Benzenesulfonamide derivatives

TECHNICAL FIELD
The present invention relates to a benzenesulfonamide derivative or a pharmacologically acceptable salt thereof exhibiting excellent activity as a drug.
BACKGROUND ART
Phospholipase A is an enzyme catalyzing the hydrolysis of the acyl linkage of glycerophospholipid and includes phospholipase A.sub.1 catalyzing the hydrolysis of 1-ester linkage of glycerophospholipid and phospholipase A.sub.2 catalyzing that of 2-ester linkage thereof. Although both of the phospholipases are widely distributed in the biological world, they have recently been noted from the standpoint of their connection to various diseases.
For example, in ischemic diseases such as cardiac infarction, it is believed that phospholipase is activated to disintegrate membrane phospholipid, giving an increased infarct size. Furthermore, studies have been made on the connection of the phospholipase to other various troubles.
Under these circumstances, various phospholipase A.sub.2 inhibitors have been proposed from the standpoint that the inhibition of phospholipase, particularly phospholipase A.sub.2 (PLA.sub.2) is effective in the prevention and treatment of various diseases (see Japanese Patent Laid-Open Nos. 255,749/1985, 175,466/1987, 2,968/1988 and 258,854/1988).
The inventors of the present invention have eagerly studied for many years on substances which can inhibit phospholipase A.sub.2 to find out that a benzenesulfonamide derivative or a pharmacologically acceptable salt thereof which will be described below exhibits a high inhibitory activity against phospholipase A2 and therefore is useful in the prevention and treatment of various diseases, for example, ischemic diseases such as cardiac infarction. The present invention has been accomplished on the basis of this finding.
DISCLOSURE OF INVENTION
The compound of the present invention is a sulfonamide derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof: ##STR2## wherein a plurality of R.sup.1 groups each independently stand for a hydrogen atom, a cyano, nitro or hydroxyl group, a halogen atom, a lower alkoxy group, an acyloxy group, a group represented by the formula: --SO.sub.2 --R.sup.8 (wherein R.sup.8 stands for a lower alkyl group), a heteroaryl or glycyloxy group or a group represented by the formula: ##STR3## (wherein p is an integer of 1 to 3), and n is an integer of 1 to 4;
R.sup.2 stands for a hydrogen atom or a pyridyl group;
R.sup.3 stands for a hydrogen atom or a lower alkyl, cyano or pyridyl group;
R.sup.4 stands for a hydrogen atom or a lower alkyl group;
R.sup.5 and R.sup.6 may be the same or different from each other and each stand for a hydrogen atom, a lower alkyl group, a group represented by the formula: --(CH.sub.2).sub.q --A [wherein q is an integer of 1 to 4; and A stands for a hydroxyl group, a group represented by the formula: ##STR4## (wherein R.sup.9 and R.sup.10 may be the same or different from each other and each stand for a hydrogen atom or a lower alkyl group), a group represented by the formula: ##STR5## (wherein R.sup.11 stands for a hydrogen atom or a lower alkyl group) or a group represented by the formula: ##STR6## wherein s is an integer of 2 to 5)], an unsubstituted or substituted cycloalkyl group, a bicycloalkyl, tricycloalkyl or azabicycloalkyl group or a group represented by the formula: ##STR7## (wherein g and h are each an integer of 1 to 4; and B stands for a lower alkyl group, a substituted or unsubstituted arylalkyl group or a substituted or unsubstituted pyridylalkyl group), or alternatively R.sup.5 and R.sup.6 may be combined together to form a 6- or 7-membered ring which may contain a nitrogen or oxygen atom in addition to the nitrogen atom to which R.sup.5 and R.sup.6 are bonded, and said 6- or 7-membered ring may be substituted with a lower alkyl, arylalkyl, cycloalkylalkyl or heteroarylalkyl group;
a plurality of R.sup.7 groups each independently stand for a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom; and r is an integer of 1 or 2, provided that when r is 2, the two R.sup.7 groups may form a ring together with two adjacent carbon atoms constituting the benzene ring; and
m is an integer of 1 or 2.
In the above definition of the compound (I) according to the present invention, the lower alkyl group defined with respect to R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.11 and B is a straight-chain or branched alkyl group having 1 to 6 carbon atoms and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl(amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl groups. Among these groups, methyl, ethyl, propyl and isopropyl groups are desirable, among which methyl group is most desirable.
The lower alkoxy group defined with respect to R.sup.1 and R.sup.7 is one derived from the above-mentioned lower alkyl group having 1 to 6 carbon atoms and preferable examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy groups.
The halogen atom defined with respect to R.sup.1 and R.sup.7 is chlorine, bromine, iodine or fluorine.
The acyloxy group defined with respect to R.sup.1 is a group wherein an oxygen atom is bonded to an acyl group which is a residue of an organic acid such as aliphatic saturated or unsaturated carboxylic acid or carbocyclic or heterocyclic carboxylic acid, and particular examples of the acyl group include lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutylryl, valeryl, isovaleryl and pivaloyl groups; aroyl groups such as benzoyl, toluoyl and naphthoyl groups; and heteroaroyl groups such as furoyl, nicotinoyl and isonicotinoyl groups.
Among the groups represented by the formula: --SO.sub.2 --R.sup.8 in the definition of R.sup.1, methylsulfonyl group which corresponds to a group represented by the formula wherein R.sup.8 is a methyl group is most desirable.
The heteroaryl group defined with respect to R.sup.1 is a group derived from a heterocycle containing a nitrogen, oxygen or sulfur atom. Particular examples thereof include pyridyl, furyl and imidazolyl groups, among which imidazolyl group is most desirable.
Among the groups represented by the formula: ##STR8## (wherein s is an integer of 2 to 5) in the definition of R.sup.5 and R.sup.6, a group represented thereby wherein s is 4 or 5 is most desirable.
That is, a group represented by the above formula wherein the group represented by the formula: ##STR9## is one represented by the formula: ##STR10## is most desirable.
The unsubstituted cycloalkyl group defined with respect to R.sup.5 and R.sup.6 includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and cyclododecyl groups.
The substituted cycloalkyl group is a cycloalkyl group as described above which is either substituted with a lower alkyl group such as a methyl group or a halogen atom or condensed with an aromatic ring such as a benzene ring or a heterocyclic ring such as a pyridine ring at adjacent carbon atoms constituting the cyclcoalkyl group to form a condensed ring group represented by the formula: ##STR11##
The bicycloalkyl or tricycloalkyl group is an aliphatic saturated hydrocarbon group which is composed only of two or three rings with at least two carbon atoms being jointly owned by the rings.
Representative examples of the bicycloalkyl group include ##STR12##
The tricycloalkyl group is, for example, an adamantyl group.
The azabicycloalkyl group is a bicycloalkyl group described above in which one of the carbon atoms constituting the bicycloalkyl group is replaced by a nitrogen atom. Examples thereof include ##STR13##
In the formula: ##STR14## in the definition of R.sup.5 and R.sup.6, g and h are each an integer of 1 to 4. Examples of the group represented by the formula include ##STR15##
The substituted or unsubstituted arylalkyl group defined with respect to B is one derived from an aryl group (such as a phenyl or naphthyl group) which may be substituted with a lower alkyl group such as a methyl or ethyl group, a halogen atom or a lower alkoxy group such as a methoxy group and examples thereof include benzyl and phenethyl groups. Further, the substituted or unsubstituted pyridylalkyl group defined with respect thereto is one derived from a pyridyl group which may be substituted with a lower alkyl group such as a methyl or ethyl group, a halogen atom or a lower alkoxy group such as a methoxy group. Preferable examples of the group represented by the above formula include ##STR16##
Preferable examples of the 6- or 7-membered ring formed by the groups R.sup.5 and R.sup.6 which may contain a nitrogen or oxygen atom in addition to the nitrogen atom to which the groups are bonded are as follows: ##STR17##
These 6- or 7-membered rings may be each substituted with a B group such as a lower alkyl, arylalkyl, cycloalkylalkyl or heteroarylalkyl group. The arylalkyl, cycloalkylalkyl and heteroarylalkyl groups are each the same as that defined above.
Particular examples thereof are as follows: ##STR18##
Among the groups defined with respect to R.sup.7, a hydrogen atom is most desirable, i.e., the benzene ring is most desirably an unsubstituted one. When r is 2, the two R.sup.7 groups may form a ring together with adjacent two carbon atoms constituting the benzene ring. Particular examples of such a ring are as follows: ##STR19##
In the general formula (I), the groups represented by the formula: (R.sup.1).sub.n each independently stand for a hydrogen atom, a cyano, nitro or hydroxyl group, a halogen atom, a lower alkoxy group, an acyloxy group, a group represented by the formula: --SO.sub.2 --R.sup.8 (wherein R.sup.8 stands for a lower alkyl group), a heteroaryl group a glycyloxy group or a group represented by the formula ##STR20## (wherein p is an integer of 1 to 3) and n is an integer of 1 to 4. The term "each independently" used in this description means that when n is an integer of 2 to 4, the substituents on the benzene ring may be either the same or different from each other.
In other words, the general formula (I) can be replaced by the following formula (I'): ##STR21## wherein R.sup.2, R.sup.3, m, R.sup.4, R.sup.7, R.sup.5 and R.sup.6 are each as defined above; and R.sup.a, R.sup.b, R.sup.c and R.sup.d may be the same or different from each other and each stand for a hydrogen atom, a cyano, nitro or hydroxyl group, a halogen atom, a lower alkoxy group, an acyloxy group, a group represented by the formula: --SO.sub.2 --R.sup.8 (wherein R.sup.8 stands for a lower alkyl roup), a heteroaryl group, a glycyloxy group or a group represented by the formula: ##STR22## (wherein p is an integer of 1 to 3).
That is, the benzenesulfonamide derivative according to the present invention may be mono-, di-, tri- or tetra-substituted with the groups described above, the groups being either the same or different from each other. Among these substituted derivatives, preferred ones are those wherein the benzene ring is monosubstituted with a lower alkylsulfonyl group such as a methylsulfonyl group or an imidazolyl, cyano or nitro group at the p-position (i.e., 4-position) or is di-substituted with two members selected from among halogens and a hydroxyl group, for example, 3-fluoro-4-hydroxy and 3,4-dihydroxy derivatives.
The pharmacologically acceptable salt according to the present invention may be any conventional nontoxic one and examples thereof include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate; organic acid salts such as acetate, maleate, tartrate, methanesulfonate, benzenesulfonate and toluenesulfonate; and amino acid salts such as argininate, aspartate and glutamate.
Further, the derivative according to the present invention may form a metal salt such as sodium, potassium or calcium salt depending upon the substituents.
Although the compound of the present invention may be present as a geometrical isomer, cis or trans, because it has a double bond as shown by its structural formula, it is needless to say that the present invention includes both of the isomers.
In order to represent more precisely that the present invention include both of the cis and trans isomers, the general formula (I) specifying the compound of the present invention can be replaced by the following formula: ##STR23## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, n and m are each as defined above.
Representative processes for the preparation of the compound according to the present invention will now be described.
PREPARATION PROCESS A ##STR24## (in the above reaction scheme, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, m and n are each as defined above; Ac stands for an acetyl group; and X stands for a halogen atom)
PREPARATION PROCESS B
A compound represented by the general formula (I) wherein at least one R.sup.1 group is an acetyloxy or methoxy group can be converted into another objective compound (XIV) by the following process: ##STR25## [wherein R.sup.e stands for an acetyloxy (OAc) group or an alkoxy group such as a methoxy group; and t and u are each an integer of 1 to 4 with the proviso that they satisfy the relationship: t+u.ltoreq.4.] ##STR26## (wherein R.sup.f O stands for an acyloxy or glycyloxy group)
PREPARATION PROCESS C
A compound represented by the general formula (I) wherein R.sup.6 is a group represented by the formula: ##STR27## (wherein g and h are each an integer of 1 to 4) can be prepared also by the following processes: ##STR28## (wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, B, g, h, m and n are each as defined above) ##STR29## (in the above reaction scheme, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.12, g, h, m and n are each as defined above)
PREPARATION PROCESS D
A compound represented by the general formula (I) wherein R.sup.5 and R.sup.6 form a 6- or 7-membered ring which may contain another nitrogen atom in addition to the nitrogen atom to which R.sup.5 and R.sup.6 are bonded and which may be substituted can be prepared also by, e.g., the processes which will be described below.
A case wherein the ##STR30## group is one represented by the formula: ##STR31## (wherein i and j are each an integer of 2 to 3; and B stands for a hydrogen atom or a substituent described above) will now be described. ##STR32## (in the above reaction scheme, R.sup.1, R.sup.2, R.sup.3, R.sup.4, B, i, j, m and n are each as defined above) ##STR33## (wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.12, i, j, m and n are each as defined above)
Step 1
In this step, a ketone or aldehyde (II) which is known in itself or can be prepared by a known process is converted into a cinnamic acid derivative (III) through Wittig reaction, aldol condensation or Knoevenagel reaction. When the conversion is conducted through Wittig reaction, a compound (II) is reacted with a Wittig reagent such as triethylphosphonoacetate, triethylphosphonocrotonate or triethylphosphonopropionate generally in an inert solvent such as dimethylformamide, ether, tetrahydrofuran, dioxane, benzene, toluene or dimethyl sulfoxide in the presence of a base such as potassium butoxide, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride or n-butyllithium at a temperature of -78.degree. to 150.degree. C. according to a conventional process to give a compound
The compound (III) can be prepared also through aldol condensation or Knoevenagel reaction according to a conventional process.
Step 2
In this step, the compound (III) prepared in Step 1 is converted into a carboxylic acid derivative (IV) through the hydrolysis of an ester linkage. For example, the hydrolysis is conducted in a dilute aqueous solution of an alkali or a mineral acid, preferably a mixture comprising a 0.5 to 3N aqueous solution of sodium hydroxide and ethanol at a ratio of 1:1 or in a 2 to 6N aqueous solution of hydrochloric acid at room temperature to refluxing temperature.
Step 3
In this step, the compound (IV) prepared in Step 2 is halogenated into an acid halide derivative (V). The halogenation is conducted by reacting the compound (IV) with oxalyl chloride, thionyl chloride, phosphorus trichloride or phosphorus tribromide in an inert solvent such as dichloromethane, chloroform, dichloroethane, benzene or toluene at room temperature to refluxing temperature according to a conventional process. When oxalyl chloride is used, it is preferable to use dimethylformamide as a catalyst.
In some cases, the compound (IV) may be converted into other reactive derivative, for example, acid azide, active ester with N-hydroxybenzotriazole or N-hydroxysuccinimide, symmetric acid anhydride or mixed acid anhydride with alkylcarbonic or p-toluenesulfonic acid. These reactive derivatives may be also used in Step 7.
Step 4
In this step, an acetanilide derivative (VI) which is known in itself or can been prepared by a known process is sulfochlorinated into a compound (VII). For example, the compound (VI) is reacted with excess chlorosulfonic acid in an inert solvent such as chloroform, dichloroethane, trichloroethane or nitrobenzene or in the absence of any solvent at room temperature to 100.degree. C. to give a compound (VII).
Step 5
In this step, the sulfonyl chloride derivative (VII) prepared in Step 4 is reacted with an amine (VIII) which is known in itself or can be prepared by a known process to prepare a sulfonamide derivative (IX). For example, the objective compound (IX) can be prepared by reacting the derivative (VII) with an amine (VIII) in a solvent such as water, methanol, ethanol, propanol, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, benzene or toluene in the presence of a base such as sodium acetate, sodium hydrogencarbonate, sodium carbonate, triethylamine or pyridine at a temperature of 0.degree. C. to room temperature.
Step 6
In this step, the sulfonamide derivative (IX) prepared in Step 5 is converted into an aniline derivative (X) through the hydrolysis of the N-acyl group. The hydrolysis is conducted in a dilute aqueous solution of an alkali or a mineral acid. Preferably, it is conducted in a 2 to 6N aqueous solution of hydrochloric acid or a 0.5 Lo 3N aqueous solution of sodium hydroxide at 50.degree. C. to refluxing temperature.
Step 7
In this step, an amide derivative (XI) is prepared by the reaction of the acid halide or other reactive derivative (V) prepared in Step 3 with the aniline derivative (X) prepared in Step 6.
In the above reaction, the compounds (V) and (X) are used in equimolar amounts or either of them is used in slight excess. The reaction is conducted in an inorganic solvent inert to the reaction, for example pyridine, tetrahydrofuran, dioxane, ether, benzene, toluene, xylene, dichloromethane or chloroform. In some cases, the addition of a base such as diisopropylamine, triethylamine, pyridine, picoline, lutidine, N,N-dimethylaniline, 4-dimethyaminopyridine, potassium carbonate or sodium hydroxide is effective in making the reaction proceed smoothly. Although the reaction temperature varies depending upon the kind of the reactive derivative and therefore is not particularly limited, the reaction is generally conducted at a temperature of -20.degree. C. to refluxing temperature to give an objective compound (XI).
Step 8
Among the compounds (XI) prepared in Step 7, a compound (XII) having an acetoxy group as R.sup.1 is converted into a phenol derivative (XIII) in this step through the hydrolysis of the acetyl group.
The hydrolysis is conducted according to a conventional process, for example, either in a solvent such as water, methanol, ethanol, propanol, acetonitrile, tetrahydrofuran or dioxane in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or sodium hydrogencarbonate, or in a 0.5 to 6N solution of a mineral acid, at a temperature of 0.degree. C. to refluxing temperature.
Step 9
Among the compounds (XI) prepared in Step 7, a compound (XII) having an alkoxy group such as a methoxy group as R.sup.1 is converted into a phenol derivative (XIII) through the dealkylation of the alkoxy group in this step.
The dealkylation is conducted according to a conventional process, for example, in an inert solvent such as dichloromethane, chloroform, dichloroethane or nitrobenzene in the presence of a dealkylating agent, for example, boron halide such as boron tribromide, boron trichloride or boron triiodide or aluminum halide such as aluminum trichloride or aluminum tribromide at 0.degree. C. to refluxing temperature.
Step 10
In this step, the phenol derivative (XIII) prepared in Step 8 or 9 is acylated into a compound (XIV). The acylation is preferably conducted by reacting the phenol derivative (XIII) with an amino acid such as glycine, alanine or valine or a carboxylic acid such as nicotinic acid in an inert solvent such as acetonitrile, tetrahydrofuran, dioxane, ether, benzene, toluene, dichloromethane, chloroform, dimethylformamide or dimethyl sulfoxide in the presence of a condensing agent such as dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, ethyl chloroformate, diethyl azodicarboxylate or dipyridyl disulfide at a temperature of 0.degree. C. to refluxing temperature.
Step 11
In this step, a sulfonamide derivative (XVI) is prepared by reacting the sulfonyl chloride derivative (VII) prepared in Step 4 with an amine derivative (XV) wherein R.sup.12 is a nitrogen-protective group such as a benzyl, methoxybenzyl, t-butoxycarbonyl or benzyloxycarbonyl group which is known in itself or can be prepared by a known process. This reaction may be conducted in a similar manner to that described in Step 5.
Step 12
In this step, the compound (XVI) prepared in Step 11 is freed from the N-protective group to give an amine derivative (XVII).
When R.sup.12 is a benzyl, methoxybenzyl or benzyloxycarbonyl group, it can be removed according to a conventional process. For example, it can be removed by hydrogenating the compound (XVI) in a solvent such as water, methanol, ethanol, propanol, acetonitrile, dioxane, tetrahydrofuran, ether, ethyl acetate or dimethylformamide in the presence of a catalyst such as palladium/carbon, palladium black, platinum oxide or Raney nickel at room temperature to refluxing temperature. In some cases, the coexistence of an acid such as acetic or hydrochloric acid is preferable. When R.sup.12 is a t-butoxycarbonyl group, it can be removed by treating the compound (XVI) in a 1 to 3N solution of hydrochloric acid in a solvent such as water, methanol or ethanol at a temperature of 0.degree. C. to room temperature or by reacting the compound (XVI) with a fluoride reagent such as KF or tetraalkylammonium fluoride in a solvent such as methanol, ethanol, acetonitrile, tetrahydrofuran, dioxane or dichloromethane at a temperature of 0.degree. C. to room temperature, though it can be removed also by a conventional process as described above.
Step 13
In this step, the amine derivative (XVII) prepared in Step 12 is converted into a compound (XX) through N-alkylation. The alkylation is conducted by a conventional process. For example, when the alkylating agent is a compound (XVIII), the compound (XX) can be prepared by reacting the compound (XVII) with the compound (XVIII) in a solvent, for example, dimethylformamide, dimethyl sulfoxide, a lower alkyl alcohol such as methanol, ethanol or propanol, acetone, benzene, chloroform or dichloromethane in the presence of a base at room temperature to refluxing temperature. The base includes potassium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium methoxide, sodium ethoxide and sodium hydride. In some cases, the additional use of lithium bromide or potassium iodide gives better results.
When the alkylating agent is a compound (XIX), the objective compound (XX) can be prepared by reacting the compound (XIX) with the amine derivative (XVII) in a polar solvent such as water, methanol, ethanol, dioxane tetrahydrofuran or acetonitrile or a mixture thereof with water in the presence of a small amount of hydrochloric acid, acetic acid or sodium acetate at a temperature of 50.degree. C. to refluxing temperature.
When B is a substituted or unsubstituted pyridylalkyl group, the compound (XX) can be prepared by the condensation of the compound (XVII) with an alkylating agent represented by the formula (XVIII): B--Z. Particularly, when B is a substituted or unsubstituted pyridylethyl group (i.e., when the alkyl group in the above definition is an ethyl group), the compound (XX) can be prepared also by the addition reaction of the compound (XVII) with a compound represented by the formula (XIX) E--CH.dbd.CH.sub.2.
When E is a pyridyl group which is unsubstituted or substituted with a lower alkyl group, the formula (XIX) can be replaced by the following formula: ##STR34##
Step 14
In this step, the compound (XX) prepared in Step 13 is converted into an aniline derivative (XXI) through the hydrolysis of the N-acyl group. The hydrolysis can be conducted in a similar manner to that of Step 6.
Step 15
In this step, an amide derivative (XXII) is prepared by reacting the aniline derivative (XXI) prepared in Step 14 with the acid halide or other reactive derivative (V) prepared in Step 3. This reaction can be conducted in a similar manner to that of Step 7.
Steps 16 to 24
These steps can be each conducted in a similar manner to that described in one of the above-mentioned steps. The steps corresponding to them respectively are as follows:
(Step 16.fwdarw.Step 12)
(Step 17.fwdarw.Step 13)
(Step 18.fwdarw.Step 5)
(Step 19.fwdarw.Step 12)
(Step 20.fwdarw.Step 13)
(Step 21.fwdarw.Step 6)
(Step 22.fwdarw.Step 7)
(Step 23.fwdarw.Step 12)
(Step 24.fwdarw.Step 13)
Representative compounds of the present invention will now be described in order to facilitate the understanding of the present invention, though it is needless to say that the present invention is not limited by them. They are all represented in free forms.
1. N-[1-(2-phenylethyl)-4-piperidyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,
2. N-(1-benzyl-4-piperidyl)-4-{N-methyl-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,
3. N-methyl-N-[2-(6-methyl-2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,
4. (.+-.)N-[1-(2-pyridylmethyl)-3-hexamethyleneimino]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,
5. (E)-N-methyl-N-{4-[4-(2-phenylethyl)homopiperazinyl]sulfonylphenyl}-3-(4-methylsulfonylphenyl)-2-propenamide,
6. (.+-.)-[1-benzyl-3-hexamethyleneimino]-4-{N-methyl-N-[(E)-N-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,
7. N-[1-(2-methylpiopyl)-4-piperidyl)-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,
8. N-[1-methyl-4-piperidyl)-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,
9. N-(3-quinuclidyl)-4-{N-methyl-N-[(E)-3 -(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,
10. N-[3-(N,N-dimethylamino)propyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,
11. N-pycloheptyl-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,
12. N-[2-(6-methyl-2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4 -methylsulfonylphenyl)-2 -propenoyl]amino}benzenesulfonamide,
13. N-[3-(4-pyridyl)propyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,
14. N-methyl-N-[2-(2-pyridyl)ethyl]-4 -{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,
15. N-[2-(2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4 -methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,
16. N-(2-pyridylmethyl)-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzensulfonamide,
17. (E)-N-methyl-N-[4-(4-cyclohexylmethyl-1-homopiperazinyl)sulfonylphenyl]-3-(4-methylsulfonylphenyl)- 2-propenamide,
18. (E)-N-methyl-N-[4-(4-benzyl-1-homopiperazinyl)sulfonylphenyl]-3-(4 -methylsulfonylphenyl)-2-propenamide,
19. (E)-N-methyl-N-{4-[4-(2-phenylethyl)piperazinyl]sulfonylphenyl}-3-(4-methylsulfonylphenyl)-2-propenamide,
20. (E)-N-methyl-N-{4-[4-(3-pyridylmethyl)piperazinyl]sulfonylphenyl}-3-(4-methylsulfonylphenyl)-2-propenapide,
21. (E)-N-methyl-N-[4-(4-benzylpiperazinyl)sulfonylphenyl]-3-(4-methylsulfonylphenyl)-2-propenamide,
22. N-cycloheptyl-4-{N-methyl-N-[(E)-3-(4-cyanophenyl)-2-propenoyl]amino}benzenesulfonamide,
23. N-(1-benzyl-4-piperidyl)-4-{N-methyl-N-[(E)-3-(4-cyanophenyl)-2-propenoyl]amino}benzenesulfonamide,
24. N-(2-indanyl)-4-{N-methyl-N-[(E)-3-[4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide,
25. N-[1-(1,2,3,4-tetrahydro)naphthyl]-4-{N-methyl-N-[(E)-3-(4-(1-imidazoyl)phenyl]-2-propenoyl]amino}benzenesulfonamide,
26. N-cycloheptyl-4-{N-methyl-N-[(E)-3-[4-(1 -imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide,
27. N-cyclooctyl-4-{N-methyl-N-[(E)-3-[4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide,
28. (.+-.)-N-(exo-2-norbornyl)-4-{N-methyl-N-[(E)-3-[4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide,
29. (.+-.)-N-(endo-2-norbornyl)-4-{N-methyl-N-[(E)-3-[4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide,
30. N-(2-indanyl)-4-{N-methyl-N-[(E)-3-[4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide,
31. N-cyclohexyl-N-methyl-4-{N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide,
32. N-cyclohexyl-4-{N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide,
33. N-cyclohexyl-4-{N-methyl-N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide,
34. N-cyclohexyl-N-methyl-4-{N-methyl-N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide,
35. N-cycloheptyl-4-{N-methyl-N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide,
36. N-cycloheptyl-4-{N-methyl-N-[(2E, 4E)-5-(4-nitrophenyl)-2,4-pentadienoyl]amino}benzenesulfonamide,
37. N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(3,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
38. N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
39. 4-{(E)-1-[N-methyl-N-[4-(2-indanyl)aminosulfonylphenyl]amino]-3-propenoyl}phenoxyacetic acid,
40. N-cyclobutyl-4-{N-methyl-N-I (E)-3-(3-fluoro-4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
41. N-cycloheptyl-4-{N-methyl-N-[(2E, 4E)-5-(3,5-dibromo-4-hydroxyphenyl)-2,4-pentadienoyl]amino}benzenesulfonamide,
42. N-cycloheptyl-4-{N-methyl-N-[(E)-3-(4-fluorophenyl)-2-propenoyl]amino}benzenesulfonamide,
43. N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
44. N-(2-indanyl)-4-{N-methyl-N-[(2E, 4E)-5-(3,4-dihydroxyphenyl)-2,4-pentadienoyl]amino}benzenesulfonamide,
45. N-[2-(1,2,3,4-tetrahydro)naphthyl]-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
46. N-[2-(1,2,3,4-tetrahydro)naphthyl]-4-{N-methyl-N-[(2E, 4E)-5-(3,4-hydroxyphenyl)-2,4-pentadienyl]amino}benzenesulfonamide,
47. N-cycloheptyl-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
48. N-cycloheptyl-4-{N-methyl-N-[(2E, 4E)-5-(3,4-dihydroxyphenyl)-2,4-pentadienoyl]amino}benzenesulfonamide,
49. N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(2-chloro-3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
50. N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(3-chloro-3,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
51. N-(2-indanyl)-4-{N-methyl-N-{(E)-3-(2-chloro-4,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
52. N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(3-bromo-4,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
53. N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(2-bromo-4,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
54. N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-methyl-2-propenoyl]amino}benzenesulfonamide,
55. N-cyclopentyl-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
56. N-cyclohexyl-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
57. N-(1-indanyl)-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
58. N-[2-(2-pyridyl)ethyl-4-{N-methyl-N-[3-(3,4 -dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
59. N-(2-thiazolyl)-4-{N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
60. N-[2-(4,6-dimethyl)pyrimidyl]-4-{N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
61. N-(2-(hydroxyethyl)-4-{N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
62. N-cyclohexyl-4-{N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
63. 4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
64. 4-{N-isopropyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
65. N-[2-(N,N-dimethylamino)ethyl]-4-(N-methyl-N-[(E)-3-(3.4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
66. N-methyl-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
67. N-isopropyl-4-{N-methyl-N-[(E)-3-(3,4 -dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
b 68. (E)-N-methyl-N-[4-(4-morpholinyl)sulfonylphenyl]-3-(4-methylsulfonylphenyl)-2-propenamide,
69. 4-{N-(E)-3-(3,4-dimethoxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
70. 4-{N-(Z)-3-(3,4-dimethoxyphenyl)-3-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide,
71. 4-{N-(E)-3-(3,4-dimethoxyphenyl)-3-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide,
72. 4-{N-(Z)-3-(3,4-dihydroxyphenyl)-3-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide,
73. 4-{N-(E)-3-(3,4-dihydroxyphenyl)-3-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide,
74. 4-{N-(Z)-3-(3,4-dihydroxyphenyl)-2-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide,
75. 4-{N-(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
76. N-[4-(1-piperidylmethyl) benzyl]-4-{N-methyl-N-(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,
77. N-[1-(2-(3,4-dimethoxyphenyl)ethyl]-4-piperidyl]-4-{N-methyl-N-(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,
78. N-[1-(2-(3-pyridyl)ethyl]-4-piperidyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl] amino}benzenesulfonamide,
79. N-[1-(2-(6-methyl-2-pyridyl)ethyl]-4-piperidyl-4-{N-methyl-N-(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,
80. N-[4-(1-pyrrolidylmethyl) benzyl]-4-{N-methyl-N-(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,
81. N-[8-(5,6,7,8-tetrahydro)quinolyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide,
82. N-cyclohexyl-4-{N-[(E)-3-(3-fluoro-4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
83. N-cyclohexyl-4-methyl-4-{N-[(E)-3-(3-fluoro-4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
84. N-cycloheptyl-4-{N-methyl-N-[(E)-3-(4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
85. N-cyclooctyl-4-{N-methyl-N-[(E)-3-(3-fluoro-4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
86. N-cycloheptyl-4-{N-[(E)-3-[4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide,
87. 4-{N-[(E)-3-(3-acetoxy-4-methoxyphenyl]-2-propenoyl]amino}benzenesulfonamide,
88. N-cycloheptyl-4-{N-[(E)-3-([3,4-dihydroxyphenyl] -2-methyl-2-propenoyl]amino}benzenesulfonamide,
89. N-cyclohexyl-4-{N-methyl-N-[(E)-3-([3,5-dihydroxyphenyl]-2-propenoyl]amino}benzenesulfonamide,
90. N-(2-indanyl)-4-{N-methyl-N-[(E)-3-[4-hydroxy-3-methoxyphenyl)-2-cyano-2-propenoyl]amino}benzenesulfonamide,
91. 4-{N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}-5,6,7,8-tetrahydro-1-naphthalenesulfonamide,
92. N-(2-indanyl)-4-{N-methyl-N-[(E)-3-[3,4-diglycyloxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
93. N-isopropyl-4-{N-methyl-N-[(E)-3-(2-chloro-3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
94. 4-{N-[(E)-3-(2-bromo-4,5-dihdyroxyphenyl)-2-propenoyl]amino}benzenesulfonamide,
95. N-(2-thiazolyl)-4-{N-[(Z)-3-(3,4-dimethoxyphenyl)-2-(3-pyridyl-2-propenoyl]amino}benzenesulfonamide,
96. 4-{N-[(Z)-3-(3,4-dimethoxyphenyl)-2-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide,
97. N-(thiazolyl)-4-{N-[(E)-3-(3,4-dimethoxyphenyl-2-propenoyl]amino}benzenesulfonamide,
98. 4-{N-[(E)-3-(4-hydroxy-3-methoxyphenyl)-2 -propenoyl]amino}benzenesulfonamide, and
99. N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(3,4-diacetoxyphenyl)-2-propenoyl]amino}benzenesulfonamide.
Pharmacological Experiment Examples with respect to representative compounds according to the present invention will now be described in order to illustrate the effects of the present invention in more detail.
PHARMACOLOGICAL EXPERIMENT EXAMPLES
A. Inhibitory activity against phospholipase A.sub.2 (PLA.sub.2) contained in the membrane fraction of rabbit heart or the supernatant fraction thereof
Method
1. Preparation of membrane fraction of rabbit heart and supernatant fraction thereof
An NZW male rabbit was anesthetized by the intravenous administration of pentobarbital sodium to take out its heart. This heart was washed with ice-cooled physiological saline to recover a ventricle, followed by the addition of ice-cooled 0.25 M sucrose/20 mM tris hydrochloride buffer (pH: 8.0) in an amount of 5 ml per g of the ventricle. The obtained mixture was mashed with a homogenizer in ice water for 30 minutes and centrifuged at 1,000 g for 10 min. The supernatant was further centrifuged at 105,000 g for 60 min. The centrifugation was conducted at 0.degree. to 4.degree. C. The obtained supernatant was used as such as the supernatant fraction for examination. The precipitate was suspended in the same buffer as that described above and used as the membrane fraction for examination. The protein concentrations of these fractions were each adjusted to 5 mg/ml as determined by Lowry method.
2. Determination of PLA.sub.2 -inhibitory activity
A 100 mM CaCl.sub.2 solution was added to the above membrane fraction in an amount of 100 .mu.l per 10 ml of the fraction, while a 100 mM solution of ethylene glycol bis(.beta.-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) was added to the above supernatant fraction in an amount of 500 .mu.l per 10 ml of the fraction. The obtained mixtures were each poured into test tubes in an amount of 0.2 ml per tube, followed by the addition of 2 .mu.l of a solution of a test compound in dimethyl sulfoxide (DMSO) into each of the tubes, while 2 .mu.l of DMSO was poured into a test tube for control. 5 .mu.l of an 8 mM ethanol solution of phosphatidylcholine (1-palmitoyl-2-[1-.sup.14 C]arachidonyl, 1.184 MBq/ml) was added to each of the test tubes. The test tubes of the membrane fraction were kept at 37.degree. C. for 30 minutes for incubation, while those of the supernatant fraction were kept at 37.degree. C. for 5 minutes for incubation. Each incubation was stopped by the addition of 1 ml of Dole reagent. The .sup.14 C-arachidonic acid was extracted with heptane and the heptane layer was passed through silica gel to remove the phosphatidylcholine contained therein by adsorption. The amount of .sup.14 C was determined with a liquid scintillation counter.
Mepacrine was selected as a comparative compound.
Results
The results are given in Table 1.
TABLE 1______________________________________ PLA.sub.2 -inhibitory activity IC.sub.30 (.mu.M)Compound membrane supernatant(Example No.) fraction fraction______________________________________ 2 4.48 40 3 2.4 nt 4 0.032 >100 5 0.007 49 6 0.056 >100 7 0.018 >100 8 0.029 >100 9 0.015 6114 0.016 >3015 0.081 6118 0.18 >10020 0.045 9221 0.055 >10022 0.050 >10025 0.16 6826 0.24 5929 0.45 9030 0.66 >10031 0.42 2938 0.12 2941 0.98 4643 3.49 6244 5.1 3948 1.7 3249 1.8 5650 1.05 3858 1.5 6465 16 nt72 41 nt77 20 >10079 0.03 >10081 0.044 >10086 0.62 4687 2.1 ntmepacrine >100 >100______________________________________
B. Influence on the cardiac infarct size of rat
Sixty-one male rats (weight: 220 to 300 g) were made to get myocardial ischemia by the ligation of the coronary artery. After 3 hours from the ligation, hearts were taken out of the rats and cut into round slices to obtain preparations. These preparations were stained with myoglobin. The area unstained therewith was regarded as a cardiac infarction nidus and the area ratio of the nidus to the left ventricle was determined by the image analysis and regarded as the cardiac infarct size.
The cardiac infarct size was reduced as compared with that of the control rat by 21% or 20% by the administration of the compound of Example 4 or 6 through the tail vein in a dose of 1 mg/kg before 15 minutes prior to the ligation of the coronary artery.
C. Toxicity test
A small amount of 1N HCl was added to each of the compounds of Examples 4, 6, 7, 8 and 15 to form aqueous solutions. These solutions were each intravenously administered to the groups of three male SD rats of 7 weeks of age in a dose of 50 mg/kg. All of the groups of rats were observed for 3 hours after the administration. No rat died.
It can be understood from the results of the above Pharmacological Experiment Examples that each of the compounds of the present invention has a remarkably high inhibitory activity against phospholipase A.sub.2 to arrest the course of a series of ischemic cell diseases which are thought to be caused by the activation of phospholipase A.sub.2, for example, cardiac infarction.
Particularly, the phospholipase A.sub.2 -inhibitory activity of each of the compounds according to the present invention is remarkably higher than that of mepacrine used as a comparative compound.
Accordingly, the compounds of the present invention are useful as a remedy or preventive for various diseases for which the phospholipase A.sub.2 -inhibitory action is efficacious.
Particularly, the compounds of the present invention are usable as a remedy for various heart diseases, an antithrombotic drug or the like.
More particularly, the compounds of the present invention are effective in the treatment and prevention of cardiac infarction; angina pectoris; coogestive cardiac insufficiency accompanied with edema, pulmonary congestion, hepatomegaly or the like; cerebrovascular diseases such as TIA (transient ischemic attack), cerebral infarction (thrombosis and embolism) or (brain edema, cerebrovascular spasm) cerebral arteriosclerosis; postoperative thrombosis and embolism and bloodstream disturbance attendant on the operation of the vessel or the extracorporeal circulation of blood; Buerger disease; and peripheral bloodstream disturbance due to the obliteration and stenosis of appendicular arteries, for example, arteriosclerosis obliterans, SLE or while finger disease, the prevention of relapse of these diseases and the improvement of prognosis thereof.
Further, the compounds of the present invention are efficacious for diseases caused by metabolism intermediates of the arachidonic acid liberated by the action of phospholipase A.sub.2, for example, thromboxanes such as thromboxane A.sub.2, prostaglandins or leukotrienes, while the diseases include inflammatory disease, rheumatoid arthritis and allergoses such as asthma and atopic dermatitis.
Particularly among these diseases, the compounds of the present invention are thought to be able to arrest the course of a series of ischemic cell diseases caused by the activation of phospholipase A.sub.2. The compounds of the present invention are highly valuable in this sense.
When the compounds of the present invention are used as drugs, they may be each administered orally or parenterally (as injection, suppository or external preparation). Although the dose thereof varies depending upon the symptom, age, sex, weight and sensitivity of a patient; the method, timing and interval of administration; the properties, dispensing and kind of preparation; and the kind of an active ingredient and is not particularly limited, the does thereof per adult a day is about 0.1 to 2,000 mg, desirably about 1 to 1,000 mg, more desirably about 5 to 500 mg, most desirably about 20 to 100 mg, which may be generally administered in 1 to 4 portions a day.
A solid preparation for oral administration according to the present invention is prepared by adding a filler and, if necessary, a binder, disintegrator, lubricant, color and/or corrigent to an active ingredient and shaping the obtained mixture into a tablet, coated tablet, granule, powder or capsule.
Examples of the filler include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide; those of the binder include polyvinyl alcohol, polyvinyl ether, ethylcellblose, methylcellulose, acacia, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin and pectin; those of the lubricant include magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oil; those of the color include those authorized as pharmaceutical additives; and those of the corrigent include cocoa powder, mentha, herb, aromatic powder, mentha oil, borncol and powdered cinnamon bark. Of course, the tablet and granule may be suitably coated with sugar, gelatin or the like, if necessary.
An injection according to the present invention is prepared by adding a pH modifier, buffer, suspending agent, solubilizing agent, stabilizer, tonicity agent and/or preservative to an active ingredient at need and converting the mixture into an injection for intravenous, subcutaneous or intramuscular administration, or administration into coronary arteries by a conventional process. If necessary, the injection may be freeze-dried according to a conventional method.
Examples of the suspending agent include methylcellulose, Polysorbate 80, hydroxyethylcellulose, acacia, tragacanth powder, carboxymethylcellulose sodium and polyoxyethylene sorbitan monolaurate.
Examples of the solubilizing agent include polyoxyethylene hardened castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, Macrogol and ethyl ester of castor oil fatty acid.
Further, examples of the stabilizer include sodium sulfite, sodium metasulfite and ether and those of the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.

EXAMPLE
Examples of the present invention will now be described below, though it is needless to say that the present invention is not limited to them. The preparation of the starting compounds for preparing the compounds of the present invention will be described in the following Preparative Examples preceding Examples.
PREPARATIVE EXAMPLE 1
4-(Methylthio)benzaldehyde dimethyl acetal ##STR35##
A suspension of K-10 (32 g) in trimethyl orthoformate (115 ml, 1.05 mol) was added to a solution of 4-(methylthio)benzaldehyde (31.0 g, 0.203 mol) in dichloromethane (300 ml) at 0.degree. C. The obtained mixture was stirred at room temperature for 20 minutes and filtered to remove the K-10. The filter cake was washed with dichloromethane. The filtrate and washings were together washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt, dried over magnesium sulfate and concentrated in a vacuum to give the title compound as a pale-yellow oil (39.0 g, 96%).
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 7.29 (4H, brs), 5.36 (1H, s), 3.26 (6H, s), 2.50 (3H, s).
PREPARATIVE EXAMPLE 2
4-(Methylsulfonyl)benzaldehyde dimethyl acetal ##STR36##
m-Chloroperbenzoic acid (115.0 g, 0.567 mol) was added to a suspension of the 4-(methylthio)benzaldehyde dimethyl acetal (50.0 g, 0.252 mol) prepared in Preparative Example 1 and sodium hydrogencarbonate (73.1 g) in dichloromethane (1.00 l) at 0.degree. to 10.degree. C. in portions (over a period of about one hour and 20 minutes). The obtained suspension was stirred at room temperature for 18 hours and poured into an aqueous solution (1 l) of sodium sulfite (100.0 g) under cooling to decompose excess peracid. The resulting solution was extracted with dichloromethane and the organic layer was washed with a saturated aqueous solution of common salt, dried over magnesium sulfate and concentrated in a vacuum. The obtained solid residue was recrystallized from hexane/isopropyl ether/ethyl acetate to give the title compound as a colorless crystal (53.9 g, yield: 93%).
m.p. (.degree.C.): 100 to 110
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 7.92 (2H, d, J=7.9), 7.61 (2H, d, J=7.9), 5.50 (1H, s), 3.28 (6H, s), 3.24 (3H, s).
PREPARATIVE EXAMPLE 3
4-Methylsulfonyl)benzaidehyde ##STR37##
1N Hydrochloric acid (200 ml) was added to a solution of the 4-(methylsulfonyl)benzaldehyde dimethyl acetal (39.4 g, 0.171 mol) prepared in Preparative Example 2 in dioxane (200 ml). The obtained mixture was stirred under heating at 100.degree. C. for 20 minutes to conduct a reaction. The reaction mixture was cooled by allowing to stand and concentrated in a vacuum to give a crystal. This crystal was recovered by filtration, washed with water and dried to give the title compound as a colorless crystal (30.9 g, 98%).
m.p. (.degree.C.): 153 to 157
.sup.1 H-NMR (90 MHz, CDCl.sub.3) .delta.: 10.10 (1H, s), 8.06 (4H, s), 3.10 (3H, s).
PREPARATIVE EXAMPLE 4
Ethyl (E)-3-(4-methylsulfonyl)phenyl-2-propenoate ##STR38##
A solution of ethyl diethylphosphonoacetate (46.2 ml, 0.233 mol) in tetrahydrofuran (180 ml) was dropped into a solution of sodium hydride (60% in mineral oil, 9.20 g, 0,230 mol) in tetrahydrofuran (250 ml) at 0.degree. C. The obtained solution was stirred at that temperature for 10 minutes. A solution of the 4-(methylsulfonyl)benzaldehyde (40.4 g, 0,219 mol) prepared in Preparative Example 3 in dimethylformamide (300 ml)/tetrahydrofuran (50 ml) was dropped into the resulting solution at 0.degree. C. The obtained mixture was stirred at room temperature for 2 hours and cooled with ice again, followed by the addition of an aqueous solution (1.0 l) of ammonium chloride (25 g). The obtained mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of common salt, dried over magnesium sulfate and concentrated in a vacuum. The solid residue was recrystallized from hexane/isopropyl ether to give the title compound as a colorless crystal (48.8 g, yield: 87%).
m.p. (.degree.C.): 91 to 92
.sup.1 H-NMR (90 MHz, CDCl.sub.3) .delta.: 7.96 (2H, d, J=8.6), 7.70 (1H, d, J=15.8), 7.68 (2H, d, J=8.6), 6.54 (1H, d, J=15.8), 4.29 (2H, q, J=7.0), 3.07 (3H, s), 1.35 (3H, t, J=7.0).
PREPARATIVE EXAMPLE 5
(E)-3-(4-Methylsulfonyl)phenyl-2-propenoic acid ##STR39##
The ethyl (E)-3-(4-methylsulfonyl)phenyl-2-propenoate (48.1 g, 0.189 mol) prepared in Preparative Example 4 was suspended in a mixture comprising ethanol (300 ml) and 1N aqueous sodium hydroxide (300 ml). The obtained suspension was stirred at 50.degree. C. for one hour.
The obtained solution was cooled with ice and 1N hydrochloric acid (330 ml) was dropped thereinto to precipitate a crystal. This crystal was recovered by filtration, washed with water and isopropyl ether and dried to give the title compound as a colorless crystal (42.4 g, 99%).
m.p. (.degree.C.): 230 to 240
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 7.95 (4H, s), 7.67 (1H, d, J=15.8), 6.70 (1H, d, J=15.8), 3.24 (3H, s).
The same procedure as that of Preparative Example 4 or 5 was repeated except that 3-fluoro-4-methoxybenzaldehyde, 3,5-dibromo-4-hydroxybenzaldehyde, 3-(3,4-dimethoxybenzoyl)pyridine or 3,4-dimethoxybenzaldehyde was used instead of 4-(methylsulfonyl)benzaldehyde or that triethyl-4-phosphonocrotonate or triethyl-2-phosphonopropionate was used instead of triethylphosphonoacetate to prepare the compounds listed in Table 2.
TABLE 2__________________________________________________________________________Prep. m.p.Ex. Structural formula (.degree.C.) .sup.1 H-NMR .delta.__________________________________________________________________________ ##STR40## 185-195 ##STR41##7 ##STR42## 201-205 ##STR43##8 ##STR44## 103-131 ##STR45##9 ##STR46## 216-218 ##STR47##__________________________________________________________________________
PREPARATIVE EXAMPLE 10
Ethyl (Z)-3-{3,4-dimethoxyphenyl)-2-(3-pyridyl)-2-propenoate ##STR48##
n-Butyllithium (1.6M hexane solution, 99.2 ml) was dropped into a solution of diisopropylamine (23.4 ml, 166.6 mmol) in tetrahydrofuran (320 ml). The obtained mixture was stirred at 0.degree. C. for 30 minutes. A solution of ethyl 3-pyridylacetate (24.0 ml, 158.9 mmol) in tetrahydrofuran (20 ml) was dropped into the resulting mixture at -70.degree. C. and the obtained mixture was stirred at 0.degree. C. for 15 minutes. A solution of 3,4-dimethoxybenzaldehyde (27.6 g, 166.0 mmol) in tetrahydrofuran (100 ml) was dropped into the mixture at 0.degree. C. The obtained mixture was stirred at room temperature overnight, followed by the addition of water. The obtained mixture was extracted with ether. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate and concentrated. The oily residue was purified by flash column chromatography (ethyl acetate/hexane=3:2) to give the title compound as a pale yellow oil (18.19 g, yield: 37%).
.sup.1 H-NMR (400 MHz, CDCl.sub.3) .delta.: 8.58 (1H, brd, J=4.1), 8.50 (1H, brs), 7.88 (1H, s), 7.60 (1H, dt, J=7.7, 1.8), 7.33 (1H, dd, J=7.7, 4.9), 6.79 (1H, dd, J=8.5, 2.2), 6.72 (1H, d, J=8.5), 6.41 (1H, d, J=2.2), 4.25 (2H, q, J=7.0), 3.81 and 3.45 (each 3H, s), 1.30 (3H, q, J=7.0).
NOE: 7.88 .dwnarw..fwdarw.6.79 (7.4%), 6.41 (4.2%); 6.41.dwnarw..fwdarw.7.88 (4.6%), 3.45 (10.47%).
PREPARATIVE EXAMPLE 11
(Z)-3-(3,4-Dimethoxyphenyl)-2(3-pyridyl)-2-propenoic acid ##STR49##
The ethyl (Z)-3-(3,4-dimethoxyphenyl)-2-(3-pyridyl-2-propionate (2.00 g, 6.39 mmol) prepared in Preparative Example 10 was dissolved in a mixture comprising 1N aqueous sodium hydroxide (5 ml) and ethanol (5 ml). The obtained solution was stirred at room temperature for 5 hours and washed with ethanol (20 ml). The pH of the obtained aqueous layer was adjusted to about 7 by the addition of 1N aqueous hydrochloric acid (about 5.0 ml) to thereby precipitate a crystal. This crystal was recovered by filtration and washed with water and ether to give the title compound as a white crystal (0.71 g, yield: 39%).
m.p. (.degree.C.): 190 to 191
.sup.1 H-NMR (90 MHz, DMSO.sub.4 -d.sub.6) .delta.: 8.54 (1H, dd, J=4.8, 1.8), 8.34 (1H, dd, J=1.8, 0.9), 7.81 (1H, s), 7.66 (1H, dt, J=8.0, 1.8), 7.43 (1H, ddd, J=8.1, 4.8, 0.9), 6.86 (1H, d, J=8.8), 6.72 (1H, dd, J=8.8, 1.5), 6.49 (1H, d, J=1.5).
PREPARATIVE EXAMPLE 12
4-(N-Acetyl-N-methylamino)benzenesulfonyl chloride ##STR50##
N-Methylacetanilide (25.0 g, 188.0 mmol) was added to chlorosulfonic acid (62.8 ml) under cooling with ice in portions at such a rate as not to raise the temperature of the resulting mixture to 50.degree. C. or above, which took about 10 minutes. The obtained mixture was stirred at 80.degree. C. for 2.5 hours and poured into a mixture comprising ice (200 ml), hexane (30 ml) and isopropyl ether (30 ml) under cooling with ice at 20.degree. C. or below in portions to decompose excess chlorosulfonic acid. The precipitated crystal was recovered by filtration, washed with water and dissolved in ethyl acetate. The obtained solution was washed with water and a saturated aqueous solution of common salt. The organic layer was dried over magnesium sulfate and concentrated to give the title compound as a white crystal (19.4 g, yield: 42%).
m.p. (.degree.C.): 139 to 140
.sup.1 H-NMR (90 MHz, CDCl.sub.3) .delta.: 8.04 (2H, d, J=9.0), 7.43 (2H, d, J=9.0), 3.36 (3H, s), 2.08 (3H, s).
PREPARATIVE EXAMPLE 13
N-Cycloheptyl-4-(N-methylamino)benzenesulfonamide ##STR51##
Cycloheptylamine (2.26 ml, 17.8 mmol) was added to a suspension of the 4-(N-acetyl-N-methylamino)benzenesulfonyl chloride (4.00 g, 16.2 mmol) prepared in Preparative Example 12 and sodium acetate (3.98 g) in ethanol (40 ml). The obtained mixture was stirred at room temperature for 4 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate and the organic layer was washed with water and a saturated aqueous solution of common salt, and dried over magnesium sulfate.
Ethanol (20 ml) and 1N aqueous sodium hydroxide (20 ml) were added to the obtained white crystal [N-cycloheptyl-4-(N-acetyl-N-methylamino)benzenesulfonamide] (4.72 g, 90%). The obtained mixture was heated under reflux overnight, acidified by the addition of 1N aqueous hydrochloric acid and adjusted to pH 8 with sodium hydrogencarbonate. The resulting mixture was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate and concentrated to precipitate a crystal. This crystal was recovered by filtration and washed with ether to give the title compound as a white crystal (1.92 g, 44%).
m.p. (.degree.C.): 111 to 113
.sup.1 H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.47 (2H, d, J=8.8), 7.09 (1H, d, J=7.2), 6.57 (2H, d, J=8.8), 6.44 (1H, brq, J=4.8), 2.72 (3H, d, J=4.8).
EXAMPLE 14
N-(2-Indanyl)-4-(N-methylamino)benzenesulfonamide ##STR52##
2-Indanylamine hydrochloride (9.68 g, 57.1 mmol) was added to a suspension of the 4-(N-acetyl-N-methylamino)benzenesulfonyl chloride (12.84 g, 51.9 mmol) prepared in Preparative Example 12 and sodium acetate (18.73 g) in ethanol (100 ml). The obtained mixture was stirred at room temperature for 3 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give N-(2-indanyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide as a white crystal (16.92 g, 95%). Ethanol (80 ml) and 1N aqueous sodium hydroxide (80 ml) were added to the white crystal. The obtained mixture was heated under reflux overnight, acidified with 1N aqueous hydrochloric acid, adjusted to pH 8 with sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to precipitate a crystal. This crystal was recovered by filtration and washed with ether to give the title compound as a white crystal (6.79 g, 46%).
m.p. (.degree.C.): 136 to 137
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 7.85 (2H, d, J=8.8), 7.53 (2H, d, J=8.8), 7.08 (4H, s), 3.90 (1H, m), 3.24 (3H, s), 3.12.about.2.54 (4H, m).
PREPARATIVE EXAMPLE 15
N-[2-(6-Methyl-2-pyridyl)ethyl]-4-(N-methylamino)benzenesulfonamide ##STR53##
N-Methyl-N-[2-(6-methyl-2-pyridyl)ethyl]amine (14.66 g, 97.7 mmol) was added to a suspension of the 4-(N-acetyl-N-methylamino)benzenesulfonyl chloride (24.2 g, 97.3 mmol) prepared in Preparative Example 12 and sodium acetate (24.0 g) in ethanol (140 ml). The obtained mixture was stirred at room temperature overnight, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give N-[2-(6-methyl-2-pyridyl)ethyl]-4-(N-acetyl-N-methylamino)benzenesulfonamide as a colorless oil. This oil was dissolved in 4N aqueous hydrochloric acid. The solution was heated under reflux for 2 hours. The pH of the mixture was adjusted to about 8 by the addition of an aqueous solution of sodium hydrogencarbonate. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give an oily residue. This residue was purified by flash column chromatography (chloroform/methanol/aqueous ammonia=97:3:0.3) to give the title compound as a light brown oil (25.8 g, overall yield of two steps: 83%).
.sup.1 H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.56 (2H, d, J=8.8), 7.49 (1H, t, J=8.0), 7.03 (1H, d, J=8.0), 6.98 (1H, d, J=8.0), 6.57 (2H, d, J=8.8), 4.28 (1H, brq, J=5.2), 3.36 (2H, t, J=7.2), 2.99 (2H, t, J=7.2), 2.87 (3H, d, J=5.2), 2.69 (3H, s), 2.50 (3H, s).
PREPARATIVE EXAMPLE 16
N-(1-Benzyl-4-piperidyl)-4-(N-methylamino)benzenesulfonamide dihydrochloride ##STR54##
4-Amino-1-benzylpiperidine (3.63 ml, 17.8 mmol) was added to a suspension of the 4-(N-acetyl-N-methylamino)benzenesulfonyl chloride (4.00 g, 16.2 mmol) prepared in Preparative Example 12 and sodium acetate (2.65 g) in ethanol (40 ml). The obtained mixture was stirred at room temperature for 4 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give N-(1-benzyl-4-piperidyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide as a colorless viscous oil. This oil was dissolved in 4N aqueous hydrochloric acid and the obtained solution was heated under reflux for 3 hours. The resulting mixture was concentrated to give a solid residue. This residue was recrystallized from ethyl acetate to give the title compound as a white crystal (highly hygroscopic one) (5.80 g, overall yield of two steps: 80%).
m.p. (.degree.C.): amorphous (highly hygroscopic)
.sup.1 H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.60 (1H, m), 7.54 (2H, m), 7.50 (2H, d, J=8.8), 7.44 (1H, m), 7.42 (2H, m), 6.60 (2H, d, J=8.8), 4.13 (2H, s), 3.18 (2H, m), 3.08 (2H, m), 2.87 (2H, m), 2.71 (3H, s), 1.73 (4H, m).
PREPARATIVE EXAMPLE 17
N-(4-piperidyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide acetate ##STR55##
N-(1-Benzyl-4-piperidyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide was prepared as a colorless oil from the 4-(N-acetyl-N-methylamino)benzenesulfonyl chloride (20.0 g, 80.8 mmol) and 4-amino-1-benzylpiperidine (18.16 ml, 88.9 mmol) in a similar manner to that described in Preparative Example 16. This oil was dissolved in ethanol (200 ml), followed by the addition of glacial acetic acid (10.0 ml). The obtained mixture was stirred in the presence of 10% palladium/carbon (water-containing one, 2.00 g) in a hydrogen atmosphere (1 atm) at 50.degree. C. for 5 hours and filtered to remove the catalyst. The filtrate was concentrated to precipitate a crystal. The resulting mixture was washed with ethyl acetate and filtered to give the title compound as a white crystal (29.70 g, overall yield of two steps: 100%).
m.p.: 177 to 184
.sup.1 H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.84 (2H, d, J=8.8), 7.55 (2H, d, J=8.8), 3.22 (3H, s), 3.11 (1H, m), 2.90 (2H, m), 2.47 (2H, m), 1.90 (3H, brs), 1.85 (3H, s), 1.57 (2H, m), 1.32 (2H, m).
PREPARATIVE EXAMPLE 18
N-[1-(2-Phenylethyl)-4-piperidyl]-4-(N-methylamino)benzenesulfonamide dihydrochloride ##STR56##
The N-(4-piperidyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide acetate (3.71 g, 10.6 mmol) prepared in Preparative Example 17 was dissolved in a suspension of sodium hydrogencarbonate (2.52 g) and potassium iodide (3.32 g) in dimethylformamide (50 ml), followed by the addition of 2-bromoethylbenzene (1.49 ml, 11.0 mmol). The obtained mixture was stirred at 70.degree. C. for 3 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give N-[1-(2-phenylethyl)-4-piperidyl]-4-(N-acetyl-N-methylamino)benzenesulfonamide as a colorless oil (3.19 g, yield: 77%).
This oil was dissolved in 1N aqueous sodium hydroxide (50 ml). The obtained solution was heated under reflux for 2 hours and acidified with 1N aqueous hydrochloric acid. The pH of the solution was adjusted to about 8 with an aqueous solution of sodium hydrogencarbonate. The resulting mixture was extracted with ethyl acetate and the organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give the title compound in free form as a colorless oil (2.60 g). This oil was converted into a hydrochloride in ethyl acetate-ethanol to give the title compound as a white crystal (2.55 g, yield: 74%).
m.p. (.degree.C.): amorphous (hygroscopic)
.sup.1 H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.55 (2H, d, J=8.8), 7.31 (3H, m), 7.22 (2H, m), 6.67 (2H, d, J=8.8), 3.45.about.3.00 (6H, m), 2.92 (2H, m), 2.72 (3H, s), 1.75 (4H, m).
PREPARATIVE EXAMPLE 19
N-{1-[2-(6-Methyl-2-pyridyl)ethyl]-4-piperidyl}-4-(N-methylamino)benzenesulfonamide ##STR57##
The N-(4-piperidyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide acetate (3.71 g, 10.0 mmol), 6-methyl-2-vinylpyridine (1.43 g, 12.0 mmol ) and sodium acetate (0.82 g) were dissolved in a mixture comprising methanol (20 ml) and water (20 ml). The obtained solution was heated under reflux for 5 hours, followed by the addition of sodium hydroxide (3.20 g). The obtained mixture was heated under reflux for additional three hours and acidified with 2N aqueous hydrochloric acid. The pH of the mixture was adjusted to about 8 with an aqueous solution of sodium hydrogencarbonate. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate and concentrated. The obtained oily residue was purified by column chromatography (chloroform:methanol:aqueous ammonia=90:9:1) and recrystallized from ethyl acetate/ether to give the title compound as a white crystal (2.71 g, overall yield of two steps: 70%).
m.p. (.degree.C.): 80 to 84
.sup.1 H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.53 (1H, t, J=8.0), 7.49 (2H, d, J=8.8), 7.20 (2H, d, J=7.2), 7.01 (2H, d, J=8.0), 6.58 (2H, d, J=8.8), 6.47 (1H, brq, J=5.2), 2.75 (6H, m), 2.72 (3H, d, J=5.2), 2.52 (2H, t, J=7.2), 1.88 (2H, brt), 1.52 (2H, m), 1.31 (2H, m), 2.40 (3H, s).
PREPARATIVE EXAMPLE 20
N-Methyl-4-[4-(2-phenylethyl)homopiperazinyl]sulfonylaniline ##STR58##
A-suspension of 1-(2-phenylethyl)homopiperazine dihydrochloride (7.0 g, 25 mmol) in dichloromethane (100 ml) was cooled with ice, followed by the gradual addition of a solution of triethylamine (15.0 ml, 108 mmol) in dichloromethane (50 ml) thereto. The solid 4-(N-acetyl-N-methylamino)benzenesulfonyl chloride (6.20 g, 25.0 mmol) prepared in Preparative Example 12 was added as such to the obtained solution at 0.degree. C., followed by the addition of dichloromethane (50 ml). The ice bath was taken out to raise the temperature of the resulting mixture to room temperature. The mixture was stirred for one hour and 40 minutes.
A saturated aqueous solution (100 ml) of sodium hydrogencarbonate was added to the obtained suspension to conduct phase separation. The aqueous layer was further extracted with dichloromethane. The organic layers were combined, washed with a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated in a vacuum. The obtained oil (10.4 g) was purified by column chromatography [benzene/acetone (3:1).fwdarw.(1:1)] to give N-acetyl-N-methyl-4-[4-(2-phenylethyl)homopiperazinyl]sulfonylaniline as an oil (9.9 g, 94%).
This oil (9.9 g) was dissolved in dioxane (40 ml), followed by the addition of 4N hydrochloric acid (100 ml). The obtained mixture was heated under reflux for one hour and 15 minutes.
The obtained solution was cooled by allowing to stand and concentrated in a vacuum. The obtained residue was cooled with ice, followed by the successive addition of water (50 ml) and concentrated aqueous ammonia (50 ml) in this order. The obtained mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of common salt, dried over magnesium sulfate and dried in a vacuum. The obtained oil (9.0 g) was purified by column chromatography [benzene/acetone (10:1).fwdarw.(5:1)] to give the title compound as an oil (8.26 g, 93%).
.sup.1 H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.58 (2H, d, J=8.9), 7.26 (2H, m), 7.17 (3H, m), 6.58 (2H, d, J=8.9), 4.23 (1H, brq, J=5.1), 3.34 (4H, m), 2.88 (3H, d, J=5.1), 2.75 (4H, m), 2.73 (4H, s), 1.83 (2H, quint, J=6.0).
PREPARATIVE EXAMPLES 21 TO 58
Amine derivatives of Preparative Examples 21 to listed in Table 3 were each prepared in a similar manner to that described in one of Preparative Examples 12 to 20.
TABLE 3__________________________________________________________________________ ##STR59## ##STR60## ##STR61## ##STR62## ##STR63## ##STR64##__________________________________________________________________________21 H ##STR65## 102.about.107 ##STR66##22 H ##STR67## 139.about.140 ##STR68##23 H ##STR69## 119.about.122 ##STR70##24 CH.sub.3 NHCH.sub.3 143.about.148 (90 MHz, DMSO-d.sub.6): 7.56 (2H, br, D.sub.2 O exchange), 7.50 (2H, d, J=8.4), 6.75 (2H, d, J=8.4), 2.72 (3H, s), 2.32 (3H, s)25 CH.sub.3 ##STR71## ##STR72## ##STR73##26 CH.sub.3 ##STR74## oil ##STR75##27 CH.sub.3 ##STR76## 143.about.147 ##STR77##28 CH.sub.3 NH.sub.2 166.about.167 400 MHz, DMSO-d.sub.6): 7.51 (2H, d, J=8.8), 6.91 (2H, s), 6.57 (2H, d, J=8.8), 6.37 (1H, brq, J=5.0), 2.71 (3H, d, J = 5.0)29 CH.sub.3 ##STR78## 130.about.131 ##STR79##30 CH.sub.3 ##STR80## 126.about.127 ##STR81##31 CH.sub.3 ##STR82## 130.about.135 ##STR83##32 CH.sub.3 ##STR84## 117.about.119 ##STR85##33 CH.sub.3 ##STR86## 161.about.162 ##STR87##34 CH.sub.3 ##STR88## 110.about.113 ##STR89##35 CH.sub.3 ##STR90## 196.about.201 ##STR91##36 CH.sub.3 ##STR92## 99.about.100 ##STR93##37 CH.sub.3 ##STR94## oil ##STR95##38 CH.sub.3 ##STR96## 170.about.172 ##STR97##39 CH.sub.3 ##STR98## 139.about.143 ##STR99##40 CH.sub.3 ##STR100## ##STR101## ##STR102##41 CH.sub.3 ##STR103## 169.about.176 ##STR104##42 CH.sub.3 ##STR105## 109.about.110 ##STR106##43 CH.sub.3 ##STR107## oil ##STR108##44 CH.sub.3 ##STR109## 102.about.103 ##STR110##45 CH.sub.3 ##STR111## amorphous ##STR112##46 CH.sub.3 ##STR113## 145.about.146 ##STR114##47 CH.sub.3 ##STR115## 123.about.124 ##STR116##48 ##STR117## NH.sub.2 138-139 ##STR118##49 CH.sub.3 ##STR119## 150.about.152 ##STR120##50 CH.sub.3 ##STR121## oil ##STR122##51 CH.sub.3 ##STR123## 146.about.147 ##STR124##52 CH.sub.3 ##STR125## 155.about.156 ##STR126##53 CH.sub.3 ##STR127## 203-204 ##STR128##54 CH.sub.3 ##STR129## 140.about.141 ##STR130##55 CH.sub.3 ##STR131## 122.about.123 ##STR132##56 CH.sub.3 ##STR133## 120.about.128 ##STR134##57 CH.sub.3 ##STR135## 136.about.140 ##STR136##58 CH.sub.3 ##STR137## 125.about.127 ##STR138##__________________________________________________________________________ In Preparative Examples 21 to 23, known 4(N-acetylamino)benzenesulfonyl chloride was used instead of the 4(N-acetyl-N-methylamino)benzenesulfonyl chloride prepared in Preparative Example 12.
EXAMPLE 1
Synthesis of Compound 99
N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(3,4-diacetoxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR139##
A solution of 3,4-diacetoxycinnamoyl chloride (5.61 g, 19.9 mmol) in dichloromethane (50 ml) was dropped into a solution of the N-(2-indanyl)-4-(methylamino)benzenesulfonamide (5.00 g, 16.6 mmol) prepared in Preparative Example 14 in pyridine (50 ml) at 0.degree. C. The obtained mixture was stirred at room temperature for 2 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give a solid residue. This residue was recrystallized from ethyl acetate/ether/isopropyl ether to give the title compound as a white crystal (8.90 g, 100%).
m.p. (.degree.C.): 152.about.153 (iso-Pr.sub.2 O)
.sup.1 H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.11 (1H, d, J=7.2), 7.91 (2H, d, J=8.8), 7.58 (2H, d, J=8.8), 7.58.about.7,42 (3H, m), 7.20 (1H, d, J=8.4), 7.11 (4H, s), 6.61 (1H, brd, J=15.4), 3.94 (1H, m), 3.38 (3H, s), 2.98 (2H, dd, J=16.8), 2.75 (2H, dd, J=16.8), 2.26 (3H, s), 2.18 (3H, s)
Mass m/e (FAB): 549 (MH.sup.+), 507, 307, 205, 154 (base)
______________________________________elemental analysis as C.sub.29 H.sub.28 N.sub.2 O.sub.7 S C H N______________________________________calculated (%) 63.49 5.14 5.11found (%) 63.57 5.19 4.87______________________________________
EXAMPLE 2
N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR140##
The N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide (8.90 g, 16.6 mmol) prepared in Example 1 was suspended in a mixture comprising methanol (80 ml) and tetrahydrofuran (80 ml), followed by the addition of concentrated hydrochloric acid (30 ml). The obtained mixture was stirred at 60.degree. C. for 20 minutes, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give a solid residue. The residue was recrystallized from ether to give the title compound as a white crystal (7.17 g, yield: 93%).
m.p. (.degree.C.): 201.about.203 (Et.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.20, 8.00 (each 1H, br, D.sub.2 O exchange), 7.92 (2H, d, J=8.3Hz), 7.55 (2H, d, J=8.4Hz), 7.40 (1H, d, J=15.4Hz), 7.11 (4H, s), 6.87.about.6.35 (3H, m), 6.22 (1H, d, J=15.4Hz), 3.88 (1H, m, D.sub.2 O sharpen), 3.35 (3H, s), 3.15.about.2.55 (4H, m)
Mass m/e (FD): 464 (M.sup.+)
______________________________________elemental analysis as C.sub.25 H.sub.24 N.sub.2 O.sub.5 S C H N______________________________________calculated (%) 64.64 5.21 6.03found (%) 64.80 5.37 5.92______________________________________
EXAMPLE 3
N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(3,4-diglycyloxyphenyl)-2-propenoyl]amino}benzenesulfonamide dihydrochloride ##STR141##
Dicyclohexylcarbodiimide (DCC, 0.27 g) was added to a suspension of the N-(2-indanyl)-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide (0.30 g, 0.65 mmol) and N-(tert-butoxycarbonyl)glycine (0.23 g, 1.29 mmol) in ethyl acetate (7 ml). The obtained mixture was stirred at room temperature overnight and filtered. The filtrate was concentrated to give an N-BOC derivative of the title compound as a white crystal (0.47 g, yield: 92 %). This crystal (0.42 g, 0.537 mmol) was dissolved in ethyl acetate (2.0 ml), followed by the addition of a 1.5N solution (2.0 ml) of hydrochloric acid in ethyl acetate. The obtained mixture was stirred at room temperature for one hour.
The precipitated crystal was recovered by filtration to give the title compound as a white crystal (0.32 g, yield: 91%).
m.p. (.degree.C.): 120.about.127 (AcOEt)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.73 (6H, br, D.sub.2 O exchange), 8.17 (1H, d, J=7.0H.sub.2, D.sub.2 O exchange), 7.92 (2H, d, J=8.8Hz), 6.91.about.7.75 (6H, m), 7.11 (4H, s), 6.60 (1H, d, J=15.4Hz), 4.19 (4H, m), 3.98 (3H, m), 3.39 (3H, s), 3.20.about.2.56 (4H, m)
Mass m/e (FAB): 579 (MH.sup.+), 522, 465, 410, 282, 225, 185 (base)
______________________________________elemental analysis as C.sub.29 H.sub.30 N.sub.4 O.sub.7 S.2HCl.1/3H.sub.2 C H N______________________________________calculated (%) 52.98 4.70 8.52found (%) 52.78 5.10 8.15______________________________________
EXAMPLE 4
N-(1-Benzyl-4-piperidyl)-4-{N-methyl-N-I(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR142##
The 3-(4-methylsulfonyl) cinnamic acid (1.56 g, 6.67 mmol) prepared in Preparative Example 5 was suspended in dichloromethane (20 ml), followed by the addition of oxalyl chloride (2.01 ml, 23.3 mmol) and dimethylformamide (two drops). The obtained mixture was stirred at room temperature for one hour and concentrated to give 3-(4-methylsulfonyl)cinnamoyl chloride as a white crystal. This chloride was dissolved in dichloromethane (25 ml) to obtain a solution. This solution was dropped into a solution of the N-(1-benzyl-4-piperidyl)-4-(N-methylamino)benzenesulfonamide dihydrochloride (2.62 g, 6.06 mmol) prepared in Preparative Example 16 in pyridine (25 ml) at 0.degree. C. The obtained mixture was stirred at room temperature for 2 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give a solid residue. This residue was purified by flash column chromatography (chloroform/methanol/aqueous ammonia=98:2:0.2) and recrystallized from ethyl acetate/ether to give the title compound as a white crystal (2.60 g, yield: 76%).
m.p. (.degree.C.): 189.about.190 (AcOEt-Et.sub.2 O)
.sup.1 H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.95 (2H, d, J=8.6Hz), 7.88 (2H, d, J=8.4Hz), 7.74 (1H, d, J=15.4Hz), 7.50 (2H, d, J=8.4Hz), 7.36 (2H, d, J=8.6Hz), 7.27 (5H, m), 6.45 (1H, d, J=15.4Hz), 4.27 (1H, d, J=7.7Hz), 3.46 (2H, s), 3.46 (3H, s), 3.27 (1H, m), 3.02 (3H, s), 2.75 (1H, brd, J=12.1Hz), 2.05 (2H, t like, J=8Hz), 1.80 (2H, m), 1.52 (2H, m)
Mass m/e (FAB): 568 (MH.sup.+), 490, 360, 209, 189, 172 (base)
______________________________________elemental analysis as C.sub.29 H.sub.33 N.sub.3 O.sub.5 S.sub.2 C H N______________________________________calculated (%) 61.36 5.85 7.40found (%) 61.08 5.98 7.42______________________________________
EXAMPLE 5
N-[1-(2-Phenylethyl)-4-piperidyl)-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR143##
A solution of 3-(4-methylsulfonyl)cinnamoyl chloride [3.10 mmol, prepared from 3-(4-methylsulfonyl)cinnamic acid (0.70 g) in a similar manner to that of Example 4] in dichloromethane (10 ml) was dropped into a solution of the N-11-(2-phenylethyl)-4-piperidyl]-4-(N-methylamino)benzenesulfonamide dihydrochloride (1.26 g, 2.82 mmol) prepared in Preparative Example 18 in pyridine (20 ml) at 0.degree. C. The obtained mixture was stirred at room temperature for 2 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give a solid residue. The residue was recrystallized from ethyl acetate/ether to give the title compound as a white crystal (1.04 g, yield: 63%).
m.p. (.degree.C.): 173.about.176 (AcOEt-Et.sub.2 O)
.sup.1 H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.96 (2H, d, J=8.6Hz), 7.87 (2H, d, J=8.4Hz), 7.74 (1H, d, J=15.6Hz), 7.50 (2H, d, J=8.4Hz), 7.37 (2H, d, J=8.6Hz), 7.28 (2H,m), 7.17 (3H, m), 6.46 (1H, d, J=15.6Hz), 4.68 (1H, d, J=6.0), 3.46 (3H, s), 3.28 (1H, m), 3.01 (3H, s), 2.86 (2H, brd, J=12.3Hz), 2.75 (2H, m), 2.56 (2H, m), 2.11 (2H, brt, J=8Hz), 1.87 (2H, m), 1.55 (2H, m)
Mass m/e (FAB): 582 (MH.sup.+), 490, 307, 154 (base)
______________________________________elemental analysis as C.sub.30 H.sub.35 N.sub.3 O.sub.5 S.sub.2 C H N______________________________________calculated (%) 6.194 6.06 7.22found (%) 61.67 6.09 7.05______________________________________
EXAMPLES 6 TO 99
The compounds of Examples 6 to 99 which will be described below were each prepared in a similar manner to that of Example 4 or 5.
EXAMPLE 6
N-Methyl-N-[2-(6-methyl-2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide hydrochloride ##STR144##
m.p. (.degree.C.): 164.about.167 (EtOH-AcOEt)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.38 (1H, t, J=7.9Hz), 8.00.about.7.44 (11H, m), 6.76 (1H, d, J=15.4Hz), 3.60.about.3.20 (4H, m), 3.40 (3H, s), 3.21 (3H, s), 2.83 (3H, s), 2.78 (3H, s)
Mass m/e (FAB): 528 (MH.sup.+ base), 314, 209, 170, 149, 107
______________________________________elemental analysis as C.sub.26 H.sub.29 N.sub.3 O.sub.5 S.sub.2.HCl C H N______________________________________calculated (%) 55.36 5.36 7.45found (%) 55.26 5.15 7.29______________________________________
EXAMPLE 7
(E)-N-Methyl-N-{4-[4-(2-phenylethyl]homopiperazinyl]sulfonylphenyl}-3-(4-methylsulfonylphenyl)-2-propenamide ##STR145##
m.p. (.degree.C.): 203.about.207 (EtOH-AcOEt-MeOH)
.sup.1 H-NMR (400 MHz, CDCl.sub.3 -DMSOd.sub.6 (10:1)) .delta.: 7.92 (2H, d, J=8.4 Hz), 7.85 (2H, d, J=8.4 Hz), 7.76 (1H, d, J=15.5 Hz), 7.56 (2H, d, J=8.4 Hz), 7.44 (2H, d, J=8.4 Hz), 7.35.about.7.23 (5H, m), 6.51 (1H, d, J=15.5 Hz), 3.81 (2H, m), 3.49 (3H, s), 3.27 (6H, m), 3.06 (3H, s), 2.48 (6H, m)
Mass m/e (FAB): 582 (MH.sup.+), 490, 372, 111 (base)
______________________________________elemental analysis as C.sub.30 H.sub.35 N.sub.3 O.sub.5 S.sub.2.HCl C H N______________________________________calculated (%) 58.28 5.87 6.80found (%) 58.20 5.67 6.71______________________________________
EXAMPLE 8
(.+-.)-N-[1-(2-Pyridylmethyl)-3-hexamethyleneimino]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide dihydrochloride ##STR146##
m.p. (.degree.C.): 145.about.148 (Et.sub.2 O-AcOEt)
1H-NMR (400 MHz, DMSO-d.sub.6 .delta. (free form): 7.87 (2H, d, J=8.4 Hz), 7.85 (2H, d, J=8.8 Hz), 7.73 (1H, d, J=15.6 Hz), 7.51 (2H, d, J=8.2 Hz), 7.37.about.7.21 (6H, m), 6.44 (1H, d, J=15.6 Hz), 3.87 (1H, d, J=13.2 Hz), 3.51 (1H, dd, J=14.2, 3.9 Hz), 3.44 (3H, s), 3.35 (1H, m), 3.28 (1H, m), 3.07 (1H, dd, J=14.2, 7.6 Hz), 3.02 (3H, s), 2.92 (1H, m), 2.00.about.1.60 (4H, m), 1.47 (2H, m)
Mass m/e (FAB): 582 (MH.sup.+), 475, 374, 203, 106 (base)
High MASS: as C.sub.29 H.sub.34 N.sub.4 O.sub.5 S.sub.2 calculated (%) 582.1970 (M.sup.+) found (%) 582.1964
EXAMPLE 9
(.+-.)-N-[1-Benzyl-3-hexamethyleneimino]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR147##
m.p. (.degree.C.): 88.about.92 (amorphous, iso-Pr.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.00.about.7.32 (10H, m), 7.23 (5H, m), 6.61 (1H, d, J=15.3 Hz), 3.49 (2H, s), 3.18 (3H, s), 1.80.about.1.20 (6H, m)
Mass m/e (FAB): 582 (MH.sup.+, base), 232, 203, 188
High MASS: as C.sub.30 H.sub.35 N.sub.3 O.sub.5 S.sub.2 calculated (%) 582.2097 (MH.sup.+) found (%) 582.2102
EXAMPLE 10
N-[1-(2-Methylpropyl)-4-piperidyl)-4-{N-methyl-N-(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR148##
m.p. (.degree.C.): 147.about.148 (AcOEt-Et.sub.2 O )
.sup.1 H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.96 (2H, d, J=8.6 Hz), 7.87 (2H, d, J=8.4 Hz), 7.74 (1H, d, J=15.6 Hz), 7.50 (2H, d, J=8.4 Hz), 7.37 (2H, d, J=8.6 Hz), 6.45 (1H, d, J=15.6 Hz), 4.82 (1H, br), 3.46 (3H, s), 3.27 (1H, m), 3.02 (3H, s), 2.78 (1H, brd, J=12.3 Hz), 2.09 (2H, d, J=6.0 Hz), 2.04 (2H, brt, J=8 Hz), 1.90.about.1.64 (3H, m), 1.60 (2H, m)
Mass m/e (FAB): 582 (MH.sup.+), 490, 324, 209, 140 (base), 112
______________________________________elemental analysis as C.sub.26 H.sub.35 N.sub.3 O.sub.5 S.sub.2.0.4H.sub.2 O C H N______________________________________calculated (%) 57.73 6.67 7.77found (%) 57.50 6.39 7.54______________________________________
EXAMPLE 11
N-(1-Methyl-4 -piperidyl)-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR149##
m.p. (.degree.C.): 122.about.125 (AcOEt)
.sup.1 H-NMR (90 MHz, CDCl.sub.3) .delta.: 7.96 (2H, d, J=8.6 Hz), 7.88 (2H, d, J=8.6 Hz), 7.74 (1H, d, J=15.8 Hz), 7.49 (2H, d, J=8.6 Hz), 7.37 (2H, d, J=8.6 Hz), 6.44 (1H, d, J=15.8 Hz), 3.47 (3H, s), 3.3 (1H, m), 3.03 (3H, s), 2.7 (2H, m), 2.24 (3H, s), 2.1.about.1.4 (6H, m)
Mass m/e (FAB): 492 (MH.sup.+, base), 315, 282, 209, 170
______________________________________elemental analysis as C.sub.23 H.sub.29 N.sub.3 O.sub.5 S.sub.2 C H N______________________________________calculated (%) 56.19 5.95 8.55found (%) 56.13 6.11 8.17______________________________________
EXAMPLE 12
N-(3-Quinuclidyl)-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR150##
m.p. (.degree.C.): 221.about.222 (EtOH-MeOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.46 (1H, d, J=6.5 Hz, D.sub.2 O exchange), 8.00.about.7.40 (9H, m), 6.73 (1H, d, J=15.4 Hz), 3.39 (3H, s), 3.21 (3H, s), 3.80.about.2.80 (8H, m), 2.10.about.1.50 (4H, m)
Mass m/e (FAB): 504 (MH.sup.+), 277, 185 (base), 125
______________________________________elemental analysis as C.sub.24 H.sub.29 N.sub.3 O.sub.5 S.sub.2.2.5H.sub.2 O C H N______________________________________calculated (%) 52.53 6.24 7.66found (%) 52.18 5.57 7.34______________________________________
EXAMPLE 13
N-[3-(N,N-Dimethylamino)propyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2propenoyl]amino}benzenesulfonamide hydrochloride ##STR151##
m.p. (.degree.C.): 201.about.204 (MeOH)
.sup.1 H NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.94 (1H, t, J=6.0 Hz), 7.88 (2H, d, J=7.7 Hz), 7.86 (2H, d, J=8.4 Hz), 7.78 (2H, d, J=7.7 Hz), 7.62 (1H, d, J=15.6 Hz), 7.56 (2H, d, J=8.4 Hz), 6.76 (1H, brd, J=15.6 Hz), 3.38 (3H, s), 3.36 (3H, s), 3.01 (2H, dd, J=7.0, 6.0 Hz), 2.86 (2H, q, J=6.0 Hz), 1.82 (2H, quint, J=7.7 Hz)
Mass m/e (FAB): 480 (MH.sup.+, base), 259, 209, 167, 149
______________________________________elemental analysis as C.sub.22 H.sub.29 N.sub.3 O.sub.5 S.sub.2 HCl C H N______________________________________calculated (%) 51.20 5.86 8.14found (%) 50.86 5.86 7.99______________________________________
EXAMPLE 14
N-Cycloheptyl-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR152##
m.p. (.degree.C.): 146.about.148 (MeOH)
.sup.1 H-NMR (90 MHz, CDCl.sub.3) .delta.: 7.94 (1H, d, J=8.8 Hz), 7.87 (2H, d, J=8.4 Hz), 7.74 (1H, d, J=15.4 Hz), 7.49 (2H, d, J=8.4 Hz), 7.36 (2H, d, J=8.8 Hz), 6.43 (1H, d, J=15.4 Hz), 4.59 (1H, d, J=8.4 Hz), 3.46 (3H, s), 3.46 (1H, m), 3.03 (3H, s), 2.00.about.1.30 (12H, m)
Mass m/e (FD): 490 (M.sup.+)
______________________________________elemental analysis as C.sub.24 H.sub.30 N.sub.2 O.sub.5 S.sub.2 C H N______________________________________calculated (%) 58.75 6.16 5.71found (%) 58.51 6.15 5.60______________________________________
EXAMPLE 15
N-[2-(6-methyl-2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide hydrochloride ##STR153##
m.p. (.degree.C.): 169.about.175 (AcOEt)
.sup.1 H-NMR (400 MHz, CMSO-d.sub.6) .delta.: 7.94 (2H, d, J=8.6 Hz), 7.83 (2H, d, J=8.2 Hz), 7.72 (1H, d, J=15.6 Hz), 7.48 (3H, m), 7.34 (2H, d, J=8.6 Hz), 7.00 (1H, d, J=7.5 Hz), 6.90 (1H, d, J=7.7 Hz), 6.60 (1H, brt), 6.43 (1H, d, J=15.6 Hz), 3.44 (3H, s), 3.42 (2H, m), 2.94 (2H, t, J=6.0 Hz), 2.48 (3H, s), 3.02 (3H, s)
Mass m/e (FAB): 514 (MH.sup.+, base), 498, 304
______________________________________elemental analysis as C.sub.25 H.sub.27 N.sub.3 O.sub.5 S.sub.2.0.2H.sub.2 O C H N______________________________________calculated (%) 54.23 5.17 7.59found (%) 54.07 5.03 7.42______________________________________
EXAMPLE 16
N-[3-(4-Pyridyl)propyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2 -propenoyl]amino}benzenesulfonamide ##STR154##
m.p. (.degree.C.): amorphous (CH.sub.2 Cl.sub.2)
.sup.1 H-NMR (400 MHz, CDCl.sub.3) .delta.: 8.48 (2H, d, J=6.0 Hz), 7.93 (2H, d, J=8.6 Hz), 7.87 (2H, d, J=8.4 Hz), 7.75 (1H, d, J=15.6 Hz), 7.51 (2H, d, J=8.4 Hz), 7.38 (2H, d, J=8.6 Hz), 7.09 (2H, d, J=6.0 Hz), 6.47 (1H, d, J=15.6 Hz), 5.05 (1H, t, J=7 Hz), 3.46 (3H, s), 3.05 (2H, m), 2.69 (2H, t, J=7.7 Hz), 1.89 (2H, quint, J=7.7 Hz)
Mass m/e (FAB):
High MASS: as C.sub.25 H.sub.27 N.sub.3 O.sub.5 S.sub.2 calculated (%) 514.1470 (MH.sup.+) found (%) 514.1471
EXAMPLE 17
N-Methyl-N-[2-(2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide hydrochloride ##STR155##
m.p. (.degree.C.): 153.about.159 (AcOEt)
.sup.1 H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.79 (1H, d, J=8 Hz), 8.46 (1H, t, J=8 Hz), 7.97 (1H, d, J=8 Hz), 7.85 (3H, m), 7.76 (4H, m), 7.60 (1H, d, J=15.6 Hz), 7.55 (2H, dd, J=8.2 Hz), 6.74 (1H, d, J=15.6 Hz), 3.46 (2H, d, J=6 Hz), 3.38 (3H, s), 3.30 (2H, t, J=6 Hz), 3.18 (3H, s), 2.79 (3H, s)
Mass m/e (FAB): 514 (MH.sup.+, base), 378, 314, 209, 170
______________________________________elemental analysis as C.sub.25 H.sub.27 N.sub.3 O.sub.5 S.sub.2.HCl.0.1H.sub.2 O C H N______________________________________calculated (%) 54.40 5.33 7.61found (%) 51.17 5.01 7.38______________________________________
EXAMPLE 18
N-[2-(2-Pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR156##
m.p. (.degree.C.): 143.about.144 (Et.sub.2 O -EtOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.43 (1H, d like, J=6.0 Hz), 7.96.about.7.40 (10H, m), 7.17 (1H, d like, J=7.5 Hz), 6.71 (1H, d, J=15.4 Hz), 3.39 (3H, s), 3.19 (3H, s), 3.30.about.3.00 (2H, m), 2.85 (1H, t like, J=6.6 Hz)
Mass m/e (FD): 499 (M.sup.+)
______________________________________elemental analysis as C.sub.24 H.sub.25 N.sub.3 O.sub.5 S.sub.2.0.5H.sub.2 O C H N______________________________________calculated (%) 56.67 5.15 8.26found (%) 56.67 4.93 8.17______________________________________
EXAMPLE 19
N-(2-Pyridylmethyl)-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide hydrochloride ##STR157##
m.p. (.degree.C.): 125.about.128 (CH.sub.2 Cl.sub.2 -EtOH-MeOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.78 (1H, d D.sub.2 O exchange), 8.68 (1H, d, J=5.0 Hz), 8.34 (1H, t, J=8.0 Hz), 8.00.about.7.45 (11H, m), 6.74 (1H, d, J=15.8 Hz), 4.45 (2H, s), 3.39 (3H, s), 3.20 (3H, s)
Mass m/e (FAB): 486 (MH.sup.+), 314, 278, 209, 170, 131, 107 (base)
______________________________________elemental analysis as C.sub.23 H.sub.23 N.sub.3 O.sub.5 S.sub.2.HCl C H N______________________________________calculated (%) 52.92 4.63 8.05found (%) 52.85 4.57 7.70______________________________________
EXAMPLE 20
(E)-N-Methyl-N-[4-(4-cyclohexylmethyl-1-homopiperazinyl)sulfonylphenyl]-3-(4-methylsulfonylphenyl)-2-propenamide hydrochloride ##STR158##
m.p. (.degree.C.): 212.about.216 (AcOEt-MeOH-EtOH)
.sup.1 H-NMR (400 MHz, CDCl.sub.3) .delta.: 11.95 (1H, brs), 7.91 (2H, d, J=8.2 Hz), 7.82 (2H, d, J=8.2 Hz), 7.75 (1H, d, J=15.5 Hz), 7.54 (2H, d, J=8.2 Hz), 7.41 (2H, d, J=8.2 Hz), 6.48 (1H, d, J=15.5 Hz), 3.95.about.3.55 (5H, m), 3.48 (3H, s), 3.30.about.2.85 (6H, m), 3.05 (3H, s), 2.20 (1H, m), 2.05.about.1.65 (6H, m), 1.35.about.1.00 (5H, m)
Mass m/e (FAB): 574 (MH.sup.+), 394, 364, 195 (base)
______________________________________elemental analysis as C.sub.29 H.sub.39 N.sub.3 O.sub.5 S.sub.2.HCl.0.3H.sub.2 O C H N______________________________________calculated (%) 56.58 6.65 6.83found (%) 56.60 6.48 6.69______________________________________
EXAMPLE 21
(E)-N-Methyl-N-[4-(4-benzyl-1-homopiperazinyl)sulfonylphenyl]-3-(4-methylsulfonylphenyl)-2-propenamide hydrochloride ##STR159##
m.p. (.degree.C.): 196.about.199 (AcOEt)
.sup.1 H-NMR (400 MHz, CDCl.sub.3 -DMSO-d.sub.6) .delta.: 11.95 (1H, brs), 7.91 (2H, d, J=8.4 Hz), 7.82 (2H, d, J=8.9 Hz), 7.73 (1H, d, J=15.6 Hz), 7.70 (2H, m), 7.58 (2H, d, J=8.9 Hz), 7.45 (2H, d, J=8.4 Hz), 7.45 (3H, m), 6.54 (1H, d, J=15.6 Hz), 4.38 (1H, m), 4.28 (1H, m), 3.91 (1H, m), 3.73 (1H, m), 3.57 (2H, m), 3.48 (3H, s), 3.33.about.3.11 (3H, m), 3.08 (3H, s), 2.75 (1H, m), 2.17 (1H, m)
Mass m/e (FAB): 568 (MH.sup.+), 359, 315, 209, 189 (base)
______________________________________elemental analysis as C.sub.29 H.sub.33 N.sub.3 O.sub.5 S.sub.2.HCl C H N______________________________________calculated (%) 57.65 5.67 6.96found (%) 57.36 5.77 6.61______________________________________
EXAMPLE 22
(E)-N-Methyl-N-{4-{4-(2-phenylethyl)piperazinyl]sulfonylphenyl}-3-(4-methylsulfonylphenyl)-2-propenamide ##STR160##
m.p. (.degree.C.): 193.about.194 (AcOEt)
.sup.1 H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.90 (2H, d, J=8.3 Hz), 7.86 (2H, d, J=8.6 Hz), 7.77 (1H, d, J=15.6 Hz), 7.54 (2H, d, J=8.3 Hz), 7.42 (2H, d, J=8.6 Hz), 7.28 (2H, m), 7.21 (1H, d, J=6.2 Hz), 7.17 (2H, d, J=6.8 Hz), 6.48 (1H, d, J=15.6 Hz), 3.48 (1H, s), 3.14 (3H, s), 3.04 (3H, s), 2.77 (2H, m), 2.66 (4H, m)
Mass m/e (FAB): 568 (MH.sup.+), 476, 209, 136 (base)
______________________________________elemental analysis as C.sub.29 H.sub.33 N.sub.3 O.sub.5 S.sub.2 C H N______________________________________calculated (%) 61.35 5.86 7.40found (%) 61.36 5.87 7.21______________________________________
EXAMPLE 23
(E)-N-Methyl-N-{4-[4-(3-pyridylmethyl)piperazinyl]sulfonylphenyl}-3-(4-methylsulfonylphenyl)-2-propenamide ##STR161##
m.p. (.degree.C.): 194.about.196 (CH.sub.2 Cl.sub.2 -EtOH-isoPr.sub.2 O)
.sup.1 H-NMR (400 MHz, CDCl.sub.3) .delta.: 8.50 (2H, s), 7.88 (2H, d, J=8.2 Hz), 7.82 (2H, d, J=8.4 Hz), 7.73 (1H, d, J=15.4 Hz), 7.56 (1H, brd, J=7.7 Hz), 7.51 (2H, d, J=8.2 Hz), 7.39 (2H, d, J=8.4 Hz), 7.23 (1H, dd, J=7.7, 4.8 Hz), 6.45 (1H, d, J=15.4 Hz), 3.53 (2H, s), 3.46 (3H, s), 3.09 (4H, brs), 3.02 (3H, s), 2.57 (4H, t, J=4.6 Hz)
Mass m/e (FAB): 555 (MH.sup.+), 347, 209, 176 (base)
______________________________________elemental analysis as C.sub.27 H.sub.30 N.sub.4 O.sub.5 S.sub.2 C H N______________________________________calculated (%) 58.46 5.45 10.10found (%) 58.17 5.37 9.95______________________________________
EXAMPLE 24
(E)-N-methyl-N-[4-(4-benzylpiperazinyl)sulfonylphenyl]-3-(4-methylsulfonylphenyl)-2-propenamide hydrochloride ##STR162##
m.p. (.degree.C.): 194.about.196 (CH.sub.2 Cl.sub.2)
.sup.1 H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.89 (4H, s), 7.80 (2H, d, J=7.2 Hz), 7.65 (1H, d, J=15.6 Hz), 7.63 (2H, d, J=7.2 Hz), 7.60 (2H, m), 7.43 (3H, m), 6.76 (1H, brd, J=15.6 Hz), 4.30 (2H, brs), 3.74 (2H, brs), 3.39 (3H, s), 3.3 (4H), 3.19 (3H, s), 2.95 (2H, brs)
Mass m/e (FAB): 554 (MH.sup.+), 346, 259, 207, 149, 115 (base)
______________________________________elemental analysis as C.sub.28 H.sub.31 N.sub.3 O.sub.5 S.sub.2.HCl.0.5H.sub.2 O C H N______________________________________calculated (%) 56.13 5.55 7.01found (%) 55.85 5.48 6.99______________________________________
EXAMPLE 25
N-Cycloheptyl-4-{N-methyl-N-I(E)-3-(4-cyanophenyl)-2-propenoyl]amino}benzenesulfonamide ##STR163##
m.p. (.degree.C.): 170.about.171 (Et.sub.2 O -AcOEt)
.sup.1 H-NMR (90 MHz, CDCl.sub.3) .delta.: 8.00.about.7.40 (10H, m), 6.63 (1H, d, J=15.8 Hz), 3.40 (3H, s), 3.20 (1H, m), 1.80.about.1.00 (12H, m)
Mass m/e (FAB): 438 (MH.sup.+, base), 342, 262, 156, 136
______________________________________elemental analysis as C.sub.24 H.sub.27 N.sub.3 O.sub.3 S C H N______________________________________calculated (%) 65.88 6.22 9.60found (%) 65.83 6.17 9.41______________________________________
EXAMPLE 26
N-(1-Benzyl-4-piperidyl)-4-{N-methyl-N-[(E)-3-(4-cyanophenyl)-2-propenoyl]amino}benzenesulfonamide hydrochloride ##STR164##
m.p. (.degree.C.): 180.about.183 (AcOEt)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.12 (1H, d, J=7.0 Hz, D.sub.2 O exchange), 8.00.about.7.32 (14H, m), 6.67 (1H, d, J=15.9 Hz), 4.20 (2H, m, D.sub.2 O exchange), 3.40 (3H, s), 3.60.about.2.60 (5H, m), 2.20.about.1.60 (4H, m)
Mass m/e (FD): 514 (MH.sup.+)
______________________________________elemental analysis as C.sub.29 H.sub.30 N.sub.4 O.sub.3 S.HCl.0.7H.sub.2 C H N______________________________________calculated (%) 61.79 5.75 9.93found (%) 61.84 5.59 9.95______________________________________
EXAMPLE 27
N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(4-(1-imidazoyl)phenyl]-2-propenoyl]amino}benzenesulfonamide ##STR165##
m.p. (.degree.C.): 213.about.215 (AcOEt)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.25 (1H, s), 8.20 (1H, d, J=7.5 Hz, D.sub.2 O exchange), 8.04 (2H, d, J=9.2 Hz), 7.80.about.7.40 (3H, m), 7.61 (4H, s), 7.09 (4H, s), 6.60 (1H, d, J=15.4 Hz), 3.92 (1H, m), 3.40 (3H, s), 3.20.about.2.57 (4H, m)
Mass m/e (FD): 498 (M.sup.+)
______________________________________elemental analysis as C.sub.28 H.sub.26 N.sub.4 O.sub.3 S C H N______________________________________calculated (%) 67.45 5.26 11.24found (%) 67.19 5.20 11.17______________________________________
EXAMPLE 28
N-[1-(1,2,3,4-Tetrahydro)naphthyl]-4-{N-methyl-N-[(E)-3-(4-(1-imidazolyl)phenyl)-2-propenoyl]amino}benzenesulfonamide ##STR166##
m.p. (.degree.C.): 221.about.222 (AcOEt)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.28 (1H, s), 8.16 (1H, d, J=7.9 Hz), 7.96 (2H, d, J=8.3 Hz), 7.79.about.7.43 (4H, m), 7.61 (4H, s), 7.08 (4H, s), 7.08 (1H, s), 6.55 (1H, d, J=15.8 Hz), 4.43 (1H, m), 3.39 (3H, s), 2.65 (2H, m), 1.65 (4H, m)
Mass m/e (FD): 512 (M.sup.+)
______________________________________elemental analysis as C.sub.29 H.sub.28 N.sub.4 O.sub.3 S.0.1H.sub.2 O C H N______________________________________calculated (%) 67.71 5.52 10.89found (%) 67.95 5.42 10.81______________________________________
EXAMPLE 29
N-Cycloheptyl-4-{N-methyl-N-I(E)-3-(4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide ##STR167##
m.p. (.degree.C.): 173.about.174 (AcOEt-Et.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.29 (1H, brs), 7.87 (2H, d, J=8.4 Hz), 7.83.about.7.40 (11H, m), 7.11 (1H, brs), 6.52 (1H, d, J=15.4 Hz), 3.37 (3H, s), 3.16 (1H, m), 1.88.about.1.05 (12H, m)
Mass m/e (FAB): 479 (MH.sup.+, base), 383, 303, 197, 170, 144
______________________________________elemental analysis as C.sub.26 H.sub.30 N.sub.4 O.sub.3 S C H N______________________________________calculated (%) 65.25 6.32 11.71found (%) 65.13 6.45 11.54______________________________________
EXAMPLE 30
N-Cyclooctyl-4-{N-methyl-N-[(E)-3-(4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide ##STR168##
m.p. (.degree.C.): 173.about.174 (AcOEt-Et.sub.2 O ).
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.29 (1H, brs), 7.87 (2H, d, J=8.4 Hz), 7.83.about.7.40 (11H, m), 7.11 (1H, brs), 6.52 (1H, d, J=15.4 Hz), 3.37 (3H, s), 3.16 (1H, m), 1.88.about.1.05 (12H, m)
Mass m/e (FAB): 479 (MH.sup.+, base), 383, 303, 197i 170, 144
______________________________________elemental analysis as C.sub.26 H.sub.30 N.sub.4 O.sub.3 S C H N______________________________________calculated (%) 65.25 6.32 11.71found (%) 65.13 6.45 11.54______________________________________
EXAMPLE 31
(.+-.)-N-(exo-2-Norbornyl)-4-{N-methyl-N-[(E)-3-(4-(1-imidazolyl) phenyl]-2-propenoyl]amino}benzenesulfonamide ##STR169##
m.p. (.degree.C.): 187.about.188 (AcOEt-E.sub.t 2O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.28 (1H, s), 7.86 (2H, J=8.8 Hz), 7.74 (1H, s), 7.69.about.7.40 (4H, m), 7.61 (4H, s), 7.10 (1H, s), 6.53 (1H, d, J=15.8 Hz), 3.37 (1H, s), 3.00 (1H, m), 2.20.about.1.90 (2H, m), 1.64.about.0.80 (8H, m)
Mass m/e (FD): 477 (MH.sup.+)
______________________________________elemental analysis as C.sub.26 H.sub.28 N.sub.4 O.sub.3 S.0.7H.sub.2 O C H N______________________________________calculated (%) 63.83 6.06 11.45found (%) 63.83 5.77 11.46______________________________________
EXAMPLE 32
(.+-.)-N-(endo-2-Norbornyl)-4-{N-methyl-N-[(E)-3-(4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide hydrochloride ##STR170##
m.p. (.degree.C.): 191.about.195 (AcOEt-EtOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.71 (1H, s), 8.27 (1H, s), 8.00.about.7.40 (11H, m), 6.61 (1H, d, J=15.8 Hz), 3.38 (1H, s), 2.03 (2H, m), 2.00.about.0.70 (8H, m)
Mass m/e (FAB): 477 (MH.sup.+, base), 303, 197, 144, 115
______________________________________elemental analysis as C.sub.26 H.sub.28 N.sub.4 O.sub.3 S.HCl.0.1H.sub.2 C H N______________________________________calculated (%) 63.83 6.06 11.45found (%) 63.83 5.77 11.46______________________________________
EXAMPLE 33
N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide ##STR171##
m.p. (.degree.C.): 241.about.242 (AcOEt-iso-Pr.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.14 (2H, d, J=8.8 Hz), 8.1 (1H), 7.93 (2H, d, J=8.8 Hz), 7.76 (2H, d, J=8.8 Hz), 7.66 (1H, d, J=15.6 Hz), 7.58 (2H, d, J=8.8 Hz), 7.10 (4H, s), 6.76 (1H, d, J=15.6 Hz), 3.99 (1H, m), 3.41 (3H, s), 2.99 (2H, dd, J=15.8, 7.5 Hz), 2.70 (2H, dd, J=15.8, 7.5 Hz)
Mass-m/e (FD): 477 (MH.sup.+)
______________________________________elemental analysis as C.sub.25 H.sub.23 N.sub.3 O.sub.5 S C H N______________________________________calculated (%) 62.88 4.86 8.80found (%) 62.75 4.91 8.52______________________________________
EXAMPLE 34
N-Cyclohexyl-N-methyl-4-{N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide ##STR172##
m.p. (.degree.C.): 247.about.250 (AcOEt)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.70 (1H, s), 8.30 (2H, d, J=8.8 Hz), 7.91 (2H, d, J=8.8 Hz), 7.91 (2H, d, J=8.8 Hz), 7.76 (2H, d, J=8.8 Hz), 7.75 (1H, d, J=15.8 Hz), 7.00 (1H, d, J=15.8 Hz), 3.6 (1H, m), 2.67 (3H, s), 1.8.about.1.0 (10H, m)
Mass m/e (FD): 443 (MH.sup.+)
______________________________________elemental analysis as C.sub.22 H.sub.25 N.sub.3 O.sub.5 S.0.25H.sub.2 O C H N______________________________________calculated (%) 58.97 5.74 9.38found (%) 59.11 5.75 9.19______________________________________
EXAMPLE 35
N-Cyclohexyl-4-{N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide ##STR173##
m.p. (.degree.C.): 261.about.262 (AcOEt-H.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.63 (1H, brs), 8.26 (2H, d, J=8.8 Hz), 7.86 (2H, d, J=8.8 Hz), 7.72 (2H, d, J=8.8 Hz), 7.71 (1H, d, J=16.2 Hz), 7.49 (1H, d, J=7.9 Hz, D.sub.2 O exchange), 6.98 (1H, d, J=16.2 Hz), 2.90 (1H, m), 1.8.about.1.0 (10H, m)
Mass m/e (FD): 429 (MH.sup.+)
______________________________________elemental analysis as C.sub.21 H.sub.23 N.sub.3 O.sub.5 S C H N______________________________________calculated (%) 58.73 5.40 9.78found (%) 58.45 5.45 9.49______________________________________
EXAMPLE 36
N-Cyclohexyl-4-{N-methyl-N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide ##STR174##
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.17 (2H, d, J=8.8 Hz), 7.88 (2H, d, J=8.8 Hz), 7.73 (2H, d, J=8.8 Hz), 7.65 (1H, d, J=16.1 Hz), 7.55 (2H, d, J=8.8 Hz), 6.70 (1H, d, J=16.1 Hz), 3.38 (3H, s), 2.96 (1H, m), 1.8.about.1.0 (10H, m)
Mass m/e (FD): 443 (MH.sup.+)
______________________________________elemental analysis as C.sub.22 H.sub.25 N.sub.3 O.sub.5 S C H N______________________________________calculated (%) 59.58 5.68 9.48found (%) 59.58 5.64 9.36______________________________________
EXAMPLE 37
N-Cyclohexyl-N-methyl-4-{N-methyl-N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide ##STR175##
m.p. (.degree.C.): 124.about.125 (AcOEt-iso-Pr.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.18 (2H, d, J=8.8 Hz), 7.87 (2H, d, J=8.8 Hz), 7.74 (2H, d, J=8.8 Hz), 7.64 (1H, d, J=15.8 Hz), 7.56 (2H, d, J=8.8 Hz), 6.70 (1H, d, J=15.8 Hz), 3.64 (1H, m), 3.39 (1H, s), 2.72 (3H, s), 1.8.about.1.0 (10H, m)
Mass m/e (FD): 457 (MH.sup.+)
______________________________________elemental analysis as C.sub.23 H.sub.27 N.sub.3 O.sub.5 S C H N______________________________________calculated (%) 60.38 5.95 9.18found (%) 60.33 5.89 8.93______________________________________
EXAMPLE 38
N-cycloheptyl-4-{N-methyl-N-[(E)-3-(4-nitrophenyl)-2-propenoyl]amino}benzenesulfonamide ##STR176##
m.p. (.degree.C.): 187.about.188 (AcOEt-iso-Pr.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.19 (2H, d, J=8.6 Hz), 7.96 (2H, d, J=8.6 Hz), 7.75 (1H, d, J=15.4 Hz), 7.46 (2H, d, J=8.6 Hz), 7.37 (2H, d, J=8.6 Hz), 6.44 (1H, d, J=15.4 Hz), 4.51 (1H, brd, J=7.9 Hz), 3.47 (3H, s), 3.4 (1H, m), 2.0.about.1.2 (12H, m)
Mass m/e (FD): 457 (MH.sup.+)
______________________________________elemental analysis as C.sub.23 H.sub.27 N.sub.3 O.sub.5 S C H N______________________________________calculated (%) 60.38 5.95 9.18found (%) 60.33 5.96 9.02______________________________________
EXAMPLE 39
N-Cycloheptyl-4-{N-methyl-N-[(2E, 4E)-5-(4-nitrophenyl)-2,4-pentadienoyl]amino}benzenesulfonamide ##STR177##
m.p. (.degree.C.): 208.about.210 (AcOEt-iso-Pr.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.13 (2H, d, J=8.8 Hz), 7.84 (2H, d, J=8.8 Hz), 7.71 (2H, d, J=8.8 Hz), 7.67 (2H, d, J=7.2 Hz, D.sub.2 O exchange), 7.49 (2H, d, J=8.8 Hz), 7.4.about.7.0 (3H, m), 6.13 (1H, m), 3.33 (1H, m), 3.22 (3H, m), 2.0.about.1.2 (12H, m)
Mass m/e (FD): 483 (MH.sup.+)
______________________________________elemental analysis as C.sub.25 H.sub.29 N.sub.3 O.sub.5 S C H N______________________________________calculated (%) 62.09 6.05 8.69found (%) 62.03 6.02 8.68______________________________________
EXAMPLE 40
N-(2-Indanyl-4-{N-methyl-N-[(E)-3-(3,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR178##
m.p. (.degree.C.): 243.about.244 (AcOEt)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.36 (2H, s), 8.13 (1H, d, J=6.6 Hz), 7.93 (2H, d, J=8.4 Hz), 7.57 (2H, d, J=8.4 Hz), 7.36 (1H, d, J=15.8 Hz), 7.11 (4H, s), 6.33 (1H, d, J=15.8 Hz), 6.27 (3H, brs), 3.33 (3H, s), 3.02 (2H, dd, J=16.0, 7.5 Hz), 2.73 (2H, dd, J=16.0 Hz)
Mass m/e (FD): 464 (MH.sup.+)
______________________________________elemental analysis as C.sub.25 H.sub.24 N.sub.2 O.sub.5 S.0.6H.sub.2 O C H N______________________________________calculated (%) 63.17 5.34 5.89found (%) 63.15 5.67 4.93______________________________________
EXAMPLE 41
N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR179##
m.p. (.degree.C.): 215.about.217 (iso Pr.sub.2 O-Et.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.88 (1H, s, D.sub.2 O exchange), 8.08 (1H, d, J=7.0 Hz, D.sub.2 O exchange), 7.91 (2H, d, J=8.8 Hz), 7.5 (2H, d, J=8.8 Hz), 7.48 (1H, d, J=15.4 Hz), 7.29 (2H, d, J=8.8 Hz), 7.11 (4H, s), 6.69 (2H, d, J=8.4 Hz), 6.31 (1H, d, J=15.4 Hz), 3.94 (1H, m), 3.36 (3H, s), 3.16.about.2.52 (4H, m)
Mass m/e (FD): 449 (MH.sup.+)
______________________________________elemental analysis as C.sub.25 H.sub.24 N.sub.2 O.sub.4 S C H N______________________________________calculated (%) 66.96 5.39 6.25found (%) 66.63 5.23 6.04______________________________________
EXAMPLE 42
Disodium salt of 4-{(E)-1-[N-methyl-N-[4-(2-indanyl)aminosulfonylphenyl]amino]-3-propenoyl}phenoxyacetic acid ##STR180##
m.p. (.degree.C.): 223.about.237 (EtOH-H.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 7.74 (2H, d, J=8.8 Hz), 7.45 (1H, d, J=15.4 Hz), 7.24 (4H, ABq), 7.02 (4H, m), 6.73 (2H, d, J=8.3 Hz), 6.22 (1H, d, J=15.4 Hz), 4.13 (2H, s), 3.29 (3H, s), 3.72 (1H, m), 2.96.about.2.35 (4H, m)
Mass m/e (FAB): 551 (MNa.sup.+, base), 529 (MH.sup.+), 207, 137, 115
______________________________________elemental analysis as C.sub.27 H.sub.24 N.sub.2 O.sub.6 Na.sub.2.4.1H.sub.2 O C H N______________________________________calculated (%) 51.94 5.20 4.49found (%) 51.58 4.90 4.40______________________________________
EXAMPLE 43
N-Cycloheptyl-4-{N-methyl-N-[(E)-3-(3-fluoro-4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR181##
m.p. (.degree.C.): 190.about.191 (AcOEt-iso Pr.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 7.87 (2H, d, J=8.4 Hz), 7.68 (1H, d, J=7.9 Hz), 7.52 (2H, d, J=8.4 Hz), 6.96 (1H, d, J=15.6 Hz), 7.5.about.6.7 (3H, m), 6.28 (1H, d, J=15.6 Hz), 3.34 (3H, s), 3.2 (3H, m), 1.8.about.1.1 (12H, m)
Mass m/e (FD): 446 (M.sup.+)
______________________________________elemental analysis as C.sub.23 H.sub.27 FN.sub.2 O.sub.4 S C H N______________________________________calculated (%) 61.86 6.10 6.27found (%) 61.73 6.04 6.13______________________________________
EXAMPLE 44
N-Cycloheptyl-4-{N-methyl-N-[(2E; 4E)-5-(3,5-dibromo-4-hydroxyphenyl)-2,4-pentadienoyl]amino}benzenesulfonamide ##STR182##
m.p. (.degree.C.): 201.about.202 (EtOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 7.87 (2H, d, J=8.3 Hz), 7.70 (2H, s), 7.69 (1H, d, J=7.5 Hz), 7.51 (2H, d, J=8.3 Hz), 7.40.about.7.00 (2H, m), 7.00.about.6.80 (2H, m), 5.97 (1H, d, J=14.1 Hz), 3.30 (3H, s), 1.80.about.1.00 (12H, m)
Mass m/e (FAB): 613 (MH.sup.+), 331, 307, 289, 154 (base)
______________________________________elemental analysis as C.sub.25 H.sub.28 Br.sub.2 N.sub.2 O.sub.4 S C H N______________________________________calculated (%) 49.03 4.61 4.57found (%) 48.79 4.40 4.53______________________________________
EXAMPLE 45
N-Cycloheptyl-4-{N-methyl-N-[(E)-3-(4-fluorophenyl-2-propenoyl)amino}benzenesulfonamide ##STR183##
m.p. (.degree.C.): 168.about.169 (AcOEt-isoPr.sub.2 O)
.sup.1 H-NMR (90 MHz, CDCl.sub.3) .delta.: 7.94 (2H, d, J=8.6 Hz), 7.68 (1H, d, J=15.6 Hz), 7.36 (2H, d, J=8.6 Hz), 7.31 (2H, dd, J=8.8, 5.3 Hz), 6.98 (2H, J=8.8 Hz), 6.24 (1H, d, J=15.6 Hz), 4.61 (1H, d, J=8.4 Hz), 3.44 (3H, s), 3.44 (1H), 2.0.about.1.3 (12H, m)
Mass m/e (FD): 430 (M.sup.+)
______________________________________elemental analysis as C.sub.23 H.sub.27 FN.sub.2 O.sub.3 S C H N______________________________________calculated (%) 64.16 6.32 6.51found (%) 64.15 6.28 6.40______________________________________
EXAMPLE 46
N-(2-Indanyl)-4-{N-methyl-N-[(2E, 4E)-5-(3,4-dihydroxyphenyl)-2,4-pentadienoyl]amino}benzenesulfonamide ##STR184##
m.p. (.degree.C.): 194.about.197 (AcOEt-isoPr.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.11 (1H, d, J=6.6 Hz, D.sub.2 O exchange), 7.90 (2H, d, J=8.8 Hz), 7.52 (2H, d, J=8.8 Hz), 7.11 (4H, s), 6.87.about.6.50 (4H, m), 5.98 (1H, d, J=15.4 Hz), 3.32 (3H, s), 3.20.about.2.52 (4H, m)
Mass m/e (FD): 491 (MH.sup.+)
______________________________________elemental analysis as C.sub.27 H.sub.26 N.sub.2 O.sub.5 S C H N______________________________________calculated (%) 64.52 5.48 5.57found (%) 64.52 5.53 5.58______________________________________
EXAMPLE 47
N-[2-(1,2,3,4-Tetrahydro)naphthyl]-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR185##
m.p. (.degree.C.): 277.about.280 (isoPr.sub.2 O-Etzo)
.sup.1 H-H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.20 (1H, br, D.sub.2 O exchange), 7.92 (2H, d, J=8.3 Hz), 7.90 (1H, br, D.sub.2 O, exchange), 7.53 (2H, d, J=8.3 Hz), 7.39 (1H, d, J=15.8 Hz), 7.10.about.6.80 (4H, m), 6.80.about.6.52 (3H, m), 6.19 (1H, d, J=15.8 Hz), 2.72 (4H, m), 2.00.about.1.60 (2H, m)
3 Mass m/e (FD): 479 (MH.sup.+)
______________________________________elemental analysis as C.sub.26 H.sub.26 N.sub.2l O.sub.5 S C H N______________________________________calculated (%) 65.25 5.48 5.85found (%) 65.20 5.51 5.64______________________________________
EXAMPLE 48
N-[2-(1,2,3,4-Tetrahydro)naphthyl]-4-{N-methyl-N-[(2E, 4E)-5-(3,4-dihydroxyphenyl)-2,4-pentadienoyl]amino}benzenesulfonamide ##STR186##
m.p. (.degree.C.): 190.about.194 (isoPr.sub.2 O-Et.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 7.91 (2H, d, J=8.4 Hz), 7.90 (1H, d, D.sub.2 O exchange), 7.51 (2H, d, J=8.8 Hz), 7.37.about.6.59 (10H, m), 5.96 (1H, d, J=14.5 Hz), 3.32 (3H, s), 2.72 (4H, m), 1.77 (2H, m)
Mass m/e (FAB): 505 (MH.sup.+), 189, 131 (base)
______________________________________elemental analysis as C.sub.28 H.sub.27 N.sub.2 O.sub.5 S.0.5H.sub.2 O C H N______________________________________calculated (%) 65.48 5.69 5.45found (%) 65.37 5.88 5.25______________________________________
EXAMPLE 49
N-Cycloheptyl-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR187##
m.p. (.degree.C.): 207.about.210 (AcOEt-Et.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 7.86 (2H, d, J=8.4 Hz), 7.51 (2H, d, J=8.8 Hz), 7.37 (2H, d, J=15.4 Hz), 6.82.about.6.59 (3H, m), 6.13 (1H, d, J=15.4 Hz), 3.32 (3H, s), 1.90.about.1.00 (12H, m)
Mass m/e (FD): 444 (M.sup.+)
______________________________________elemental analysis as C.sub.23 H.sub.28 N.sub.2 O.sub.5 S C H N______________________________________calculated (%) 62.14 6.35 6.30found (%) 61.99 6.27 6.17______________________________________
EXAMPLE 50
N-Cycloheptyl-4-{N-methyl-N-[(2E, 4E)-5-(3,4-dihydroxyphenyl)-2,4-pentadienoyl]amino}benzenesulfonamide ##STR188##
m.p. (.degree.C.): 213.about.215 (AcOEt-Et.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.30, 8.36 (each 1H, s, D.sub.2 O exchange), 7.85 (2H, d, J=8.4 Hz), 7.68 (1H, d, J=7.4 Hz, D.sub.2 O exchange), 7.49 (2H, d, J=8.8 Hz), 7.33.about.6.39 (6H, m), 5.89 (1H, d, J=14.1 Hz), 3.29 (3H, s), 3.20 (1H, m), 1.44 (12H, m)
Mass m/e (FD): 470 (M.sup.+)
______________________________________elemental analysis as C.sub.25 H.sub.30 N.sub.2 O.sub.5 S.0.5H.sub.2 O C H N______________________________________calculated (%) 62.61 6.52 5.84found (%) 62.54 6.37 5.66______________________________________
EXAMPLE 51
N-(2-Indanyl)-4-{N-methyl-N-I(E)-3-(2-chloro-3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR189##
m.p. (.degree.C.): 201.about.205 (isoPr.sub.2 O-AcOEt)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.25, 8.00 (each 1H, br, D.sub.2 O exchange), 7.92 (2H, d, J=8.3 Hz), 7.78 (1H, d, J=15.4 Hz), 7.57 (2H, d, J=8.3 Hz), 7.10 (4H, s), 6.86 (1H, d, J=8.0 Hz), 6.64 (1H, d, J=8.0 Hz), 6.37 (1H, d, J=15.4 Hz), 3.37 (3H, s), 3.20.about.2.52 (4H, m)
Mass m/e (FD): 498 (M.sup.+)
______________________________________elemental analysis as C.sub.25 H.sub.23 ClN.sub.2 O.sub.5 S C H N______________________________________calculated (%) 60.18 4.65 5.61found (%) 60.24 4.81 5.62______________________________________
EXAMPLE 52
N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(3-chloro-4,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR190##
m.p. (.degree.C.): 234.about.235 (AcOEt-CH.sub.2 Cl.sub.2 -EtOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.00.about.9.00, 8.00 (each 1H, br, D.sub.2 O exchange), 7.91 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.4 Hz), 7.38 (1H, d, J=15.8 Hz), 7.09 (4H, s) 6.98 (1H, brs), 6.79 (1H, brs), 6.29 (1H, d, J=15.4 Hz), 3.92 (1H, br), 3.35 (3H, s), 3.16.about.2.55 (4H, m)
Mass m/e (FD): 498 (M.sup.+)
______________________________________elemental analysis as C.sub.25 H.sub.23 ClN.sub.2 O.sub.5 S C H N______________________________________calculated (%) 60.18 4.65 5.61found (%) 59.88 4.76 5.52______________________________________
EXAMPLE 53
N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(2-chloro-4,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR191##
m.p. (.degree.C.): 226.about.228 (AcOEt-CH.sub.2 Cl.sub.2)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.12 (1H, d, J=6.1 Hz, D.sub.2 O exchange), 7.92 (2H, d, J=8.4 Hz), 7.74 (1H, d, J=15.4 Hz), 7.57 (2H, d, J=8.8 Hz), 7.10 (4H, s), 6.85 (1H, s), 6.80 (1H, s), 6.30 (1H, d, J=15.4 Hz), 3.94 (1H, m), 3.36 (3H, s), 3.20.about.2.54 (4H, m)
Mass m/e (FD): 498 (M.sup.+)
______________________________________elemental analysis as C.sub.25 H.sub.23 ClN.sub.2 O.sub.5 S.H.sub.2 O C H N______________________________________calculated (%) 58.09 4.87 5.42found (%) 58.20 4.70 5.36______________________________________
EXAMPLE 54
N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(3-bromo-4,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR192##
m.p. (.degree.C.): 221.about.222 (MeOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.90, 9.55 (each 1H, br, D.sub.2 O exchange), 8.11 (1H, d, J=6.4 Hz, D.sub.2 O exchange), 7.92 (2H, d, J=8.8 Hz), 7.56 (2H, d, J=8.8 Hz), 7.39 (1H, d, J=15.4 Hz), 7.10 (4H, s), 7.10 (1H, s), 6.82 (1H, d, J=2 Hz), 6.29 (1H, d, J=15.4 Hz), 3.92 (1H, m), 3.36 (3H, s), 3.20.about.2.56 (4H, m)
Mass m/e (FD): 543 (M.sup.+)
______________________________________elemental analysis as C.sub.25 H.sub.23 BrN.sub.2 O.sub.5 S C H N______________________________________calculated (%) 55.25 4.27 5.16found (%) 55.15 4.32 4.75______________________________________
EXAMPLE 55
N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(2-bromo-4,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR193##
m.p. (.degree.C.): 231.about.233 (AcOEt-MeOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.56 (2H, brs), 8.08 (1H, brd, J=6 Hz), 7.93 (2H, d, J=8.6 Hz), 7.71 (1H, d, J=14.3 Hz), 7.58 (2H, d, J=8.6 Hz), 7.11 (4H, s), 6.97 (1H, s), 6.86 (1H, s), 6.26 (1H, d, J=14.3 Hz), 3.92 (1H, brq, J=7 Hz), 3.34 (3H, s), 3.01 (2H, dd, J=15.8, 7.0 Hz), 2.72 (2H, dd, J=15.8, 7.0 Hz)
Mass m/e (FAB): 544, 542 (M.sup.+); 243, 241, 162 (base); 117
______________________________________elemental analysis as C.sub.25 H.sub.23 BrN.sub.2 O.sub.5 S C H N______________________________________calculated (%) 55.25 4.27 5.16found (%) 54.95 4.33 4.96______________________________________
EXAMPLE 56
N-(2-indanyl)-4-{N-methyl-N-I(E)-3-(3,4-dihydroxyphenyl)-2-methyl-2-propenoyl]amino}benzenesulfonamide ##STR194##
m.p. (.degree.C.): 155.about.156 (isoPr.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.98 (2H, br, D.sub.2 O exchange), 7.96 (1H, br, D.sub.2 O exchange), 7.80 (2H, d, J=8.4 Hz), 7.47 (2H, d, J=8.8 Hz), 7.03 (4H, m), 6.73.about.6.31 (4H, m), 3.80 (1H, m), 3.34 (3H, s), 3.04.about.2.44 (4H, m), 1.83 (3H, s)
Mass m/e (FAB): 479 (MH.sup.+), 282, 177 (base), 149, 131
______________________________________elemental analysis as C.sub.26 H.sub.26 ClN.sub.2 O.sub.5 S C H N______________________________________calculated (%) 65.25 5.48 5.85found (%) 65.09 5.54 5.74______________________________________
EXAMPLE 57
N-Cyclopentyl-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR195##
m.p. (.degree.C.): 209.about.211 (AcOEt-Et.sub.2 o)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.10 (1H, br, D.sub.2 O exchange), 7.87 (2H, d, J=8.8 Hz), 7.52 (2H, d, J=8.4 Hz), 7.38 (2H, d, J=15.4 Hz), 6.82.about.6.60 (3H, m), 6.13 (1H, d, J=15.3 Hz), 3.32 (3H, s), 3.10.about.3.60 (1H, m), 1.90.about.1.10 (8H, m)
Mass m/e (FD):
416 (M.sup.+)
______________________________________elemental analysis as C.sub.21 H.sub.24 N.sub.2 O.sub.5 S C H N______________________________________calculated (%) 60.56 5.81 6.73found (%) 60.56 5.91 6.46______________________________________
EXAMPLE 58
N-Cyclohexyl-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR196##
m.p. (.degree.C.): 224.about.225 (AcOEt-isoPr.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.16 (2H, brs), 7.88 (2H, d, J=8.6 Hz), 7.64 (1H, brd, J=7 Hz), 7.52 (2H, d, J=8.6 Hz), 7.38 (2H, d, J=15.9 Hz), 6.77 (1H, brs), 6.69 (2H, s), 6.13 (1H, d, J=15.9 Hz), 3.34 (3H, s), 3.00 (1H, m), 1.8.about.1.0 (10H, m)
Mass m/e (FD): 430 (M.sup.+)
______________________________________elemental analysis as C.sub.22 H.sub.26 N.sub.2 O.sub.5 S C H N______________________________________calculated (%) 61.38 6.09 6.51found (%) 61.19 6.17 6.11______________________________________
EXAMPLE 59
N-(1-Indanyl)-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR197##
m.p. (.degree.C.): 202.about.206 (isoPr.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.10, 8.15 (each 1H, br, D.sub.2 O exchange), 7.95 (2H, d, J=8.4 Hz), 7.56 (2H, d, J=8.3 Hz), 7.39 (1H, d, J=15.4 Hz), 7.82.about.7.57 (3H, m), 7.23.about.7.05 (4H, m), 6.19 (1H, d, J=15.4 Hz), 4.62 (1H, m), 3.34 (3H, s), 2.72 (2H, m), 2.30.about.1.40 (2H, m)
Mass m/e (FD): 465 (MH.sup.+)
______________________________________elemental analysis as C.sub.25 H.sub.24 N.sub.2 O.sub.5 S C H N______________________________________calculated (%) 64.64 5.21 6.03found (%) 64.69 5.32 6.05______________________________________
EXAMPLE 60
N-[2-(2-pyridyl)ethyl]-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR198##
m.p. (.degree.C.): 95.about.105 (amorphous, isoPr.sub.2 O-Et.sub.2 O -AcOEt)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.39, 9.07 (each 1H, s, D.sub.2 O exchange), 8.44 (1H, m), 7.83 (2H, d, J=8.3 Hz), 7.51 (2H, d, J=8.4 Hz), 7.70.about.7.40 (1H, m), 7.30.about.7.05 (3H, m), 6.80.about.6.50 (3H, m), 6.19 (1H, d, J=15.4 Hz), 3.32 (3H, s), 3.40.about.2.60 (4H, m)
Mass m/e (FD): 454 (M.sup.+)
______________________________________elemental analysis as C.sub.23 H.sub.23 N.sub.3 O.sub.5 S.0.3H.sub.2 O C H N______________________________________calculated (%) 60.12 5.19 9.14found (%) 60.15 5.36 8.90______________________________________
EXAMPLE 61
N-(2-Thiazolyl)-4-{N-I (E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR199##
m.p. (.degree.C.): 219.about.220 (MeOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.37, 9.49, 9.21 (each 1H, brs, D.sub.2 O exchange), 7.78 (4H, s), 7.44 (1H, d, J=16.2 Hz), 7.24 (2H, d, J=4.8 Hz), 7.03.about.6.67 (3H, m), 6.80 (1H, d, J=4.8 Hz), 6.52 (1H, d, J=16.2 Hz)
Mass m/e (FD): 417 (M.sup.+)
______________________________________elemental analysis as C.sub.18 H.sub.15 N.sub.3 O.sub.5 S.sub.2 C H N______________________________________calculated (%) 51.79 3.62 10.07found (%) 51.39 3.61 10.03______________________________________
EXAMPLE 62
N-[2-(4,6-Dimethyl)pyrimidyl]-4-{N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR200##
m.p. (.degree.C.): 174.about.177 (MeOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.56 (1H, brs, D.sub.2 O exchange), 7.96 (2H, d, J=8.8 Hz), 7.81 (1H, d, J=8.8 Hz), 7.45 (1H, d, J=15.7 Hz), 7.09.about.6.71 (4H, m), 6.57 (1H, d, J=15.7 Hz), 2.27 (6H, s)
Mass m/e (FD): 440 (M.sup.+)
______________________________________elemental analysis as C.sub.21 H.sub.20 N.sub.4 O.sub.5 S.3H.sub.2 O C H N______________________________________calculated (%) 51.01 5.30 11.32found (%) 50.86 4.70 10.99______________________________________
EXAMPLE 63
N-(2-Hydroxyethyl)-4-{N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR201##
m.p. (.degree.C.): 216.about.219 (MeOH-H.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.41 (1H, s), 9.60.about.9.00 (2H, br, D.sub.2 O exchange), 7.79 (4H, ABq), 7.60.about.7.36 (2H, m), 7.09.about.6.68 (3H, m), 6.72 (1H, d, J=16.3 Hz), 3.36 (2H, t, J=6.6 Hz), 2.78 (2H, q like, J=6.2 Hz)
Mass m/e (FD): 378 (M.sup.+)
______________________________________elemental analysis as C.sub.17 H.sub.8 N.sub.2 O.sub.6 S C H N______________________________________calculated (%) 53.96 4.80 7.40found (%) 53.91 4.81 7.02______________________________________
EXAMPLE 64
N-Cyclohexyl-4-{N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR202##
m.p. (.degree.C.): 120.about.124 (AcOEt-isoPr.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.39 (1H, s), 9.49 (1H, s), 9.20 (1H, s), 7.87 (2H, d, J=8.8 Hz), 7.73 (2H, d, J=8.8 Hz), 7.50 (1H, d, J=7.9 Hz), 7.46 (1H, d, J=15.4 Hz), 7.02 (1H, brs), 6.96 (1H, brd, J=7.9 Hz), 6.77 (1H, d, J=7.9 Hz), 6.54 (1H, d, J=15.4 Hz), 2.91 (1H, m), 1.8.about.1.1 (10H, m)
Mass m/e (FD): 416 (M.sup.+)
______________________________________elemental analysis as C.sub.21 H.sub.24 N.sub.2 O.sub.5 S.0.3H.sub.2 O C H N______________________________________calculated (%) 59.78 5.88 6.64found (%) 60.06 5.91 6.12______________________________________
EXAMPLE 65
4-{N-Methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR203##
m.p. (.degree.C.): 205.about.206 (AcOEt-Et.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.38 (1H, brs, D.sub.2 O exchange), 9.07 (1H, brs, D.sub.2 O exchange), 7.86 (2H, d, J=8.3 Hz), 7.48 (2H, d, J=8.3 Hz), 7.37 (2H, d, J=15.4 Hz), 7.40 (2H, s, D.sub.2 O exchange), 6.69 (3H, m), 6.16 (1H, d, J=15.4 Hz), 3.29 (3H, s)
Mass m/e (FD): 348 (M.sup.+)
______________________________________elemental analysis as C.sub.16 H.sub.16 N.sub.2 O.sub.5 S C H N______________________________________calculated (%) 55.16 4.63 8.04found (%) 55.06 4.68 7.64______________________________________
EXAMPLE 66
4-{N-Isopropyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR204##
m.p. (.degree.C.): 224.about.228 (H.sub.2 O-MeOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.20 (1H, br, D.sub.2 O exchange), 7.94 (2H, d, J=7.9 Hz), 7.80.about.7.20 (1H, br, D.sub.2 O exchange), 7.44 (2H, d, J=7.9 Hz), 7.39 (1H, d, J=15.4 Hz), 6.67 (3H, s), 5.80 (1H, d, J=15.4 Hz), 4.92 (1H, m), 1.05 (6H, d, J=6.5 Hz)
Mass m/e (FD): 376 (M.sup.+)
______________________________________elemental analysis as C.sub.18 H.sub.20 N.sub.2 O.sub.5 S C H N______________________________________calculated (%) 57.43 5.36 7.44found (%) 57.38 5.36 7.30______________________________________
EXAMPLE 67
N-[2-(N,N-Dimethylamino)ethyl]-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide hydrochloride ##STR205##
m.p. (.degree.C.): 177.about.180 (AcOEt)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.40 (1H, br, D.sub.2 O exchange), 9.6.about.8.8, 8.22 (each 1H, br, D.sub.2 O exchange), 7.92 (2H, d, J=8.3 Hz), 7.56 (2H, d, J=8.3 Hz), 7.43 (1H, d, J=15.4 Hz), 6.92.about.6.64 (3H, m), 6.22 (1H, d, J=15.4 Hz), 3.34 (3H, s), 3.17 (4H, brs), 2.76 (6H, s)
Mass m/e (FD): 420 (MH.sup.+)
______________________________________elemental analysis as C.sub.20 H.sub.25 N.sub.3 O.sub.5 S.HCl.0.3H.sub.2 C H N______________________________________calculated (%) 52.07 5.81 9.11found (%) 52.13 5.66 8.88______________________________________
EXAMPLE 68
N-methyl-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR206##
m.p. (.degree.C.): 180.about.182 (Et.sub.2 O -AcOEt-EtOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.20 (2H, br, D.sub.2 O exchange), 7.85 (2H, d, J=8.4 Hz), 7.54 (2H, d, J=8.3 Hz), 7.40 (1H, d, J=15.3 Hz), 6.84.about.6.60 (3H, m), 6.21 (1H, d, J=15.3 Hz), 3.34 (3H, s), 2.47 (3H, s, D.sub.2 O sharpen)
Mass m/e (FD): 362 (M.sup.+)
______________________________________elemental analysis as C.sub.17 H.sub.18 N.sub.2 O.sub.5 S.0.1H.sub.2 O C H N______________________________________calculated (%) 56.06 5.04 7.69found (%) 56.28 5.06 7.30______________________________________
EXAMPLE 69
N-Isopropyl-4-{N-methyl-N-[(E)-3-(3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR207##
m.p. (.degree.C.): 197.about.199 (H.sub.2 O-MeOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.50.about.8.50 (1H, br), 7.87 (2H, d, J=8.8 Hz), 7.70.about.7.24 (4H, m), 6.80.about.6.60 (3H, m), 6.13 (1H, d, J=15.3 Hz), 3.32 (3H, s), 0.98 (6H, d, J=7.0 Hz)
Mass m/e (FAB): 391 (MH.sup.+), 289, 228, 236
______________________________________elemental analysis as C.sub.19 H.sub.22 N.sub.2 O.sub.5 S C H N______________________________________calculated (%) 58.45 5.68 7.18found (%) 58.33 5.64 6.98______________________________________
EXAMPLE 70
(E)-N-Methyl-N-[4-(4-morpholinyl)sulfonylphenyl]-3-(4-methylsulfonylphenyl)-2-propenamide ##STR208##
m.p. (.degree.C.): 265.about.266 (THF-MeOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.40, 9.03 (each 1H, br, D.sub.2 O exchange), 7.81 (2H, d, J=8.4 Hz), 7.59 (2H, d, J=8.8 Hz), 7.40 (1H, d, J=15.4 Hz), 6.86.about.6.60 (3H, m), 6.22 (1H, d, J=15.4 Hz), 3.65 (4H, m), 3.36 (3H, s), 2.91 (4H, m)
Mass m/e (FD): 418 (M.sup.+)
______________________________________elemental analysis as C.sub.20 H.sub.22 N.sub.2 O.sub.6 S C H N______________________________________calculated (%) 57.40 5.30 6.70found (%) 57.24 5.37 6.52______________________________________
EXAMPLE 71
4-{N-[(E)-3-(3,4-Dimethoxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR209##
m.p. (.degree.C.): 251.about.2.52 (CH.sub.2 Cl.sub.2)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.40 (1H, br, D.sub.2 O exchange), 7.82 (4H, s), 7.59 (1H, d, J=16.2 Hz), 7.24 (2H, brs, D.sub.2 O exchange), 7.35.about.7.11 (2H, m), 7.01 (1H, d, J=8.1 Hz), 6.70 (1H, d, J=16.2 Hz), 3.34 (6H, s)
Mass m/e (FD): 362 (M.sup.+)
______________________________________elemental analysis as C.sub.17 H.sub.18 N.sub.2 O.sub.5 S C H N______________________________________calculated (%) 56.34 5.01 7.73found (%) 56.27 4.94 7.56______________________________________
EXAMPLE 72
4-{N-[(Z)-3-(3,4-Dimethoxyphenyl)-3-(3-Pyridyl)-2-propenoyl]amino}benzenesulfonamide ##STR210##
m.p. (.degree.C.): 168.about.171 (CH.sub.2 Cl.sub.2 -EtOH-MeOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.69 (1H, brs), 8.68 (1H, m), 8.59 (1H, brs), 7.88 (1H, dt, J=7.9, 2.2 Hz), 7.71 (4H, s), 7.22 (2H, brs, D.sub.2 O exchange), 7.09 (1H, d, J=1.7 Hz), 7.01 (1H, d, J=8.4 Hz), 6.91 (1H, s), 6.76.about.6.52 (1H, m), 6.62 (1H, dd, J=8.4, 1.7 Hz), 3.78 (6H, s)
Mass m/e (FD): 439 (M.sup.+)
______________________________________elemental analysis as C.sub.22 H.sub.21 N.sub.3 O.sub.5 S.1.7H.sub.2 O C H N______________________________________calculated (%) 56.21 5.23 8.94found (%) 55.84 4.67 8.70______________________________________
EXAMPLE 73
4-{N-[(E)-3-(3,4-Dimethoxyphenyl)-3-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide ##STR211##
m.p. (.degree.C.): 207.about.208 (CH.sub.2 Cl.sub.2)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10-43 (1H, s, D.sub.2 O exchange), 8.49.about.8.63 (2H, m), 7.71 (4H, s), 7.64 (1H, dt, J=7.9, 2.2 Hz), 7.41 (1H, dd, J=7.9, 3.9 Hz), 7.22 (2H, s, D.sub.2 O exchange), 6.96 (1H, d, J=8.3 Hz), 6.82 (1H, d, J=1.7 Hz), 6.71 (1H, dd, J=8.3, 1.8 Hz), 6.62 (1H, s), 3.77, 3.63 (each 3H, s)
Mass m/e (FAB): 440 (MH.sup.+), 397, 289, 268
______________________________________elemental analysis as C.sub.22 H.sub.21 N.sub.3 O.sub.5 S C H N______________________________________calculated (%) 60.13 4.82 9.56found (%) 60.15 4.77 9.36______________________________________
EXAMPLE 74
4-{N-[(Z)-3-(3,4-Dihydroxyphenyl)-3-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide hydrobromide ##STR212##
m.p. (.degree.C.): 255.about.256 (EtOH-MeOH-H.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.41 (1H, brs, D.sub.2 O exchange), 9.40, 9.11 (each 1H, s, D.sub.2 O exchange), 8.51 (2H, dd, J=4.9, 1.8 Hz), 8.33 (1H, brd, J=1.8 Hz), 7.69 (4H, s), 7.55 (1H, d, J=7.9 Hz), 7.38 (1H, dd, J=7.9, 4.9 Hz), 7.21 (2H, s, D.sub.2 O exchange), 6.94.about.6.52 (4H, m)
Mass m/e (FAB): 412 (MH.sup.+), 307, 289, 240
______________________________________elemental analysis as C.sub.20 H.sub.17 N.sub.3 O.sub.5 S.HBr.0.7H.sub.2 C H N______________________________________calculated (%) 47.57 3.84 8.32found (%) 47.65 4.03 7.61______________________________________
EXAMPLE 75
4-{N-[(E)-3-(3,4-Dihydroxyphenyl)-3-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide ##STR213##
m.p. (.degree.C.): 195.about.201 (CH.sub.2 Cl.sub.2 --H.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.37 (1H, brs, D.sub.2 O exchange), 10.00 (1H, br, D.sub.2 O exchange), 8.72.about.8.48 (2H, m), 7.82.about.7.60 (1H, m), 7.70 (4H, s), 7.45 (1H, dd, J=7.9, 3.9 Hz), 7.21 (2H, s, D.sub.2 O exchange), 6.70 (1H, d, J=7.9 Hz), 6.61 (1H, d, J=1.8 Hz), 6.49 (1H, s), 6.45 (1H, dd, J=7.9, 1.8 Hz)
Mass m/e (FD): 411 (M.sup.+)
______________________________________elemental analysis as C.sub.20 H.sub.17 N.sub.3 O.sub.5 S.1.5H.sub.2 O C H N______________________________________calculated (%) 54.79 4.60 9.58found (%) 54.90 4.18 8.96______________________________________
EXAMPLE 76
4-{N-[(Z)-3-(3,4-Dihydroxyphenyl)-2-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide hydrobromide ##STR214##
m.p. (.degree.C.): 233.about.235 (MeOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.30 (1H, s), 8.89 (2H, m), 8.35 (1H, brd, J=8.0 Hz), 8.01 (1H, dd, J=8.0, 4.8 Hz), 7.80 (4H, s), 7.71 (1H, s), 7.29 (1H, br, D.sub.2 O exchange), 6.67 (1H, d, J=8.8 Hz), 6.42 (1H, brs), 6.50 (1H, dd, J=8.8, 1.5 Hz)
Mass m/e (FD): 411 (M.sup.+)
______________________________________elemental analysis as C.sub.20 H.sub.17 N.sub.3 O.sub.5 S.HBr.0.3H.sub.2 C H N______________________________________calculated (%) 48.26 3.78 8.44found (%) 48.45 3.94 7.86______________________________________
EXAMPLE 77
4-{N-[(E)-3-(3,4-Dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR215##
m.p. (.degree.C.): 292.about.294 (MeOH-H.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.26 (2H, br, D.sub.2 O exchange), 7.78 (4H, s), 7.44 (1H, d, J=16.2 Hz), 7.20 (3H, br, D.sub.2 O exchange), 7.10.about.6.60 (3H, m), 6.51 (1H, d, J=16.2 Hz)
Mass m/e (FD): 334 (M.sup.+)
______________________________________elemental analysis as C.sub.15 H.sub.14 N.sub.2 O.sub.5 S C H N______________________________________calculated (%) 53.89 4.22 8.38found (%) 53.64 4.13 8.15______________________________________
EXAMPLE 78
N-[4-(1-Piperidylmethyl)-benzyl]-4-{N-methyl-N-[(E)-3-(4-methylpulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide hydrochloride ##STR216##
m.p. (.degree.C.): 162.about.164 (AcOEt-EtOH-MeOH)
.sup.1 H-NMR (400 MHz, CDCl.sub.3) .delta.: 11.30 (1H, brs), 8.12 (2H, d, J=8.2 Hz), 7.88 (2H, d, J=8.1 Hz), 7.74 (2H, d, J=15.5 Hz), 7.70 (1H, t, J=6.3 Hz), 7.55 (2H, d, J=8.4 Hz), 7.54 (1H, d, J=8.1 Hz), 7.40 (2H, d, J=8.2 Hz), 7.39 (2H, d, J=7.7 Hz), 6.50 (1H, d, J=15.5 Hz), 4.15 (2H, d, J=6.3 Hz), 4.03 (2H, d, J=5.1 Hz), 3.47 (3H, s), 3.41 (2H, d, J=10.8 Hz), 3.05 (3H, s), 2.61 (2H, q, J=10 Hz), 2.15 (2H, q, J=10 Hz), 1.79 (3H, m), 1.36 (1H, q, J=10 Hz)
Mass m/e (FAB): 582 (MH.sup.+), 372, 203
______________________________________elemental analysis as C.sub.30 H.sub.35 N.sub.3 O.sub.5 S.sub.2.HCl C H N______________________________________calculated (%) 58.28 5.87 6.80found (%) 57.92 5.79 6.67______________________________________
EXAMPLE 79
[1-[2-(3,4-Dimethoxyphenyl)ethyl]-4-piperidyl]-4{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR217##
m.p. (.degree.C.): 146.about.150 (Et.sub.2 O-AcOEt)
.sup.1 H-NMR (90 MHz, CDCl.sub.3) .delta.: 7.98 (2H, d, J=8.6 Hz), 7.89 (2H, d, J=8.4 Hz), 7.74 (1H, d, J=15.6 Hz), 7.51 (2H, d, J=8.4 Hz), 7.38 (2H, d, J=8.6 Hz), 6.81.about.6.70 (3H, m), 6.47 (1H, d, J=15.6 Hz), 4.88 (1H, brd), 3.85 (3H, s), 3.84 (3H, s), 3.47 (3H, s), 3.32 (1H, m), 3.02 (3H, s), 2.82 (2H, m), 2.75 (2H, m), 2.60 (2H, t, like), 2.09 (2H, m), 1.90 (2H, m), 1.62 (2H, m)
Mass m/e (FAB): 642 (MH.sup.+), 490, 265, 264, 209, 165 (base)
______________________________________elemental analysis as C.sub.32 H.sub.39 N.sub.3 O.sub.7 S.0.5H.sub.2 O C H N______________________________________calculated (%) 59.06 6.19 6.46found (%) 58.94 6.04 6.06______________________________________
EXAMPLE 80
N-[1-[2-(3-Pyridyl)ethyl]-4-piperidyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide hydrochloride ##STR218##
m.p. (.degree.C.): 182.about.185 (AcOEt)
.sup.1 H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.46 (2H, brd), 8.00 (1H, m), 7.88 (4H, d, J=8.2 Hz), 7.77.about.7.63 (3H, m), 7.62.about.7.50 (3H, m), 7.35 (1H, brd), 6.70 (1H, brd, J=15 Hz), 3.37 (3H, s), 3.19 (3H, s), 3.35.about.2.85 (9H, m), 1.78 (4H, m)
Mass m/e (FAB): 583 (MH.sup.+, 490, 277, 185 (base), 106
______________________________________elemental analysis as C.sub.29 H.sub.35 N.sub.4 O.sub.5 S.sub.2.HCl.H.sub.2 O C H N______________________________________calculated (%) 54.66 5.85 8.79found (%) 54.76 5.76 8.99______________________________________
EXAMPLE 81
N-[1-[2-(6-Methyl-2-pyridyl)ethyl]-4-piperidyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]aminolbenzenesulfonamide ##STR219##
m.p. (.degree.C.): 161.about.162 (Et.sub.2 O -AcOEt)
.sup.1 H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.96 (2H, d, J=8.6 Hz), 7.88 (2H, d, J=8.4 Hz), 7.74 (1H, d, J=15.4 Hz), 7.50 (2H, d, J=8.4 Hz), 7.46 (1H, t, J=8.0 Hz), 7.37 (2H, d, J=8.6 Hz), 6.95 (2H, d, J=8.2 Hz), 6.47 (1H, d, J=15.4 Hz), 4.72 (1H, brd), 3.46 (3H, s), 3.30 (1H, m), 3.02 (3H, s), 2.70 (4H, m), 2.49 (3H, s), 2.18 (2H, t, J=7.0 Hz), 1.85 (2H, m), 1.56 (2H, m)
Mass m/e (FAB): 597 (MH.sup.+), 490, 282, 201 (base), 175
______________________________________elemental analysis as C.sub.30 H.sub.36 N.sub.4 O.sub.5 S.sub.2 C H N______________________________________calculated (%) 60.38 6.08 9.39found (%) 60.09 6.01 9.25______________________________________
EXAMPLE 82
N-[4-[1-pyrrolidylmethyl)benzyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR220##
m.p. (.degree.C.): 180.about.182 (AcOEt-CH.sub.2 Cl.sub.2)
.sup.1 H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.94 (2H, d, J=8.8 Hz), 7.87 (2H, d, J=8.2 Hz), 7.74 (1H, d, J=15.4 Hz), 7.51 (2H, d, J=8.2 Hz), 7.35 (2H, d, J=8.8 Hz), 7.26 (2H, d, J=8.2 Hz), 7.16 (2H, d, J=8.2 Hz), 6.47 (1H, d, J=15.4 Hz), 4.20 (2H, s), 3.58 (2H, s), 3.46 (3H, s), 3.03 (3H, s), 2.49 (4H, brs), 1.77 (4H, m)
Mass m/e (FAB): 568 (MH.sup.+), 358, 314, 209, 119 (base)
______________________________________elemental analysis as C.sub.29 H.sub.33 N.sub.3 O.sub.5 S.sub.2.0.7H.sub.2 O C H N______________________________________calculated (%) 60.02 5.98 7.24found (%) 59.97 5.73 7.08______________________________________
EXAMPLE 83
N-[8-(5,6,7,8-Tetrahydro)quinolyl]-4-{N-methyl-N-[(E)-3-(4-methylsulfonylphenyl)-2-propenoyl]amino}benzenesulfonamide hydrochloride ##STR221##
m.p. (.degree.C.): 147.about.150 (AcOEt-MeOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 8.62 (1H, d, J=6 Hz), 8.55 (1H, brs), 8.13 (1H, d, J=8 Hz), 7.98 (2H, d, J=8.8 Hz), 7.88.about.7.60 (6H, m), 7.58 (2H, d, J=8.8 Hz), 6.69 (1H, d, J=15.8 Hz), 4.78 (1H, m), 3.39 (3H, s), 3.20 (3H, s), 2.80 (2H, m), 1.70 (4H, m)
Mass m/e (FD): 525 (M.sup.+)
______________________________________elemental analysis as C.sub.26 H.sub.27 N.sub.5 O.sub.5 S.sub.2.HCl.1.5H.sub.2 O C H N______________________________________calculated (%) 53.01 5.30 7.13found (%) 52.64 5.08 7.07______________________________________
EXAMPLE 84
N-Cyclohexyl-4-{N-[(E)-3-(3-fluoro-4-hydroxyphenyl-2-propenoyl]}aminobenzenesulfonamide ##STR222##
m.p. (.degree.C.): 148.about.150 (AcOEt)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.38 (2H, brs), 7.82 (2H, d, J=8.8 Hz), 7.69 (2H, d, J=8.8 Hz), 7.6.about.6.9 (4H, m), 6.61 (1H, d, J=15.1 Hz), 2.9 (1H, m), 1.8.about.0.9 (10H, m)
Mass m/e (FD): 418 (M.sup.+)
______________________________________elemental analysis as C.sub.21 H.sub.23 FN.sub.2 O.sub.5 S C H N______________________________________calculated (%) 60.27 5.54 6.69found (%) 60.27 5.61 6.50______________________________________
EXAMPLE 85
N-Cyclohexyl-N-methyl-4-{N-[(E)-3-(3-fluoro-4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR223##
m.p. (.degree.C.): 115.about.120 (AcOEt-isoPr.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.42 (2H, brs), 7.85 (2H, d, J=8.8 Hz), 7.70 (2H, d, J=8.8 Hz), 7.6.about.6.8 (3H, m), 7.33 (1H, d, J=15.1 Hz), 6.62 (1H, d, J=15.1 Hz), 3.6 (1H, m), 2.68 (3H, s), 1.8.about.1.0 (10H, m)
Mass m/e (FD): 432 (M.sup.+)
______________________________________elemental analysis as C.sub.22 H.sub.25 FN.sub.2 O.sub.4 S C H N______________________________________calculated (%) 61.09 5.83 6.48found (%) 60.89 5.98 6.24______________________________________
EXAMPLE 86
N-Cycloheptyl-4-{N-methyl-N-[(E)-3-(4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR224##
m.p. (.degree.C.): 187.about.189 (AcOEt-isoPr.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.80 (1H, br, D.sub.2 O exchange), 7.87 (2H, d, J=8.3 Hz), 7.68 (1H, d, J=7.5 Hz, D.sub.2 O exchange), 7.52 (2H, d, J=8.3 Hz), 7.46 (1H, d, J=15.4 Hz), 7.23 (2H, d, J=8.8 Hz), 6.70 (2H, d, J=8.4 Hz), 6.20 (1H, d, J=15.4 Hz), 3.33 (3H, s), 3.16 (1H, s), 3.33 (3H, s), 1.80.about.1.00 (12H, m)
Mass m/e (FAB): 429 (MH.sup.+), 309, 253, 147 (base), 107
______________________________________elemental analysis as C.sub.23 H.sub.28 N.sub.2 O.sub.4 S C H N______________________________________calculated (%) 64.46 6.59 6.54found (%) 64.38 6.70 6.36______________________________________
EXAMPLE 87
N-Cyclooctyl-4-{N-methyl-N-[(E)-3-(3-fluoro-4-hydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR225##
m.p. (.degree.C.): 190.about.191 (isoPr.sub.2 O-AcOEt)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 7.87 (2H, d, J=8.7 Hz), 7.67 (1H, d, J=7.7 Hz, D.sub.2 O exchange), 7.51 (2H, d, J=8.8 Hz), 7.44 (1H, d, J=15.4 Hz), 7.35.about.6.85 (3H, m), 6.27 (1H, d, J=15.4 Hz), 3.33 (3H, s), 2.84.about.1.05 (14H, m)
Mass m/e (FAB): 461 (MH.sup.+, base), 351, 271, 165, 137
______________________________________elemental analysis as C.sub.24 H.sub.29 FN.sub.2 O.sub.4 S C H N______________________________________calculated (%) 62.59 6.35 6.08found (%) 62.52 6.17 6.03______________________________________
EXAMPLE 88
N-Cycloheptyl-4-{N-[(E)-3-[4-(1-imidazolyl)phenyl]-2-propenoyl]amino}benzenesulfonamide ##STR226##
m.p. (.degree.C.): 178.about.180 (isoPr.sub.2 O-AcOEt)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.46 (1H, s, D.sub.2 O exchange), 7.70 (4H, ABq), 7.59.about.7.20 (5H, m), 6.90 (1H, t like, J=8.0 Hz), 6.66 (1H, d, J=15.4 Hz), 3.12 (1H, m), 1.80.about.1.00 (12H, m)
Mass m/e (FAB): 433 (MH.sup.+, base), 337, 320, 257, 165, 112
______________________________________elemental analysis as C.sub.22 H.sub.25 N.sub.2 O.sub.4 S C H N______________________________________calculated (%) 61.09 5.83 6.48found (%) 60.96 5.73 6.34______________________________________
EXAMPLE 89
4-{N-[(E)-3-(3-Acetoxy-4-methoxyphenyl)-2-propenoyl]amino}benzenesulfonamid ##STR227##
m.p. (.degree.C.): 237.about.239 (AcOEt)
.sup.1 H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 7.86 (1H, d, J=8.8 Hz), 7.79 (2H, d, J=8.8 Hz), 7.63 (1H, d, J=15.7 Hz), 7.40 (1H, d, J=1.8 Hz), 7.26 (2H, m), 7.17 (1H, d, J=7.9 Hz), 6.83 (1H, d, J=15.7 Hz), 3.84 (3H, s), 2.27 (3H, s)
Mass m/e (FAB): 391 (MH.sup.+), 349, 219, 177 (base), 145
______________________________________elemental analysis as C.sub.18 H.sub.18 N.sub.2 O.sub.6 S C H N______________________________________calculated (%) 55.38 4.65 7.18found (%) 55.46 4.58 6.94______________________________________
EXAMPLE 90
N-Cycloheptyl-4-{N-[(E)-3-(3,4-dihydroxyphenyl)-2-methyl-2-propenoyl]amino}benzenesulfonamide ##STR228##
m.p. (.degree.C.): 206.about.207 (Et.sub.2 O -EtOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.26, 9.09 (each 1H, br, D.sub.2 O exchange), 7.46 (1H, d, J=6.6 Hz, D.sub.2 O exchange), 7.18 (brs), 6.98.about.6.70 (3H, m), 3.08 (1H, m), 2.10 (3H, s), 1.82.about.1.00 (12H, m)
Mass m/e (FAB): 445 (MH.sup.+), 349, 269, 177, 149, 131
______________________________________elemental analysis as C.sub.23 H.sub.28 N.sub.2 O.sub.5 S C H N______________________________________calculated (%) 62.14 6.35 6.30found (%) 61.99 6.41 6.20______________________________________
EXAMPLE 91
N-Cyclohexyl-4-{N-methyl-N-[(E)-3-(3,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR229##
m.p. (.degree.C.): 240.about.241 (AcOEt-isoPr.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.29 (2H, s), 7.84 (2H, d, J=8.6 Hz), 7.67 (2H, d, J=7.9 Hz), 7.48 (2H, d, J=8.6 Hz), 7.28 (1H, d, J=15.5 Hz), 6.22 (1H, d, J=15.5 Hz), 3.34 (3H, s), 2.99 (1H, m), 1.8.about.1.0 (10H, m)
Mass m/e (FD): 430 (M.sup.+)
______________________________________elemental analysis as C.sub.22 H.sub.26 N.sub.2 O.sub.5 S C H N______________________________________calculated (%) 61.38 6.09 6.51found (%) 61.43 6.17 6.13______________________________________
EXAMPLE 92
N-(2-Indanyl)-4-{N-methyl-N-[(E)-3-(4-hydroxy-3methoxyphenyl)-2-cyano-2-propenoyl]amino}benzenesulfonamide ##STR230##
m.p. (.degree.C.): 185.about.186 (MeOH-THF)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.19 (1H, br, D.sub.2 O exchange), 8.07 (1H, d, J=7.5 Hz), 7.83 (2H, d, J=8.4 Hz), 7.83 (1H, d, J=8.4 Hz), 7.59 (2H, d, J=8.4 Hz), 7.59 (1H, d, J=8.4 Hz), 7.36 (1H, dd, J=8.2 Hz), 7.06 (4H, s), 6.84 (1H, d, J=8.4 Hz), 3.68 (3H, s), 3.40 (3H, s), 3.24.about.2.50 (4H, m)
Mass m/e (FD): 503 (M.sup.+)
______________________________________elemental analysis as C.sub.27 H.sub.25 N.sub.3 O.sub.5 S C H N______________________________________calculated (%) 64.40 5.00 8.35found (%) 64.42 5.01 7.98______________________________________
EXAMPLE 93
4-{N-[(E)-3-(3,4-Dihydroxyphenyl)-2-propenoyl]amino}-5,6,7,8-tetrahydro-1-naphthalenesulfonamide ##STR231##
m.p. (.degree.C.): 270.about.272 (MeOH-H.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 9.58 (1H, br, D.sub.2 O exchange), 9.29 (1H, brs, D.sub.2 O exchange), 9.15 (1H, br, D.sub.2 O exchange), 7.69 (2H, s), 7.42 (1H, d, J=15.8 Hz), 7.30 (2H, s, D.sub.2 O exchange), 7.08.about.6.60 (4H, m), 3.15 (2H, m), 2.71 (2H, m), 1.75 (4H, m)
Mass m/e (FD): 388 (M.sup.+)
______________________________________elemental analysis as C.sub.19 H.sub.20 N.sub.2 O.sub.5 S.0.4H.sub.2 O C H N______________________________________calculated (%) 57.68 5.30 7.08found (%) 57.83 5.24 6.90______________________________________
EXAMPLE 94
N-Isopropyl-4-{N-methyl-N-[(E)-3-(2-chloro-3,4-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR232##
m.p. (.degree.C.): 247.about.248 (CH.sub.2 Cl.sub.2 -Et.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.50.about.8.50 (2H, br, D.sub.2 O exchange), 7.86 (2H, d, J=8.4 Hz), 7.76 (1H, d, J=15.4 Hz), 7.53 (2H, d, J=8.8 Hz), 6.78 (1H, d, J=8.8 Hz), 6.63 (1H, d, J=8.8 Hz), 6.28 (1H, d, J=15.4 Hz), 3.34 (3H, s), 3.20 (1H, m), 0.96 (6H, d, J=6.6 Hz)
Mass m/e (FD): 424 (M.sup.+)
______________________________________elemental analysis as C.sub.19 H.sub.21 ClN.sub.2 O.sub.5 S.0.2H.sub.2 O C H N______________________________________calculated (%) 53.26 5.03 6.54found (%) 53.14 5.07 6.27______________________________________
EXAMPLE 95
4-{N-[(E)-3-(2-Bromo-4,5-dihydroxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR233##
m.p. (.degree.C.): 271.about.273 (MeOH-H.sub.2 O)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 7.81 (4H, s), 7.80 (1H, br, D.sub.2 O exchange), 7.75 (1H, d, J=15.4 Hz), 7.20 (1H, br, DzO exchange), 7.14 (1H, s), 7.01 (1H, s), 6.58 (1H, d, J=15.4 Hz)
Mass m/e (FD): 413 (M.sup.+)
______________________________________elemental analysis as C.sub.15 H.sub.13 BrN.sub.2 O.sub.5 S.0.25H.sub.2 C H N______________________________________calculated (%) 43.13 3.26 6.71found (%) 43.32 3.42 6.31______________________________________
EXAMPLE 96
N-(2-Thiazolyl)-4-{N-[(Z)-3-(3,4-dimethoxyphenyl)-2-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide ##STR234##
m.p. (.degree.C.): 220.about.223 (EtOH-MeOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 10.22 (1H, brs), 8.52 (1H, dd, J=4.8, 1.8 Hz), 8.35 (1H, d like, J=1.8 Hz), 7.75 (4H, m, ABq), 7.67 (1H, dt, J=8.0, 1.8 Hz), 7.53 (1H, s), 7.42 (1H, dd, J=8.0, 4.8 Hz), 7.20 (1H, d, J=4.8 Hz), 6.86 (1H, d, J=8.8 Hz), 6.77 (1H, d, J=4.8 Hz), 6.70 (1H, brd, J=8.8 Hz), 6.48 (1H, brs), 3.72 and 3.39 (each 3H, s)
Mass m/e (FD): 522 (M.sup.+)
______________________________________elemental analysis as C.sub.25 H.sub.22 N.sub.4 O.sub.5 S.sub.2.0.5H.sub.2 O C H N______________________________________calculated (%) 56.48 4.36 10.54found (%) 56.74 4.26 10.57______________________________________
EXAMPLE 97
4-{N-[(Z)-3-(3,4-Dimethoxyphenyl)-2-(3-pyridyl)-2-propenoyl]amino}benzenesulfonamide ##STR235##
m.p. (.degree.C.): 236.about.237 (EtOH-MeOH)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta. 10.32 (1H, s), 8.64 (1H, m), 8.44 (1H, brs), 7.80 (4H, m, ABq), 7.83.about.7.65 (1H, m), 7.62 (1H, s), 7.53 (1H, dd, J=8.1, 4.8 Hz), 7.27 (2H, s, D.sub.2 O exchange), 6.88 (1H, d, J=8.8 Hz), 6.74 (1H, dd, J=8.8, 1.5 Hz), 6.51 (1H, d, J=1.5 Hz), 3.72 and 3.40 (each 3H, s)
Mass m/e (FD): 439 (M.sup.+)
______________________________________elemental analysis as C.sub.22 H.sub.21 N.sub.3 O.sub.5 S C H N______________________________________calculated (%) 60.13 4.82 9.56found (%) 60.13 4.77 9.50______________________________________
EXAMPLE 98
N-(Thiazolyl)-4-{N-[(E)-3-(3,4-dimethoxyphenyl)-2-propenoyl]amino}benzenesulfonamide ##STR236##
m.p. (.degree.C.): 256.about.258 (CH.sub.2 Cl.sub.2)
.sup.1 H-NMR (90 MHz, DMSO-d.sub.6) .delta.: 7.79 (4H, s), 7.57 (1H, d, J=15.6 Hz), 7.24 (1H, d, J=4.8 Hz), 7.26.about.7.05 (2H, m), 7.00 (1H, d, J=9.2 Hz), 6.81 (1H, d, J=4.8 Hz), 6.69 (1H, d, J=15.6 Hz), 3.82 and 3.80 (each 13H, s)
Mass m/e (FD): 445 (M.sup.+)
______________________________________elemental analysis as C.sub.20 H.sub.19 N.sub.3 O.sub.5 S.sub.2.0.25H.sub.2 O C H N______________________________________calculated (%) 53.38 4.37 9.34found (%) 53.55 4.37 9.08______________________________________
EXAMPLE 99
4-{N-[(E)-3-(4-Hydroxy-3-methoxyphenyl)-2-propenoyl]amino}benzenesulfonamid ##STR237##
m.p. (.degree.C.): 242.about.243 (EtOH)
.sup.1 H-NMR (400 MHz, DMSO-d.sub.6) .delta.: 10.38 (1H, s), 9.53 (1H, s), 7.80 (2H, d, J=8.4 Hz), 7.73 (2H, d, J=8.4 Hz), 7.49 (1H, d, J=15.9 Hz), 7.20 (2H, s), 7.16 (1H, s), 7.04 (1H, d, J=8.1 Hz), 6.79 (1H, d, J=8.1 Hz), 6.61 (1H, d, J=15.9 Hz), 3.79 (3H, s)
Mass m/e (FD): 348 (M.sup.+)
______________________________________elemental analysis as C.sub.16 H.sub.16 N.sub.2 O.sub.5 S.0.3H.sub.2 O C H N______________________________________calculated (%) 54.43 4.69 7.92found (%) 54.42 5.00 7.56______________________________________

Number	Date	Country	Kind
2-27071	Feb 1990	JPX
PCT/JP91/00149	Feb 1991	WOX

Number	Name	Date
4925861	Hayashi et al.	May 1990
4992469	Ozawa et al.	Feb 1991
5281626	Oinuma et al.	Jan 1994

Number	Date	Country
0227431	Jul 1987	EPX
0248597	Dec 1987	EPX
0255749	Dec 1985	JPX
2175466	Aug 1987	JPX
63-2968	Jan 1988	JPX
3258854	Oct 1988	JPX

Benzenesulfonamide derivatives

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