PBS through the tube. A quantitative
 measurement of .sup.99m Tc-DTPA was conducted for 60 min. With the aid of
 a gamma-scintillation dector while a gamma camera, such as ADAC
 VERTEX/SOLUS Gamma Camera, equipped with a low energy high resolution
 apparatus, was operated to take photographs of the sponge at 60 frames
 each which took 60 sec. to achieve. The continuous images thus obtained
 were input into a computer (Pegasys Sun Computer) for analysis.
 The clearance of .sup.99m Tc-DTPA was calculated according to the following
 mathematical formula 3 and the results are given in Table 7a, below.
 [Mathematical Formula 3]
 ##EQU3##
 TABLE 7a
 Suppressive Effect of Compounds of Formula 1 Against
 Angiogenesis
 Dose Clearance
 Test Drug (mg/kg) (p.o) of .sup.99m TC (%)
 Control (PBS) -- -- 30.3
 Control AII (100 nmol) -- -- 44.71
 Test Group 0.1 26.90
 (AII (100 nmol) + Example 24 0.3 18.22
 Test Drug 1.0 3.38
 p.o. per oral
 As apparent from the data of Table 7a, Angiotensin II induced the formation
 of new blood vessels by comparing the clearance of .sup.99 mTc-DTPA
 between the PBS-administered control group (30.3%) and the Angiotensin
 II-administered control group (44.71%). When being administered at a dose
 of 0.1 mg/kg, the compound of Example 24 showed a .sup.99m Tc-DTPA
 clearance of 26.90%, which clearly demonstrates the suppressive effect of
 the compound against the angiogenesis. In addition, the administration of
 the compound of Example 24 at doses of 0.3 and 1.0 mg/kg elicited .sup.99m
 Tc-DTPA clearances of 18.22% and 3.38%, respectively, showing that the
 compound of the present invention suppresses the formation of new blood
 vessels in a dose-dependent manner. In particular, at a dose of 1.0 mg/kg,
 the compound of Example 24 showed almost complete suppression against the
 angiogenesis induced by Angiotensin II with the clearance of .sup.99m
 Tc-DTPA as low as 3.38%.
 (2) Inhibitory Effect on HUVEC Tube Formation
 In order to examine whether the compounds of the formula 1 had inhibitory
 effect on the formation of new blood vessels on cell level, experiments
 were conducted as follows.
 HUVEC, (Human umbilical vein endotheilal cells, ATCC CRL-1730) were
 cultured, and tubulogenesis was induced in vascular endothelial cells by
 plating them onto the surface of Matrigel for several hours. The effects
 on tube formation o)f the test compounds were compared with the vehicle
 treated controls, then confirmed their in vitro anti-arigiocenic effect
 indirectly. The results are given in table 7b).
 TABLE 7b
 Inhibitory Effects on HUVEC Tube Formation
 Inhibitory Effects
 on Tube Formation
 Concentration 10 uM 100 uM
 Example 2 + ++
 Example 10 + ++
 Example 16 +/- +/-
 Example 24 nd +
 Example 40 + ++
 Example 52 +/- ++
 -; no effect, +/-; week effect,
 +; moderate effect, ++; strong effect
 nd; not determined
 As seen in table 7b, HUVEC tube formation was inhibited ed at concentration
 of 10 uM, and strongly inhibited at concentration of 100 uM in the
 compounds of example 2, 10, 40, and 52, in a dose-dependent manner.
 With such an excellent suppressive activity against angiogenesis, the
 compounds of the present invention can be usefully applied for the medical
 treatment of various diseases induced by angiogenesis, such as rheumatoid
 arthritis, psoriasis, AIDS complications, cancers, diabetic retinopathy,
 etc.
 Experimental Example 9
 Inhibitory Effect on Intracellular ROS Induced by Hydrogen peroxide
 In order to examine whether the compounds of the formula 1 suppress the
 formation of intracellular ROS induced by H.sub.2 O.sub.2, experiments
 were conducted as follows.
 Measurement of intracellular ROS (Reactive Oxygen Species) was determined
 using H.sub.2 DCFDA (2',7'-dichlorodihydrofluorescein diacetate, Molecular
 Probes, Eugene, Oreg., USA) . H.sub.2 DCFDA is a non-polar compound that
 readily diffused into cells, where it is hydrolyzed by intracellular
 esterase to polar derivative H.sub.2 DCF
 (2',7'-dichlorodihydrofluorescein) which can not cross the cell membrane,
 and thereby trapped within the cell. H.sub.2 DCF is low-fluorescent, but
 converted to high-fluorescent DCF (2', 7'-dichlorofluorescein) by
 intracellular a ROS. Therefore, the intracellular ROS formation can be
 determined from the amount of converted DCF. HUVEC (Human umbilical
 Vascular Endothelial Cells) or A7r5 (Rat thoracic aorta smooth muscle
 cells) were used. HUVEC were cultured in Kaighn's F12K medium supplemented
 with 10% heat-inactivated EBS,0.1 mg/ml heparin sodium, 0.03-0.0 5 mg/ml
 ECGS (Endothelial cell growth supplement) and 1% antibiotics, and A7r5
 were cultured in DMEM supplemented with 10% heat inactivated FBS and
 antibiotics. To measure the intracellular ROS, HUVEC or A7r5 were
 proincubated for 30 min in the presence of test compounds (10.sup.-7
 -10.sup.-5 M). Thereafter, cells were stimulated with H.sub.2 O.sub.2
 (10.sup.-6 and 10.sup.-5 M for 20 min), and then incubated in the dark for
 2 hr at 37.degree. C. in 50 mM phosphate buffer (pH 7.4) containing 5 uM
 H.sub.2 DCFDA. The quantity of DCF fluorescence (485 nm excitation, 530 nm
 emission) was measured using Fluorescence plate reader (FL600, Biotek
 Instruments). The results are given in Table 8.
 TABLE 8
 Inhibitory Effects against intracellular ROS
 induced by H.sub.2 O.sub.2
 Inhibition (%)
 Conc. H.sub.2 O.sub.2 H.sub.2 O.sub.2
 Cell Compounds (M) (10.sup.-6 M) (10.sup.-5 M)
 HUVEC Toco- 10.sup.-7 13.8 8.8
 pherol 10.sup.-6 43.2 30.7
 10.sup.-5 60.8 51.0
 Example 10.sup.-7 17.6 12.0
 40 10.sup.-6 46.1 25.8
 10.sup.-5 63.1 54.9
 A7r5 Probucol 10.sup.-7 72.0
 10.sup.-6 184.1
 10.sup.-5 185.3
 Example 10.sup.-7 72.0
 24 10.sup.-6 110.7
 10.sup.-5 185.3
 As seen in table 8, the compound of example 40 inhibited H.sub.2 O.sub.2
 -induced ROS in HUVEC cells, which is similar or a little superior to that
 of tocopherol. The compound of example 24 completely inhibited ROS at
 concentration of 10.sup.-6 and 10.sup.-5 M.
 With excellent antioxidant effects to inhibit intracellular ROS formation,
 the compounds of the present invention can be used for the prevention and
 treatment of neurodegenerative diseases such as cerebral stroke and
 dementia; inflammatory diseases such as arthritis; atherosclerosis;
 cardiac infarction; and acute/chronic tissue damage, which may be caused
 by ROS.
 Experimental Example 10
 ORAC Assay
 In order to examine whether the compounds of the formula 1 remove the
 oxygen-radical, experiments were conducted as follows.
 The ORAC (Oxygen-radical absorbance capacity) assay is an in vitro method
 capable of assessing the radical absorbing capacity of a drug in a watery
 environment. The method utilized .beta.-PE (.beta.-phycoerythrin) as an
 indicator protein, and AAPH (2,2'-azobis(2-amidinopropane)
 dihydrochloride) as a peroxy radical generator. Reaction mixtures listed
 of test compounds (10.sup.-6 M and 10.sup.-4 M), .beta.-PE
 (1.76.times.10.sup.-8 M), and AAPH (3.times.10.sup.-3 M) in 75 mM
 phosphate buffer (pH 7.0). A final volume of 2 ml was used in 24 well
 plates. Test compounds were first dissolved in acetone and then added to
 the reaction mixture. Once AAPH was added, the reaction was initiated at
 37.degree. C. and the fluorescence (485 nm excitation, 590 nm emission)
 was measured every 5 min using Fluorescence reader (FL600, Biotek
 Instrument). The ORAC units were calculated based on the area under the
 fluorescence curve of .beta.-PE in the presence of the test compound
 compared to the area generated by 1 uM Trolox. 1 ORAC unit represents the
 net protection provided by 1 uM Trolox. The results are given in table 9.
 TABLE 9
 ORAC Assay
 Compound Conc. (M) ORAC units
 Tocopherol 10.sup.-5 1.0
 10.sup.-4 1.568
 Probucol 10.sup.-6 1.327
 10.sup.-4 1.566
 Example 40 10.sup.-6 2.047
 10.sup.-4 3.250
 As seen in tabLe 9, the compound of example 40 showed around 2-Limes higher
 ORAC units compared to those of tocopherol and probucol at concentration
 of both 10.sup.-6 and 10.sup.-4 M, showing excellent radical absorbing
 capacity.
 With excellent antioxidant effects to remove oxygen radicals, the compounds
 of the present invention can be used for the prevention and treatment of
 neurodeaenerative diseases such as cerebral stroke and dementia;
 inflammatory diseases such as arthritis; atherosclerosis; cardiac
 infarction; and acute/chronic tissue damage, which may be caused by free
 radicals.
 Experimental Example 11
 Protection Effects on Ischemic Retinal, Cells
 In order to examine whether the compounds of the formula 1 protect the
 ischemic retinal cells, experiments were conducted as follows.
 Test compounds were dissolved in DMSO to prepare stock solution (100 mM),
 which was diluted with physiological saline to the concentration of 100,
 50 and 30 uM. Test compounds were administered by vitreous injection
 before 30 min of ischemia.
 Adult rats were anaesthetized with ip (intra peritoneum) injection of
 chloral hydrate (400 mg/Kg), then the right eyes were treated with 1%
 tropicamide to dilate the pupils. The intraocular pressure (TO)P was
 raised to 160-180 mmHg, higher than normal blood pressure (140 mmHg), by
 cannulation of the anterior chamber connected to hydrostatic pressure
 device. Interruption of blood flow was confirmed ophtalmoscopically, the
 elevated IOP was maintained for 30 min. After 30 min of ischemia, both
 eyes were enucleated, and the retina was separated, of which cellular
 damage was observed. Number of cells in ganglion cell layer (250.times.25
 um) and innernuclear layer (150.times.25 um) were counted, then calculated
 as a % of living cells compared to those of non-operated left eyes as a
 normal control. The results are given in table 10.
 TABLE 10
 Protective Effects on Ischemic Retinal cells
 Living cell (%)
 Ganglion Innernuclear
 Cell layer layer
 Normal control 100 100
 Ischemia 34.5 51.7
 Example 40 30 uM 40.7 54.8
 50 uM 60.2 69.8
 100 uM 77.9 82.6
 As seen in table 10, the compound of example 40 protected neurons both in
 ganglion and innernuclear layers after retinal ischemia, in a dose
 dependent manner.
 With excellent protective effects to inhibit ischemic neuronal cell death
 in ganglion and innernuclear layers in retina, the compounds of the
 present invention can be used for the treatment of glaucoma, optical
 neuropathy, which may caused by ischemia.
 Experimental Example 12
 Effects on MNCV (Motor Nerve Conduction Velocity) in Diabetic Rats
 In order to examine whether the compounds of the formula 1 improve impaired
 MNCV in diabetic rats, experiments were conducted as follows. Diabetes was
 induced with i.p. (intra peritoneum) injection of streptozocin (65 mg/Kg)
 in rats, then test compounds dissolved in 2 ml of media (physiological
 saline:ethanol:tween 80=8:1:1), were orally administered once a day. Rats
 were anesthetized with halothane, then the sciatic nerve was exposed to
 measure MNCV. The nerve was stimulated at two points. The first stimulus
 electrode was inserted at proximal end, and second stimulating electrode
 was inserted at the sciatic notch. The coaxial. needle electrode was
 inserted into interdigital muscle, then the muscle action potential
 induced by two point stimulation. The conduction velocity was calculated
 by dividing the distance between two stimulus points by the latency
 difference. Lipoic acid (100 mg/Kg) was used in comparison with the
 compound of formula 1 in recovery of impaired MNCV in diabectic rats. The
 recovery (%) of MNCV was calculated according to the following
 mathematical formula 4. The results are
 [Mathematical formula 4]
 ##EQU4##
 TABLE 11
 Effects on MNCV in diabetic rats
 MNCV (sec) Recovery (%)
 Normal control 51.937 100
 Diabetic rat 40.647 --
 Lipoic acid 56.070 136.6
 (100 mg/Kg)
 Example 40 47.756 63.0
 (30 mg/Kg)
 As seen in table 11, MNCV of diabetic rats were significantly decreased
 compared to that of normal control. Treatment of lipoic acid (100 mg/Kg)
 completely recovered impaired MNCV in diabetic rats. Administration of
 example 40 (30 mg/Kg) significantly improved MNCV in diabetic rats.
 Experimental Example 13
 Nociceptive Test (Hot Plate Test) in Diabetic Rats
 In order to examine whether the compounds of the formula 1 improve impaired
 nociceptive responses in diabetic rats, experiments were conducted as
 follows.
 Effects on nociceptive responses of test compounds in rats were examined
 using hat plate.
 The same methods were applied for the induction of diabetes and treatment
 of test compound in rats. Rats were placed onto 50.degree. C. hot plate,
 then latencies of nociceptive action such as licking were determined. The
 recovery (%) of nociceptive responses in diabetic rats was calculated
 according to the following mathematical formula 4. The results are given
 in table 12.
 [Mathematical formula 5]
 ##EQU5##
 TABLE 12
 Effects on Nociceptive responses in Diabetic Rats
 Nociceptive
 response (sec) Recovery (%)
 Normal control 4.698 100
 Diabetic control 3.986 --
 Lipoic acid 4.371 60.2
 Example 40 4.791 106.5
 As seen in table 12, Lipoic acid significantly improved impaired
 nociceptive responses in diabetic rats. On the contrary, the compound of
 example 40 completely recovered impaired nociceptive responses of diabetic
 rats in hot plate test.
 With excellent improving activity against impaired MNCV and nociceptive
 responses of diabetic rats as seen in the above experimental example 12
 and 13 as well as antioxidant and neuronal cell protection effects, the
 compounds of the present invention can be used for the prevention and
 treatment of diabetic neuropathy and diabetic peripheral disturbances.
 Experimental Example 14
 Protection Effects on Hypoxic Brain Injury
 In order to examine whether the compounds of the formula 1 protect hypoxic
 brain injury in newborn rats, experiments were conducted as follows, using
 MRS (magnetic resonance spectrum).
 Focal, hypoxic brain injury model in newborn rats are being most frequently
 used to study infant asphyxia, because whose maturity of brain is similar
 to that of human infant, and it is easy to get enough number of animals
 required for the determination of effects. It was reported that the lipid
 peak was increased in MRS (magnetic resonamce spectroscopy) by ischemic
 neuronal cell injury due to the destruction of cell membrane including
 blood-brain barrier [A. Bizzi et. al., Magnetic Resonance Imagin 14
 581-592 (1996)], and also the concentration of lipid and apotosis are
 closely correlated to apotosis[Van der A. Toorn et al., Magnetic Resonance
 in Medicine, 36 , 914-922 (1996)]. N-Acetylaspartae (NAA) and creatine
 (Cr) are markers of neuronal coinS. Then it was confirmed that the value
 of lipid/NAA N-acetylaspartae) and lipid/Cr (creatine) are correlated with
 the morphological change and severity of apoptosis on hypoxic brain
 damage.
 New born rats (within 7 days, 10-15 g) were placed in hypoxic chamber for 2
 hr to induce hypoxia, and test compounds were intraperitoneally injected
 before 1 hr of hypoxia. Proton MPS was obtained at 1 day after brain
 injury, then the value of lipid/NAA and lipid/Cr were determined.
 TABLE 13
 Protective Effects on Hypoxic Brain Injury
 Lipid/NAA Lipid/Cr
 Hypoxic control 4.63 4.11
 Example 40 2.51 2.33
 (50 mg/Kg)
 As seen in table 13, the compound of example 40 reduced the value of both
 Lipid/NAA and Lipid/Cr significantly, which represented protection effect
 on brain injury. With excellent protection effect on hypoxic brain injury
 in newborn rats, the compounds of the present invention can be used for
 the prevention and treatment of infant asphyxia.
 Experimental Example 15
 Inhibitory Effects on Proliferation of Vascular Smooth Muscle Cells
 In order to examine whether the compounds of the formula 1 inhibit
 proliferation of vascular smooth muscle cells, experiments were conducted
 as follows.
 Inhibitory effects on cell proliferation was evaluated by measurement of
 incorporation of [.sup.3 H]-thymidine into DNA. Rat aortic smooth muscle
 cells were grown in 24 well plate for 3 days to near confluence in DMEM
 containing 10% FBS, then DMEM containing FBS was washed out. Cells were
 cultured again in DMEM without serum for 48 hr to be quiescent. Test
 compounds were added 15 min before addition of angiotensin II (10-7M),
 which stimulate cell proliferation, then cells were incubated for 72 hr.
 During the last 4 hours of incubation, [.sup.3 H]-thymidine (1 uCi/ml) was
 added. Radioactive medium was removed and cells were washed 3 times with
 DMEM (3.times.1 ml) to remove non-incorporated isotopes, and treated with
 an aqueous solution of 15% TCA (trichloroacetic acid)for at least 2 hr
 followed by addition of an aqueous solution of 0.2 N NaOH (0.25 ml) for 30
 min. The samples were filtered through glass microfiber filter (GF/B.
 Whatmann) under vacuum. After washing the filters 3 times with 2 ml of an
 aqueous solution of 5% TCA, the radioactivity incorporated into NA was
 counted by Liquid Scintilation Counter (Packard, TRI-CARB, 2100TR), then
 calculated incorporation % of [.sup.3 H]-thymidine. The results are given
 in table 14.
 TABLE 14
 Effects on [.sup.3 H]-thymidine incorporation (%) into DNA
 Compounds Incorporation %
 Angiotensin II 100
 Example 7 37.8
 Example 5 53.6
 Example 2 59.0
 Example 14 60.0
 Example 22 64.0
 As seen in table 14, compounds of example 2, 5, and 7 significantly inhibit
 the synthesis of DNA, representing below 60% of [.sup.3 H]-thymidine
 incorporation. Especially, the compound of example 7 represented 37.8% of
 low incorporation %.
 With excellent inhibitory effect on proliferation of vascular smooth muscle
 cells, the compounds of the present invention can be used for the
 prevention and treatment of restenosis occurred after percutaneous
 coronary interventions of coronary artery occlusion.
 Experimental Example 16
 Acute Oral Toxicity Test in Rats
 The test to confirm the toxicity of the compounds of formula 1 was carried
 out as follows.
 In this test six-week old SPF SD rats were used with two rats assigned to
 each group. The compounds of examples 1, 2, 3, 5, 7, 8, 9, 10, 13, 14, 15,
 19, 22, 23, 24, 25, 26, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,
 40, 41, 44, 46, 47, 48, 49, 51, 52, 57, 58, 60, 62, 64, 67, 68, 69, 71 and
 72 were suspended in 0.5% methyl cellulose, respectively, and administered
 orally at a single dose of 1 g/kg using a ball-tipped needle. The dosing
 volume was 10 ml/kg. After the administration, the animals were observed
 for clinical signs of toxicity or mortality and the body weight changes
 were measured. All survivors at the end of the observation period
 underwent laparotomy under ether anesthesia and the blood samples were
 taken from the abdominal aorta for hematological tests and biochemical
 analysis. After sacrificing the animals, autopsy was performed for
 macroscopic observation of the organs and tissues. Tissue samples of vital
 organs from macroscopic legion were removed and fixed in 10% neutral
 buffered formalin solution, then processed by standard procedures for
 histopathology and examined under light microscope. There were no
 significant changes in clinical symptoms, body weight and mortalities.
 Also in hematology, serum chemistry parameters and macroscopic
 observation, no drug-related changes were observed. As a result all the
 compounds tested did not show toxicity in rats up to a dose of 1 g/kg, and
 the lethal dose (LD.sub.50) for oral administration was determined to be
 offer 1 g/kg in rats.
 The present invention has been described in an illustrative manner, and it
 is to be understood that the terminology used is intended to be in the
 nature of description rather than of Imitation. Many modifications and
 variations of the present invention are possible in light of the above
 teachings. Therefore, it is to be understood that within the scope of the
 appended claims, the invention may be practiced otherwise than as
 specifically described.