Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-02-17
1997-03-25
Fan, Jane
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
5462831, 549399, 548454, 544240, G07D40504
Patent
active
056146337
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/JP93/01150 Aug. 17, 1993 now WO94/04521.
[FIELD OF THE INVENTION]
The present invention relates to novel benzopyran and benzoxazine derivatives which are useful as medicine.
[PRIOR ART]
Hitherto, benzopyran derivatives having various pharmacological effects have been known. For example, various benzopyran derivatives in which the 4-position carbon atom of a benzopyran ring is directly linked to a nitrogen atom are disclosed in Japanese Patent Public Disclosure (Kokai) Nos. 97974/1985, 47416/1986, 165317/1988, 196581/1988, 201182/1988, 303977/1988, 26578/1989, 38087/1989, 129184/1990 and Journal of Medicinal Chemistry, vol.33, No.6, pp.1529-1541 (1990). In the above documents it is disclosed that said compounds have an anti-hypertension effect and can be used for a treatment for diseases such as heart diseases.
Among the benzopyran derivatives disclosed in the above documents, Cromakalim represented by the following formula has recently been remarked as a new kind of a hypotensive drug having an effect on K.sup.+ channel together with Nicorandil and Pinacidil. ##STR2##
Besides, benzopyran derivatives in which the 4-position carbon atom of a benzopyran ring is not directly linked to a nitrogen atom are also disclosed in Japanese Patent Public Disclosure (Kokai) Nos.303977/1988 and 38087/1989, Official Gazette of WO90/14346, Journal of Heterocyclic Chemistry, Vol.11 (5), pp.797-802 (1974) and Journal of Medicinal Chemistry, vol.33, No.6, pp.1529-1541 (1990). Particularly, in the Official Gazette of WO90/14346 are disclosed compounds similar to the compounds of the present invention containing an amide group or a thioamide group at the 4-position of a benzopyran ring.
The present inventors have studied diligently the synthesis of a benzopyran derivative which has the equivalent or more excellent K.sup.+ channel opening activities than said similar compounds and Cromakalim and in which the 4-position carbon atom of a benzopyran ring is not directly linked to a nitrogen atom and about K.sup.+ channel opening activities. As a result, they have found that novel benzopyran and benzoxazine derivatives as described below, which are disclosed in no prior document, the above-mentioned pharmacological activities and accomplished the present invention on the basis of this finding.
[DISCLOSURE OF THE INVENTION]
The compounds of the present invention are novel compounds represented by the following general formula (I) having excellent K.sup.+ channel opening activities.
A novel benzopyran or benzoxazine derivative represented by the general formula: ##STR3## wherein
R.sub.1 and R.sub.2, which may be the same or different, represent a lower haloalkyl group,
R.sub.3 represents a hydrogen atom or is directly bonded to X to represent a single bond,
R.sub.4 represents a substituted or unsubstituted amino group, a saturated or unsaturated heterocyclic group or A--O-- wherein A represents a saturated or unsaturated carbocyclic group or a saturated or unsaturated heterocyclic group,
R.sub.5 and R.sub.6, which may be the same or different, represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower haloalkyl group, a nitro group or a cyano group,
X represents .dbd.N--, N.sup.+ --O.sup.- or ##STR4## wherein R.sub.7 and R.sub.8, which may be the same or different, represent a hydrogen atom, a hydroxyl group or a lower acyloxy group, or R.sub.7 is directly bonded to R.sub.3 to represent a single bond.
In the definition of the compounds represented by the general formula (I), a lower alkyl group and an alkyl moiety in a lower haloalkyl group mean an alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples of such a lower alkyl group include a methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group and t-butyl group. A halogen atom in a lower haloalkyl group means a chlorine, fluorine, bromine and iodine, preferably chlorine and fluorine. Examples of a lower haloalkyl group include a fluoromethyl group, difluoromethyl group,
REFERENCES:
Buckle et al, A Novel, Potent Airway-Selective Potassium Channel Activator, Bioorganic & Medical Chemistry Letters, vol. 2, No. 9, pp. 1161-1164. 1992.
Bergmann et al, 4-Heterocyclyloxy-2H-1-Benzopyran Potassium Channel Activators, J. Med. Chem, vol. 33, pp. 2759-2767, 1990.
Bergmann et al, Synthesis and Anithypertensive Activity . . . Potassium Channel Activators, J. Med Chem., vol. 33, 492-504, 1990.
Buckle et al, Relaxant Activity of 4-Amido-3, 44-dihydro-2H-1-Benzopyran-3 ols . . . Trachealis, J. Med. Chem., vol. 33, pp. 3028-3034, 1990.
Evans et al, Synthesis and Antihypertensive of Substituted trans-4-Amino-3, . . . 3-ols, J. Med. Chem., vol. 26, pp. 1582-1589, 1983.
Ashwood et al, Synthesis and Antihypertensive Activity of 4-(Cyclic amindo) . . . Benzopyrans, J. Med. Chem., vol. 29, pp. 2194-2201, 1986.
Pinder et al. Journal of Pharmaceutical Sciencs, vol. 56, No. 8, pp. 970-973, Aug. 1967.
Topliss, Journal of Medical Chemistry, 1972, vol. 15, No. 10, pp. 1006-1010 .
Ishizawa Takenori
Koga Hiroshi
Nabata Hiroyuki
Sato Haruhiko
Chugai Seiyaku Kabushiki Kaisha
Fan Jane
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