Benzenesulfonamide compounds

Details Benzenesulfonamide compounds Benzenesulfonamide compounds

1998-05-14

2001-05-22

Barts, Samuel (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S538000, C514S562000, C514S618000, C560S012000, C562S427000, C562S430000, C564S090000

Reexamination Certificate

active

06235777

ABSTRACT:

SUMMARY
The present invention relates to the benzenesulfonamide compounds. More detailed, the present invention relates to
(1) the compounds of the formula (I):
 wherein, all symbols are the same meaning as defined hereinafter,
(2) the process for the preparation of them and
(3) Prostaglandin E
2
receptor antagonists which comprise them as an active ingredient.
BACKGROUND
Prostaglandin E
2
(abbreviated as PGE
2
) has been known as metabolite in the arachidonate cascade. It has been known that PGE
2
possesses cyto-protective activity, uterine contraction, induce of pain, promotion of digestive peristalsis, awakening effect, suppression of gastric acid secretion or reduction of blood pressure and diuretic activity etc.
In the recent study, it was found that PGE
2
receptor was divided into some subtypes which possess different physical role from each other. At present, four receptor subtypes are known and they are called EP1, EP2, EP3 and EP4 (Negishi M. et al, J. Lipid Mediators Cell Signalling 12, 379-391 (1995)).
PGE
2
possesses a variety of physiological activities, so the undesired action other than the aimed one is shown as side effect. The research for the role of each receptor subtype and the investigation of the compound which only shows the effect on the specific subtype have been carried out to overcome such a problem.
In these subtypes, it has been known that EP1 subtype relates to induce of pain, fever and diuresis (Br. J. Pharmacol. 1994, 112, 735-40; European J. Pharmacol. 152 (1988) 273-279; Gen Pharmacol. September 1992, 23(5) p805-809). Therefore, to antagonize against this receptor is considered to be useful as analgesics, as antipyretic agent and as treating agent for pollakiuria.
The present inventors et. al. have studied to find the compound which can bind to EP1 receptor selectively, have found that the benzenesulfonamide compounds of the formula (I) can bind to EP1 receptor selectively and strongly and scarcely bind to other receptor subtypes, and then have achieved the present invention.
RELATED ARTS
As for the compound having a similar structure of the present invention compound of the formula (I), the following related arts have been known.
In the specification of Japanese Patent Application Kokai Hei 6-279395 (U.S. Pat. No. 5,663,417 or European Patent Publication No. 608,847), it was disclosed that the sulfonamide compound possessing carbocyclic ring of the formula (A)
wherein, the symbol
is (i) the group of the formula
or (ii) the group of the formula
R
100
is C4-7 alkylene or C4-7 alkenylene,
R
200
is hydroxy, C1~20 alkoxy or NR
230
R
240
in which each R
230
and R
240
is, independently, hydrogen, C1~4 alkyl or NR
230
R
240
is amino acid residue,
R
300
is single bond or C1~4 alkylene,
R
400
is hydrogen or C1~4 alkyl,
each R
500
and R
900
is, independently,
(i)
 wherein, R
600
is hydrogen, C1~4 alkyl, C1~4 alkoxy, hydroxy, halogen, trifluoromethyl or nitro, and nn is 1, 2 or 3,
(ii)
 wherein, R
610
is hydrogen, C1~4 alkyl, C1~4 alkoxy, hydroxy, halogen, trifluoromethyl or nitro, and mm is 1, 2 or 3,
(iii)
 wherein, R
620
is hydrogen, C1~4 alkyl, C1~4 alkoxy, hydroxy, halogen, trifluoromethyl or nitro, and kk is 1, 2 or 3,
(iv) C1~7 alkyl or
(v) hydrogen,
cyclodextrin clathrate thereof and non-toxic salt thereof, and
the compound of the formula (B)
wherein, R
1
is i) COOR
11
, or ii) CONR
13
R
14
in which R
11
is hydrogen, C1~20 alkyl, and each R
13
and R
14
is hydrogen, C1~4 alkyl, or NR
13
R
14
is amino acid residue,
and the symbol
wherein, the symbol
is the group of the formula
Ba is i)—CH
2
—CH
2
—(CH
2
)
m
— or
ii) cis-CH═CH—(CH
2
)
m
—
in which m is 1~6,
R
2a
is single bond or C1~4 alkylene,
R
3a
is benzene, naphthalene or C4-7 cycloalkyl unsubstituted or substituted by 1 to 3 of C1~4 alkyl, C1~4 alkoxy, hydroxy, cyano, halogen, trifluoromethyl or nitro, or R
2a
and R
3a
together forms C1~12 alkyl,
the symbol
 is the group of the formula
Xb is i) single bond, ii) C1~4 alkylene or iii) C2~4 alkenylene, with the proviso that group of -&agr;CH═CH—CH
2
&bgr;- and -&agr;CH
2
—CH═CH—CH
2
&bgr;- is excluded,
R
2b
is hydrogen, C1~4 alkyl, C1~4 alkoxy, hydroxy, cyano, halogen, trifluoromethyl or nitro,
configuration of C5-C6 double bond in the formula (Ab) is cis,
the symbol
 is the group of the formula
Lc is C1~4 alkylene,
R
2c
is hydrogen, C1~4 alkyl, C1~4 alkoxy, hydroxy, cyano, halogen, trifluoromethyl or nitro, and
the configuration of C5-C6 bond in the formula (Ac) is cis or trans,
cyclodextrin clathrate thereof and non-toxic salt thereof are useful for the prevention and/or treatment of abortifacient, pain, diarrhea or sleeping disorder as PGE
2
receptor antagonist or for the prevention and/or treatment of constipation, ulcer, gastritis and hypertension, or induction of labor as PGE
2
agonist.
On the other hand, there are the following two patent applications relate to similar structure compound showing the different activity.
That is to say, in Japanese patent application Kokai Hei 2-180862 (U.S. Pat. No. 5,168,101 or European Patent Publication No. 312,906) and Japanese patent application Kokai Sho 63-139161 (U.S. Pat. No. 4,861,913 or European Patent Publication No. 226,346), it was disclosed that the compounds having a similar structure of the present invention compounds showed Thromboxane A2 antagonistic activity.
DISCLOSURE OF THE INVENTION
The present invention relates to
(1) the benzenesulfonamide compounds of the formula (I)
 wherein, the formula
is the group of the formula
R
1
is hydroxy, C1~4 alkoxy or the group of the formula
NR
6
R
7
 in which each R
6
and R
7
is, independently, hydrogen or C1~4 alkyl,
R
2
is hydrogen or C1~4 alkyl,
R
3
and R
4
are C1~4 alkyl, halogen or trifluoromethyl,
R
5
is hydrogen, C1~4 alkyl, halogen or trifluoromethyl,
Y is cis-vinylene or trans-vinylene, and
 the symbol
is single bond or double bond,
non-toxic salt thereof or cyclodextrin clathrate thereof,
(2) the process for preparation of them and
(3) an antagonist of EP1 receptor which is a PGE
2
receptor subtype comprising them as an active ingredient.
In the formula (I), C1~4 alkyl represented by R
2
to R
7
means methyl, ethyl, propyl, butyl and isomer thereof.
In the formula (I), C1~4 alkoxy represented by R
1
means methoxy, ethoxy, propoxy, butoxy and isomer thereof.
In the formula (I), halogen represented by R
3
to R
5
means fluorine, chlorine, bromine and iodine.
Unless otherwise specified, in the present invention, the symbol
indicates that the substituent attached thereto is in front of the sheet and the symbol
indicates that the substituent attached thereto is behind the sheet as clear for the skilled person in the art.
Unless otherwise specified, all isomers are included in the present invention. For example, alkyl includes straight-chain or branched-chain ones. Isomers generated by asymmetric carbon(s) e.g. branched alkyl are also included in the present invention.
In the present invention compounds of the formula (I), the compounds described in the Examples, 5-cis type compounds of the following Tables, the corresponding ester and/or 5-trans type compounds and the corresponding amide and/or 5-trans type compounds are preferable. These ester and amide compounds are preferable as prodrug of the corresponding carboxylic acid compounds.
In the present invention compounds of the formula (I), the compounds of the formula (I-1)
wherein, R
1a
is hydroxy or C1~4 alkoxy, and the other symbols are the same meaning as defined hereinbefore are also preferable.
Salts
The compounds of the present invention of the general formula (I) may be converted into the corresponding salts by known methods. Non-toxic and water-soluble salts are preferable. Suitable salts, for example, are as follows: salts of alkaline metals (potassium, sodium etc.), salts of alkaline earth metals (calcium, magnesium etc.), ammonium salts, salts of pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, cycl

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