Sulfonamide derivatives

Details Sulfonamide derivatives Sulfonamide derivatives

2000-11-21

2002-10-01

Shah, Mukund J. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S214000, C548S236000, C548S248000, C548S333500, C548S374100, C548S335500, C514S406000, C514S365000, C514S372000, C514S374000, C514S399000, C514S378000

Reexamination Certificate

active

06458960

ABSTRACT:

TECHNICAL FIELD
The present invention relates to sulfonamide derivatives having tubulin polymerization inhibitory activity, and tubulin polymerization inhibitory agents, anticancer agents, and agents useful as preventives or remedies for rheumatism such as inflammatory rheumatism containing these derivatives as the active ingredients.
BACKGROUND ART
Rheumatism is a refractory disease. Rheumatoid arthritis (RA), for example, has the basal lesion in proliferation of synovial cells accompanied with abnormalities in immune system caused by various factors. RA often causes progressive dysfunctions in articulation. To prevent from dysfunctions by RA, which is considered to be an auto immune disease, agents correcting immune abnormalities are used in combination to general antiphlogistics under the expectation of altering natural couse of RA.
For remedy of arthritis, steroidal agents such as adrenocortical hormones including cortisone, non-steroidal anti-inflammatory agents such as aspirin, piroxicam and indometacin, antirheumatic agents such as gold preparations including aurothiomalate, D-penicillamines, and immunosuppressive agents such as cyclophosphamide and azathioprine have been used.
Recent Japanese reports suggest that an intermittent administration in low dose of methotrexate(MTX) result in high efficiency and rapid response. However, it has many side effects including interstitial pneumonia, stomatitis, gastrointestinal symptons such as nausea and vomition, fibrous liver, and marrow suppression. Furthermore, a long term of the therapeutic administrations may cause high infectiousness and complicated malignancy. There has been found no desirable drug which is really effective and has little side effects with respect to this disease.
Although many compounds having tubulin polymerization inhibitory activity have been reported, nothing but colchicine(an arthrifuge) and vincristine(an antineoplastic) (Cancer Reseach, vol.20, p1023, 1960) among them are applicable for therapeutic agents. Rheumacon, the glycoside extracted from the natural material having antirheumatic effect is reported to show tubulin polymerization inhibitory effect(British Journal of rheumatology, Vol.32, p804, 1993), but it has the unknown chemical structural formula and many side effects such as moon face, suffusion, and gastrointestinal disorder are reported.
The JP Laid-Open No.39256/1993 discloses that the other sulfonamides than those of the present invention are useful antineoplastics. N-[2-((4-hydroxyphenyil) amino)-3-pyridinyl]-4-methoxybenzenesulfonamide described in the publication is reported to show tubulin polymerization inhibitory effect (Cancer Research, Vol.54, p1702, 1994).
However, the above agent has the severe side effects which make impossible its continuous administrations, the poor sustained therapeutic effects, or no effects for some patients. The clinical therapy demands low toxic agents which can protect and remedy patients from RA through new mechanism.
DISCLOSURE OF THE INVENTION
For solving the above problem, the present inventors made diligent studies to achieve low toxic anticancer agents and agents useful as preventives or remedies for rheumatism such as inflammatory rheumatism. As the result, it has been found that the novel sulfonamides derivatives having tubulin polymerization inhibitory activity as described below are lowly toxic, effective as anticancer agents, and useful as preventives or remedies for rheumatism such as inflammatory rheumatism. This finding has led to the completion of the present invention.
The compounds of the present invention as shown by the general formula(1) are novel(except the case that A is triazol in the formula(1) ) and their medical uses are unknown together with the case that A is triazol.
The present invention relates to the foliowing(i) to (x i).
(i) Sulfonamide derivatives represented by the general formula(1)
[wherein R
1
, R
2
may be the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxy group, a cyano group, a C
1
to C
8
acyl group, an optionally substituted phenoxy group, or an optionally substituted amino group;
R
3
, R
4
may be the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxy group, a group as shown by the general formula(2) described below:
—(CH
2
)
n
—CO—R
7
  (2)
(wherein R
7
represents a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, or an optionally substituted amino group, and n means an integer of 1-5), a group as shown by the general formula(3) described below:
—(CH
2
)
n
—B  (3)
(wherein B represents an imidazolyl group, a triazolyl group, a tetrazolyl group, or an optionally substituted amino group, and n means any integer of 1-5), a group as shown by the general formula(4) described below:
(wherein R
8
represents a lower alkyl group, a C
1
to C
5
alkyl group substituted by 1 or 2 hydroxy group(s), a C
1
to C
5
alkyl group substituted by a C
1
to C
5
alkoxycarbonyl group, a C
1
to C
5
acyl group, or a pyridyl group; R
9
represents a lower alkyl group or a hydroxy group; a and n means any integer of 0-3 and 0-6 respectively), a group as shown by the general formula(5) described below:
(wherein R
9
represents a lower alkyl group or a hydroxy group; b and n means any integer of 0-3 and 0-6 respectively), a group as shown by the general formula(6) described below:
(wherein R
9
represents a lower alkyl group or a hydroxy group; c and n means any integer of 0-3 and 0-6 respectively; Q represents an oxygen atom, a sulfur atom, or a group as shown by the general formula(7) described below:
(wherein d means 1 or 2) ), a group as shown by the general formula(8) described below:
—(CH
2
)
n
—N R
10
R
11
  (8)
(wherein R
10
, R
11
may be the same or different and each independently represents a hydrogen atom, a lower alkyl group or an optionally substituted amino lower alkyl group; n means any integer of 0-6), a group as shown by the general formula(9) described below:
—(CH
2
)
n
—S(O)
e
—R
12
  (9)
(wherein R
12
represents a hydrogen atom, a lower alkyl group or an aryl group, an aralkyl group or an optionally substituted amino group; e and n means any integer of 0-3 and 0-6 respectively) or a group as shown by the general formula(10) described below:
—(CH
2
)
n
—OR
13
  (10)
(wherein R
13
represents a hydrogen atom, a lower alkyl group or an acyl group, a phosphate group or an optionally substituted aminoalkyl group; and n means any integer of 1-6),
R
5
, R
6
may be the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, an acyl group, or an optionally substituted amino group; A represents any group of (1) an optionally substituted 5-membered heterocyclic group (except triazol) whose ring members include at least 1 nitrogen atom and may include any atom(s) selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, (2) an optionally substituted alicyclic group, and (3) an alicyclic group whose ring members include at least 1 nitrogen atom and may include any atom(s) selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom], and the pharmaceutically acceptable salts thereof.
(ii) Sulfonamide derivatives as defined in (i), wherein R
1
is a lower alkoxy group, and R
2
, R
3
, R
4
, R
5
, and R
6
may be the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, or an optionally substituted amino group, and the pharmaceutically acceptable salts thereof.
(iii) Sulfonamide derivatives as defined in (i), wherein R
1
is a lower alkoxy group, and R
2
R
3
, R
4
R
5
and R
6
may be the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, or an optionally substituted amino group, and A represents an optional

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