U.S. patent application number 10/615836 was filed with the patent office on 2005-02-17 for pyrrolothiazine and pyrrolothiazephine compounds having serotonin-2 receptor antagonistic and alpha-1-blocking action.
This patent application is currently assigned to Daiichi Suntory Pharma Co., Ltd.. Invention is credited to FUKAMI, Harukazu, INOMATA, Norio, KAMEI, Tomoe, MIZUNO, Akira, SHIBATA, Makoto.
Application Number | 20050038242 10/615836 |
Document ID | / |
Family ID | 18487593 |
Filed Date | 2005-02-17 |
United States Patent
Application |
20050038242 |
Kind Code |
A2 |
MIZUNO, Akira ; et
al. |
February 17, 2005 |
PYRROLOTHIAZINE AND PYRROLOTHIAZEPHINE COMPOUNDS HAVING SEROTONIN-2
RECEPTOR ANTAGONISTIC AND ALPHA-1-BLOCKING ACTION
Abstract
A pyrrolesulfonamide derivative, Compound (I), which has strong
serotonin-2 receptor antagonistic action and low toxicity and less
side effects, and is useful as a therapeutic for circulatory
diseases such as ischemic heart diseases, cerebrovascular
disturbances and peripheral circulatory disturbances.
Inventors: |
MIZUNO, Akira; (Kyoto-shi,
JP) ; SHIBATA, Makoto; (Ashikaga-shi, JP) ;
KAMEI, Tomoe; (Takatsuki-shi, JP) ; FUKAMI,
Harukazu; (Kyoto-shi, JP) ; INOMATA, Norio;
(Mino-shi, JP) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
Daiichi Suntory Pharma Co.,
Ltd.
5-7-2, Kojimachi Chiyoda-ku
Tokyo
JP
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 0127705 A1 |
July 1, 2004 |
|
|
Family ID: |
18487593 |
Appl. No.: |
10/615836 |
Filed: |
July 10, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10615836 |
Jul 10, 2003 |
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09/871,655 |
Jun 4, 2001 |
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6624314 |
Sep 23, 2003 |
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09/871,655 |
Jun 4, 2001 |
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09/367,841 |
Aug 26, 1999 |
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6271223 |
Aug 7, 2001 |
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09/367,841 |
Aug 26, 1999 |
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PCT/JP98/05954 |
Dec 25, 1998 |
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Current U.S.
Class: |
544/48 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 9/06 20180101; A61P 9/12 20180101; C07D 513/04 20130101; A61P
9/08 20180101; A61P 9/10 20180101; A61P 9/02 20180101; A61P 9/00
20180101; C07D 207/36 20130101 |
Class at
Publication: |
544/048 ;
514/211.09; 514/226.5; 540/552 |
International
Class: |
C07D 498/02; A61K
031/542; A61K 031/554 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 26, 1997 |
JP |
366756/1997 |
Claims
What is Claimed is:
1. A pyrrolesulfonamide derivative or a salt thereof, said
pyrrolesulfonamide derivative being represented by the following
formula (I): 48 whereinthe ring p represented by 49 means a pyrrole
ring represented by the following structure: 50 in which R
represents an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl
group or a substituted or unsubstituted aralkyl group;the dashed
line indicates the presence or absence of a bond; and, when the
bond indicated by the dashed line is present, Z.sub.2 is not
present and Z.sub.1 represents a hydrogen atom but, when the bond
indicated by the dashed line is absent, Z.sub.1 represents a
hydrogen atom and Z.sub.2 represents a hydroxyl group; or Z.sub.1
and Z.sub.2 are combined together to represent an oxygen atom or a
group NOR.sub.1 in which R.sub.1 represents a hydrogen atom, a
substituted or unsubstituted alkyl group, a substituted or
unsubstituted aralkyl group or a substituted or unsubstituted aryl
group;l represents 0 or 1;A represents a substituted or
unsubstituted alkylene group, a substituted or unsubstituted
alkenylene group or a substituted or unsubstituted alkynylene
group; andY represents a group 51 in which W represents CH, C.dbd.
or a nitrogen atom; and, when W represents CH, m stands for 0 or 1,
B represents a carbonyl group, a sulfonyl group, an alkylene group,
an alkenylene group, a group -C(OH)R.sub.2- in which R.sub.2
represents a substituted or unsubstituted aryl group, a group
-CHR.sub.3- in which R.sub.3 represents a substituted or
unsubstituted aryl group, or a substituted or unsubstituted cyclic
or acyclic acetal group; when W represents C.dbd., m stands for 1,
B represents a group 52 in which the double bond is coupled with W
and R.sub.4 represents a substituted or unsubstituted aryl group-or
a substituted or unsubstituted aralkyl group; when W represents a
nitrogen atom, m stands for 0 or 1, and B represents a carbonyl
group, a sulfonyl group, an alkylene group, an alkenylene group or
a group -CHR.sub.5- in which R.sub.5 represents a substituted or
unsubstituted aryl 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.
2. A pyrrolesulfonamide derivative or a salt thereof according to
claim 1, wherein in the formula (I), Z.sub.1 represents a hydrogen
atom and Z.sub.2 represents a hydroxyl group.
3. A pyrrolesulfonamide derivative or a salt thereof according to
claim 1, wherein in the formula (I), Z.sub.1 and Z.sub.2 are
combined together to represent an oxygen atom or a group NOH.
4. A pyrrolesulfonamide derivative or a salt thereof according to
claim 1, 2 or 3, wherein in the formula (I), A is a trimethylene
group.
5. A pyrrolesulfonamide derivative or a salt thereof according to
claim 1, 2, 3 or 4, wherein in the formula (I), W represents a
nitrogen atom, m stands for 0, and D represents a substituted or
unsubstituted phenyl group.
6. A pyrrolesulfonamide derivative or a salt thereof according to
claim 1, 2, 3, 4 or 5, wherein in the formula (I), E.sub.1 and
E.sub.2 both represent hydrogen atoms.
7. A pyrrolesulfonamide derivative or a salt thereof according to
claim 1, 2, 3, 4, 5 or 6, wherein in the formula (I), the ring P
represents the following formula: 53 wherein R has the same meaning
as defined above.
8. A process for the preparation of a pyrrolesulfonamide derivative
represented by the following formula (Ia): 54 wherein A, the ring
P, Y and l have the same meanings as defined above, which
comprises:reacting a compound, which is represented by the
following formula (III):X-A-X` (III)wherein A has the same-meaning
as defined above and X and X` represent the same or different
eliminative groups, to a compound represented by the following
formula (II): 55 wherein the ring P and l have the same meanings as
defined above, thereby obtaining a compound represented by the
following formula (IV): 56 wherein A, the ring P, X and l have the
same meanings as defined above; and thenreacting a
nitrogen-containing compound represented by the following formula
(V):H-Y (V)wherein Y has the same meaning as defined above.
9. A process for the preparation of a pyrrolesulfonamide derivative
represented by the following formula (Ia): 57 wherein A, the ring
P, Y and l have the same meanings as defined above, which
comprises:reacting a compound, which is represented by the
following formula (VI):X-A-Y (VI)wherein A, X and Y have the same
meanings as defined above, to a compound represented by the
following formula (II): 58 wherein the ring P and l have the same
meanings as defined above.
10. A process for the preparation of a pyrrolesulfonamide
derivative represented by the following formula (Ic): 59 wherein A,
the ring P, R.sub.1 and l have the same meanings as defined above,
and Y` represents a group 60 in which when W represents CH, B`
represents a sulfonyl group, an alkylene group, an alkenylene
group, a group -C(OH)R.sub.2- in which R.sub.2 represents a
substituted or unsubstituted aryl group, a group -CHR.sub.3- in
which R.sub.3 represents a substituted or unsubstituted aryl group,
or a substituted or unsubstituted cyclic or acyclic acetal group;
when W represents C.dbd., B` represents a group 61 in which the
double bond is coupled with W and R.sub.4 represents a substituted
or unsubstituted aryl group or a substituted or unsubstituted
aralkyl group; when W represents a nitrogen atom, B` represents a
carbonyl group, a sulfonyl group, an alkylene group, an alkenylene
group or a group -CHR.sub.5- in which R.sub.5 represents a
substituted or unsubstituted aryl group; and D, E.sub.1, E.sub.2
and m have the same meanings as defined above, which
comprises:reacting a hydroxylamine or a derivative thereof, which
is represented by the following formula (VII):NH.sub.2OR.sub.1
(VII)wherein R.sub.1 has the same meaning as defined above, with a
pyrrolesulfonamide derivative represented by the following formula
(Ib): 62 wherein A, the ring P, Y` and l have the same meanings as
defined above.
11. A process for the preparation of a pyrrolesulfonamide
derivative represented by the following formula (Id): 63 wherein A,
the ring P, Y` and l have the same meanings as defined above, which
comprises:reducing a pyrrolesulfonamide derivative represented by
the following formula (Ib): 64 wherein A, the ring P, Y` and l have
the same meanings as defined above.
12. A process for the preparation of a pyrrolesulfonamide
derivative represented by the following formula (Ie): 65 wherein A,
the ring P, R.sub.1, Y and l have the same meanings as defined
above, which comprises: reacting a hydroxylamine or a derivative
thereof, which is represented by the following formula
(VII):NH.sub.2OR.sub.1 (VII)wherein R.sub.1 has the same meaning as
defined above, to a compound represented by the following formula
(IV): 66 wherein A, the ring P, X and l have the same meanings as
defined above, thereby obtaining a compound represented by the
following formula (VIII): 67 wherein A, the ring P, R.sub.1, X and
l have the same meanings as defined above; and thenreacting a
nitrogen-containing compound represented by the following formula
(V):H-Y (V)wherein Y has the same meaning as defined above.
13. A process for the preparation of a pyrrolesulfonamide
derivative represented by the following formula (If): 68 wherein A,
the ring P, Y and l have the same meanings as defined above, which
comprises:reducing a compound represented by the following formula
(IV): 69 wherein A, the ring P, X and l have the same meanings as
defined above, thereby obtaining a compound represented by the
following formula (IX): 70 wherein A, the ring P, X and l have the
same meanings as defined above; and then reacting a
nitrogen-containing compound represented by the following formula
(V):H-Y (V)wherein Y has the same meaning as defined above.
14. A process for the preparation of a pyrrolesulfonamide
derivative represented by the following formula (Ig): 71 wherein A,
the ring P, Y and l have the same meanings as defined above, which
comprises:subjecting a compound, which is represented by the
following formula (IX): 72 wherein A, the ring P, X and l have the
same meanings as defined above, to dehydration treatment, thereby
obtaining a compound represented by the following formula (X): 73
wherein A, the ring P, X and l have the same meanings as defined
above; and thenreacting a nitrogen-containing compound represented
by the following formula (V):H-Y (V)wherein Y has the same meaning
as defined above.
15. A process for the preparation of a pyrrolesulfonamide
derivative represented by the following formula (Ig): 74 wherein A,
the ring P, Y and l have the same meanings as defined above, which
comprises:subjecting a compound, which is represented by the
following formula (If): 75 wherein A, the ring P, Y and l have the
same meanings as defined above, to dehydration treatment.
16. A compound represented by the following formula (II): 76
wherein the ring P and l have the same meanings as defined
above.
17. A compound represented by the following formula (XI): 77
wherein the dashed line, A, the ring P, X, Z.sub.1, Z.sub.2 and l
have the same meanings as defined above.
18. A process for the preparation of a pyrrolesulfonamide
derivative represented by the following formula (IIa) or (IIa`): 78
wherein R and l have the same meanings as defined above, which
comprises:converting a 1-substituted-pyrrole-3-sulfonic acid or a
salt thereof, which is represented by the following formula (XII):
79 wherein M represents a hydrogen ion, an alkali metal ion, an
alkaline earth metal ion or a quaternary ammonium ion, p stands for
1 when M represents a hydrogen ion, an alkali metal ion or a
quaternary ammonium ion or p stands for 2 when M represents an
alkaline earth metal ion, q stands for 0 or 1, and R has the same
meaning as defined above, into a compound represented by the
following formula (XIII): 80 wherein X" represents a chlorine atom
or a bromine atom; causing glycine or -alanine or a derivative
thereof, which is represented by the following formula
(XIV):NH.sub.2(CH.sub.2)lCH.sub.2- COOR.sub.6 (XIV)wherein R.sub.6
represents a hydrogen atom or a carboxyl-protecting group, to act,
thereby obtaining a compound represented by the following formula
(XV): 81 wherein R, R.sub.6 and l have the same meanings as defined
above; and then subjecting said compound to ring closure.
19. A process for the preparation of a pyrrolesulfonamide
derivative represented by the following formula (IIa) or (IIa`): 82
wherein R and l have the same meanings as defined above, which
comprises: reacting a compound, which is represented by the formula
(XVIa) or (XVIb):R-X"` (XVIa) (RO).sub.2SO.sub.2 (XVIb)wherein X"`
represents an eliminative group and R has the same meaning as
defined above, with a compound represented by the following formula
(IIb) or (IIb`): 83 wherein l has the same meaning as defined
above.
20. A compound represented by the following formula (XV): 84
wherein R, R.sup.6 and l have the same meanings as defined
above.
21. A compound represented by the following formula (XII): 85
wherein M, R, p and q have the same meanings as defined above.
22. A compound according to claim 21, wherein in the formula (XII),
R is a methyl group, M is a sodium ion, p is 1, and q is 0 or
1.
23. A process for the preparation of a
1-substituted-pyrrole-3-sulfonic acid or a salt thereof, which
comprises treating a 1-substituted-pyrrole with sulfur
trioxide-pyridine complex.
24. A process for the preparation of a compound represented by the
following formula (XII): 86 wherein M, R, p and q have the same
meanings as defined above, which comprises treating a compound,
which is represented by the following formula (XVII): 87 wherein R
has the same meaning as defined above, with trimethylsilyl
chlorosulfonate, followed by alkali hydrolysis.
25. A pharmaceutical comprising, as an effective ingredient, a
pyrrolesulfonamide derivative or a salt thereof according to claim
1.
26. A therapeutic for circulatory diseases, comprising as an
effective ingredient a pyrrolesulfonamide derivative or a salt
thereof according to claim 1.
27. A serotonin-2 receptor antagonist, comprising as an effective
ingredient a pyrrolesulfonamide derivative or a salt thereof
according to claim 1.
Description
Detailed Description of the Invention
TECHNICAL FIELD
[0001] This invention relates to novel pyrrolesulfonamide
derivatives. More specifically, this invention is concerned with
pyrrolo[2,3-e][1,2]thiazine derivatives,
pyrrolo[3,4-e][1,2]thiazine derivatives,
pyrrolo[2,3-f][1,2]thiazepine derivatives and
pyrrolo-[3,4-f][1,2]thiazepine derivatives, and salts thereof, said
derivatives and salts having strong serotonin-2 receptor
antagonistic action of excellent selectivity and being useful, for
example, 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, peripheral circulatory disturbances
such as arteriosclerosis obliterans, thromboangiitis obliterans and
Raynaud disease, and hypertension; their preparation processes; and
pharmaceuticals containing them as effective ingredients.
BACKGROUND ART
[0002] 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 release of various platelet aggregation
factors through activation of serotonin-2 receptors in the
platelets and vascular smooth muscle cells and also on
vasoconstriction by norepinephrine through .sub.1 receptors,
thereby inducing strong platelet aggregation and vasoconstriction
[P. M. Vanhoutte, "Journal of Cardiovascular Pharmacology", Vol. 17
(Supple. 5), S6-S12 (1991)].
[0003] Serotonin is also known to potentiate proliferation of
vascular smooth muscle cells [S. Araki et al., "Atherosclerosis",
Vol. 83, pp.29-34 (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, pp.641-648(1991), Y. Takiguchi et al.,
"Thrombosis and Haemostasis", Vol. 68(4), pp.460-463(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.
[0004] Several compounds, led by sarpogrelate, are known to have
serotonin-2 receptor antagonistic action. They however do not
include anything having the pyrrolo[2,3-e][1,2]thiazine skeleton,
pyrrolo[3,4-e][1,2]thiazine skeleton, pyrrolo[2,3-f][1,2]thiazepine
skeleton or pyrrolo[3,4-f][1,2]thiazepine skeleton. Those known to
have serotonin-2 receptor antagonistic action are accompanied with
many problems to be improved in potency, toxicity, side effects or
the like. On the other hand, medicines which have anti-serotonin
action and .sub.1-blocking action in combination are considered to
become extremely effective medicines for the treatment and
prevention of hypertension and ischemic heart diseases, because
they have possibility to reduce side effects, such as orthostatic
hypotension and reflex tachycardia, induced by antihypertensive
action on the basis of the .sub.1-blocking action and hypertension
is a serious risk factor for ischemic heart diseases.
DISCLOSURE OF THE INVENTION
[0005] In view of the foregoing circumstances, the present
inventors have proceeded with extensive research toward compounds
which have strong serotonin-2 receptor antagonistic action and low
toxicity and less side effects and are useful for the treatment and
prevention of ischemic heart diseases, cerebrovascular disturbances
and peripheral circulatory disturbances. As a result, it has been
found that pyrrolesulfonamides represented by the below-described
formula (I) meet the above conditions. It has also been found that
the compounds according to the present invention include those also
having .sub.1-blocking action in combination and that such
compounds are useful as antihypertensives or the like having less
side effects and are widely usable for the treatment and prevention
of circulatory diseases.
[0006] The present invention has been completed based on the above
described findings. A first object of the present invention is to
provide a pyrrolesulfonamide derivative or a salt thereof, said
pyrrolesulfonamide derivative being represented by the following
formula (I):1
[0007] wherein
[0008] the ring P represented by2
[0009] means a pyrrole ring represented by the following
structure:3
[0010] in which R represents an alkyl group, a cycloalkyl group, a
cycloalkyl-alkyl group or a substituted or unsubstituted aralkyl
group;
[0011] the dashed line indicates the presence or absence of a bond;
and, when the bond indicated by the dashed line is present, Z.sub.2
is not present and Z.sub.1 represents a hydrogen atom but, when the
bond indicated by the dashed line is absent, Z.sub.1 represents a
hydrogen atom and Z.sub.2 represents a hydroxyl group; or Z.sub.1
and Z.sub.2 are combined together to represent an oxygen atom or a
group NOR.sub.1 in which R.sub.1 represents a hydrogen atom, a
substituted or unsubstituted alkyl group, a substituted or
unsubstituted aralkyl group or a substituted or unsubstituted aryl
group;
[0012] l represents 0 or 1;
[0013] A represents a substituted or unsubstituted alkylene group,
a substituted or unsubstituted alkenylene group or a substituted or
unsubstituted alkynylene group; and
[0014] Y represents a group4
[0015] in which W represents CH, C.dbd. or a nitrogen atom; and,
when W represents CH, m stands for 0 or 1, B represents a carbonyl
group, a sulfonyl group, an alkylene group, an alkenylene group, a
group -C(OH)R.sub.2- in which R.sub.2 represents a substituted or
unsubstituted aryl group, a group -CHR.sub.3- in which R.sub.3
represents a substituted or unsubstituted aryl group, or a
substituted or unsubstituted cyclic or acyclic acetal group; when W
represents C.dbd., m stands for 1, B represents a group5
[0016] in which the double bond is coupled with W and R.sub.4
represents a substituted or unsubstituted aryl group or a
substituted or unsubstituted aralkyl group; when W represents a
nitrogen atom, m stands for 0 or 1, and B represents a carbonyl
group, a sulfonyl group, an alkylene group, an alkenylene group or
a group -CHR.sub.5- in which R.sub.5 represents a substituted or
unsubstituted aryl 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.
[0017] Another object of the present invention is to provide a
preparation process of the pyrrolesulfonamide derivative (I) or its
salt.
[0018] A further object of the present invention is to provide a
pharmaceutical which comprises the pyrrole-sulfonamide derivative
(I) or its pharmaceutically-acceptable salt as an effective
ingredient and is usable for the treatment or the like of
circulatory diseases.
BEST MODES FOR CARRYING OUT THE INVENTION
[0019] In the pyrrolesulfonamide derivatives (I) of the present
invention, the ring P represents one of the following pyrrole
rings:6
[0020] wherein R has the same meaning as defined above.
[0021] Preferred examples of the group R bonded to the nitrogen
atom of the pyrrole ring can include linear or branched alkyl
groups having 1-8 carbon atoms preferably, such as methyl, ethyl,
n-propyl, isopropyl and n-pentyl; cycloalkyl groups having 3-8
carbon atoms, such as cyclopropyl, cyclopentyl and cyclohexyl;
cycloalkyl-alkyl groups having 4-8 carbon atoms, such as
cyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl; and
aralkyl groups having 7-22 carbon atoms, such as diphenylmethyl,
benzyl and phenethyl. For example, one or more hydrogen atoms of
each of these groups may be substituted by a like number of halogen
atoms such as fluorine, chlorine and/or bromine atoms, alkyl groups
having 1-4 carbon atoms preferably, such as methyl and/or ethyl,
and/or alkoxy groups having 1-4 carbon atoms preferably, such as
methoxy and/or ethoxy. Among these, particularly preferred are
methyl and ethyl.
[0022] Further, l stands for 0 or 1 in the compound (I) according
to the present invention. As the combination between the ring P and
l, preferred examples can be (A) and 1, (A) and 0, and (B) and 1.
Of these, the combinations of (A) and 1 and (A) and 0 are
particularly preferred.
[0023] On the other hand, preferred examples of the group A in the
compound (I) according to the present invention can include linear
or branched alkylene groups having 2-10 carbon atoms, such as
ethylene, trimethylene, tetramethylene, pentamethylene and
octamethylene; linear or branched alkenylene groups having 4-10
carbon atoms, such as 2-butenylene and 3-pentenylene; and linear or
branched alkynylene groups having 4-10 carbon atoms, such as
2-butynylene and 3-pentynylene. One or more of the hydrogen atoms
of each of these groups may be substituted by a like number of
halogen atoms such as fluorine, chlorine and/or bromine atoms.
Among the above groups, trimethylene and tetramethylene are
particularly preferred.
[0024] Further, preferred examples of the group Z.sub.1 and the
group Z.sub.2 in the compound (I) according to the present
invention can include the following combinations: when the bond
indicated by the dashed line is present, Z.sub.2 is not present and
Z.sub.1 represents a hydrogen atom; when the bond indicated by the
dashed line is absent, Z.sub.1 represents a hydrogen atom and
Z.sub.2 represents a hydroxyl group, or Z.sub.1 and Z.sub.2 are
combined together to represent an oxygen atom or the group
NOR.sub.1.
[0025] Preferred examples of R.sub.1 in the group NOR.sub.1 can
include a hydrogen atom; linear or branched alkyl groups having 1-4
carbon atoms preferably, such as methyl and ethyl; aryl groups
having 6-14 carbon atoms, such as phenyl and naphthyl; and aralkyl
groups having 7-22 carbon atoms, such as benzyl and phenethyl. One
or more of the hydrogen atoms of each of these groups may be
substituted by a like number of halogen atoms such as fluorine,
chlorine and/or bromine atoms, alkyl groups having 1-4 carbon atoms
preferably, such as methyl and/or ethyl, and/or alkoxy groups
having 1-4 carbon atoms preferably, such as methoxy and/or ethoxy.
Of these, hydrogen atom and methyl group are particularly
preferred.
[0026] In the compound (I) according to the present invention, Y is
a group7
[0027] wherein B, D, E.sub.1, E.sub.2, W and m have the same
meanings as defined above. The group represented by the following
formula:8
[0028] wherein E.sub.1, E.sub.2 and W have the same meanings as
defined above is a heterocyclic group derived from piperidine or
piperazine, and two or less of the hydrogen atoms on the ring may
be substituted by a like number of alkyl groups having
1-4-carbon-atoms preferably, such as methyl and/or ethyl.
[0029] When the above group is a heterocyclic group derived from
piperidine, m stands for 0 or 1 (with the proviso that m stands for
1 when W represents C.dbd.), and B represents a carbonyl group, a
sulfonyl group, an alkylene group (an alkylene group having 1-4
carbon atoms preferably, with a methylene group being particularly
preferred), an alkenylene group (an alkenylene group having 2-5
carbon atoms preferably, with a 2-propenylene group being
particularly preferred), a group -C(OH)R.sub.2- in which R.sub.2 is
an aryl group having 6-14 carbon atoms, such as phenyl or naphthyl,
in which one or more of the hydrogen atoms may be substituted, a
group -CHR.sub.3- in which R.sub.3 is an aryl group having 6-14
carbon atoms, such as phenyl or naphthyl, in which one or more of
the hydrogen atoms may be substituted, a group9
[0030] in which the double bond is coupled with W, R.sub.4
represents an aryl group having 6-14 carbon atoms, such as phenyl
or naphthyl, or an aralkyl group having 7-22 carbon atoms, such as
benzyl or phenethyl, and these groups may be in substituted forms,
or a cyclic or acyclic acetal group in which one or more of the
hydrogen atoms may be substituted.
[0031] Exemplary cyclic or acyclic acetal groups include:10
[0032] In the above-described definition of B, preferred examples
of substituents on the groups R.sub.2, R.sub.3 and R.sub.4 can
include one or more alkyl groups having 1-4 carbon atoms, such as
methyl and ethyl; aryl groups having 6-14 carbon atoms, such as
phenyl and naphthyl; halogen atoms such as fluorine atoms, chlorine
atoms and bromine atoms; alkoxy groups having 1-4 carbon atoms,
such as methoxy and ethoxy; hydroxyl groups; cyano groups; and
nitro groups.
[0033] Further, illustrative of substituents on the cyclic or
acyclic acetal are halogen atoms such as fluorine atoms, chlorine
atoms, and bromine atoms; alkyl groups having 1-4 carbon atoms,
such as methyl and ethyl; aryl groups having 6-14 carbon atoms,
such as phenyl and naphthyl; aralkyl groups having 7-22 carbon
atoms, such as benzyl and phenethyl; and alkylidene groups having
1-4 carbon atoms preferably, such as methylidene and
ethylidene.
[0034] As a particularly preferred example of B, a carbonyl group
can be mentioned.
[0035] When the heterocyclic group is a group derived from
piperazine, m stands for 0 or 1 (preferably 0), and B represents a
carbonyl group, a sulfonyl group, an alkylene group (preferably, an
alkylene group having 1-4 carbon atoms, with a methylene group
being particularly preferred), an alkenylene group (preferably, an
alkenylene group having 3-6 carbon atoms, with a 2-propenylene
group being particularly preferred), a group -CHR.sub.5- in which
R.sub.5 represents an aryl group having 6-14 carbon atoms, such as
phenyl or naphthyl.
[0036] The above-described R.sub.5 may be substituted further, for
example, by one or more of halogen atoms such as fluorine, chlorine
and/or bromine, alkyl groups having 1-4 carbon atoms preferably,
such as methyl and/or ethyl, alkoxy groups having 1-4 carbon atoms
preferably, such as methoxy and/or ethoxy, hydroxyl groups, and/or
the like.
[0037] As a preferred example of the above-described B, a
substituted or unsubstituted phenylmethylene group can be
mentioned.
[0038] Preferred examples of group D can include aromatic
hydrocarbon groups having 6-28 carbon atoms preferably, such as a
phenyl group in which one or more of the hydrogen atoms may be
substituted and a naphthyl group in which one or more of the
hydrogen atoms may be substituted.
[0039] Other preferred examples of D can include aromatic
heterocyclic groups, preferably those each of which is monocyclic
or bicyclic and contains three or less hetero atoms, such as
pyridyl, pyrimidinyl, benzisothiazolyl, benzisoxazolyl, indazolyl
and indolyl groups in which one or more of hydrogen atoms may be
substituted. Examples of the hetero atoms can include oxygen,
sulfur and nitrogen atoms.
[0040] Examples of the substituents for the above aromatic
hydrocarbon group or aromatic heterocyclic group can include
halogen atoms such as fluorine, chlorine and bromine; alkyl groups
having 1-4 carbon atoms preferably, such as methyl and ethyl;
alkoxyl groups having 1-4 carbon atoms preferably, such as methoxy
and ethoxy; aryl groups having 6-14 carbon atoms, such as phenyl
and naphthyl; aralkyl groups having 7-22 carbon atoms, such as
benzyl and phenethyl; aralkyloxy groups having 7-22 carbon atoms
preferably, such as benzyloxy; cyano groups; nitro groups; carboxyl
groups; alkoxycarbonyl groups (with an alcohol moiety thereof
having 1-6 carbon atoms preferably); lower alkylsulfonylamino
groups (with an alkyl moiety thereof having 1-4 carbon atoms
preferably); carbamoyl groups; and hydroxyl groups.
[0041] Among these examples of group D, preferred ones can include
phenyl groups which may be unsubstituted or substituted by one or
more of halogen atoms, alkoxy groups and/or hydroxyl groups;
benzisothiazolyl groups which may be unsubstituted or substituted
by one or more halogen atoms; benzisoxazolyl groups which may be
unsubstituted or substituted by one or more halogen atoms; and
indazolyl groups which may be unsubstituted or substituted by one
or more halogen atoms. Particularly preferred are an unsubstituted
phenyl group; and phenyl groups substituted by one or more of
fluorine atoms, methoxy groups and/or hydroxyl groups.
[0042] 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.
[0043] The pyrrolesulfonamide derivatives (I) according to the
present invention can be prepared by various processes. It is
however preferred to prepare each of them, for example, by using a
pyrrolesulfonamide derivative (IIa) or (IIa`), which is available
by Process 1 to be described below, and following any one of the
processes to be described as Process 2 onwards.
[0044] Process 1:
[0045] Pyrrolesulfonamide derivatives (IIa) and (IIa`) useful as
starting materials can be synthesized, for example, by the
following process:
[0046] Process (a)
[0047] Compounds represented by the formula (IIa) and (IIa`) can be
obtained in accordance with the following reaction scheme, namely,
by converting a 1-substituted pyrrole-3-sulfonic acid represented
by the formula (XII) or a salt thereof into a 1-substituted
pyrrole-3-sulfonyl halide represented by the formula (XIII),
reacting glycine, -alanine or a derivative thereof represented by
the formula (XIV) or an organic or inorganic acid salt thereof with
the compound (XIII) and, if necessary, conducting deprotection to
obtain a compound represented by the formula (XV) and then
subjecting the thus-obtained compound to a ring-closing
reaction.11
[0048] wherein M represents a hydrogen ion, an alkali metal ion, an
alkaline earth metal ion or a quaternary ammonium ion, p stands for
1 when M represents a hydrogen ion, an alkali metal ion or a
quaternary ammonium ion or p stands for 2 when M represents an
alkaline earth metal ion, q stands for 0 or 1, R.sub.6 represents a
hydrogen atom or a carboxyl-protecting group, X" represents a
chlorine atom or a bromine atom, and R and l have the same meanings
as defined above.
[0049] Illustrative of M in the compound represented by the formula
(XII) in the above scheme are hydrogen ion; alkali metal ions such
as sodium ion and potassium ion; alkaline earth metal ions such as
barium ion; and quaternary ammonium ions such as pyridinium ion. As
representative preparation processes of the compound represented by
the formula (XII), the following two processes can be
mentioned.
[0050] [Preparation Process of the Compound (XII)-1]
[0051] The compound represented by the formula (XII) can be
obtained in accordance with the following formula, namely, by
causing a sulfonating agent such as sulfur trioxide-pyridine
complex to act on a 1-substituted pyrrole (XVIII) and, if
necessary, treating the resultant compound with an acid such as
hydrochloric acid or sulfuric acid or a base such as sodium
hydroxide, sodium carbonate, sodium hydrogencarbonate or barium
hydroxide.12
[0052] wherein M, R, p and q have the same meanings as defined
above.
[0053] [Preparation Process of the Compound (XII)-2]
[0054] The compound represented by the formula (XII) can be
obtained in accordance with the following formula, namely, by
causing trimethylsilyl chlorosulfonate (XIX) to act on a
1-substituted-2-tri-n-butylstannylpyrro- le represented by the
formula (XVII) in a solvent, which does not take part in the
reaction, such as carbon tetrachloride or 1,2-dichloroethane and
then hydrolyzing the resultant compound. Here, a basic substance
may be allowed to exist concurrently, whereby the reaction product
can be obtained as a salt.13
[0055] wherein M, R, p and q have the same meanings as defined
above.
[0056] Further, the compound (XIII) can be obtained by causing
phosphorus pentachloride or phosphorus pentabromide to act on the
compound (XII) in a solvent which does not take part in the
reaction, such as ethyl ether or toluene.
[0057] In addition, as the carboxyl-protecting group represented by
the group R.sub.6 in the compound (XIV), it is possible to use, in
addition to lower alkyl groups such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl and t-butyl and aralkyl groups having
7-20 carbon atoms, such as benzyl and 9-anthrylmethyl, conventional
protecting groups such as those described in T. W. Greene:
"Protective Groups in Organic Synthesis" (John Wiley & Sons,
Inc.) and the like.
[0058] Further, as an illustrative synthesis process of the
compound (XV), a process can be mentioned in which a base is added
to the compound (XIII), as needed, and glycine, -alanine or a
derivative thereof or an organic or inorganic acid salt thereof is
caused to act. Usable examples of the base can include organic
bases such as triethylamine and pyridine, and inorganic bases such
as sodium hydrogencarbonate, potassium carbonate and sodium
hydroxide.
[0059] The compound (XV) so obtained is subjected to a cyclizing
reaction, optionally after removing the protecting group by virtue
of a suitable method such as the action of an acid or a base, or
catalytic reduction. This cyclizing reaction is conducted by
treating the compound (XV) together with an organic acid such as
methanesulfonic acid, an inorganic acid such as sulfuric acid or
polyphosphoric acid or a mixture of such an organic or inorganic
acid and phosphorus pentoxide at room temperature to 170.degree.C.,
preferably at 80-120.degree.C.
[0060] In this case, a solvent which does not take part in the
reaction may be added as needed.
[0061] Further, the cyclizing reaction can also be practiced by,
optionally after addition of a catalyst such as dimethylformamide
to the compound (XV) in which R.sub.6 is a hydrogen atom, treating
the compound with oxalyl chloride, thionyl chloride, thionyl
bromide, oxalyl bromide, phosgene, phosphorus trichloride,
phosphorus tribromide, phosphoryl chloride, phosphoryl bromide or
the like to convert it into its corresponding acid halide and then
treating the acid halide at -20.degree.C. to reflux temperature in
the presence of a Lewis acid such as aluminum chloride, aluminum
bromide, boron trifluoride-ether complex or tin tetrachloride in a
solvent such as dichloromethane, 1,2-dichloroethane or
nitromethane. In the above-described reactions, the compound (IIa)
and the compound (IIa`) can be formed at varied ratios by changing
the reaction conditions.
[0062] Process (b)
[0063] Compounds represented by the formula (IIb) and (IIb`) can be
obtained in accordance with the following reaction scheme, namely,
by converting a pyrrole-3-sulfonic acid represented by the formula
(XX) or a salt thereof into a pyrrole-3-sulfonyl halide represented
by the formula (XXI), reacting glycine, -alanine or a derivative
thereof represented by the formula (XIV) or an organic or inorganic
acid salt thereof with the compound (XXI) and, if necessary,
conducting deprotection to obtain a compound represented by the
formula (XXII) and then subjecting the thus-obtained compound to a
ring-closing reaction. The compound (IIa) and compound (IIa`) can
then be obtained by introducing groups R to the pyrrole-nitrogen
atoms of the compounds (IIb), (IIb`), respectively.14 15
[0064] wherein X"` represents an eliminative group, and M, R,
R.sub.6, X", l and p have the same meanings as defined above.
[0065] In the above scheme, the compound represented by the formula
(XX) can be synthesized from pyrrole as a starting material by
following the preparation process of the compound (XII)-1 under
Process (a) of Process 1. Further, the conversion of the compound
(XX) into the compound (IIb) and the compound (IIb`) can be
effected in a similar manner as in the conversion of the compound
(XII) into the compound (IIa) and the compound (IIa`) in Process
(a) of Process 1.
[0066] The conversion from the compound (IIb) into the compound
(IIa) can be effected by treating the compound (IIb) with an
organic or inorganic base and then reacting the compound
represented by the formula (XVIa) or (XVIb), or by causing the
compound (XVIa) or the compound (XVIb) to act on the compound (IIb)
in the presence of such a base.
[0067] Examples of the eliminative group represented by the group
X"` in the compound (XVIa) can include halogen atoms such as
chlorine, bromine and iodine, alkylsulfonyloxy groups such as
methanesulfonyloxy, and arylsulfonyloxy groups such as
p-toluenesulfonyloxy. Exemplary organic or inorganic bases can
include potassium carbonate, sodium carbonate, potassium hydroxide,
sodium hydroxide, sodium hydride, triethylamine, sodium methoxide,
and potassium t-butoxide. Further, illustrative solvents usable in
the above reaction include acetone, 2-butanone, acetonitrile,
tetrahydrofuran, dioxane, dimethylformamide, and dimethylsulfoxide.
The reaction is conducted at -20.degree.C to reflux
temperature.
[0068] On the other hand, the conversion from the compound (IIb`)
into the compound (IIa`) can also be effected under the same
conditions as in the above-described conversion from the compound
(IIb) into the compound (IIa).
[0069] Process 2:
[0070] Among the pyrrolesulfonamide derivatives (I), compounds (Ia)
in each of which Z.sub.1 and Z.sub.2 are combined together to
represent an oxygen atom can be synthesized, for example, by any
one of the following processes.
[0071] Process (a)
[0072] Each compound (Ia) can be obtained in accordance with the
following reaction scheme, namely, by reacting a compound
represented by the formula (II) with a compound represented by the
formula (III) to convert the compound (II) into a compound
represented by the formula (IV) and then reacting a
nitrogen-containing compound represented by the formula (V) or a
salt thereof with the compound (IV).16
[0073] wherein X and X` represent the same or different eliminative
groups, and A, the ring P, Y and l have the same meanings as
defined above.
[0074] In the above-described reaction, the conversion from the
compound (II) into the compound (IV) can be effected by treating
the compound (II) with an organic or inorganic base and then
reacting the compound (III) with the compound (II), or by causing
the compound (III) to act on the compound (II) in the presence of
such a base.
[0075] The groups X and X` in the compound (III) are eliminative
groups. Illustrative can be halogen atoms such as chlorine and
bromine, alkylsulfonyloxy groups such as methanesulfonyloxy, and
arylsulfonyloxy groups such as p-toluenesulfonyloxy.
[0076] Exemplary inorganic bases or organic bases can include
sodium carbonate, potassium carbonate, sodium hydroxide, potassium
hydroxide, sodium hydride, triethylamine, sodium ethoxide, sodium
bis(trimethylsilyl)amide, and potassium t-butoxide. The reaction
can be conducted at -78.degree.C to reflux temperature in a solvent
which does not take part in the reaction.
[0077] To prepare the compound (Ia) from the thus-obtained compound
(IV) and 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 (IV),
optionally together with an organic base such as triethylamine,
pyridine, collidine or potassium t-butoxide or an inorganic base
such as potassium carbonate, sodium carbonate, sodium
hydrogencarbonate, sodium hydroxide or sodium hydride and
optionally with the addition of an alkali iodide such as potassium
iodide or sodium iodide, in a solventless manner or in a solvent
such as acetone, 2-butanone, acetonitrile, dimethylformamide,
methanol, ethanol or the like at room temperature to
150.degree.C.
[0078] Examples of the nitrogen-containing compound (V) can 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-diphenylmethylpiperazi- ne, 1-cinnamylpiperazine,
1-benzoylpiperazine, 1-(4-benzyloxybenzoyl)piper- azine,
1-(4-hydroxybenzoyl)piperazine, 1-(2-furoyl)piperazine,
1-(1,2-benzisoxazol-3-yl)piperazine, 4-phenylpiperidine,
4-benzylpiperidine, ,-bis(4-fluorophenyl)-4-piperidinemethanol,
4-(4-fluorobenzoyl)piperidine, 4-benzoylpiperidine,
4-(4-methoxybenzoyl)piperidine, 4-(4-chlorobenzoyl)piperidine,
4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine,
4-(6-fluoro-1H-indazol-3-yl- -)piperidine,
4-[(4-fluorophenyl)sulfonyl]piperidine,
4-[bis(4-fluorophenyl)methylene]piperidine, and
4-(4-fluorobenzoyl)piperi- dine ethylene acetal.
[0079] These compounds are either known in the art or readily
available by processes known per se in the art or by processes
similar to such known processes.
[0080] Process (b)
[0081] Further, the compound (Ia) can also be obtained by causing a
nitrogen-containing compound represented by the formula (VI) to act
on the compound represented by the formula (II) in accordance with
the following reaction formula:17
[0082] wherein A, the ring P, X, Y and l have the same meanings as
defined above.
[0083] The conversion from the compound (II) into the compound (Ia)
is conducted by causing the compound (VI) to act either after
treatment of the compound (II) with an inorganic base or an organic
base or in the presence of an inorganic base or an organic base.
Reaction conditions are similar to those employed upon conversion
from the compound (II) into the compound (IV) and described above
under Process (a) of Process 2. Further, the compound (VI) can be
synthesized by reacting the compound (III) with the compound (V) in
a manner known per se in the art.
[0084] Process 3:
[0085] Among the pyrrolesulfonamide derivatives (I), the compounds
(Ic) and (Ie) in each of which Z.sub.1 and Z.sub.2 are combined
together to represent a group NOR.sub.1 can each be synthesized by
any one of the following processes.
[0086] Process (a)
[0087] Each compound (Ie) is obtained in accordance with the
following reaction scheme, namely, by causing hydroxylamine or a
derivative thereof (VII) or a salt thereof to act on a compound
represented by the formula (IV) and then causing a
nitrogen-containing compound (V) to act.18
[0088] wherein A, the ring P, R.sub.1, X, Y and l have the same
meanings as defined above.
[0089] The reaction between the compound (IV) and the hydroxylamine
or its derivative (VII) is effected, if necessary, in the presence
of an organic base such as pyridine, triethylamine, collidine 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.
[0090] The reaction is conducted at 0.degree.C. to reflux
temperature, preferably 0.degree.C-100C by using a suitable
solvent, for example, methanol, ethanol, propanol, tetrahydrofuran,
dimethylformamide or dimethylsulfoxide as needed.
[0091] Further, the conversion from the thus-obtained compound
(VIII) into the compound (Ie) can be effected under similar
conditions as in the conversion from the compound (IV) into the
compound (Ia) shown above under Process (a) of Process 2.
[0092] Process (b)
[0093] Each compound (Ic) is obtained by causing hydroxylamine or
its derivative (VII) or a salt thereof to act on a compound (Ib) in
accordance with the following reaction formula.19
[0094] wherein A, the ring P, R.sub.1 and l have the same meanings
as defined above, and Y` represents a group20
[0095] in which when W represents CH, B` represents a sulfonyl
group, an alkylene group, an alkenylene group, a group
-C(OH)R.sub.2- in which R.sub.2 represents a substituted or
unsubstituted aryl group, a group -CHR.sub.3- in which R.sub.3
represents a substituted or unsubstituted aryl group, or a
substituted or unsubstituted cyclic or acyclic acetal group; when W
represents C.dbd., B` represents a group21
[0096] in which the double bond is coupled with W and R.sub.4
represents a substituted or unsubstituted aryl group or a
substituted or unsubstituted aralkyl group; when W represents a
nitrogen atom, B` represents a carbonyl group, a sulfonyl group, an
alkylene group, an alkenylene group or a group -CHR.sub.5- in which
R.sub.5 represents a substituted or unsubstituted aryl group; and
D, E.sub.1, E.sub.2 and m have the same meanings as defined
above.
[0097] The conversion from the compound (Ib) into the compound (Ic)
can be effected under similar conditions as the conversion from the
compound (IV) into the compound (VIII) shown above under Process
(a) of Process 3.
[0098] Process 4:
[0099] Among the pyrrolesulfonamide derivatives (I), the compounds
(Id) and (If) in each of which Z.sub.1 represents a hydrogen atom
and Z.sub.2 represents a hydroxyl group can each be synthesized by
any one of the following processes.
[0100] Process (a)
[0101] Each compound (If) is obtained in accordance with the
following reaction scheme, namely, by reducing a compound
represented by the formula (IV) and then causing a
nitrogen-containing compound (V) to act.22
[0102] wherein A, the ring P, X, Y and l have the same meanings as
defined above.
[0103] The conversion from the compound (IV) into the compound (IX)
is conducted by treating the compound represented by the formula
(IV) with a reducing agent such as sodium borohydride, potassium
borohydride or sodium cyanoborohydride at -78C. to reflux
temperature, preferably -20.degree.C. to room temperature in a
conventionally used solvent.
[0104] The conversion from the compound (IX) into the compound (If)
can be effected under similar conditions as the conversion from the
compound (IV) into the compound (Ia) shown above under Process (a)
of Process 2.
[0105] Process (b)
[0106] Each compound (Id) is obtained by reducing a compound
represented by the formula (Ib) in accordance with the following
reaction formula.23
[0107] wherein A, the ring P, Y` and l have the same meanings as
defined above.
[0108] The conversion from the compound (Ib) into the compound (Id)
can be effected under similar conditions as in the conversion from
the compound (IV) into the compound (IX) shown above under Process
(a) of Process 4.
[0109] Process 5:
[0110] Among the pyrrolesulfonamide derivatives (I), the compounds
(Ig) in each of which the bond indicated by the dashed line is
present and Z.sub.1 represents a hydrogen atom can be synthesized
by any one of the following processes.
[0111] Process (a)
[0112] Each compound (Ig) is obtained in accordance with the
following reaction scheme, namely, by subjecting a compound
represented by the formula (IX) to a dehydration reaction to obtain
a compound represented by the formula (X) and then causing a
nitrogen-containing compound (V) to act on the compound (X).24
[0113] wherein A, the ring P, X, Y and l have the same meanings as
defined above.
[0114] In the above-described reaction, the conversion from the
compound (IX) into the compound (X) can be effected by treating the
compound (IX) with an acid such as hydrogen chloride, hydrogen
bromide, sulfuric acid, methanesulfonic acid or p-toluenesulfonic
acid at -20C. to 100C., preferably at -20C. to room temperature in
a solvent such as water, methanol, ethanol, ethyl acetate,
chloroform or toluene.
[0115] As an alternative, the conversion into the compound (X) can
also be effected by causing methanesulfonyl chloride,
p-toluenesulfonyl chloride, phosphorus trichloride, phosphorus
oxychloride, thionyl chloride or the like and a base such as
triethylamine, pyridine or collidine to act on the compound (IX),
if necessary, in a solvent such as dichloromethane, chloroform or
toluene.
[0116] The conversion from the compound (X) into the compound (Ig)
can be effected under similar conditions as in the conversion from
the compound (IV) into the compound (Ia) described above under
Process (a) of Process 2.
[0117] Process (b)
[0118] Each compound (Ig) is obtained by subjecting a compound
represented by the formula (If) to a dehydration reaction in
accordance with the following reaction formula:25
[0119] wherein A, the ring P, Y and l have the same meanings as
defined above.
[0120] In the above-described reaction, the conversion from the
compound (If) into the compound (Ig) can be effected under similar
conditions as in the conversion from the compound (IX) into the
compound (X) described above under Process (a) of Process 5.
[0121] If necessary, 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 into its
salt. Then, the resulting salt can be purified by a method such as
recrystallization or column chromatography.
[0122] Exemplary acids usable for the conversion of the
pyrrolesulfonamide derivatives (I) into their salts can 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.
[0123] Further, the compounds (I) according to the present
invention include those containing asymmetric centers. Each racemic
mixture can be isolated by one or more of various methods, whereby
a single optically-active substance can be obtained. Usable methods
include, for example:
[0124] (1) Isolation by an optically active column.
[0125] (2) Isolation by recrystallization subsequent to conversion
into a salt with an optically active acid.
[0126] (3) Isolation by an enzyme reaction.
[0127] (4) Isolation by a combination of the above methods (1) to
(3).
[0128] The pyrrolesulfonamide derivatives (I) and their salts,
which are obtained as described above, have strong serotonin-2
blocking action as will be demonstrated in tests to be described
subsequently herein. Moreover, the compounds (I) according to the
present invention have also been found to include those also having
.sub.1 blocking action. From the results of toxicity tests, the
compounds (I) according to the present invention have also been
found to possess high safety.
[0129] The compounds (I) according to the present invention can
therefore be used as pharmaceuticals for the treatment of
circulatory diseases such as ischemic heart diseases,
cerebrovascular disturbances, peripheral circulatory disturbances
and hypertension.
[0130] When the pyrrolesulfonamide derivatives (I) according to
this invention are used as pharmaceuticals, 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.
[0131] Exemplary preparation forms as medicines 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.
[0132] 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.
[0133] When the compounds (I) according to the present invention
are used as pharmaceuticals, their dose varies depending on the
administration purpose, the age, body weight, conditions, etc. of
the patient to be administered. In oral administration, the daily
dose may generally be about 0.01-1,000 mg.
[0134] The present invention will next be described in further
detail by the following referential examples, examples and tests.
It is however to be noted that the present invention is by no means
limited to the following examples.
REFERENTIAL EXAMPLE 1
[0135] Synthesis of sodium 3-pyrrolesulfonate (Compound 1)
[0136] A mixture consisting of 30.0 g (447 mmol) of pyrrole, 75.0 g
(471 mmol) of sulfur trioxide-pyridine complex and 250 ml of
1,2-dichloroethane was refluxed for 16 hours. The top layer of the
reaction mixture was removed by decantation. To the residue, 150 ml
of water and 30 g of sodium carbonate were added successively.
After the resulting mixture was boiled, the solvent was distilled
off under reduced pressure. Ethanol-water (9:1 v/v, 500 ml) was
added to the residue, followed by reflux for 1 hour. The reaction
mixture was subjected to hot filtration, and the filtrate was
allowed to cool down. Precipitated crystals were collected, washed
with chilled ethanol and diethyl ether, and then dried under
reduced pressure, whereby 17.0 g of powdery crystals were
obtained.
REFERENTIAL EXAMPLE 2
[0137] Synthesis of Benzyl 2-(3-pyrrolesulfonamide)acetate
(Compound 2)
[0138] A suspension of 16.9 g (100 mmol) of Compound 1 and 22.9 g
(110 mmol) of phosphorus pentachloride in 750 ml of diethyl ether
was stirred at room temperature for 2 hours, and was then refluxed
for 4 hours. After the reaction mixture was allowed to cool down,
it was filtered. The filtrate was washed successively with ice
water (twice), a chilled, saturated aqueous solution of sodium
hydrogencarbonate, ice water and a chilled, saturated aqueous
solution of sodium chloride. The organic layer was dried over
anhydrous sodium sulfate and then concentrated under reduced
pressure, whereby 11.2 g of 3-pyrrolesulfonyl chloride were
obtained as crude crystals.
[0139] After a mixture consisting of the whole amount of the
thus-obtained crude crystals, 32.6 g (96.6 mmol) of glycine benzyl
ester p-toluenesulfonate, 19.6 g (193 mmol) of triethylamine and
250 ml of tetrahydrofuran (hereinafter called "THF") was refluxed
for 6 hours, the reaction mixture was concentrated under reduced
pressure. Ethyl acetate was added to the residue. The resulting
mixture was washed successively with a 10% aqueous solution of
citric acid, water and a saturated aqueous solution of sodium
chloride, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure. The residue was treated with
activated carbon under heat in methanol and then recrystallized
from methanol, whereby 12.6 g of the title compound were obtained
(yield: 43% based on sodium 3-pyrrolesulfonate).
REFERENTIAL EXAMPLE 3
[0140] Synthesis of Benzyl 3-(3-pyrrolesulfonamide)propionate
(Compound 3)
[0141] A mixture consisting of 1.66 g (10 mmol) of
3-pyrrolesulfonyl chloride obtained by the process of Referential
Example 2, 7.03 g (20 mmol) of -alanine benzyl ester
p-toluenesulfonate, 4.05 g (40 mmol) of triethylamine and 100 ml of
THF was refluxed for 16 hours. The reaction mixture was
concentrated under reduced pressure, and ethyl acetate was added to
the residue. The organic layer was washed successively with a
saturated aqueous solution of sodium hydrogencarbonate, water, a
10% aqueous solution of citric acid, water and a saturated aqueous
solution of sodium chloride, dried over anhydrous sodium sulfate,
and then concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (Merck & Co.
Inc. No. 9385) (the same silica gel were used in the subsequent
examples) (eluent: ethyl acetate/hexane=1/1), whereby 2.82 g of the
title compound were obtained-(yield: 92%).
REFERENTIAL EXAMPLE 4
[0142] Synthesis of 2-(3-pyrrolesulfonamide)acetic Acid (Compound
4)
[0143] To a solution of 4.85 g (16 mmol) of Compound 2 in 150 ml of
THF, 480 mg of 10% palladium on charcoal were added, followed by
stirring at room temperature for 15 hours under a hydrogen gas
stream. The reaction mixture was filtered and the filtrate was
concentrated under reduced pressure. The residue was recrystallized
from acetonitrile, whereby 2.87 g of the title compound were
obtained (yield: 88%).
REFERENTIAL EXAMPLE 5
[0144] Synthesis of 3-(3-pyrrolesulfonamide)propionic Acid
(Compound 5)
[0145] To a solution of 19.60 g (64 mmol) of Compound 3 in 400 ml
of THF, 1.96 g of 5% palladium on charcoal were added, followed by
stirring at room temperature for 4 hours under a hydrogen gas
stream. The reaction mixture was filtered and the filtrate was
concentrated under reduced pressure. The residue was recrystallized
from ethyl acetate, whereby 11.96 g of the title compound were
obtained (yield: 86%).
REFERENTIAL EXAMPLE 6
[0146] Synthesis of
2,3,4,5-tetrahydropyrrolo[2,3-e][1,2]thiazin-4-one 1,1-dioxide
(Compound 6) and 2,3,4,6-tetrahydropyrrolo[3,4-e][1,2]thiazin-
-4-one 1,1-dioxide (Compound 7)
[0147] Under ice cooling, 5.00 g (24.5 mmol) of Compound 4, 4.27 ml
(49 mmol) of oxalyl chloride, 120 ml of THF and 3 droplets of DMF
were mixed, and the resulting mixture was stirred for 1 hour. The
reaction mixture was concentrated under reduced pressure, and 120
ml of 1,2-dichloroethane were added to the residue. Under
ice-cooled stirring, 6.53 g (49 mmol) of aluminum chloride were
added, followed by stirring for 2.5 hours at the same temperature.
Under ice cooling, 43 ml of 6 N hydrochloric acid were added. After
the resultant mixture was saturated with sodium chloride, the
thus-obtained mixture was extracted with THF (three times). The
organic layer was washed with a saturated aqueous solution of
sodium chloride, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure. The residue was separated by
chromatography on a silica gel column (eluent: ethyl
acetate/hexane=1/1.fwdarw.2/1), whereby 2.27 g of Compound 6 and 62
mg of Compound 7 were obtained (yields: 50% and 1%,
respectively).
REFERENTIAL EXAMPLE 7
[0148] Synthesis of
3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepin-5-o- ne
1,1-dioxide (Compound 8) and
3,4,5,7-tetrahydro-2H-pyrrolo[3,4-f][1,2]t- - hiazepin-5-one
1,1-dioxide (Compound 9)
[0149] A mixture consisting of 6.00 g (27.5 mmol) of Compound 5 and
300 g of polyphosphoric acid was stirred for 1 hour over an oil
bath of 100C. The reaction mixture was ice-cooled and was then
poured into ice water. A concentrated aqueous solution of sodium
hydroxide was added to adjust the pH to 4. Subsequent to saturation
with sodium chloride, the resulting mixture was extracted with THF
(3 times). The organic layer was washed with a saturated aqueous
solution of sodium chloride, dried over anhydrous sodium sulfate,
and then concentrated under reduced pressure. The residue was
separated by chromatography on a silica gel column (eluent: ethyl
acetate/hexane=2/1), whereby 2.50 g of Compound 8 and 497 mg of
Compound 9 were obtained (yields: 46% and 9%, respectively).
EXAMPLE 1
[0150] Synthesis of Sodium 1-methylpyrrole-3-sulfonate Monohydrate
(Compound 10)
[0151] Under an argon gas atmosphere, a solution of 9.44 g (50
mmol) of trimethylsilyl chlorosulfonate in 50 ml of carbon
tetrachloride was gradually added under stirring to a solution of
18.5 g (50 mmol) of 1-methyl-2-tri-n-butylstannylpyrrole in 150 ml
of carbon tetrachloride, followed by stirring at 50C. for 30
minutes and further at room temperature for 30 minutes. To the
reaction mixture, 300 ml of a saturated aqueous solution of sodium
hydrogencarbonate were added, followed by stirring at room
temperature for 20 minutes. The reaction mixture was allowed to
separate into two layers. The water layer was collected and then
washed with ethyl ether (100 ml ( 3 times). From the water layer,
water was distilled off under reduced pressure, followed by the
addition of ethanol to the residue. The resulting mixture was
boiled and then subjected to hot filtration. The solvent in the
filtrate was distilled off under reduced pressure, and the
thus-obtained solid was washed with n-pentane (200 ml ( 2 times)
and then dried under reduced pressure. Colorless powdery crystals
(6.67 g) were obtained.
EXAMPLE 2
[0152] Synthesis of sodium 1-methylpyrrole-3-sulfonate monohydrate
(Compound 10) (Alternative Process)
[0153] A mixture consisting of 48.3 g (595 mmol) of
1-methylpyrrole, 100 g (628 mmol) of sulfur trioxide-pyridine
complex and 325 ml of 1,2-dichloroethane was refluxed for 24 hours.
The top layer of the reaction mixture was removed by decantation,
and 225 ml of water and 100 g of sodium carbonate were successively
added to the residue. The resulting mixture was boiled, and the
solvent was distilled off under reduced pressure. Ethanol-water
(9:1 v/v, 1167 ml) was added to the residue. The thus-obtained
mixture was refluxed for 30 minutes and was then subjected to hot
filtration. The filtrate was concentrated under reduced pressure
and the residue was recrystallized from water-ethanol, whereby 7.05
g of powdery crystals were obtained.
EXAMPLE 3
[0154] Synthesis of benzyl
2-[3-(1-methylpyrrole)sulfonamide]propionate (Compound 11)
[0155] A suspension of 7.40 g (36.8 mmol) of the sodium
1-methylpyrrole-3-sulfonate monohydrate obtained in Example 1 and
9.25 g (44.4 mmol) of phosphorus pentoxide in 303 ml of diethyl
ether was stirred at room temperature for 2 hours. The reaction
mixture was filtered, and the filtrate was washed successively with
chilled water, a chilled, half-saturated aqueous solution of sodium
hydrogencarbonate, chilled water and a chilled, saturated aqueous
solution of sodium chloride. The organic layer was dried over
anhydrous sodium sulfate and then concentrated under reduced
pressure, whereby 4.14 g of 3-(1-methylpyrrole)sulfonyl chloride
were obtained as crude crystals.
[0156] After a mixture consisting of the whole amount of the
thus-obtained crude crystals, 12.18 g (34.65 mmol) of -alanine
benzyl ester p-toluenesulfonate, 7.01 g (69.3 mmol) of
triethylamine and 200 ml of THF was refluxed for 17 hours, the
reaction mixture was allowed to cool down and was then filtered.
The filtrate was concentrated under reduced pressure. Ethyl acetate
was added to the residue. The resulting mixture was washed
successively with water, a 10% aqueous solution of citric acid,
water and a saturated aqueous solution of sodium chloride, dried
over anhydrous sodium sulfate, and then concentrated under reduced
pressure. The residue was purified by chromatography on a silica
gel column (eluent: ethyl acetate/hexane=1/1), whereby 5.97 g of
the title compound were obtained (yield: 50%).
EXAMPLE 4
[0157] Synthesis of 3-[3-(1-methylpyrrole)sulfonamide]-propionic
Acid (Compound 12)
[0158] To a solution of 5.595 g (17.36 mmol) of Compound 11 in 200
ml of THF, 560 mg of 5% palladium on charcoal were added, followed
by stirring at room temperature for 24 hours under a hydrogen gas
stream. The reaction mixture was filtered and the filtrate was
concentrated under reduced pressure. The residue was recrystallized
from 2-propanol-diisopropyl ether, whereby 3.49 g of the title
compound were obtained (yield: 81%).
EXAMPLE 5
[0159] Synthesis of
5-methyl-2,3,4,5-tetrahydropyrrolo-[2,3-e][1,2]thiazin- -4-one
1,1-dioxide (Compound 13)
[0160] A suspension of 2.06 g (14 mmol) of Compound 6, 1.3 ml (14
mmol) of dimethyl sulfate, 1.90 g (14 mmol) of potassium carbonate
in 140 ml of acetone was stirred at room temperature for 5 hours.
The reaction mixture was filtered, and the filtrate was
concentrated under reduced pressure. The residue was purified by
chromatography on a silica gel column (eluent: THF/methylene
chloride=1/7), whereby 2.40 g of the title compound were obtained
(yield: 86%).
EXAMPLE 6
[0161] Synthesis of
6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thia- zepin-5-one
1,1-dioxide (Compound 14)
[0162] A suspension of 200 mg (1 mmol) of Compound 8, 126 mg (1
mmol) of dimethyl sulfate and 138 mg (1 mmol) of potassium
carbonate in 20 ml of acetone was refluxed for 12 hours. The
reaction mixture was concentrated under reduced pressure, followed
by the addition of a saturated aqueous solution of sodium chloride
to the residue. The resultant mixture was extracted with chloroform
(3 times). The organic layer was dried over anhydrous sodium
sulfate and then concentrated under reduced pressure. The residue
was purified by chromatography on a silica gel column, (eluent:
methanol/chloroform=1/19), whereby 135 mg of the title compound
were obtained (yield: 63%).
EXAMPLE 7
[0163] Synthesis of
7-methyl-3,4,5,7-tetrahydro-2H-pyrrolo[3,4-f][1,2]thia- zepin-5-one
1,1-dioxide (Compound 15)
[0164] A suspension of 480 mg (2.4 mmol) of Compound 9, 303 mg (2.4
mmol) of dimethyl sulfate and 332 mg (2.4 mmol) of potassium
carbonate in 50 ml of acetone was stirred at room temperature for
22 hours. The reaction mixture was concentrated under reduced
pressure, and water and 1 g of citric acid were added to the
residue. The thus-obtained mixture was extracted with chloroform (3
times). The organic layer was washed with a saturated aqueous
solution of sodium chloride, dried over anhydrous sodium sulfate,
and then concentrated under reduced pressure. The residue was
purified by chromatography on a silica gel column (eluent:
methanol/chloroform=1/19), whereby 347 mg of the title compound
were obtained (yield: 68%).
EXAMPLE 8
[0165] Synthesis of
7-methyl-3,4,5,7-tetrahydro-2H-pyrrolo[3,4-f][1,2]thia- zepin-5-one
1,1-dioxide (Compound 15) (Alternative Process)
[0166] A mixture consisting of 497 mg (2 mmol) of Compound 12 and
25 g of polyphosphoric acid was stirred for 1 hour over an oil bath
of 100.degree.C. The reaction mixture was added to about 200 ml of
ice water, and potassium carbonate was added to adjust the pH to 4.
Subsequent to saturation with sodium chloride, the resultant
mixture was extracted with chloroform (3 times). The organic layer
was washed with water and a saturated aqueous solution of sodium
chloride, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure. The residue was purified by
chromatography on a silica gel column (eluent: ethyl acetate),
whereby 80 mg of the title compound were obtained (yield: 17%).
EXAMPLE 9
[0167] Synthesis of
2-(3-chloropropyl)-5-methyl-2,3,4,5-tetrahydropyrrolo[- -
2,3-e][1,2]thiazin-4-one 1,1-dioxide (Compound 16)
[0168] A suspension of 200 mg (1 mmol) of Compound 13, 189 mg (1.2
mmol) of 1-bromo-3-chloropropane and 345 mg (2.5 mmol) of potassium
carbonate in 5 ml of acetone was refluxed for 6 hours. The reaction
mixture was filtered, and the filtrate was concentrated under
reduced pressure. The residue was purified by chromatography on a
silica gel column (eluent: ethyl acetate/methylene chloride=1/30),
whereby 125 mg of the title compound were obtained (yield:
45%).
EXAMPLE 10
[0169] Synthesis of
2-(3-bromopropyl)-5-methyl-2,3,4,5-tetrahydropyrrolo[2- -
,3-e][1,2]thiazin-4-one 1,1-dioxide (Compound 17)
[0170] A suspension of 500 mg (2.5 mmol) of Compound 13, 2.5 g
(12.5 mmol) of 1,3-dibromopropane and 690 mg (5 mmol) of potassium
carbonate in 25 ml of acetone was refluxed for 12 hours. The
reaction mixture was filtered, and the filtrate was concentrated
under reduced pressure. The residue was purified by chromatography
on a silica gel column (eluent: ethyl acetate/methylene
chloride=1/40), whereby 274 mg of the title compound were obtained
(yield: 34%).
EXAMPLE 11
[0171] Synthesis of
2-(3-chloropropyl)-6-methyl-3,4,5,6-tetrahydro-2H-pyrr-
olo[2,3-f][1,2]thiazepin-5-one 1,1-dioxide (Compound 18)
[0172] A suspension of 214 mg (1 mmol) of Compound 14, 630-mg
(4-mmol) of 1-bromo-3-chloropropane and 276 mg (2 mmol) of
potassium carbonate in 5 ml of acetone was refluxed for 6 hours.
The reaction mixture was filtered, and the filtrate was
concentrated under reduced pressure. The residue was purified by
chromatography on a silica gel column (eluent: ethyl
acetate/hexane=1/2), whereby 275 mg of the title compound were
obtained (yield: 95%).
EXAMPLE 12
[0173] Synthesis of
2-(3-chloropropyl)-4-hydroxyimino-5-methyl-2,3,4,5-tet-
rahydropyrrolo[2,3-e][1,2]thiazine 1,1-dioxide (Compound 19)
[0174] A suspension of 300 mg (1.08 mmol) of Compound 16, 113 mg
(1.62 mmol) of hydroxylamine hydrochloride and 159 mg (1.62 mmol)
of potassium acetate in 10 ml of methanol was refluxed for 7 hours.
To the reaction mixture, 75 mg (1.08 mmol) of hydroxylamine
hydrochloride and 106 mg (1.08 mmol) of potassium acetate were
added, followed by further refluxing for 13 hours. Post treatment
and purification were conducted as in Example 9, whereby 277 mg of
the title compound were obtained (yield: 88%).
EXAMPLE 13
[0175] Synthesis of
2-(3-chloropropyl)-5-hydroxyimino-6-methyl-3,4,5,6-tet-
rahydro-2H-pyrrolo[2,3-f][1,2]-thiazepine-1,1-dioxide (Compound
20)
[0176] A suspension of 404 mg (1.39 mmol) of Compound 18, 290 mg
(4.17 mmol) of hydroxylamine hydrochloride and 342 mg (4.17 mmol)
of sodium acetate in 40 ml of methanol was refluxed for 22 hours.
To the reaction mixture, 97 mg (1.39 mmol) of hydroxylamine
hydrochloride and 114 mg (1.39 mmol) of sodium acetate were added,
followed by further refluxing for 19 hours. The reaction mixture
was concentrated under reduced pressure and a half-saturated
aqueous solution of potassium carbonate was added to the residue.
The thus-obtained mixture was extracted with chloroform (3 times).
The organic layer was washed successively with water and a
saturated aqueous solution of sodium chloride, dried over anhydrous
sodium sulfate, and then concentrated under reduced pressure. The
residue was purified by chromatography on a silica gel column
(eluent: chloroform), whereby 338 mg of the title compound were
obtained (yield: 80%).
EXAMPLE 14
[0177] Synthesis of
2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-5-methy-
l-1-2,3,4,5-tetrahydropyrrolo-[2,3-e][1,2]thiazin-4-one 1,1-dioxide
(Compound 21)
[0178] A suspension of 54 mg (0.17 mmol) of Compound 17, 46 mg
(0.25-mmol) of 1-(4-fluorophenyl)piperazine and 57 mg (0.68 mmol)
of sodium hydrogencarbonate in 3.4 ml of dioxane was refluxed for 7
hours. Post treatment and purification were conducted as in Example
9, whereby 67 mg of the title compound were obtained (yield:
94%).
EXAMPLE 15
[0179] Synthesis of
2-[3-[4-(4-fluorobenzoyl)piperidino]propyl]-6-methyl-3-
,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepin-5-one 1,1-dioxide
(Compound 22)
[0180] A suspension of 116 mg (0.4 mmol) of Compound 18, 97 mg (0.4
mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride, 134 mg (1.6
mmol) of sodium hydrogencarbonate and 120 mg (0.8 mmol) of sodium
iodide in 5 ml of acetonitrile was refluxed for 17 hours. Post
treatment was conducted as in Example 13, and the residue was
purified by chromatography on a silica gel column (eluent:
methanol/chloroform=3/97), whereby 137 mg of the title compound
were obtained (yield: 74%).
EXAMPLE 16
[0181] Synthesis of
2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-6-methy-
l-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepin-5-one
1,1-dioxide (Compound 23)
[0182] A suspension of 116 mg (0.4 mmol) of Compound 18, 108 mg
(0.6 mmol) of 1-(4-fluorophenyl)piperazine, 83 mg (0.6 mmol) of
potassium carbonate and 120 mg (0.8 mmol) of sodium iodide in 6 ml
of acetonitrile was refluxed for 19 hours. The reaction mixture was
concentrated under reduced pressure, a half-saturated aqueous
solution of potassium carbonate was added to the residue, and the
resultant mixture was extracted with ethyl acetate. The organic
layer was washed successively with water and a saturated aqueous
solution of sodium chloride, dried over anhydrous sodium sulfate,
and then concentrated under reduced pressure. The residue was
purified by chromatography on a silica gel column (eluent:
methanol/chloroform=3/97), whereby 173 mg of the title compound
were obtained (yield: 100%).
EXAMPLE 17
[0183] Synthesis of
2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-7-methy-
l-3,4,5,7-tetrahydro-2H-pyrrolo[3,4-f][1,2]thiazepin-5-one
1,1-dioxide (Compound 24)
[0184] A suspension of 236 mg (1.1 mmol) of Compound 15, 308 mg
(1.2 mmol) of 1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine and
304 mg (2.2 mmol) of potassium carbonate in 15 ml of 2-butanone was
refluxed for 16 hours. The reaction mixture was filtered, and the
filtrate was concentrated under reduced pressure. The residue was
purified by chromatography on a silica gel column (eluent: ethyl
acetate), whereby 276 mg of the title compound were obtained
(yield: 58%).
EXAMPLE 18
[0185] Synthesis of
2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-4-hydro-
xyimino-5-methyl-2,3,4,5-tetrahydropyrrolo[2,3-e][1,2]thiazine
1,1-dioxide (Compound 25)
[0186] A suspension of 116 mg (0.4 mmol) of Compound 19, 108 mg
(0.6 mmol) of 1-(4-fluorophenyl)piperazine, 134 mg (1.6 mmol) of
sodium hydrogencarbonate and 120 mg (0.8 mmol) of sodium iodide in
8 ml of acetonitrile was refluxed for 23 hours. The reaction
mixture was filtered, and the filtrate was concentrated under
reduced pressure. The residue was purified by chromatography on a
silica gel column (eluent: methanol/methylene chloride=1/20),
whereby-152 mg of the title compound were obtained (yield:
87%).
EXAMPLE 19
[0187] Synthesis of
2-[3-[4-(4-fluorobenzoyl)piperidino]-propyl]-4-hydroxy-
imino-5-methyl-2,3,4,5-tetrahydropyrrolo-[2,3-e][1,2]thiazine
1,1-dioxide (Compound 26)
[0188] A suspension of 116 mg (0.4 mmol) of Compound 19, 389 mg
(0.6 mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride, 134 mg
(1.6 mmol) of sodium hydrogencarbonate and 120 mg (0.8 mmol) of
sodium iodide in 8 ml of acetonitrile was refluxed for 24 hours.
The reaction mixture was filtered, and the filtrate was
concentrated under reduced pressure. The residue was purified by
chromatography on a silica gel column (eluent: methanol/methylene
chloride=1/15), whereby 90 mg of the title compound were obtained
(yield: 49%).
EXAMPLE 20
[0189] Synthesis of
2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-5-hydro-
xyimino-6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepine
1,1-dioxide (Compound 27)
[0190] A suspension of 112 mg (0.4 mmol) of Compound 20, 108 mg
(0.6 mmol) of 1-(4-fluorophenyl)piperazine, 83 mg (0.6 mmol) of
potassium carbonate and 120 mg (0.8 mmol) of sodium iodide in 6 ml
of acetonitrile was refluxed for 18 hours. The reaction mixture was
concentrated under reduced pressure, and a half-saturated aqueous
solution of potassium carbonate was added to the residue. The water
layer was saturated with sodium chloride, and the thus-obtained
mixture was extracted with THF. The organic layer was dried over
anhydrous sodium sulfate and then concentrated under reduced
pressure. The residue was purified by chromatography on a silica
gel column (eluent: methanol/chloroform=3/97), whereby 53 mg of the
title compound were obtained (yield: 29%).
EXAMPLE 21
[0191] Synthesis of
2-[3-[4-(4-fluorobenzoyl)piperidino]-propyl]-5-hydroxy-
imino-6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepine
1,1-dioxide (Compound 28)
[0192] A suspension of 112 mg (0.4 mmol) of Compound 20, 97 mg (0.4
mmol) of 4-(4-fluorobenzoyl)piperidine hydrochloride, 134 mg (1.6
mmol) of sodium hydrogencarbonate and 120 mg (0.8 mmol) of sodium
iodide in 5 ml of acetonitrile was refluxed for 14 hours. Post
treatment and purification were conducted as in Example 15, whereby
181 mg of the title compound were obtained (yield: 95%).
EXAMPLE 22
[0193] Synthesis of
2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-4-hydro-
xy-5-methyl-2,3,4,5-tetrahydropyrrolo[2,3-e][1,2]thiazine
1,1-dioxide (Compound 29)
[0194] To a suspension of 42 mg (0.1 mmol) of Compound 21 in 5 ml
of ethanol, 38 mg (1 mmol) of sodium borohydride were added
gradually under ice-cooled stirring. The resulting mixture was
stirred under ice cooling for 1 hour and further at room
temperature for 13 hours. Water (5 ml) was added to the reaction
mixture. The thus-obtained mixture was stirred at room temperature
for 5 hours and then concentrated under reduced pressure. Post
treatment and purification were conducted as in Example 15, whereby
36 mg of the title compound were obtained (yield: 85%).
EXAMPLE 23
[0195] Synthesis of
2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-5-hydro-
xy-6-methyl-3,4,5,6-tetrahydro-2H-pyrrolo[2,3-f][1,2]thiazepine
1,1-dioxide (Compound 30)
[0196] To a suspension of 240 mg (0.57 mmol) of Compound 23 in 5 ml
of ethanol, 200 mg (5.3 mmol) of sodium borohydride were added
gradually under ice-cooled stirring. The resulting mixture was
stirred under ice cooling for 1 hour and further at room
temperature for 4 hours. A saturated aqueous solution of ammonium
chloride was added to the reaction mixture under ice cooling,
followed by the addition of a saturated aqueous solution of sodium
hydrogencarbonate so that the mixture was alkalinized. The water
layer was extracted with methylene chloride. The organic layer was
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by chromatography on a
silica gel column (eluent: methanol/methylene chloride=1/20),
whereby 186 mg of the title compound were obtained (yield:
77%).
EXAMPLE 24
[0197] Synthesis of
2-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-5-hydro-
xy-7-methyl-3,4,5,7-tetrahydro-2H-pyrrolo[3,4-f][1,2]thiazepine
1,1-dioxide (Compound 31)
[0198] To a suspension of 174 mg (0.4 mmol) of Compound 24 in 8 ml
of ethanol, 151 mg (4 mmol) of sodium borohydride were added
gradually under ice-cooled stirring. The resulting mixture was
stirred under ice cooling for 1 hour and further at room
temperature for 13 hours. Water (80 ml) was added to the reaction
mixture. The thus-obtained mixture was stirred at room temperature
for 30 minutes and then concentrated under reduced pressure. Post
treatment and purification were conducted as in Example 15, whereby
151 mg of the title compound were obtained (yield: 86%).
[0199] Physical data of the compounds obtained in Examples 1-24 are
shown in Tables 1-6.
1TABLE 1 Comp'd Structural Property NMR (.delta. ppm)* IR
(cm.sup.-1) No. formula m.p. (recryst'n solvent) ( ): observation
frequency ( ): measuring method 10 26 Colorless powdery crystals
.gtoreq.250.degree. C. (400Mhz) (D.sub.2O/TSP-d.sub.4**) 3.67 (3H,
s), 6.37 (1H, s), 6.75 (1H, s), 7.11 (1H, s) (KBr) 3446, 3132,
1636, 1526, 1186, 1148, 1060, 1048, 942, 802, 699, 662 11 27
Colorless oil (400Mhz) 2.60 (2H, t, J=6.2Hz), 3.23 (2H, m), 3.66
(3H, s), 4.93 (1H, br. t), 6.38 (1H, m), 6.59 (1H, m), 7.11 (1H,
m), 7.28-7.41 (5H, m) (film) 3283, 1732, 1519, 1323, 1155, 1119,
801, 699 12 28 Pale yellow powdery Crystals 95.5-98.0.degree. C.
(isopropanol- isopropyl ether) (400MHz)(DMSO-d.sub.s/TMS) 2.37 (2H,
t, J-7.2Hz), 2.92 (2H, m), 3.66 (3H, s), 6.27 (1H, m), 6.83 (1H,
m), 6.99 (1H, br), 7.25 (1H, m), 12.18 (1H, br) (KBr) 3281, 1718,
1522, 1422, 1310, 1241, 1150, 1040, 801, 688 *Measured in
CDCl.sub.3 with TMS as an internal standard unless otherwise
specifically indicated. **TSP-d.sub.4 = sodium
3-(trimethylsilyl)propionate-d.sub.4
[0200]
2TABLE 2 Comp'd Structural Property NMR (.delta. ppm)* IR
(cm.sup.-1) No. Formula m.p. (recryst'n solvent) ( ): observation
frequency ( ): measuring method 13 29 Colorless powdery crystals
142.0-143.0 .degree. C. (ethyl acetate-hexane) (270MHz) 3.98 (3H,
s), 4.16 (2H, d, J=7.3Hz), 5.30 (1H, t, J=7.3Hz) 6.55 (1H, d,
J=2.6Hz), 6.91 (1H, d, J=2.6Hz) (KBr) 3196, 1673, 1648, 1382, 1328,
1307, 1209, 1162, 1142, 1083, 762 14 30 Colorless prism crystals
132.0-133.5.degree. C. (chloroform) (270MHz) (DMSO-d.sub.s/TMS)
3.01 (2H, m), 3.33 (2H, m), 3.82 (3H, s), 6.52 (1H, d, J=2.6Hz),
7.22 (1H, d, J=2.6Hz), 7.86 (1H, t, J=5.6Hz) (KBr) 3303, 1652,
1481, 1403, 1321, 1200, 1151, 1094, 1018, 983, 866, 783, 766, 674
15 31 Pale yellow powdery prism crystals 135.0-138.0.degree.0 C.
(ethyl acetate- isopropyl ether) (400MHz) (DMSO-d.sub.s/TMS) 2.83
(2H, m), 3.38 (2H, m), 3.68 (3H, s), 7.43 (1H, d, J=2.4Hz), 7.45
(1H, d, J=2.4Hz), 7.75 (1H, br. s.) (KBr) 3235, 1642, 1538, 1322,
1242, 1153, 1050, 858, 755 16 32 Colorless prism crystals 96.0-97.0
.degree. C. (ethyl acetate-hexane) (270Mhz) 2.08 (2H, quint.,
J=6.6Hz), 3.35 (2H, t, J=6.6Hz), 3.65 (2H, t, J=6.6Hz), 3.99 (3H,
s), 4.22 (2H, s), 6.53 (1H, d, J=2.6Hz), 6.92 (1H, d, J=2.6Hz)
(KBr) 1680, 1387, 1326, 1210, 1150, 1011, 900, 774, 705 *Measured
in CDCl.sub.3 with TMS as an internal standard unless otherwise
specifically indicated.
[0201]
3TABLE 3 Comp'd Structural Property NMR (.delta. ppm)* IR
(cm.sup.-1) No. Formula m.p. (recryst'n solvent) ( ): observation
frequency ( ): measuring method 17 33 Colorless prism crystals
84.0-85.0.degree. C. (ethyl acetate-hexane) (270MHz) 2.16 (2H,
quint., J=6.6Hz), 3.34 (2H, t, J=6.6Hz), 3.50 (2H, t, J=6.6Hz), 399
(3H, s), 4.23 (2H, s), 6.53 (1H, d, J=2.6Hz), 6.91 (1H, d, J=2.6Hz)
(KBr) 1680, 1484, 1389, 1328, 1260, 1212, 1149, 1006, 898, 715 18
34 Colorless needle crystals 71.0-74.0.degree. C. (ethyl
acetate-hexane) (270MHz) 2.04 (2H, quint., J=6.6Hz), 3.17 (2H, t,
J=6.6Hz), 3.25 (2H, m), 3.53-3.67 (4H, m), 3.92 (3H, s), 6.66 (1H,
d, J=2.6Hz), 6.81 (1H, d, J=2.6Hz) (KBr) 3120, 2964, 1661, 1472,
1405, 1375, 1330, 1213, 1196, 1152, 1096, 1026, 964, 854, 757, 707
19 35 Colorless prism crystals 126.0-127.0.degree. C. (ethyl
acetate-hexane) (270MHz) 2,09 (2H, quint., J=6.6Hz), 3,17 (2H, t,
J=6.6Hz), 3.67 (2H, t, J=6.6Hz), 3.84 (3H, s), 4.64 (2H, s), 6.48
(1H, d, J=2.6Hz), 6.71 (1H, d, J=2.6Hz), 7.53 (1H, s) (KBr) 3465,
1610, 1483, 1365, 1298, 1207, 1148, 1023, 994, 936, 848, 795 20 36
Colorless prism crystals 110.0-111.0.degree. C. (ethyl
acetate-hexane) (400MHz) 2.04 (2H, quint., J=6.4Hz), 3.15-3.21 (4H,
m), 3.60-3.66 (4H, m), 3.73 (3H, s), 6.57(1H, d, J=2.9Hz), 6.60
(1H, d, J=2.9Hz), 7.59 (1H, s) (KBr) 3358, 3120, 2949, 1486, 1413,
1308, 1194, 1142, 1062, 988, 953, 936, 907, 870, 757 730, 707
*Measured in CDCl.sub.3 with TMS as an internal standard unless
otherwise specifically indicated.
[0202]
4TABLE 4 Property Comp'd Structural m.p.(recryst'n NMR (.delta.
ppm)* IR (cm.sup.-1) ( ): No. Formula solvent) ( ): observation
frequency measuring method 21 37 Colorless needle crystals
141.0-142.0.degree. C. (ethyl acetate-hexane) (270MHz) 1.81 (2H,
quint. J=7.3Hz), 2.47 (2H, t, J=7.3Hz), 2.58(4H, m), 3.11 (4H, m),
3.27 (2H, t, J=7.3Hz), 3.98 (3H, s), 4.23 (2H, s), 6.52 (1H, d,
J=2.6Hz), 6.84-6.99 (5H, m) (KBr) 2950, 2833, 1684, 1510, 1386,
1335, 1238, 1155, 1005, 900, 815, 782, 719 22 38 Colorless powdery
crystals 105.0-107.0.degree. C. (ethyl acetate-hexane) (270MHz)
1.69-1.89 (6H, m), 2.06 (2H, m), 2.41 (2H, m), 2.95 (2H, m), 3.06
(2H, t, J=7.3Hz), 3.18 (1H, m), 3.24 (2H, m), 3.56 (2H, m), 3.92
(3H, s), 6.65 (1H, d, J=2.6Hz), 6.80 (1H, d, J=2.6Hz), 7.14 (2H,
m), 7.96 (2H, m) (KBr) 2948, 2778, 1726, 1668, 1596, 1508, 1464,
1405, 1375, 1322, 1228, 1146, 1046, 980, 856, 755 23 39 Colorless
powdery crystals 72.0-73.5.degree. C. (ethyl acetate-hexane)
(270MHz) 1.77 (2H, quint., J=7.3Hz), 2.44(2H, t, J=7.3Hz), 2.57
(4H, m), 3.03-3.14(6H, m), 3.25 (2H, m), 3.56 (2H, m), 3.92 (3H,
s), 6.65 (1H, d, J=2.6Hz), 6.80 (1H, d, J=2.6Hz), 6.87 (2H, m),
6.95 (2H, m) (KBr) 3609, 3128, 2842, 1661, 1508, 1452, 1404, 1386,
1318, 1247, 1216, 1143, 1038, 1014, 980, 958, 930, 846, 828, 780,
710 24 40 Colorless oil (400MHz) 1.8 (2H, quint., J=7.0Hz), 2.46
(2H, t, J=7.0Hz), 2.58 (4H, m), 3.05 (2H, m), 3.10 (4H, m), 3.16
(2H, t, J=7.0Hz), 3.68 (2H, m), 3.71 (3H, s), 6.86 (2H, m), 6.95
(2H, m), 7.14 (1H, d, J=2.5Hz), 7.25 (1H, d, J=2.5Hz) (film) 3124,
2945, 2819, 1655, 1531, 1509, 1456, 1329, 1232, 1156, 1038, 959,
827, 717 *Measured in CDCl.sub.3 with TMS as an internal standard
unless otherwise specifically indicated.
[0203]
5TABLE 5 Property Comp'd Structural m.p. (recryst'n NMR (.delta.
ppm)* ( ): IR (cm.sup.-1) ( ): No. formula solvent) observation
frequency measuring method 25 41 Colorless needle crystals
177.0-178.0.degree. C. (ethanol) (270MHz) (DMSO-d.sub.s/TMS) 1.71
(2H, m), 2.38 (2H, t, J=6.6Hz), 2.47 (4H, m), 2.94 (2H, t,
J=6.6Hz), 3.05 (4H, m), 3.83 (3H, s), 4.51 (2H, s), 6.42 (1H, d,
J=3.3Hz), 6.93 (2H, m), 7.02 (2H, m), 7.06 (1H, d, J=3.3Hz), 11.89
(1H, s) (KBr) 2833, 1513, 1332, 1244, 1203, 1156, 950, 824, 725 695
26 42 Colorless needle crystals 209.0-210.0.degree. C. (decomp'd)
(ethanol) (270MHz) (DMSO-d.sub.s/TMS) 1.56 (2H, m), 2.64-2.78 (4H,
m), 2.04 (2H, m), 2.33 (2H, m), 2.85-2.95 (4H, m), 3.35 (1H, m),
3.84 (3H, s), 4.49 (2H, s), 6.42 (1H, d, J=3.3Hz), 7.08 (1H, d,
J=3.3Hz), 7.34 (2H, m), 8.04 (2H, m), 11.89 (1H, s) (Kbr) 2953,
1684, 1598, 1508, 1412, 1330, 1206, 1157, 973, 942, 837, 778, 739,
721 27 43 Colorless powdery crystals 237.0-239.0.degree. C.
(acetonitrile- isopropyl ether) (400MHz) (DMSO-d.sub.s/TMS) 1.69
(2H, quint., J=6.9Hz), 2.33 (2H, m), 2.48 (4H, m), 2.93 (2H, m),
2.99 (2H, t, J=6.9Hz), 3.05 (4H, m), 3.55 (2H, m), 3.67 (3H, s),
6.37 (1H, d, J=2.9Hz), 6.89 (1H, d, J=2.9Hz), 6.92 (2H, m), 7.02
(2H, m), 11.78 (1H, s) (KBr) 2960, 2824, 1509, 1448, 1323, 1245,
1231, 1195, 1150, 1040, 993, 995, #924, 816, 757 728, 706 28 44
Colorless powdery crystals 192.5-195.0.degree. C. (ethyl
acetate-hexane) (400MHz) 1.72-1.96 (6H, m), 2.14 (2H, m), 2.46 (2H,
m), 2.99-3.08 (4H, m), 3.16-3.28 (3H, m), 3.55 (2H, m), 3.75 (3H,
s), 6.56(1H, d, J=3.0Hz), 6.59 (1H, d, J=3.0Hz), 7.14 (2H, m), 7.95
(2H, m), 10.13 (1H, br. s) (Kbr) 3402, 2953, 1680, 1597, 1505,
1450, 1412, 1327, 1196, 1150, 993, 973, 855, 726, 700 *Measured in
CDCl.sub.3 with TMS as an internal standard unless otherwise
specifically indicated.
[0204]
6TABLE 6 Property Comp'd Structural m.p. (recryst'n NMR (.delta.
ppm)* IR (cm.sup.-1) ( ): No. formula solvent) ( ): observation
frequency measuring method 29 45 Colorless powdery crystals
157.5-161.5.degree. C. (ethyl acetate-hexane) (400MHz) 1.83 (2H,
m), 2.35 (2H, m), 2.46 (1H, m), 2.61 (2H, m), 2.70 (1H, m), 2.82
(2H, m), 2.95-3.05 (3H, m), 3.52 (1H, dd, J=2.0Hz, 14.8Hz), 3.63
(3H, s), 3.92 (1H, m), 4.20 (1H, dd, J=2.8Hz, 14.8Hz), 4.52 (1H, t,
J=2.3Hz), 6.44 (1H, d, J=3.0Hz), 6.60 (1H, d, J=3.0Hz), 6.79 (2H,
m), 6.94 (2H, m) (KBr) 3528, 2953, 2820, 2360, 1510, 1464, #1310,
1232, 1209, 1140, 1059, 1003, 958, 920, 815, 776, 738, 713 30 46
Colorless oil (270MHz) 1.82 (2H, quint. J=7.3Hz), 1.93 (1H, m),
2.14 (1H, m), 2.40 (1H, m), 2.49-2.65 (5H, m), 2.78 (1H, m), 3.10
(4H, m), 2.25-2.38 (2H, m), 3.67 (3H, s), 4.40 (1H, m), 4.92 (1H,
m), 6.43-6.45 (2H, m), 6.87 (2H, m), 6.95 (2H, m) (film) 3500,
2822, 1731, 1505, 1456, 1232, 1138, 930, 818, 706 31 47 Colorless
plate crystals 165.5-169.0.degree. C. (ethyl acetate-hexane)
(400MHz) 1.81 (2H, quint., J=7.1Hz), 1.92 (2H, m), 2.47 (2H, m),
2.59 (4H, m), 2.83 (1H, m), 3.05-4.05 (6H, m), 3.44 (1H, m), 3.62
(3H, s), 4.12 (1H, m), 4.87 (1H, br. s), 6.56 (1H, d, J=2.4Hz),
6.87 (2H, m), 6.95 (2H, m), 7.02 (1H, d, J=2.4Hz) (KBr) 3122, 2959,
2828, 1509, 1448, 1328, 1247, 1151, 1124, 1062, 1009, 928, #897,
830, 780, 758, 711, 692 *Measured in CDCl.sub.3with TMS as an
internal standard unless otherwise specifically indicated.
[0205]
[0206] Tests
[0207] With respect to certain compounds of the present invention,
their anti-serotonin (5-HT) action and anti-.sub.1 action were
investigated by the methods which will be described below. The
results of some representative compounds are shown in Table 7.
[0208] (1) Anti-Serotonin (5-HT) Action
[0209] The superior mesenteric artery of each Hartley male guinea
pig (body weight: 300-500 g) was excised. A preparation cut in a
helical form was suspended under resting-tension of 0.3 g in a
Magnus cylinder filled with the Tyrode solution which had been
aerated with a gas mixture of 95% O.sub.2 and 5% CO.sub.2 and
maintained at 37.degree.C. Using an isometric transducer ("UL-10",
manufactured by SHINKOH K.K.) and a pressure preamplifier
("DSA-605A", manufactured by SHINKOH K.K.), variations in tension
were measured. The isometric tensions were recorded on a
pen-writing recorder ("VP-6537A", manufactured by NATIONAL K.K.).
Taking the contraction induced by 10.sup.-5 M serotonin (5-HT) as
100%, the percent contractions by 10.sup.-5 M 5-HT in the presence
of each test drug at 10.sup.-7 M and 10.sup.-6 M were determined as
anti-5-HT action.
[0210] (2) Anti-.sub.1 Action
[0211] The thoracic aorta of each Hartley male guinea pig (body
weight: 300-500 g) was excised. A preparation cut in a helical form
was suspended under 1 g load in a Magnus cylinder filled with the
Tyrode solution which had been aerated with a gas mixture of 95%
O.sub.2 and 5% CO.sub.2 and maintained at 37C. Using an isometric
transducer ("TB-612J", manufactured by Nihon Kohden Corporation)
and a pressure preamplifier ("AP-620G", manufactured by Nihon
Kohden Corporation), variations in tension were measured. The
isometric tensions were recorded on a thermal pen-writing recorder
("WT-647G", manufactured by Nihon Kohden Corporation). Taking the
tonic contraction induced by 10.sup.-5 M norepinephrine (NE) as
100%, the percent contractions upon addition of each test drug at
10.sup.-8 M and 10.sup.-7 M were determined and recorded as .sub.1
action.
7 TABLE 7 Anti 5-HT action Anti .alpha..sub.1action (% of Control)
(% of Control Comp'd No. 10.sup.-7 M 10.sup.-6 M 10.sup.-8 M
10.sup.-7 M 22 75.3 21.3 91.2 64.9 25 69.8 19.6 65.3 24.1 26 54.6
18.2 99.6 73.1 27 76.2 22.7 91.2 53.0 30 83.5 37.2 102.3 88.0
[0212]
[0213] Capability of Exploitation in Industry
[0214] The pyrrolesulfonamide derivatives (I) and their salts
according to the present invention have strong serotonin-2 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 ischemic
heart diseases, cerebrovascular disturbances and peripheral
circulatory disturbances. Further, the compounds according to the
present invention include those also having .sub.1 blocking action
in combination. Since these compounds are also effective as
antihypertensives, they are extremely used for therapeutics for a
wide variety of circulatory diseases.
* * * * *