Disclosed are benzothiazine derivatives represented by the following formula (I): ##STR1## wherein the dashed line indicates the presence or absence of a bond; Z represents one of the following groups: ##STR2## in which R.sub.1 and R.sub.2 individually represent alkyl, aralkyl or the like, R.sub.3 represents H, alkyl or the like, R.sub.4 represents H, aralkyl or the like, X.sub.1, X.sub.2 and X.sub.3 individually represent O or S, and G represents substituted or unsubstituted ethylene, trimethylene or the like; Q.sub.1 and Q.sub.2 individually represent H, OH, halogen, alkoxy or the like; A represents alkylene, alkenylene or the like; Y represents CH, C.dbd. or N; when Y is CH, m stands for 0 or 1, n stands for 1 or 2, B represents O, S, carbonyl or the like, when Y is C.dbd., m stands for 1, n stands for 1 or 2, B represents: ##STR3## in which the double bond is linked to Y, R.sub.6 represents substituted or unsubstituted aryl or the like; when Y is N, m stands for 0 or 1, n stands for 2 or 3 and B represents carbonyl, sulfonyl or the like, E.sub.1 and E.sub.2 individually represent H or lower alkyl; and D represents an aromatic hydrocarbon group or an aromatic heterocyclic group; and salts thereof. The benzothiazine derivatives (I) and their salts according to the present invention have strong serotonin-2 blocking action, have excellent selectivity to this action against .alpha..sub.1 blocking action and have high safety. Accordingly, the present invention has made it possible to provide pharmaceuticals making use of antagonistic action against serotonin-2 receptors, for example, therapeutics for various circulatory diseases such as ishemic heart diseases, cerebrovascular disturbances and peripheral circulatory disturbances.

BACKGROUND OF THE INVENTION 
a) Field of the Invention 
This invention relates to novel benzothiazine derivatives. More 
specifically, this invention is concerned with benzothiazine derivatives 
and salts thereof, said derivatives and salts being useful for the 
prevention or treatment of ischemic heart diseases such as angina 
pectoris, arrhythmia, myocardial infarction, congestive heart, failure and 
post-PTCA restenosis, cerebrovascular disturbances such as cerebral 
infarction and cerebral sequelae after subarachnoid hemorrhage, and/or 
peripheral circulatory disturbances such as arteriosclerosis obliterans, 
Raynaud disease, Buerger disease and thrombophlebitis; their preparation 
process; and pharmaceuticals comprising them as effective ingredients. 
b) Description of the Related Art 
Serotonin is a compound contained abundantly in platelets, which are a 
blood component, and in a central nervous system, it acts as a 
neurotransmitter. In platelets, it is released upon stimulation by 
thromboxane A.sub.2, ADP, collagen or the like and synergistically acts on 
various platelet aggregation factors or vasoconstrictors through 
activation of serotonin-2 receptors in the platelets and vascular smooth 
muscle cells, thereby inducing strong platelet aggregation and 
vasoconstriction [P. M. Vanhoutte, "Journal of Cardiovascular 
Pharmacology", Vol. 17 (Supple. 5), S6-S12 (1991)]. 
Serotonin is also known to potentiate proliferation of vascular smooth 
muscle cells [S. Araki et al., "Atherosclerosis", Vol. 83, p29-p34(1990)]. 
It has been considered that, particularly when endothelial cells are 
injured as in arteriosclerosis or myocardial infarction, the 
vasoconstricting action and thrombus forming action of serotonin are 
exasperated, thereby reducing or even stopping blood supply to myocardial, 
cerebral and peripheral organs [P. Golino et al., "The New England Journal 
of Medicine", Vol. 324, No. 10, p641-p648(1991), Y. Takiguchi et al., 
"Thrombosis and Haemostasis", Vol. 68(4), p460-p463(1992), A. S. Weyrich 
et al., "American Journal of Physiology", Vol. 263, H349-H358(1992)]. 
Being attracted by such actions of serotonin or serotonin-2 receptors, 
various attempts are now under way to use a serotonin-2 receptor 
antagonist as a pharmaceutical for ischemic diseases of the heart, the 
brain and peripheral tissues. 
Ketanserin which has therapeutically been used as a hypotensive drug is 
known as a compound having antagonistic action against a serotonin-2 
receptor. Ketanserin has strong antagonistic action against a sympathetic 
nerve .alpha..sub.1 receptor and also against histamine-1 and dopamine 
receptors in addition to antagonistic action against serotonin-2 receptors 
so that there is the potential problem of developing excessive hypotensive 
action, neuroleptic action or the like when used for the treatment of 
ischemic heart disease or peripheral circulatory disturbance. Ketanserin 
is therefore not preferred. 
In addition, several compounds led by sarpogrelate are known to have 
serotonin-2 receptor antagonistic action. They, however, are accompanied 
with problems in the potency, the selectivity against other receptors, 
toxicity, side effects or the like. Thus, there remains still much room 
for improvements. 
SUMMARY OF THE INVENTION 
In view of the foregoing circumstances, the present inventors synthesized 
numerous compounds and investigated their pharmacological effects. As a 
result, it has been found that specific benzothiazine derivatives have 
strong serotonin-2 receptor antagonistic action, is excellent in the 
selectivity of a serotonin-2 receptor in the antagonistic action against 
various receptors, particularly in the selectivity to a serotonin-2 
receptor in the antagonistic action against .alpha..sub.1 receptor, and 
have low toxicity, leading to the completion of the present invention. 
The present invention has been completed based on the above described 
findings and a first object of the present invention is to provide a 
benzothiazine derivative represented by the following formula (I): 
##STR4## 
wherein the dashed line indicates the presence or absence of a bond and 
when the bond indicated by the dashed line is present, 
Z represents one of the following groups: 
##STR5## 
in which R.sub.1 represents a substituted or unsubstituted alkyl group or 
a substituted or unsubstituted aralkyl group but, when the bond indicated 
by the dashed line is absent, Z represents one of the following groups: 
##STR6## 
wherein R.sub.2 represents a substituted or unsubstituted alkyl group, a 
substituted or unsubstituted aryl group or a substituted or unsubstituted 
aralkyl group, R.sub.3 represents a hydrogen atom, a substituted or 
unsubstituted alkyl group, a substituted or unsubstituted aryl group or a 
substituted or unsubstituted aralkyl group, R.sub.4 represents a hydrogen 
atom, a substituted or unsubstituted alkyl group or a substituted or 
unsubstituted aralkyl group, X.sub.1, X.sub.2 and X.sub.3 each 
independently represents an oxygen atom or a sulfur atom, G represents an 
ethylene group with one or more of the hydrogen atoms thereof optionally 
substituted by a like number of halogen atoms and/or alkyl, aryl, aralkyl 
and/or alkylidene groups or a trimethylene group with one or more of the 
hydrogen atoms thereof optionally substituted by a like number of halogen 
atoms and/or alkyl, aryl, aralkyl and/or alkylidene groups, 
Q.sub.1 represents a hydrogen atom, a hydroxyl group, a halogen atom, a 
substituted or unsubstituted alkyl group, a substituted or unsubstituted 
alkoxy group, a substituted or unsubstituted aralkyl group or a 
substituted or unsubstituted aralkyloxy group, 
Q.sub.2 represents a hydrogen atom, a hydroxyl group, a halogen atom, a 
substituted or unsubstituted alkyl group, a substituted or unsubstituted 
alkoxy group, a substituted or unsubstituted aralkyl group or a 
substituted or unsubstituted aralkyloxy group, 
A represents a subs tituted or unsubstituted alkylene group, a substituted 
or unsubstituted alkenylene group or a substituted or unsubstituted 
alkynylene group, 
Y represents CH, C.dbd. or a nitrogen atom; and, when Y represents CH, m 
stands for 0 or 1, n stands for 1 or 2, and B represents an oxygen atom, a 
sulfur atom, a carbonyl group, a sulfinyl group, a sulfonyl group, an 
alkylene group, an alkenylene group, a substituted or unsubstituted 
hydroxymethylene group, a group --CHR.sub.5 -- in which R.sub.5 represents 
a substituted or unsubstituted alkyl group, a substituted or unsubstituted 
aryl group or a substituted or unsubstituted aralkyl group, or a 
substituted or unsubstituted cyclic or acyclic acetal group, when Y 
represents C.dbd., m stands for 1, n stands for 1 or 2, and B represents: 
##STR7## 
in which the double bond is linked to Y, R.sub.6 represents a substituted 
or unsubstituted alkyl group, a substituted or unsubstituted aryl group or 
a substituted or unsubstituted aralkyl group, but, when Y represents a 
nitrogen atom, m stands for 0 or 1, n stands for 2 or 3, and B represents 
a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group 
or a group --CHR.sub.7 -- in which R.sub.7 represents a substituted or 
unsubstituted alkyl group, a substituted or unsubstituted aryl group or a 
substituted or unsubstituted aralkyl group, 
E.sub.1 and E.sub.2 each independently represents a hydrogen atom or a 
lower alkyl group, and 
D represents a substituted or unsubstituted aromatic hydrocarbon group or a 
substituted or unsubstituted aromatic heterocyclic group; or a salt 
thereof. 
Another object of the present invention is to provide a preparation process 
of the benzothiazine derivative (I) or its salt. 
A further object of the present invention is to provide a pharmaceutical 
such as a therapeutic for circulatory diseases or the like, said 
pharmaceutical containing the benzothiazine derivative (I) or its 
pharmacologically-acceptable salt thereof as an effective ingredient. 
The benzothiazine derivatives (I) and their salts according to the present 
invention have strong serotonin-2 blocking action, have excellent 
selectivity to .alpha..sub.1 blocking action and have high safety. 
Accordingly, the present invention has made it possible to provide 
pharmaceuticals making use of antagonistic action against serotonin-2 
receptors, for example, therapeutics for various circulatory diseases such 
as ishemic heart diseases, cerebrovascular disturbance and peripheral 
circulatory disturbance. 
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS 
In the benzothiazine derivatives (I) of the present invention, preferred 
examples of group R.sub.1 include branched or linear C.sub.1-4 alkyl 
groups such as methyl and ethyl and C.sub.7-22 aralkyl groups such as 
benzyl and phenethyl, each of which may be substituted by one or more of 
halogen atoms such as fluorine, chlorine and bromine; alkyl groups, 
preferably C.sub.1-4 alkyl groups such as methyl and ethyl; and/or alkoxy 
groups, preferably C.sub.1-4 alkoxy groups such as methoxy and ethoxy. 
Preferred examples of group R.sub.2 include branched or linear C.sub.1-4 
alkyl groups such as methyl and ethyl, C.sub.6-14 aryl groups such as 
phenyl and naphtyl and C.sub.7-22 aralkyl groups such as benzyl and 
phenethyl, each of which may be substituted by one or more of halogen 
atoms such as fluorine, chlorine and bromine; alkyl groups, preferably 
C.sub.1-4 alkyl groups such as methyl and ethyl; and/or alkoxy groups, 
preferably C.sub.1-4 alkoxy groups such as methoxy and ethoxy. In this 
case, preferred examples of group R.sub.2 X.sub.1 -- include methoxy, 
methylthio, ethoxy and ethylthio groups. 
Preferred examples of the following group: 
##STR8## 
includes groups represented by the following formulas: 
##STR9## 
in which one or more of the hydrogen atoms may be substituted by a 
corresponding number of halogen atoms such as fluorine, chlorine and 
bromine; alkyl groups, preferably C.sub.1-4 alkyl groups such as methyl 
and ethyl; aryl groups, preferably C.sub.6-14 aryl groups such as phenyl 
and naphtyl; aralkyl groups, preferably C.sub.7-22 aralkyl groups such as 
benzyl and phenethyl; and/or alkylidene groups, preferably C.sub.1-4 
alkylidene groups such as methylidene and ethylidene. 
Preferred examples of group R.sub.3 of group NOR.sub.3 include a hydrogen 
atom, branched or linear C.sub.1-4 alkyl groups such as methyl and ethyl, 
C.sub.6-14 aryl groups such as phenyl and naphtyl and C.sub.7-22 aralkyl 
groups such as benzyl and phenethyl. Each of the exemplified groups may be 
substituted by one or more of halogen atoms such as fluorine, chlorine and 
bromine; alkyl groups, preferably C.sub.1-4 alkyl groups such as methyl 
and ethyl; and/or alkoxy groups, preferably C.sub.1-4 alkoxy groups such 
as methoxy and ethoxy. 
Preferred examples of group R.sub.4 include a hydrogen atom, branched or 
linear C.sub.1-4 alkyl groups such as methyl and ethyl and C.sub.7-22 
aralkyl groups such as benzyl and phenethyl. Each of the exemplified 
groups may be substituted by one or more of halogen atoms such as 
fluorine, chlorine and bromine; alkyl groups, preferably C.sub.1-4 alkyl 
groups such as methyl and ethyl; and/or alkoxy groups, preferably 
C.sub.1-4 alkoxy groups such as methoxy and ethoxy. 
Preferred examples of group Z include the following group: 
##STR10## 
Specifically preferred examples of the group Z include the following 
groups: 
##STR11## 
wherein G, R.sub.1, R.sub.2, R.sub.4, X.sub.1, X.sub.2 and X.sub.3 have 
the same meanings as defined above. 
Preferred examples of Q.sub.1 include a hydrogen atom; a hydroxyl group; 
halogen atoms such as fluorine, chlorine and bromine; branched or linear 
C.sub.1-4 alkyl groups such as methyl and ethyl; branched or linear 
C.sub.1-4 alkoxy groups such as methoxy and ethoxy; C.sub.7-22 aralkyl 
groups such as benzyl and phenethyl; and C.sub.7-22 aralkyloxy groups such 
as benzyloxy and phenethyloxy. Each of the exemplified groups may be 
substituted by one or more of halogen atoms such as fluorine, chlorine and 
bromine; alkyl groups, preferably C.sub.1-4 alkyl groups such as methyl 
and ethyl; and/or alkoxy groups, preferably C.sub.1-4 alkoxy groups such 
as methoxy and ethoxy. Of these Q.sub.1, particularly preferred include a 
hydrogen atom, a methoxy group, a chlorine atom and the like. 
Preferred examples of Q.sub.2 include a hydrogen atom; a hydroxyl group; 
halogen atoms such as fluorine, chlorine and bromine; branched or linear 
C.sub.1-4 alkyl groups such as methyl and ethyl; branched or linear 
C.sub.1-4 alkoxy groups such as methoxy and ethoxy; C.sub.7-22 aralkyl 
groups such as benzyl and phenethyl; and C.sub.7-22 aralkyloxy groups such 
as benzyloxy and phenethyloxy. Each of the exemplified groups may be 
substituted by one or more of halogen atoms such as fluorine, chlorine and 
bromine; alkyl groups, preferably C.sub.1-4 alkyl groups such as methyl 
and ethyl; and/or alkoxy groups, preferably C.sub.1-4 alkoxy groups such 
as methoxy and ethoxy. Of these Q.sub.2, particularly preferred include a 
hydrogen atom, a methoxy group, a chlorine atom and the like. 
Further, preferred examples of substituting positions and combinations of 
Q.sub.1 and Q.sub.2 include combinations of a hydrogen atom as Q.sub.1 and 
5-hydroxy, 5-chloro, 5-bromo, 5-methyl, 5-ethyl, 5-n-propyl, 5-isopropyl, 
5-n-butyl, 5-s-butyl, 5-methoxy, 5-ethoxy, 5-n-propoxy, 5-isopropoxy, 
5-benzyloxy, 6-hydroxy, 6-fluoro, 6-chloro, 6-methyl, 6-ethyl, 6-n-propyl, 
6-methoxy, 6-ethoxy, 6-n-propoxy, 6-benzyloxy, 7-hydroxy, 7-fluoro, 
7-chloro, 7-methyl, 7-ethyl, 7-n-propyl, 7-methoxy, 7-ethoxy, 7-n-propoxy, 
7-benzyloxy, 8-hydroxy, 8-fluoro, 8-chloro, 8-methyl, 8-ethyl, 8-n-propyl, 
8-methoxy, 8-ethoxy, 8-n-propoxy and 8-benzyloxy as Q.sub.2 ; and also 
combinations of 5,7-dihydroxy, 6,7-dichloro, 5,8-dimethyl, 6,8-dimethyl, 
5,6-dimethoxy, 5,7-dimethoxy, 5,8-dimethoxy and 6,7-dimethoxy as Q.sub.1 
and Q.sub.2. 
Preferred examples of group A include branched or linear C.sub.2-10 
alkylene groups such as ethylene, trimethylene, tetramethylene, 
pentamethylene and octamethylene, branched or linear C.sub.4-10 alkenylene 
groups such as 2-butenylene and 3-pentenylene groups; and branched or 
linear C.sub.4-10 alkynylene groups such as 2-butynylene and 3-pentynylene 
groups. Each of the exemplified group may be substituted by one or more of 
halogen atoms such as fluorine, chlorine and bromine. Among them, 
ethylene, trimethylene and tetramethylene groups are particularly 
preferred. 
The group, which is represented by the following formula: 
##STR12## 
wherein E.sub.1, E.sub.2, Y and n have the same meanings as defined above, 
is a heterocyclic group led by a pyrrolidine, piperidine, piperazine or 
homopiperazine group, in which two or less hydrogen atoms on the ring may 
be substituted by lower alkyl groups, preferably C.sub.1-4 alkyl groups 
such as methyl or ethyl. 
When the group of the above formula is a heterocylic group derived from 
pyrrolidine or piperidine, preferably a piperidine group, m stands for 0 
or 1 with the proviso that m is 1 when Y represents C.dbd., and B 
represents an oxygen atom, a sulfur atom, a carbonyl group, a sulfinyl 
group, a sulfonyl group, an alkylene group (preferably a C.sub.1-4 
alkylene group and most preferably a methylene group), an alkenylene group 
(preferably C.sub.2-5 alkenylene group and most preferably a 2-propenylene 
group), a substituted or unsubstituted hydroxymethylene group, a group 
--CHR.sub.5 -- (in which R.sub.5 preferably represents a C.sub.1-4 alkyl 
group such as methyl and ethyl; a C.sub.6-14 aryl group such as phenyl or 
naphthyl; or a C.sub.7-22 aralkyl group such as benzyl or phenethyl, which 
may be substituted), the following group: 
##STR13## 
wherein the double bond is linked to Y, and R.sub.6 represents an alkyl 
group, preferably a C.sub.1-4 alkyl group such as methyl and ethyl; an 
aryl group, preferably C.sub.6-14 aryl group such as phenyl and naphtyl; 
and an aralkyl group, preferably a C.sub.7-22 aralkyl group such as benzyl 
and phenethyl, which may be substituted), cyclic acetal or acyclic acetal 
group in which one or more of hydrogen atoms may be substituted. 
Exemplary cyclic or acylic acetal groups include the following groups: 
##STR14## 
Preferred examples of a substituent group for the hydroxylmethylene group 
represented by B include alkyl groups, preferably C.sub.1-4 alkyl groups 
such as methyl and ethyl and aryl groups, preferably C.sub.6-14 aryl 
groups such as phenyl and naphthyl, all substituted to the carbon atom of 
the methylene group. Further, they can be substituted by one or more of 
hydroxyl groups, halogen atoms such as fluorine, chlorine and bromine 
and/or alkoxy groups, preferably C.sub.1-4 alkoxy groups such as methoxy 
and ethoxy. 
Particularly preferred examples of the substituted or unsubstituted 
hydroxymethylene group include an unsubstituted hydroxymethylene group and 
hydroxymethylene groups substituted by a phenyl, fluorophenyl or 
hydroxyphenyl group. 
Further, examples of one or more substituent groups for R.sub.5 include one 
or more halogen atoms such as fluorine, chlorine and bromine; alkyl 
groups, preferably C.sub.1-4 alkyl groups such as methyl and ethyl; and 
alkoxy groups, preferably C.sub.1-4 alkoxy groups such as methoxy and 
ethoxy. 
Illustrative of one or more substituent groups for R.sub.6 include one or 
more halogen atoms such as fluorine, chlorine and bromine; alkyl groups, 
preferably C.sub.1-4 alkyl groups such as methyl and ethyl; alkoxy groups, 
preferably C.sub.1-4 alkoxy groups such as methoxy and ethoxy; and 
hydroxyl groups. Examples of one or more substituent groups for the cyclic 
or acyclic acetal include halogen atoms such as fluorine, chlorine and 
bromine; alkyl groups, preferably C.sub.1-4 alkyl groups such as methyl 
and ethyl; aryl groups, preferably C.sub.6-14 aryl groups such as phenyl 
and naphthyl; aralkyl groups, preferably C.sub.7-22 aralkyl groups such as 
benzyl and phenethyl; and alkylidene groups, preferably C.sub.1-4 
alkylidene groups such as methylidene and ethylidene. 
Among these illustrative examples of the group represented by B, especially 
preferred is a carbonyl group. 
When the heterocyclic group is a group derived from piperazine or 
homopiperazine, preferably a piperazine group, m stands for 0 or 1 
(preferably 0) and B represents a carbonyl group, a sulfonyl group, an 
alkylene group (preferably a C.sub.1-4 alkylene group, particularly a 
methylene group), an alkenylene group (preferably C.sub.3-6 alkenylene 
group, particularly 2-propenylene group) or a group --CHR.sub.7 -- (in 
which R.sub.7 represents an alkyl group, preferably a C.sub.1-4 alkyl 
group such as methyl and ethyl; an aryl group, preferably C.sub.6-14 aryl 
group such as phenyl and naphtyl; and an aralkyl group, preferably a 
C.sub.7-22 aralkyl group such as benzyl and phenethyl). 
R.sub.7 may in turn be substituted by one or more halogen atoms such as 
fluorine, chlorine and bromine; alkyl groups, preferably C.sub.1-4 alkyl 
groups such as methyl and ethyl; and/or alkoxy groups, preferably 
C.sub.1-4 alkoxy groups such as methoxy and ethoxy. 
Of the above-described examples of group B, preferred is a substituted or 
unsubstituted phenylmethylene group. 
Preferred examples of group D include aromatic hydrocarbon groups, 
preferably C.sub.6-28 aromatic hydrocarbon groups such as a phenyl group 
with one or more of its hydrogen atoms having been optionally substituted 
and a naphtyl group with one or more of its hydrogen atoms having been 
optionally substituted. Other preferred examples of group D include 
aromatic heterocyclic groups, preferably monocyclic or bicyclic ones with 
three or fewer oxygen, sulfur and/or nitrogen atoms--such as pyridyl, 
pyrimidinyl, benzisothiazolyl, benzisoxazolyl and indolyl groups with one 
or more hydrogen atoms thereof having been optionally substituted. 
Examples of substituent groups for the aromatic hydrocarbon groups and 
aromatic heterocyclic groups include halogen atoms such as fluorine, 
chlorine and bromine; alkyl groups, preferably C.sub.1-4 alkyl groups such 
as methyl and ethyl; alkoxy groups, preferably C.sub.1-4 alkoxy groups 
such as methoxy and ethoxy; aryl groups, preferably C.sub.6-14 aryl groups 
such as phenyl and naphtyl; aralkyl groups, preferably C.sub.7-22 aralkyl 
groups such as benzyl and phenethyl; aralkyloxy groups, preferably 
C.sub.7-22 aralkyloxy groups such as benzyloxy; cyano group; nitro group; 
carboxyl group; alkoxycarbonyl group (the number of carbons in the alcohol 
moiety preferably ranges from 1 to 6); lower alkylsulfonylamino groups 
(the number of carbon atoms in the alkyl moiety preferably ranges from 1 
to 4); a carbamoyl group; and a hydroxyl group. 
Of these illustrative groups represented by D, preferred are phenyl groups 
unsubstituted or substituted by one or more of halogen atoms, alkoxy 
groups and hydroxyl groups, benzisothiazolyl groups unsubstituted or 
substituted by one or more halogen atoms, benzisoxazolyl groups 
unsubstituted or substituted by one or more halogen atoms, and indazolyl 
groups unsubstituted or substituted by one or more halogen atoms. 
Particularly preferred are phenyl groups unsubstituted or substituted by 
one or more of fluorine atoms, methoxy groups and hydroxyl groups. 
Many of the compounds (I) according to the present invention have isomers. 
It is to be noted that these isomers and mixtures thereof are all embraced 
by the present invention. 
Various processes can be employed for the preparation of the benzothiazine 
derivatives (I) according to the present invention. It is however 
preferred to prepare the benzothiazine derivatives, for example, by any 
one of the following processes. 
Process 1 
Among the benzothiazine derivatives (I), each of compounds (Ib) in which Z 
is represented by one of the following formulas: 
##STR15## 
can be synthesized in accordance with any of the processes shown by the 
following schemes. 
(a) The compound (Ib) can be obtained, in accordance with the following 
reaction scheme, by reacting a compound represented by the formula (XXV) 
with a compound represented by the formula (III) to be converted to a 
compound represented by the formula (XXVI) and then reacting a 
nitrogen-containing compound represented by the formula (V) or a salt 
thereof with the compound (XXVI). 
##STR16## 
wherein A, B, D, E.sub.1, E.sub.2, Q.sub.1, Q.sub.2, Y, m and n have the 
same meanings as defined above, Z.sub.2 represents one of the following 
groups: 
##STR17## 
wherein G, R.sub.2, X.sub.1, X.sub.2 and X.sub.3 have the same meanings as 
defined above, and W and W' may be the same or different and individually 
represent a substituent easily replaceable with an amino group. 
In the above reactions, the conversion from the compound (XXV) to the 
compound (XXVI) can be effected by causing the compound (III) to act on 
the compound (XXV) after treating the compound (XXV) with an inorganic 
base or an organic base, or by causing the compound (III) to act on the 
compound (XXV) in the presence of such a base. 
Examples of group W or W' of the compound (III), which is an eliminative 
substituent and is easily replaceable with an amino group, include halogen 
atoms such as chlorine and bromine, alkylsulfonyloxy groups such as 
methanesulfonyloxy and arylsulfonyloxy groups such as 
p-toluenesulfonyloxy. 
On the other hand, exemplary inorganic or organic bases include sodium 
hydride, potassium hydride, sodium carbonate, potassium carbonate, 
triethylamine and potassium t-butoxide. Further, illustrative solvents 
useful for the above reaction include tetrahydrofuran, dioxane, 
dimethylformamide, dimethylsulfoxide, acetonitrile, N-methylpyrrolidone, 
acetone, 2-butanone and toluene. The reaction is conducted at -78.degree. 
C. to reflux temperature. 
To prepare the compound (Ib) by reacting the thus-obtained compound (XXV) 
with the nitrogen-containing compound (V), it is only necessary to react 
the nitrogen-containing compound (V) or an organic acid salt or inorganic 
acid salt thereof with the compound (XXV), optionally together with an 
organic base such as triethylamine, pyridine, collidine, 
1,8-diazabicyclo-[5.4.0]undec-7-en (DBU) or potassium t-butoxide or an 
inorganic base such as potassium carbonate, sodium carbonate, sodium 
hydrogencarbonate, sodium hydroxide or sodium hydride, optionally after 
adding an alkali iodide such as potassium iodide or sodium iodide, at 
0.degree. C. to 150.degree. C. in the solvent exemplified above or a 
solvent such as methanol, ethanol, propanol or butanol. 
Examples of the nitrogen-containing compound (V) include 
1-phenylpiperazine, 1-(2-fluorophenyl)piperazine, 
1-(3-fluorophenyl)piperazine, 1-(4-fluorophenyl)piperazine, 
1-(4-hydroxyphenyl)piperazine, 1-(2-chlorophenyl)piperazine, 
1-(3-chlorophenyl)piperazine, 1-(4-chlorophenyl)piperazine, 
1-(2-methoxyphenyl)piperazine, 1-(3-methoxyphenyl)piperazine, 
1-(4-methoxyphenyl)piperazine, 1-(4-methanesulfonamidophenyl)piperazine, 
1-(4-cyanophenyl)piperazine, 1-(4-carbamoylphenyl)piperazine, 
1-(4-methoxycarbonylphenyl)piperazine, 1-(2-pyridyl)piperazine, 
1-(2-pyrimidinyl)piperazine, 1-benzylpiperazine, 
1-diphenylmethylpiperazine, 1-cinnamylpiperazine, 1-benzoylpiperazine, 
1-(4-benzyloxybenzoyl)piperazine, 1-(4-hydroxybenzoyl)piperazine, 
1-(2-furoyl)piperazine, 1-(1,2-benzisooxazol-3-yl)piperazine, 
1-(1,2-benzisothiazol-3-yl)piperazine, 4-phenylpiperidine, 
4-benzylpiperidine, 
.alpha.,.alpha.-bis(4-fluorophenyl)-4-piperidinemethanol, 
4-(4-fluorobenzoyl)piperidine, 4-benzoylpiperidine, 
4-(4-methoxybenzoyl)piperidine, 4-(4-chlorobenzoyl)piperidine, 
3-(4-fluorobenzoyl)piperidine, 
4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine, 
4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidine, 
4-(6-fluoro-1H-indazol-3-yl)piperidine, 3-benzoylpyrrolidine, 
3-(4-fluorobenzoyl)pyrrolidine, 4-(4-fluorophenoxy)piperidine, 
4-[(4-fluorophenyl)thio]piperidine, 
4-[(4-fluorophenyl)sulfinyl]piperidine, 4-[(4-fluorophenyl)sulfonyl]-piper 
idine, 4-[bis(4-fluorophenyl)methylene]piperidine and 
4-(4-fluorobenzoyl)piperidine ethylene acetal. They are all either known 
compounds or compounds which can be readily prepared by a known process or 
a process similar to the known process. 
In the above reactions, the compound (XXV) employed as the starting 
material can be prepared using as a raw material a saccharin derivative 
represented by the formula (XXVII) in accordance with the following 
reaction scheme: 
##STR18## 
wherein G, R.sub.2, Q.sub.1, Q.sub.2, X.sub.1, X.sub.2, X.sub.3 and 
Z.sub.2 have the same meanings as defined above. 
Saccharins (XXVII) usable as starting materials in the above reactions are 
either known compounds or compounds which can be readily prepared by a 
known process or by referring to known literature. For example, 
preparation processes for saccharins substituted by one or more hydroxyl 
groups are disclosed in Japanese Patent Application Laid-Open (Kokai) No. 
SHO 56-166181, Japanese Patent Application Laid-Open (Kokai) No. SHO 
61-215382, etc., while preparation processes for saccharins substituted by 
one or more halogen atoms such as fluorine, chlorine and bromine atoms 
were proposed, for example, by W. Davies in J. Chem. Soc., 119(I), 876 
(1921), by F. Becke et al. in Liebigs Ann. Chem., 729, 146 (1969), by J. 
G. Lombardino in J. Org., Chem., 36, 1843 (1971) and by Nitta et al. in 
Yakugaku Zasshi, 84, 496 (1964) and are also disclosed in Japanese Patent 
Application Laid-Open (Kokai) No. SHO 52-71464, Japanese Patent 
Application Laid-Open (Kokai) No. SHO 56-166181, Japanese Patent 
Application Laid-Open (Kokai) No. HEI 5-194444, etc. 
Further, preparation processes for saccharins substituted by one or more 
alkyl groups such as methyl groups were proposed by J. G. Lombardino in J. 
Org. Chem., 36, 1843 (1971) and are disclosed in Japanese Patent 
Application Laid-Open (Kokai) No. SHO 52-71464, Japanese Patent 
Application Laid-Open (Kokai) No. SHO 61-215382, Japanese Patent 
Application Laid-Open (Kokai) No. HEI 5-194444, etc., and preparation 
processes for saccharins substituted by one or more alkoxy groups such as 
methoxy groups were proposed by J. G. Lombardino in J. Org. Chem., 36, 
1843 (1971) and are disclosed in Japanese Patent Application Laid-Open 
(Kokai) No. SHO 52-71464, Japanese Patent Application Laid-Open (Kokai) 
No. SHO 56-166181, Japanese Patent Application Laid-Open (Kokai) No. SHO 
61-263961, Japanese Patent Application Laid-Open (Kokai) No. HEI 5-194444, 
etc. 
Accordingly, saccharins (XXIII) containing desired substituent groups as 
Q.sub.1 and Q.sub.2 can be obtained by these processes or by processes 
derived with reference to such processes. 
The conversion from the compound (XXVII) to the compound (XXV') can be 
conducted referring to literatures [E. Eckenroth et al., Ber., 29, 329 
(1896); H. Zinnes et al., J. Org. Chem., 30, 2241 (1965); H. Zinnes et 
al., J. Org. Chem., 31, 162 (1966)]. 
On the other hand, the conversion from the compound (XXV') to the compound 
(XV) can be effected using various processes. As a typical example, an 
acid such as hydrochloric acid or acetic acid is caused to act on the 
compound (XXV'). 
Further, the conversion from the compound (XV) to the compound (XXV) can be 
conducted by choosing an appropriate process such as that described by T. 
W. Greene in Protective Groups in Organic Synthesis, John Wiley & Sons, 
Inc. As a typical example, R.sub.2 X.sub.1 H or HX.sub.2 --G--X.sub.3 H is 
caused to act on the compound (XV) in the presence of an acid. 
In addition, the compound (XXVI) can also be synthesized from the compound 
(XXV') in accordance with the following reaction scheme. 
##STR19## 
wherein A, G, Q.sub.1, Q.sub.2, R.sub.2, W, W', X.sub.1, X.sub.2, X.sub.3 
and Z.sub.2 have the same meanings as defined above. 
The conversion from the compound (XXV') to the compound (XXVI') can be 
practiced under similar conditions as the conversion from the compound 
(XXV) to the compound (XXVI). Further, the conversion from the compound 
(XXVI') to the compound (VIII) can be practiced under similar conditions 
as the conversion from the compound (XXV') to the compound (XV). Moreover, 
the conversion from the compound (VIII) to the compound (XXVI) can be 
practiced under similar conditions as the conversion from the compound 
(XV) to the compound (XXV). 
(b) The target compound can be obtained by causing a nitrogen-containing 
compound represented by the formula (VI) or a salt thereof to act on the 
compound represented by the formula (XXV) in accordance with the following 
reaction scheme: 
##STR20## 
wherein A, B, D, E.sub.1, E.sub.2, Q.sub.1 Q.sub.2, W, Y, Z.sub.2, m and n 
have the same meanings as defined above. 
The conversion from the compound (XXV) to the compound (Ib) can be 
conducted by causing the compound (VI) to act on the compound (XXV) after 
treatment of the latter compound with an inorganic base or an organic base 
or in the presence of such a base. Reaction conditions are similar to 
those employed in the conversion from the compound (XXV) to the compound 
(XXVI) in Process 1(a). In this case, it is also possible to add an alkali 
iodide such as potassium iodide or sodium iodide as needed. Incidentally, 
the compound (VI) can be synthesized by reacting the compound (V) with the 
compound (III) in a manner known per se in the art. 
Process 2 
Among the benzothiazine derivatives (I), each of compounds (Ic) in which Z 
is represented by the following formula: 
##STR21## 
can be synthesized in any one of the following processes. 
(a) The target compound can be obtained, in accordance with the following 
reaction scheme, by converting a compound (XV) or (XXVI) to a compound 
(VIII) and then reacting the compound (VIII) with a compound represented 
by the formula (V): 
##STR22## 
wherein A, B, D, E.sub.1, E.sub.2, Q.sub.1, Q.sub.2, W, W', Y, Z.sub.2, m 
and n have the same meanings as defined above. 
The conversion from the compound (XV) to the compound (VIII) can be 
effected under conditions similar to those employed upon conversion from 
the compound (XXV) to the compound (XXVI) shown in Process 1(a). Further, 
the conversion from the compound (XXVI) to the compound (VIII) can be 
effected employing the process described by T. W. Greene in "Protective 
Groups in Organic Synthesis", John Wiley & Sons, Inc. and the like. For 
instance, the conversion to the target compound (VIII) can be conducted by 
acid treatment of the compound (XXVI) when in Z.sub.2, X.sub.1 represents 
an oxygen atom or X.sub.2 and X.sub.3 both represent an oxygen atom, or by 
the treatment with mercury (II) chloride when X.sub.1 represents a sulfur 
atom or X.sub.2 and X.sub.3 both represent a sulfur atom. 
The conversion from the compound (VIII) to the compound (Ic) can be 
effected under conditions similar to those employed upon conversion from 
the compound (XXVI) to the compound (Ib) shown in Process 1(a). 
(b) The target compound can be obtained by the conversion of the group 
Z.sub.2 of the compound (Ib) to a carbonyl group in accordance with the 
following reaction scheme. 
##STR23## 
wherein A, B, D, E.sub.1, E.sub.2, Q.sub.1, Q.sub.2, Y, Z.sub.2, m and n 
have the same meanings as defined above. 
The conversion from the compound (Ib) to the compound (Ic) can be effected 
under conditions similar to those employed in the conversion from the 
compound (XXVI) to the compound (VIII) shown in Process 2(a). 
Process 3 
Among the benzothiazine derivatives (I), each of the compounds (Ig) and 
(Ie) in which Z is represented by the following formula: 
##STR24## 
can be synthesized in accordance with any one of the following processes. 
Selection of process (a) is desired where a nitrogen-containing compound 
(V) contains a group reactive to a hydroxylamine or a derivative thereof 
(VII) or a salt of the hydroxylamine or the derivative. 
(a) Each compound (Ig) can be obtained, in accordance with the following 
reaction scheme, by causing a hydroxylamine or a derivative thereof 
represented by the formula (VII) or a salt of the hydroxylamine or the 
derivative thereof to act on the compound represented by the formula 
(VIII) and then causing the nitrogen-containing compound (V) to act 
further. 
##STR25## 
wherein A, B, D, E.sub.1, E.sub.2, Q.sub.1, Q.sub.2, R.sub.3, W, Y, m and 
n have the same meanings as defined above. 
The reaction between the compound (VIII) and the hydroxylamine or its 
derivative (VII) can be practiced, if necessary, in the presence of an 
organic base such as pyridine, triethylamine, collidine, DBU or sodium 
acetate or an inorganic base such as potassium carbonate or sodium 
hydroxide. The hydroxylamine or its derivative (VII) may also be used in 
the form of an organic acid salt or an inorganic acid salt. 
The reaction is conducted at 0.degree. C. to reflux temperature, preferably 
0.degree. C. to 100.degree. C. optionally in a suitable solvent such as 
methanol, ethanol, propanol, tetrahydrofuran, dimethylformamide or 
dimethylsulfoxide. 
The conversion from the thus-obtained compound (IX) to the compound (Ig) 
can be effected under conditions similar to those employed in the 
conversion from the compound (XXVI) to the compound (Ib) shown in Process 
1(a). 
(b) Each compound (Ie) can be obtained, in accordance with the following 
reaction scheme, by causing a hydroxylamine or a derivative thereof (VII) 
or a salt of the hydroxylamine or the derivative to act on the compound 
(Id): 
##STR26## 
wherein, when Y represents CH, B' represents an oxygen atom, a sulfur 
atom, a sulfinyl group, a sulfonyl group, an alkylene group, an alkenylene 
group, a substituted or unsubstituted hydroxymethylene group, a group 
--CHR.sub.5 -- in which R.sub.5 represents a substituted or unsubstituted 
alkyl group, a substituted or unsubstituted aryl group or a substituted or 
unsubstituted aralkyl group, or a substituted or unsubstituted cyclic or 
acyclic acetal group, when Y represents C.dbd., B' represents the 
following group: 
##STR27## 
in which the double bond is linked to Y, R.sub.6 represents a substituted 
or unsubstituted alkyl group, a substituted or unsubstituted aryl group or 
a substituted or unsubstituted aralkyl group, but, when Y represents a 
nitrogen atom, B' represents a carbonyl group, a sulfonyl group, an 
alkylene group, an alkenylene group or a group --CHR.sub.7 -- in which 
R.sub.7 represents a substituted or unsubstituted alkyl group, a 
substituted or unsubstituted aryl group or a substituted or unsubstituted 
aralkyl group, and A, D, E.sub.1, E.sub.2, Q.sub.1, Q.sub.2, R.sub.3, Y, m 
and n have the same meanings as defined above. 
The conversion from the compound (Id) to the compound (Ie) can be effected 
under conditions similar to those employed in the conversion from the 
compound (VIII) to the compound (IX) shown in Process 3(a). 
Process 4 
Among the benzothiazine derivatives (I), each of compounds (Ih) and (If) in 
which Z is represented by the following formula: 
##STR28## 
can be synthesized by any one of the following processes. 
Incidentally, it is desired to select process (a) when there is a group 
reactive with a reducing agent in a nitrogen-containing compound (V). 
(a) Each compound (Ih) can be obtained, in accordance with the following 
reaction scheme, by reducing the compound represented by the formula 
(VIII) to obtain the compound (X) and then causing the nitrogen-containing 
compound (V) to act on the resulting compound. 
##STR29## 
wherein A, B, D, E.sub.1, E.sub.2, Q.sub.1, Q.sub.2, W, Y, m and n have 
the same meanings as defined above. 
The conversion from the compound (VIII) to the compound (X) can be effected 
by treating the compound represented by the formula (VIII) with a reducing 
agent such as sodium borohydride, potassium borohydride or sodium 
cyanoborohydride in a conventionally-employed solvent at -78.degree. C. to 
reflux temperature, preferably -20.degree. C. to room temperature. 
Further, the conversion from the compound (X) to the compound (Ih) can be 
effected under conditions similar to those employed in the conversion from 
the compound (XXVI) to the compound (Ib) shown in Process 1(a). 
(b) Each compound (If) can be obtained by reducing the compound (Id) in 
accordance with the following reaction scheme: 
##STR30## 
wherein A, B', D, E.sub.1, E.sub.2, Q.sub.1, Q.sub.2, Y, m and n have the 
same meanings as defined above. 
The conversion from the compound (Id) to the compound (If) can be effected 
under conditions similar to those employed in the conversion from the 
compound (VIII) to the compound (X) shown in Process 4(a). 
Process 5 
Among the benzothiazine derivatives (I), each compound (II) in which Z is a 
group represented by the following formula: 
##STR31## 
can be synthesized in accordance with the process which will be described 
hereinafter: 
The target compound can be obtained, in accordance with the following 
reaction scheme, by reacting a compound represented by the formula (XV) 
with a compound represented by the formula (XVI) to obtain a compound 
represented by the formula (XVII), reacting the resulting compound with a 
compound represented by the formula (III) to obtain a compound represented 
by the formula (XXX), and then causing a nitrogen-containing compound 
represented by the formula (V) to act on the compound (XXX). 
##STR32## 
wherein A, B, D, E.sub.1, E.sub.2, Q.sub.1, Q.sub.2, R.sub.1, W, W', Y, m 
and n have the same meanings as defined above. 
In the above reaction, the conversion from the compound (XV) to the 
compound (XVII) can be effected by causing the compound (XVI) to act on 
the compound (XV) in the presence of p-toluenesulfonic acid, boron 
trifluoride ethyl ether complex, Amberlite 15 or the like. 
Examples of the solvent usable in the above reaction may include methanol, 
ethanol, propanol and butanol. The reaction can be conducted at 
-78.degree. C. to reflux temperature. 
Further, the conversion from the compound (XVII) to the compound (Il) can 
be effected under conditions similar to those employed in the conversion 
from the compound (XXV) to the compound (Ib) shown in Process 1(a). 
Process 6 
Among the benzothiazine derivatives (I), each compound (Ii) in which Z is 
represented by the following formula: 
##STR33## 
can be synthesized in accordance with the process which will be described 
hereinafter. 
The compound represented by the formula (Ii) can be obtained, in accordance 
with the following reaction scheme, (1) by reducing a compound represented 
by the formula (XXXI) to a compound represented by the formula (XXXII) and 
reacting the resulting compound with the compound represented by the 
formula (III), or (2) by reacting a compound represented by the formula 
(XI) with a compound represented by the formula (X) to obtain a compound 
(XII), and then reacting the resulting compound with a nitrogen-containing 
compound represented by the formula (V). In this case, it is desired to 
select a suitable process from the processes (1) and (2) according to the 
kind of group R.sub.8. 
##STR34## 
wherein A, B, D, E.sub.1, E.sub.2, Q.sub.1, Q.sub.2, R.sub.8, W, W', W", 
Y, m and n have the same meanings as defined above. 
In the above reaction, the conversion from the compound (XXXI) to the 
compound (XXXII) can be conducted by treating, in the presence of a 
catalyst such as palladium-carbon or platinum, the compound (XXXI) with 
hydrogen gas in a conventionally-employed solvent at -78.degree. C. to 
reflux temperature, preferably at room temperature. The conversion from 
the compound (XXXII) to the compound (XII) can be effected under 
conditions similar to those employed in the conversion from the compound 
(XXV) to the compound (XXVI) shown in Process 1(a). 
The conversion from the compound (X) to the compound (XII) can be conducted 
by causing the compound (XI) to act on the compound (X) either after 
treatment of the compound (X) with an inorganic base or organic base or in 
the presence of such a base. 
The group W" in the compound (XI) is an eliminative substituent, and its 
examples include halogen atoms such as chlorine and bromine, 
alkylsulfonyloxy groups such as methanesulfonyloxy and arylsulfonyloxy 
groups such as p-toluenesulfonyloxy. 
Further, exemplary inorganic or organic bases usable in the above reaction 
include sodium hydride, sodium bis(trimethylsilyl)amide, lithium 
diisopropylamide and potassium t-butoxide. Illustrative solvents usable in 
the present reaction include, tetrahydrofuran, dioxane, dimethylformamide, 
dimethylsulfoxide, N-methylpyrrolidone and toluene. The reaction may be 
conducted at -78.degree. C. to reflux temperature. 
The conversion from the compound (XII) to the compound (Ii) can be effected 
under conditions similar to those employed upon conversion from the 
compound (XXVI) to the compound (Ib) in Process 1(a). 
Process 7 
Among the benzothiazine derivatives (I), each compound (Ij) in which Z is 
represented by the following formula: 
##STR35## 
can be synthesized in accordance with the process which will be described 
hereinafter. 
The compound represented by the formula (Ij) can be obtained, in accordance 
with the following reaction scheme, by subjecting a compound represented 
by the formula (X) to dehydration to obtain a compound represented by the 
formula (XIII) and then causing a nitrogen-containing compound represented 
by the formula (V) to act on the resultant compound. 
##STR36## 
wherein A, B, D, E.sub.1, E.sub.2, Q.sub.1, Q.sub.2, W, Y, m and n have 
the same meanings as defined above. 
In the above reactions, the conversion from the compound (X) to the 
compound (XIII) is conducted by causing methyanesulfonyl chloride or 
p-toluenesulfonyl chloride and a base such as triethylamine, pyridine or 
collidine to act on the compound (X) in a solvent such as dichloromethane, 
chloroform or toluene and then treating the reaction product with the 
above base or silica gel at room temperature to reflux temperature. 
Further, the conversion from the compound (XIII) to the compound (Ij) can 
be conducted under conditions similar to the conversion from the compound 
(XXVI) to the compound (Ib) shown in Process I(a). 
Process 8 
Among the benzothiazine derivatives (I), each compound (Ik) in which Z is 
represented by the following formula: 
##STR37## 
can be synthesized in accordance with the process which will be described 
hereinafter. 
The compound represented by the formula (Ik) can be obtained, in accordance 
with the following reaction scheme, by subjecting a compound represented 
by the formula (XIII) to reduction to obtain a compound represented by the 
formula (XIV) and then reacting the resultant compound with a 
nitrogen-containing compound represented by the formula (V). 
##STR38## 
wherein A, B, D, E.sub.1, E.sub.2, Q.sub.1, Q.sub.2, W, Y, m and n have 
the same meanings as defined above. 
In the above reactions, the conversion from the compound (XIII) to the 
compound (XIV) can be conducted in a manner similar to the conversion from 
the compound (XXXI) to the compound (XXXII) in Process 6. 
Further, the conversion from the compound (XIV) to the conversion (Ik) can 
be conducted under conditions similar to those employed in the conversion 
of the compound (XXVI) to the compound (Ib) shown in Process 1(a). 
The compounds (I) of the present invention obtained according to the 
above-described processes can each be reacted with one of various acids to 
convert the compound to its salt. The salt can be purified by a method 
such as recrystallization or column chromatography. 
Exemplary acids usable to convert the benzothiazine derivatives (I) to 
their salts include inorganic acids such as hydrochloric acid, nitric 
acid, sulfuric acid, phosphoric acid and hydrobromic acid; and organic 
acids such as maleic acid, fumaric acid, tartaric acid, lactic acid, 
citric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, 
adipic acid, palmitic acid and tannic acid. 
As will be demonstrated later by tests, the benzothiazine derivatives (I) 
and their salts according to the present invention, which can be obtained 
as described above, have a strong serotonin-2 blocking action and in 
addition, they have excellent selectivity to .alpha..sub.1 blocking 
action. Further, as a result of a toxicity test, they have been found to 
feature high safety. The compounds according to the present invention can 
therefore be used as therapeutics for circulatory diseases such as 
ischemic heart diseases, cerebrovascular disturbances and peripheral 
circulatory disturbances. 
When the benzothiazine derivative (I) according to this invention are used 
as drugs, they can be administered in an effective dose as they are. As an 
alternative, they can also be formulated into various preparation forms by 
known methods and then administered. 
Exemplary preparation forms as drugs include orally administrable 
preparation forms such as tablets, powders, granules, capsules and syrups 
as well as parenterally administrable preparation forms such as injections 
and suppositories. Whichever preparation form is used, a known liquid or 
solid extender or carrier usable for the formulation of the preparation 
form can be employed. 
Examples of such extender or carrier include polyvinylpyrrolidone, arabic 
gum, gelatin, sorbit, cyclodextrin, tragacanth gum, magnesium stearate, 
talc, polyethylene glycol, polyvinyl alcohol, silica, lactose, crystalline 
cellulose, sugar, starch, calcium phosphate, vegetable oil, 
carboxymethylcellulose, sodium laurylsulfate, water, ethanol, glycerin, 
mannitol, syrup, and the like. 
When the compounds (I) according to the present invention are used as 
drugs, their dose varies depending on the administration purpose, the age, 
body weight and conditions of the patient to be administered, etc. In oral 
administration, the daily dose may generally be about 0.01-1,000 mg. 
The present invention will next be described in further detail by the 
following examples and tests. It is however borne in mind that the present 
invention is not limited to the following examples and tests.