AU9720398A - Alkylenediamine derivative - Google Patents

Description

S F Ref: 353671D1

AUSTRALIA

PATENTS ACT 1990 TRUE COPY COMPLETE SPECIFICATION I certify that the following is a true and correct copy of the description and claim(s) of the original complete specification in respect of an invention entitled: Alkylenediamine Derivative Nippon By: Chemiphar Co., Ltd Registered Patent Attorney 5845

SPECIFICATION

FIELD OF THE INVENTION The present invention relates to a novel alkylenediamine derivative which shows a function to relieve urinating contraction and therefore is of value as an active ingredient of a therapeutic agent for treating dysuria.

BACKGROUND OF THE INVENTION Heretofore, flavoxate hydrochloride and oxybutynin hydrochloride which directly function peripherally on urinary bladder have been used as therapeutic agents for treating dysuria. However, these compounds may give certain side-effects to other organs such as digestive apparatus.

EP-0579169-Al (Japanese Patent Provisional Publication H6-80645) describes an alkylenediamine of the formula

(A)

SRIA H -CH--Z

A

-CH--(CH N b R2A Sin which each of RI and R2 independently represents a phenyl, naphthyl or aromatic heterocyclic group which may have one to five same or different substituents selected from the group consisting of alkyl, halogen, haloalkyl, hydroxyl, alkoxy, aryloxy, aralkyloxy, nitro, amino, alkylamino, aralkylamino, arylamino, acylamino, carboxyl, alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, amide, sulfo, alkoxysulfonyl, aralkyloxysulfonyl, aryloxysulfonyl, sulfonamide, and 1H-tetrazol-5-yl; each of R 3 A and R 4 A independently represents hydrogen, alkyl, aralkyl or aryl, otherwise R3A and R 4 A are combined in conjunction with the nitrogen atom to which R3A and R4A are attached to form 5 to 7 membered ring which may contain oxygen, sulfur or nitrogen and which may have a substituent selected from the group consisting of alkyl, aralkyl, phenyl, hydroxyl, alkoxy, carboxyl, alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl, and amide; XA represents oxygen, sulfur or imino; YA represents oxygen or sulfur; ZA represents -CH 2 or m A is an integer of 0 to 4; nA is an integer of 0 to 4; each of pA and qA independently is an integer of 0 to 5 under the condition that the total of pA and qA is in the range of 1 to 5, or its pharmacologically acceptable salt is of value as an active ingredient of a therapeutic agent for treating dysuria, because the compound can relieve urinating contraction which is observed under high intracystic pressure, and therefore is employable for treating nervous dysuria, chronic prostatitis, chronic cystitis, dysuria caused by neurogenic bladder or unstable bladder, incontinence of urine, urgency of micturition, and residual urine.

The object of the invention is to provide a novel alkylenediamine derivative showing a function to relieve urinating contraction which is observed under high intracystic pressure.

Disclosure of the Invention According to a first embodiment of the present invention, there is provided an alkylenediamine derivative having the formula p R R3 (R1 (CH 2

S-(CH

2

N-(CH

2 )m-CH-(CH 2 )n-N (R1)k R4 S(CH2)z-- C-(CH2)y I Oq (1) in which R 1 represents an atom or a group selected from the group consisting of hydrogen, alkyl having 1-8 carbon atoms, halogen, haloalkyl having 1-4 carbon atoms, hydroxyl, alkoxy having 1-8 carbon atoms, aryloxy having 4-10 carbon atoms, aralkyloxy having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, nitro, amino, cyano, alkylamino having 1-8 carbon atoms, aralkylamino Zz00077 3 having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, arylamino having 4-10 carbon atoms, aliphatic acylamino having 1-8 carbon atoms, carboxyl, alkoxycarbonyl having 2-9 carbon atoms, aralkyloxycarbonyl having 6-15 carbon atoms, its alkyl portion having 1-4 carbon atoms, aryloxycarbonyl having 5-11 carbon atoms, carbamoyl, sulfo, alkoxysulfonyl having 1-8 carbon atoms, aralkyloxysulfonyl having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, aryloxysulfonyl having 4-10 carbon atoms, sulfonamide, and yl; R 2 represents hydrogen, alkyl having 1-8 carbon atoms, alkenyl having 2-9 carbon atoms, alkoxy having 1-8 carbon atoms, or an aryl having 4-10 carbon atoms, aralkyl having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, or aromatic heterocyclic group which may have one to five same or different substituents selected from the group consisting of alkyl having 1-8 carbon atoms, halogen, haloalkyl having 1-4 carbon atoms, hydroxy, alkoxy having 1-8 carbon atoms, aryloxy having 4-10 carbon atoms, aralkyloxy having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, nitro, amino, cyano, alkyl amino having 1-8 carbon atoms, aralkyl amino having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, arylamino having 4-10 carbon atoms, aliphatic acylamino having 1-8 carbon atoms, carboxyl, alkoxycarbonyl having 2-9 carbon atoms, aralkyloxycarbonyl having 6-15 carbon atoms, its alkyl portion having 1-4 carbon atoms, aryloxycarbonyl having 5-11 carbon atoms, carbamoyl, sulfo, alkoxysulfonyl having 1-8 carbon atoms aralkyloxysulfonyl having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, aryloxysulfonyl having 4-10 carbon atoms, sulfonamide and 1H-tetrazol-5-yl; each of R 3 and R 4 independently represents hydrogen, alkyl having 1-8 carbon atoms, aralkyl having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, or aryl having 4-10 carbon atoms, or R 3 and

R

4 form in combination with the nitrogen atom to which R 3 and R 4 are attached, a hetero ring which may contain another nitrogen, oxygen or sulfur as the ringforming atom in addition to the former nitrogen atom and which may have a Ssubstituent selected from the group consisting of alkyl having 1-8 carbon atoms which may have one or two aryl having 4-10 carbon atoms, phenyl, hydroxyl, alkoxy having 1-8 carbon atoms which may have one or two aryl having 4-10 carbon atoms, aryloxy having 4-10 carbon atoms, carboxyl and cyano, provided that where

R

2 is hydrogen, R 3 and R 4 form in combination with the nitrogen atom to which R 3 and R 4 are attached, a hetero ring which may contain another nitrogen, oxygen or Zz00077 4 sulfur as the ring-forming atom in addition to the former nitrogen atom and which has a substituent selected from the group consisting of alkyl having 1-8 carbon atoms which has one or two aryl having 4-10 carbon atoms, phenyl, hydroxyl, alkoxy having 1-8 carbon atoms which may have one or two aryl having 4-10 carbon atoms, aryloxy having 4-10 carbon atoms, carboxyl and cyano where R 2 is alkyl or phenyl, there is no case wherein R 3 and R 4 are both hydrogens k is an integer of 1 to 4; each of m and n independently represents an integer of 0 to 4, under the condition that the total number of m and n is in the range of 0 to 4; p is 0, -c- I I 1 or 2; q is 0 or 1 wherein when q is 0, q is CH 2 and each of w, x, y and z independently is an integer of 0 to 2, under the condition that the total number of w, x, y and z is 1 or 2.

Among the alkylenediamine derivatives of benzothiazine type represented by the above-mentioned formula preferred is an alkylenediamine derivative having the following formula S O R2R 3 (N (C H2)iT-CH-(CH2), N (RI)k R4 0 O (2) in which R 1

R

2

R

3

R

4 k, m, and n are the same as those defined for the formula SAmong the alkylenediamine derivatives of benzothiazine type represented by the above-mentioned formula also preferred is an alkylenediamine derivative having the following formula

C

0 R) r S-+O r2 (R)k I R3

N-(CH

2

-CH-(CI

2 )ff-N SR4 0 O (3) in which R 1

R

2

R

3 R4 k, m, and n are the same as those defined for the formula Zz00077 The alkylenediamine derivative of the formula entirely differs from the alkylenediamine derivative of the aforementioned EP-0579169-AI in that the former has on one end a condensed heterocyclic ring containing sulfur and nitrogen atoms.

According to a second embodiment of the present invention, there is provided an alkylenediamine derivative of saccharin type having the formula £i 7700077 -6- Y N "R3 C 2 CH N 1 (n

R

2 in which

R

1 represents an atom or a group selected from the group consisting of hydrogen, alkyl having 1-8 carbon atoms, halogen, haloalkyl having 1-4 carbon atoms, hydroxyl, alkoxy having 1-8 carbon atoms, aryloxy having 4-10 carbon atoms, aralkyloxy having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms), nitro, amino, cyano, alkylamino having 1-8 carbon atoms, aralkylamino having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms), arylamino having 4-10 carbon atoms, aliphatic acylamino having 1-8 carbon atoms, carboxyl, alkoxycarbonyl having 2-9 carbon atoms, aralkyloxycarbonyl having 6-15 carbon atoms (its alkyl portion has 1-4 carbon atoms), aryloxycarbonyl having 5-11 carbon atoms, carbamoyl, sulfo, alkoxysulfonyl having 1-8 carbon atoms, aralkyloxysulfonyl having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms), aryloxysulfonyl having 4-10 carbon Satoms, sulfonamide, and

R

2 represents phenyl, naphthyl or aromatic heterocyclic group which may have one to five same or different substituents selected from the group consisting of alkyl having 1-8 carbon atoms, halogen, haloalkyl having 1-4 carbon atoms, hydroxyl, alkoxy having 1-8 carbon atoms, aryloxy having 4-10 carbon atoms, aralkyloxy having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms), nitro, amino, cyano, alkylamino having 1-8 carbon atoms, aralkylamino having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms), arylamino having 4-10 carbon at- Oms, aliphatic acylamino having 1-8 carbon atoms, carboxyl, alkoxycarbonyl having 2-9 carbon atoms, c a r b ox- Scarbonyl viving 2- 9 carbon a t o ms aralkyloxycarbonyl having 6-15 carbon atoms (its alkyl portion has 1-4 carbon atoms), aryloxycarbonyl having 5-11 carbon atoms, carbamoyl, sulfo, alkoxysulfonyl having 1-8 carbon atoms, aralkloxysulfol having 5-14 carbon atoms (its alkyl portio n has 1- carbon atoms), aryloxysulfonyl ha v ing 4-10 carbon atoms, sulfonamide and each of R 3 and

R

4 independently represents hydrogen, alkyl having 1-8 carbon atoms, aralkyl having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms), or aryl having 4-10 carbon atoms, or R3 and R 4 form in corbinatio r with the nitrogen atom to which R 3 and R 4 are attached, a five to seven membered hetero rin having the formul a t t a ch e d (II) ero ring having the formula

(II)

t n which Z is a group of the formula

(III):

(III)

a R in which R represents hydrogen or a group selected from the group consisting of alkyl having 1-8 carbon atoms, aralkyl having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms), phenyl, 2 -primidinyl, carboxyl, alkoxycarbonyl having 2-9 carbon atoms, aralkyl-oxycarbonyl having 6-15 carbon atoms (its alkyl portion has 1-4 carbon atoms), and aryloxycarbonyl having 5-11 carbon atoms, or

SO

2 and t is 0 or 1; in which the five to seven hetero ring may have 1 to substituents selected from the group consisting of alkyl having 1-5 carbon atoms, aralkyl having 5-14 carbon atoms (its alkyl has 1-4 carbon atoms), phenyl, hydroxyl, alkoxy having 1-8 carbon atoms, carboxyl, alkoxycarbonyl having 2-9 carbon atoms, aralkyloxycarbonyl having 6-15 carbon atoms (its alkyl has 1-4 carbon atoms), aryloxycarbonyl having 5-11 carbon atoms, aliphatic acyl having 1-8 carbon atoms, aromatic acyl having 5-11 carbon atoms, and carbamoyl; m represents an integer of 1 to 4, and n represents an integer of 0 to 4; each of p and q independently represents an integer of 0 to 5, under the condition that the total number of p and q is in the range of 1 to 5; x is 0, 1 or 2; and y is 0 or 1 wherein -c- (O)q when y is 0, is CH 2 Among the alkylenediamine derivatives of saccharin type represented by the above-mentioned formula preferred is an alkylenediamine derivative having the following formula (IV): O O S R3 (RI)m

N-(CH

2

)--CH-(CH

2 )q-N I R4 (CI-)n 0 R 2

(IV)

in which R 1

R

2

R

3

R

4 m, n, p and q are the same as those defined for the formula Among the alkylenediamine derivatives of saccharin type represented by the above-mentioned formula also preferred is an alkylenediamine derivative having the following formula

O

t S

R

3 (RI)m N-(CH 2

CH-(CH

2 )q N\ I R4 (CH2)n O R 2 (v) in which R 1 R2, R3, R4 m, n, p and q are the same as those defined for the formula Among the alkylenediamine derivatives of saccharin type represented by the above-mentioned formula also preferred is an alkylenediamine derivative having the following formula (VI): ZzO0077

(VI)

in which R 1

R

2

R

3

R

4 m, n, p and q are the same as those defined for the formula The alkylenediamine derivative of the formula entirely differs from the s alkylenediamine derivative of the aforementioned EP-0579169-AI in that the former has on one end a benzisothiazoline structure.

According to a third embodiment of the present invention, there is provided a method for the treatment or prophylaxis of dysuria in a mammal, which method comprises administering an effective amount of a compound of formula as described in the first and second embodiment of the present invention.

According to a fourth embodiment of the present invention, there is provided a use of a compound of formula for the preparation of a medicament for the treatment or prophylaxis of dysuria.

According to a fifth embodiment of the present invention, there is provided a compound of formula when used in the prophylaxis or treatment of dysuria.

Preferred Embodiments Of The Invention In the formula the halogen, represented by R 1 preferably is fluorine, chlorine or bromine, and chlorine is most preferred. The alkyl having 1-8 carbon atoms which is represented by R 1 preferably is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. The haloalkyl having 1-4 carbon atoms preferably is trifluoromethyl, chloromethyl, or fluoro methyl. The alkoxy having 1-8 carbon atoms preferably is methoxy, ethoxy, or propoxy. The aryloxy having 4-10 carbon atoms (which may have nucleus substituents such as halogen, cyano, alkyl, alkoxy, amino, or alkoxycarbonyl) preferably is phenoxy or p-chlorophenoxy. The aralkyloxy having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms) preferably is benzyloxy, pyridylmethyloxy, naphthylmethyloxy, or thenyloxy. The alkylamino having 1-8 carbon atoms preferably methylamino, dimethylamnino, ethylamino, propylamino, or isobutylamino. The aralkylamino having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms, and which may have nucleus substituents such as halogen, cyano, alkyl, alkoxy, amino, or alkoxycarbonyl) preferably is benzylamino or (4-chlorophenyl) -methylamino. The aryl amino having 4-10 carbon atoms (which may have nucleus substituents such as halogen, cyano, alkyl, alkoxy, amino, or alkoxycarbonyl) preferably is phenylamino or pchlorophenylamino. The aliphatic acylamino having 1-8 carbon atom preferably is Zz00077 acetylamino or propionylamino. The alkoxycarbonyl having 2-9 carbon atoms preferably is methoxycarbonyl, ethoxycarbonyl, or propoxycarbonyl. The aralkyloxycarbonyl having 6-15 carbon atoms (its alkyl portion has 1-4 carbon atoms) preferably is benzyioxycarbonyl, pyridylmethyloxycarbonyl, naphthyimethyloxycarbonyl, or thenyloxycarbomoyl. The azyloxycarbonyl having 11 carbon atoms preferably is phenoxycarbonyl, naphthyloxycarbonyl, or thienyl ZzOO077 -11oxycarbonyl_ The alkoxysulfonyl having 1-8 carbon atoms Preferably is methoxsulfonyl or ethoxysulfonyl. The aralkyloxysulfonyl having 5-14 carbon atoms (its alkyl Portion has 1-4 Carbon atoms) preferably is benzyloxysuifonyl, naphthylmehyloxysulfonyl, or thenyloxysulfofyl. The aryloxysulfonyl having 4-10 carbon atoms preferably is phenoxysulfonyl, naPhthyloxysufonyl, or thienyloxysulfonyl.

In the formula Particularly preferred for P. is hydrogen, halogen, alkyl having 1-8 Carbon atoms, or alkoxy having 1-8 carbon atoms.

In the formula R represents hydrogen, hydroxyl alkyl having 1-8 carbon a ersnshdoehdoy all having 1- carbon atoms, alkenyl having 2-9 carbon atoms, alkoxy having 1-8 carbon atoms, or aryl having 4- 10 carbon atoms, aralkyl having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms), or aromatic heterocyclic group which may have one to five same or different substituents The alkyl having 1-8 carbon atoms which is represented by l Preferably is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. The alkenyl having 2-9 carbon atoms preferably is allyl, 1-propenyl, 2 -methyl-2-propenyl, 2 -methyl-1-propenyl, l-butenyl, 2 -butenyl, -butenyl, 3-methyl-3-butenyl, 3-methyl-2-butenyl 4 -pentenyl, 4 -methyl-4-pentenyl, 4- mehyl-3-pentenyl 5-hexenyl, 5-methyl-5-hexenyl, yl-4-hexenyl -heptenyl, 6 -methyl-6-heptenyl, 6-methylo-heptenyl, 7 -octenyl, 7 -methyl-7-octenyl, or 7 -methyl-6octenyl. The alkoxy having 1-8 carbon atoms preferably is methoxy, ethoxy or propoxy. The aryl having 4-10 S30 carbon atoms Preferably is phenyl or naphthyl. The aralkyl having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms) Preferably is benzyl or naphthylmethyl.

The aromatic hetero ring preferably is furan ring, thio- phene ring, pyridine ring, quinoline ring, or indole ring.

The halogen which may be attached to the above-men- -12tioned aryl, aralkyl or aromatic heterocyclic group preferably is fluorine, chlorine, or bromine. The alkyl having 1-8 carbon atoms preferably is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. The haloalkyl having 1-4 carbon atoms preferably is trifluoromethyl, chloromethyl, or fluoromethyl. The alkoxy having 1-8 carbon atoms preferably is methoxy, ethoxy, or propoxy. The aryloxy having 4-10 carbon atoms (which may have nucleus substituents such as halogen, cyano, alkyl, alkoxy, amino, or alkoxycarbonyl) Preferably is phenoxy or p-chlorophenoxy Thne aralkyloxy having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms) preferably is benzyloxy, pyridylmethylxy naphthylmethyloxy, or thenyloxy. The alkylamino having 1-8 carbon atoms Preferably is methylamino, dimethylamino, ethylamino, propylamino, or isobutylamino. The aralkylamino having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms, and which may have nucleus substituents such as halogen, cyano, alkyl, alkoxy, amino, or alkoxycarbonyl) Preferably is benzylamino or (4-chlorophenyl)methylamino. The arylamino having 4-10 carbon atoms (which may have nucleus substituents such as halogen, cyano, alkyl, alkoxy, amino, or alkoxycarbonyl) Preferably is phenylamino or p-chlorophenylamino. The aliphatic acylamino having 1-8 carbon atom preferably is Sacetyaon ao orm propionyaranos The alkoxycarbonyl having 2-9 carbon atoms preferably is methoxycarbonyl, ethoxycarbonyl, or propoxycarbonyl. The aralkyloxycarbonyl having 6-15 carbon atoms (its alkyl portion has 1-4 carbon atoms) Preferably is benzyloxycarbonyl pyridylmethyloxycarbonyl, naphthylmethyloxycarbonyl, or thenyloxycarbonyl. The aryloxycarbonyl having 5-11 carbon atoms preferably is phenoxycarbonyl, PYridyloxycarbonyl, naphthyloxycarbonyl, or thienyloxyarbonyl. The alkoxysulfonyl having 1-8 carbon atoms Preferably is methoxysulfonyl or ethoxysulfonyl. The aralkyloxysulfonyl hav- -13ing 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms) preferably is benzyloxysulfonyl, naphthylmethyloxysulfonyl, or thenyloxysulfonyl The aryloxysulfonyl having 4-10 carbon atoms preferably is phenoxysulfonyl, naphthyloxysulfonyl, or thienyloxysulfonyl.

Particularly preferred for R 2 is hydrogen, alkyl having 1-8 carbon atoms, alkoxy having 1-8 carbon atoms, hydroxul or phenyl, furyl, thienyl or pyridyl which has no substituents, or phenyl having, as substituent, halogen, alkyl having 1-8 carbon atoms, or alkoxy having 1-8 carbon atoms.

In the formula the alkyl having 1-8 carbon atoms which is represented by R3 or R 4 Preferably is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

The aralkyl having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms) Preferably is benzyl, phenylethyl or phenylpropyl The aryl having 4-10 carbon atoms preferably is phenyl, PYridyl, or naphthyl.

The heterocyclic group which is formed by the combinattion of R and

R

4 and the nitrogen atom to which

R

3 and R 4 ae attached and which may further have nitrogen, oxygen, or sulfur as the ring member Preferably is a five to seven membered heterocyclic group having the formula t\ -N (Z)t in which Z is a group of the formula

R

I

_N-

[in which Rs represents hydrogen, or a group selected from the group consisting of alkyl having 1-8 carbon atoms, aralkyl having 5-14 carbon atoms (its alkyl portion has -14- 1-4 carbon atoms), phenyl, 2 -pyrimicinyl caroxl alkoxycarbonyl having 2-9 carbon atoms, aralkyloxycr bonyl having 6-ascarbon atoms (its alkyl Portion has 1-4 carbon aton) and aryloxycarbonyl having 5-11 carbon atoms] or -so 2 and t is 0 or 1, or 1 2 4tetdroisoquinoline group, or 2 3-dihy lH-benz rdel isoquinoline group.

The five to seven membered heterocyclic group repre- Sented by the formula Preferably is Morpholino pipe- ridino, homomorpholino, l-pyr0oliW. tPomorPholinop l-piPerazinyl, Perhydroazepin -yl, Soxythiomorp 0 ijo or SS-dioxythiomorpholino.

The alkyl having 1-8 carbon atoms which is represented of the forrrla for Z of the formula (4) Preferably is methyl, ethyl, propyl, isopropyl butyl, or isobutyl. The aralkyl having 5-14 carbon atoms (its alky has 1-4 carbon atoms) Preferably is benzyl, phenyl_ ethyl, or Phenylpropy. The alkoxycarbonyl having 2-9 carbon atoms Preferably is methoxycarbonyl ethoxycarbon yl, or Propoxycarbonyl. The arakyloxycarl hvng. 6carbon atoms (its alkyl Portion has 1-4 carbon atoms) preferably is benzYloxycarbonl 1- abnaos yl naphthy lOxycarbonyl, oyrdylmethyloxycarbon ylYbOxycarbonyl or then-loxycarbonyl. The having 5-11 carbon atoms Preferably is 2 bonyl. naphthyloxycarbnyl, or thienyloxycar- The five to seven membered heterocclic group of the formula (4),th 1,2,,4-tetrahydrisquinoine group, or 3-dihydo-Rbenz [delisoquinoline group may have 1 to Substituents selected from the group consisti of altyl p having 1-8 abnaoswih~~~ O1itng of alkyl n s carbon atoms which may have One or two substituents such as aryl having 4-10 carbon atoms (which may be substituted with halogen, aikyl having i-s carbon atoms, alkoxy having 1-5 carbon atoms, or aliphatic acyl having 1-5 carbon atoms), pheny., hydroxyl, alkoxy having 1-8 carbon atoms which may have One or two substituents -issuch as aryl having 4-10 carbon atoms (which may be substituted with halogen, alkyl having 1-5 carbon atoms, alkoxy having 1-5 carbon atoms, or aliphatic acyl having carbon atoms), aryloxy having 4-10 carbon atoms, aralkyithia having 5-14 carbon atoms (its alkyl portion has 1-4 Carbon atoms), aryithic having 4-10 carbon atoms, carboxyl, alkoxycarbonyl having 2-9 carbon atoms, aralkyloxycarbonyl having 6-15 carbon atoms (its alkyl portion has 1-4 carbon atoms), aryloxycarbonyl having 5-11 carbon atoms, aliphatic acyl having 1-8 carbon atoms, aromatic acyl having 5-11 carbon atoms, cyano, and carbamoyl.

Among the abovementioned su bstituents, the alkyl having 1-5 carbon atoms preferably is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl The alkyl having 1-83 carbon atoms which may have one or two substituted or uflsubstituted aryl having 4-10 carbon atoms preferably is benzyl, Phenylethyl phenylpropyl, diPhenylmethyl, chlorobenz.l, methYlbnyl, methoxyenyl acetylbenzyl, or thienylmethyl. The alkoxy having 1-8 carbon atoms which may have one or two substituted or unsubstitued aryl having 4-10 carbon atoms Preferably is mechoxy, ethoxy, propoxy, benzyloxy, diPhenylmethyloxy, phenylethyloxy, chlorobenzyloxy, methylbenzyloxy, methoxybenzyloxy, acetylbenzyloxy, 2 -thienylmethyloxy, naphthyl- methyloxy, 2 -pyridylmethyloxy, chloronaphthylmethyloxy, dichlorobenzyloxy, or di(chiorophenyl) methyloxy. The aryloxy having 4-10 carbon atoms Preferably is phenoxy, chlorophenoxy, 3-thienyloxy, methoxyphenoxy, methylphenoxy, acetylphenoxy, dichlorophenoxy, naphthyloxy, chlororaphthyloxy, or 4 -pYridyloxy. The aralkylthio having 5-14 carbon atoms (its alkyl portion has 1-4 car- bon atoms) Preferably is benzylthio, phenylethyithio, chlorobenzylthio methylbenzylthio, methoxybenzylthio, acetylbenzylthio, 2 -thienymethylthio, naphthylmethylthia, 2 -PYridylmethylthio, chlororlaphthlmethylthio, dichlorobenzylthi, or di(chlorophenyl)methylthio. The arylthio having 4-10 carbon atoms Preferably is phenyl- thic, 3-thienylthio, methoxyphenylthio, methyiphenylthic, acetylphenylthio dichlorophenylthio, naphthylthio, chloronaphthythio, or 4 -Pyridylthio. The alkoxycarbony having 2-9 carbon atoms preferably is methoxycarbonyl ethoxycarbonyl, or propoxycarbonyl. The aralkyloxycarbonyl having 6-15 carbon atoms (its alkyl portion has 1-4 carbon atoms) preferably is benzyloxycarbonyl, pyridyl- methyloxycarbonyj, naphthysmnebezt ouronl yrd methyloxycarbonyl, phthylmethyloxycarbonyl, or thenyl- oxycarbonyl. The aryloxycarbonyl having 5-11 carbon atoms Preferably is phenoxycarbonyl, naphthyloxycarbonyl, or thienyloycarbony 1 The aliphatic acyl having 1-8 carbon atoms Preferably is formyl, acetyl, or propionyl.

The aromatic acyl having 5-11 carbon atoms prelferably is benzoyl or phthaloyl. If the two or more substituents are attached, these substituents may be the same or different.

The five to seven membered heterocyclic group repre- sented by the formula Preferably is morpholino, piperidino, homomorpholino, -pyrroidinyl thiomorpholino, 1-piperazinyl, perhydroazepinr 1 -yl, Soxythiomorpholino, or S,S-dioxythiomorpholino The heterocyclic group may not have Sbstituent, or may have substituents such as alkyl having 1-8 carbon atoms, alkyl having 1-8 carbon atoms which have one or two phenyl groups, phenyl, thien- Cm yl, acyl having 1-8 carbon atoms, carbamoyl, or 2- PYrimidinyl on its carbon or nitrogen atom.

In the formula k preferably is or 2, and 1 is ANE 30 most preferred. m preferably is n preferably is 1, 2, or 3. The alkylenediamine derivative of the formula in which p, q, w, x, y and z are 2, 1, 0, 0, 1 and 0, respectively, corresponds to the alky1enediamine deriv- ative of the formula The alkylenediamine derivative of the formula in which p, q, w, x, y and z are 2, 1, 1, 0, O and 0, respectively correspo to the alkylene rspetivlycorresponds to the alkylene- -17diamine derivative of the formula In the formula if q is o, two hydrogen atoms are attached.

The alkylenediamine derivative derivative of the formula can be synthesized utilizing reactions which are known in the technical field of organic chemistry.

For instance, the alkylenediamine of the formula (2) can be prepared by reacting a ketal comrpound having the formula 0 0

~'NEI

1

(R

1

SI~

in which

R

I and k have the same meanings as defined in the formula (1) with a compound having the formula (7) R2 R3 Q H2 1 (oH2t

N

-R4 in which

R

2

R

3

R

4 m and n have the same meanings as defined in the formula and Q is a releasable group such as halogen, tosyloxy, or mesyloxy, to give an ethylene ketal compound, and then subjecting the resulting compound to de-ketal reaction.

In the above-mentioned preparation process, the Mketal compound of the formula and the compound of the formula are caused to react at a temperature from room temperature to the reflux temperature for 1 to hours, in an organic solvent such as acetone, dimethylformamide, methyl ethyl ketone, isobutyl methyl ketone, isopropyl alcohol, ethanol, or dimethoxyethane, in the -18presence of a base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydride, sodium metal, sodium ethoxide, or sodium hydroxide, to prepare an ethylene ketal compound corresponding to the compound of the formula In the reaction, 1 to 2 moles of the compound of the formula (7) and the 2 to 8 moles of the base are preferably employed per one mole of the compound of the formula Subsequently, the ethylene ketal is subjected to the reaction for removing the ketal by treating with diluted hydrochloric acid, diluted hydrochloric acid/methanol mixture, diluted hydrochloric acid/tetrahydrofuran mixture, diluted hydrochloric acid/ethnaol mixture, sulfuric acid/acetone mixture, p-toluenesulfonic acid/acetone mixture, acetic acid, silica gel/water/dichloromethane mixture, oxalic acid/water/dichloromethane mixture, sulfuric acid/water/dichloromethane mixture, or triphenylmethyl tetrafluoroborate/dichloromethane mixture, to give the alkylenediamine derivative of the formula Alternatively, the alkylenediamine derivative of the formula can be prepared by reacting a ketal compound of the formula 02 o

R

2 (RI 2-)-m-CH

(CH

2

IQ

4 30 in which R' R 2 k, m and n have the same meanings as defined in the formula and Q is a releasable group such as halogen, tosyloxy, or mesyloxy, with a compound having the formula 3 (9) R3

HNR

\R'

-19in which

R

3 and R 4 have the same meanings as defined in the formula to give an ethylene ketal compound, and then subjecting the resulting compound to de-ketal reaction.

In the above-mentioned preparation process, the ketal compound of the formula and the compound of the formula are caused to react at 50 to 150-c for 1 to 2 hours, generally, in the absence of a solvent, to give an ethylene ketal compound which corresponds to the compound of the formula The ethylene ketal compound is then subjected to a reaction for removal of ketal structure in the same manner as above, to give the alkylenediamine derivative of the formula In the reaction, 1 to 2 moles of the compound of the formula is preferably employed per one mole of the compound of the formula A compound of the formula in which p is 0 or 1, or q is 0, which is similar to the compound of the formu- la can be synthesized in a manner similar to the above-mentioned process.

The alkylenediamine derivative of the formula (3) can be prepared by reacting a compound of the formula 250

(RII

N

NH

0 in which R' and k have the same meanings as defined in the formula (1) with a compound of the aformementioned formula In the above-mentioned preparation process, the compound of the formula (10) and the compound of the formula are caused to react at a temperature from room temperature to the reflux temperature for 1 to hours, in an organic solvent such as acetone, dimethylformamide, methyl ethyl ketone, isobutyl methyl ketone, isopropyl alcohol, ethanol, or dimethoxyethane, in the presence of a base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydride, metallic sodium, sodium ethoxide, or sodium hydroxide, to prepare an ethylene ketal compound corresponding to the compound of the formula in the reaction, 1 to 2 moles of the compound of the formula (7) and the 2 to 8 moles of the base are preferably employed per one mole of the compound of the formula Alternatively, the alkylenediamine derivative of the formula can be prepared by reacting a compound of the formula (11): (11)

R

2 ~(Cd)c(CH+nQ In 30 in which R, R2, k, m and n have the same meanings as defined in the formula and Q is a releasable group as mentioned above, with a compound having the aforementioned formula In the above-mentioned preparation process, the compound of the formula (11) and the compound of the for- mula are caused to react at 50 to 150'C for 1 to hours, generally, in the absence of a solvent, to give the compound of the formula If necessary, a solvent which does not participate in the reaction can be employed.

A compound of the formula in which p is 0 or 1, or q is 0, which is similar to the compound of the formu- -21la can be synthesized in a manner similar to the above-mentioned process.

Further, a compound having the formula (12) (12) 0 0 \s^ in which RF and k have the same meanings as defined in the formula (1) can be caused to react with the cormpound of the formula to give an alkylenediamine derivative having the formula (13) (13) 0 30 in which R, R 2

R

3 k, m, and n have the same meanings as defiend in the formula (1 h a v e t h e sa me me an i n g s which belongs to the alkylenediamine derivative of the formula Furthermore, a compound having the formula (14) (14) o 0

RS

(RI

in which R I and k have the same meanings as defined in the formula (1) -22can be caused to react with the compound of the formula to give an alkylenediamine derivative having the formula in which

R

I

R, R 3

R

4 k, m, and n have the same meanings as defiend in the formula which belongs to the alkylenediamine derivative of the formula The reaction conditions for preparing the alkylenediamine derivative of the formula (13) and the alkylenediamine derivative of the formula (15) are almost the same as those adopted for the preparation of the alkylenediamine derivative of the formula starting from the the compound of the formula (10) and the compound of the formula A compound of the formula in which p is 0 or 1, or q is 0, which is similar to the compound of the formula (13) or the compound of the formula (15) can be synthesized in a manner similar to the above-mentioned process.

0< The alkylenediamine derivative of the formula (1) can be converted into a pharmacologically acceptable salt. Examples of the Pharmacologically acceptable salt of the alkylenediamine derivative of the formula (1) include acid-addition salts such as salts with an inorganic acid hydrochloric acid, sulfuric acid, hydrobromic acid, or phosphoric acid), or an organic acid fumaric acid, acetic acid, propionic acid, citric acid, tartaric acid, maleic acid, malic acid, oxalic acid, methanesulfonic acid, or p-toluenesulfonic acid).

-23- Examples of the alkl lnediamine derivatives represented by the formula are described below: 2- (4-phenoxypiperidino)propy 1 -2K-l, 2-benzothiazin-4 (3H) -one 1, '-dioxide 2- f3- (4-benzyloyiperidino)propyl -2H-1, 2-benzoth.azin-4 (3K) -one 1, l-dioxide 3- (4-benzylPiperidmoc)propylj 3-benzothiazJin-4 (3K) -one 2 2 -d-ioxide 2- 3 -morpholiophnlpr 1 l- 2 H-l,2-benzothiazin-3 (4K) -one 1, l-dioxide 3- 3 -morPholino.l.phenylpropyl) -2H-l, 3 -benzothiazin- 4 (3K) -one 1, 1-dioxide 3- 2 -hydroxy-3-morpholinopr 1y) 3-benzothiazin-4(3K) -one 2 ,2-dioxide 3- 2 -ethoxy-3-morpholp~rop 1) -lK-2, 3 -benzothiazin- 4(3K) -one 2 2 -dijoxide 2- 2 -hydroxy-3-mrholinor 1y) -2K-1,2-bezothiazi.n-4 (3K) -one 1,1ldioxide 3- 3 -morpholino-3pheylprpyl) -lK-2, 3 -benzothiazin-.

4(3K) -one 2 2 -dioxide 2- (4-benzYlpiperidino)propylJ 2 K-l,2-benzothiazm..4 (3K) -one l1 l-dioxide (11) 2- (N-benzyl-N-butylamjno)prpl-2K-i, 2-benzothiazl~n-4 (3K) -one lil-dioxide benzothiazi- 4 (3K) -one 1, i-dioxide (13) 2- (4-benzylpiperidino) ethyl] -2K-i, 2 -benzothiazin- 4(3K) -one l,i-dioxide (14) 2- (4-benzyl-l-piperazinyl)pr 11 l 2 K-1,2-benzothiazin.4 (3K)-one 1,l-dioxide 2 3 -2-(1,2,34tetryiou. lllrpl-H 1, 2 -benzothiazin- 4 -one i, i-dioxide (16) 2 3 -[4-(4-methoxybenzyl)piperidiprpl]-H12 benzothazin.

4 (3H) -one 1,1idioxide (17) 2- (3-morpholinopropyl) 2-,-bnohi 4 (3H) -one 1,1I-dioxide -24- (18) 2 3 -di ethyiamino -1i phenyipro1y) 2H-i1, 2 -benzo tbhiazin-4 (3H) -one 1, 1-dioxide (19) 2- (1pheny1-3-piperidinopropyl) -2K-i, 2 -benzothiazin- 4 (3H) -one i, 1-dioxide (20) 2- (3 -morphoiinoiphenyipropy1) -2K-i, 2 -benzothiazin- 4 (3K) -one 1, i-dioxide (21) 2- (1pheny1-3-thiomorphoiinopropy1) -2K-i, 2-benzothiazin-4 (3K) -one 1, i-dioxide (22) 2- 3 -morphoiino-i. (4-chiorophenyi)propyil -2K-i,2benzotiiiazij-4(3H)- 0 ne i,i-dioxide (23) 3- (1Phenyl-3piperdfloproy1) -iK-2, 3-benzothiiazin- 4 (3H) -one 2 ,2-dioxide (24) 3- 3 -morphoiino-iphenylpropyl) -1K-2, 3 -benzotiazin.

4 (3K) -one 2 2 -dioxide (25) 3- 3 -diethyiamino-i-phenyiproy1) -IK-2, 3-benzothiazin-4 (3K) -one 2 ,2-dioxide (26) 3- (i-phenyl-3-thoorphoinorop1) -iK-2, 3-benzothiazin-4 (3K) -one 2 ,2-dioxide (27) 3- 3 -mrpholiino>. (4-chioropheny1)propyiJ -1K-2,3benzothiazi-4 (3K)-one 2 2 -dioxide (28) 3- (3 -morphoiino-2-phenyipropyi) -iK-2, 3 -benzothiazin- 4 (3K) -one 2 2-dioxide (29) 2- (3 -morpholi 2 o-3 -phenyipropyl) -2K-i, 2 -benzothiazin.

4 (3K) -one 1, i -dioxide (3 0) 2- 3 -ch-ioropropyi) 2 K-1,2-be othiazi-4 (3K) -one i,1idioxide J(31) 2- 13- 2 ,3dihydro-lK-benzrdel ±soquino1in2-yi)propyli -2H-i, 2 -benzothiazin- 4 (3K) -one i,i-dioxide hydrochloride (32) 2- C3- (4-cyano4.phenypiperdi)pr ii l-2K-i,2benzothiazin-4(3K)-one l,i-dioxjde fuinarate (33) 2- (3-chloro-iphenylpropyl) 2 H-1,2-berizothiazin- 4 (3K) -one i, i-dioxide (34) 2- C3- (4-cyano-4-phenylpiperidio) -l-pheriylpropy1l 2K-i, 2 -benzothiazin- 4 (3H) -one 1, i-dioxide fumarate Representative examples of the alkylenediamine derivatives of the invention are set forth in Tables 1 and 2.

In Table i, the compounds of the formula and the compounds of the formula are given, in which the symbols correspond to those seen in the formulas and In Table 2, the compounds of the formula (13) and the compounds of the formula (15) are given, in which the symbols correspond to those seen in the formulas (13) and Table 1

-N-R

k m n H H morpholino 1 1 1 H H 4 -benzy1piperidino 1 1 1 H H 4 -benzyloxypiperidino 11 1 H H benzylbutylamino 1 1 H H 4 -diphenylmethyl-l-piperazinyl 1 1 H H 4 -phenoxypiperidino 11 1 H H 4 -benzylpiperidino 1 1 0 H H 4 -benzyl-l-piperazinyl 1 1 H H 1,2,3,4-tetrahydroisoquinlin-2-yl 1 1 1 H OH morpholino111 H phenyl diethylamino 1 0 2 H phenyl piperidino 1 0 2 SH phenyl morpholino 30 H phenyl thiomorpholino 1 0 2 H 4-chloro- morpholino 1 0 2 phenyl H phenyl morpholino 12 0 H H 4 -(4-methoxybezy1)piperidino 1 1 1 H ethoxy morpholino 1 1 1 H phenyl morpholino 1 1 1 -26- (R')k

-NR

k m n 5-chioro H 4 -benzylpiperidino 1 1 1 7 -chlocro methyl 4 -benzylpiperidino 1 0 2 H 4 -benzylpiperiji 10 di~chloro -f lucro

H-

S5-methyl

H

7 -f luoro

H

7 -methyl

H

H

7 -methoxy

H

5-chioro

H

7-chioro

H

luoro

H

S-methyl

H

H

7 -fluoro

H

7 -methyl

H

H

S-f luoro

H

S-methyl

H

S-methoxy

H

5-chioro

H

S-f luoro

H

7-chioro

H

H

5-chioro

H

luoro

H

7-chioro

H

S-methyl

H

7-methyl

H

5-ch].oro

H

4~ u 4 -benzylpiperidin 4 -benzylpiperidirno 4 -benzylpiperjiji.

0 4 -benzylpiperidino 4 -benzylpiperidino 4 -benzylpiperidino 4 -benzyl -1-piperazinyl 4 -benzyl -1-piperazinyl 4 -benzyl -1-piperazinyl 4 -benzyl -l-piperazinyl 4 -benzyl -1-Piperazinyl 4 -benzYl -1-piperazinyl 4 -benzyl -1-piperazinyl benzylbutylamino benzylbutylamin 0 benzylbutyl amino benzylbutyl amino 1,2, 3,4 -tetrahydrOisqinolin- 2 -yl 1, 2, 3, 4 -tetra1hydroisouinolin- 2 -yl 1,2, 3, 4 -tetrahydroisquilin 2 -yl 1,2,3, 4 -tetrahydoisioin 1 j 2 jy 4 -benzyloxypiperidino 4 -befzlyoxypiperidino 4- benzYlcaxYpiperidino 4 -benzYloxypiperdino 4 -benz'ylOxypiperdinc 4 -PhenOxypiperidin~ 1 0 1 0 1 0 10 10 10 10 10 1 0 1 0 1 0 1 0 1 0 1 0 1 0 10 10 10 10 1 0 1 0 1 0 1 0 1 0 1 0 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

N

A

2 -27-

(R

1 k k m n kmn -methyl 7-chioro 7 -methyl chioro 5 fluoro -methyl 7 chloro 7 -methyl chloro 7 -methyl chloro 7-methyl chioro 7-methyl 5- chioro 7 -methyl chioro 7-methyl -chioro 7 -methyl chioro 7 -methyl chioro 7-methyl 5 -chioro H 4 -phenoxypiperidino H 4 -phenoxypiperidino H 4 -Phenoxypiper±i.±no H 4 -phenoxypiperidino H 4 -diphenylmethyl -1-piperazinyl H 4 -di~Phen~ylmethyl -1-piperazinyl H 4 -diPhenylmethyl -1-piperazinyl H 4 -diPhenylmethyl-lpiperaziny 1 H 4 -diphenylmethyl -1-piperazinyl H 4- (4-methoxybenzyl)piperjijfl 0 H 4- (4-methoxybnyl)piperidin 0 H 4- (4-chlorobezyl)piperiio H 4- (4-chlorobenzyl)piperidijno H 4-(4aey-bny~iprdn H 4- (4-acetylbny)piperidin H 4-(4mty_ ny~iprdn H 4-(4mtybnylpprdn H 4- (3-methoxybenzyl) piperidino H 4- 2 -chlorobenzyl)piperidino H 3 -benzylpiperidjno H 3 -benzylpiperidino H 4- (4-methoxybenzyl) -l-piperazinyl H 4- (4-methoxybenzyl) -l-piperazinyl H 4- (4 -chlorobenzyl) -l-piperazinyi H 4- (4 -chlorobenz1) l-piperazinyl H 6-methOxy,234tetrhyro isoquinflij-.2-yl H -methoxy234tetrhyro isoquinoln..2-yl H 6-chloro-l,2, 3 4 -tetrahydro.

isOquinoin-2-yl 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 7 -me thyl 59 chioro 1 0 2 1 02 102 -28p3-N-R! k mn 7-methyl H 6-chlor-12,3,4tetrahydro 1 0 2 isoquinolin-2 -yl H 4 -(4-methoxybenzy)oxyiperidino 1 0 2 H 4- (4-chlorobenyl)oxyiperidino 1 0 2 H 4- (4-methoxybeny)phnoxy 1 0 2 piperidi-no H 4 -(4-chJ-orobenyl)phnoxy 1 0 2 piperidmno H H 4 -(4-methoxybenzyl)piperidino 1 0 2 H H 4 -(4-ch-lorobenzy1)piperidino 1 0 2 H H 4 -(4-acetyl-benzyl)piperidino 1 0 2 H H 4- (4-methylbenzyl)pjperidino 1 0 2 H H 4 -(3-methoybezyl)piperdin 1 0 2 H H 4 2 -chlorobenzyl)piperidirlo 1 0 2 H H 3-benzylpiperidino 1 0 2 H H 4-4mtoyeiyl--ieaiy 1 0 2 H H 4-4clrbnyl--ieaiy 1 0 2 H H 6-methoxy1,2,3,4tetrhdo- 1 0 2 isoquinolin-2 -yl 5 H H 6-Chloro-1,2,3,4tetrhdo- 1 0 2 isoquinoli-2 -yl H H 4 -diphenylmethylxpprdn 100 H 4 -diphenymethyoyiperidino 1 0 2 -7-methyl H 4 -diphenylmethyloxypiperidno 1 0 2 H H 3 -benzylthiopiperidino 1 0 2 H H 3 -phenylthiopiperidino 1 0 2 H phenyl rorpholino 1 0 1 H phenyl. torpholino 1 0 3 H phenyl 4 -acetyl-l-piperazinyl 1 0 2 H 4 -chiorophenyl rorpholino 1 0 2 H 4-methylphenyl rorpholino 1 0 2 -29-

(R

1 k R2-R km n H 3-chlorophenyl mor-pholino 1 0 2 H 2 -chlorophenyl morpholino 1 0 2 H 2 4 -dichlorophenyl thiomorpholino 1 0 2 H 4 -chl-orophenyl thiomorpholio 1 0 2 H4 4-methyiphenyl thiomorpholino 1 0 2 H 3-chlorophenyl thiomorpholno 70 2 H 2 -chlorophenyl thiomorpholino 1 0 2 H 2,4 -diChiorophenyl tiororpholino 1 0 2 H 4 -fluorophenyl thiomorpholjao 0 2 H 4 -tluorophenyl morpholino -0 2 5-chioro phenyl rorpholino 1 0 2 phenyl thiorrorpholjn 0 0 2 phenyl torpholino -0 2 7-chioro phenyl rrorpholino _0 2 phenyl morpholino -0 2 7-methyl phenyl morpholino 0 2 7-f luoro phenyl rrorpholino 1 0 2 7 -dichl-oro phenyl morpholino 2 0 2 -chloro 4 -chlorophenyl morpholirn 1 0 2 5-choro -chloropheryl nrpholino 10 2 5-chloro 2 -chlorophenyl rrorpholino 10 2 phenyl 4 -acetyl-lpperazinyl 1 0 2 H phenyl 4 -benzyl-l-piperazinyl 1 0 2 H OH 'norpholino 1 0 2 H ethoxy morphol inc 1 0 2 H methyl 4 -benzylpiperidino 1 0 2 WH phenyl 4 -benzylpiperidino. 1 0 2 H 2 -thienyl rrorpholjno 1 0 2 H 2-furyl rrorpholino 1 0 2 H 2- furyl 4 -benzylpiperidino 1 0 2 H H 4 2 -thienylmethyl)piperidi.n 1 0 2 k /R3 H H 4- 2 -thienylmethyl)piperidi H allyl morPholino H phenyl benzyibutylamno 1 4- (2-tienylmehy1) piperi.

-ciloro 4-chloro- 4 -diphenylmethyl-.

phenyl 1-piperazinyl -chlorO 4-ch.oro- diethylamni~o phenyl 4-chloro- diethylamino phenyl 2 -pyridyl thiomorpho± inc 7- chioro 2 -PYridyl 2 -benzylpiperjdino H H ,-iyr-l-ezdl isOayinclin.2 -y1 H H 4 -phenylpiperidijno H H 4 -phenyl-l-piperazinyi HH 4 2 -thienylmethyloxy)pierdin H H 4- 2 -thieInymehyl) -l-piperaziniyi H H 4 2 -thieny±)1..piperazinyl krmn no 1 0 3 102 102 102 1 02 1023 -31- Table 2 k n H phenyl morpholino 1 0 2 H H 4 -benzypiperidino 1 0 2 H H 4 -diPhenylmethy>l-piperazinyl 1 0 2 H H 4 -benzylpiperidino 1 0 1 H H 4 -benzyipiperidino 1 0 3 H 4 -benzylpiperidino 1 0 2 H phenyl thiomorpholino 1 0 2 H 2-thienyl morpholino 1 0 2 H H 6-chloro-l12,3,4-tetrahydro- 1 0 2 isoquinolin-2-yl 7-chioro H 6-chloro-1,2,3,4-tetrahydro- 1 0 2 isoquinolin-2-yl 7 -dichloro phenyl diethylamino 2 0 2 H 4 -chlorophenyl mrorpholino 1 0 2 ethoxy 4 -benzylpiperidino 1 1 1 Next, in the formula the halogen represented by R' Preferably is fluorine, chlorine or bromine, and chlorine is Most preferred. The alkyl having 1-8 carbon atoms which is represented by R- preferably is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. The haloalkyl having 1-4 carbon atoms preferably is trifluoromethyl, chloromethyl, or fluoromethyl. The alkoxy having 1-8 carbon atoms preferably is methoxy, ethoxy, or propoxy. The aryloxy having 4-10 carbon atoms (which may have nucleus substituents such as halogen, cyano, alkyl, alkoxy, amino, or alkoxycarbonyl) preferably is phenoxy or p-chlorophenoxy. The aralkyloxy having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms) preferably is benzyloxy, Pyridylmethyloxy, naphthylmethyloxy, or thenyloxy. The alkylamino having -32- 1-8 carbon atoms preferably is methylamino, dimethylamino, ethylamino, propylamino, or isobutylamino. The aralkylamino having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms, and which may have nucleus substituents such as halogen, cyano, alkyl, alkoxy, amino, or alkoxycarbonyl) preferably is benzylamino or (4-chlorophenyl)methylamino. The arylamino having 4-10 carbon atoms (which may have nucleus substituents such as halogen, cyano, alkyl, alkoxy, amino, or alkoxycarbonyl) preferably is phenylamino or p-chlorophenylamino. The aliphatic acylamino having 1-8 carbon atom preferably is acetylamino or propionylamino. The alkoxycarbonyl having 2-9 carbon atoms preferably is methoxycarbonyl, ethoxycarbonyl, or propoxycarbonyl. The aralkyloxycarbonyl having 6-15 carbon atoms (its alkyl portion has 1-4 carbon atoms) preferably is benzyloxycarbonyl, pyridylmethyloxycarbonyl, naphthylmethyloxycarbonyl, or thenyloxycarbonyl. The aryloxycarbonyl having 5-11 carbon atoms preferably is phenoxycarbonyl, naphthyloxycarbonyl, or thienyloxycarbonyl. The alkoxysulfonyl having 1-8 carbon atoms preferably is methoxysulfonyl or ethoxysulfonyl. The aralkyloxysulfonyl having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms) preferably is benzyloxysulfonyl, naphthylmethyloxysulfonyl, or thenyloxysulfonyl. The aryloxysulfonyl having 4-10 carbon atoms preferably is phenoxysulfonyl, naphthyloxysulfonyl or thienyloxysulfonyl.

In the formula Particularly preferred for R' is hydrogen, halogen, or alkoxy having 1-8 carbon atoms.

In the formula

R

2 represents a phenyl, naphthyl, or aromatic heterocyclic group which may have one to five same or different substituents. Preferred groups are phenyl, naphthyl, furan, thiophene, pyridine, quinoline, or indole, which may have one to five same or different substituents.

Among the above-mentioned substituents, the halogen -33preferably is fluorine, chlorine, or bromine. The alkyl having 1-8 carbon atoms preferably is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, or octyl. The haloalkyl having 1-4 carbon atoms S preferably is trifluoromethyl, chloromethyl, or fluoromethyl. The alkoxy having 1-8 carbon atoms preferably is methoxy, ethoxy, or propoxy. The aryloxy having 4-10 carbon atoms (which may have nucleus substituents such as halogen, cyano, alkyl, alkoxy, amino, or alkoxycarbonyl) preferably is phenoxy or p-chlorophenoxy. The aralkyloxy having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms) preferably is benzyloxy, pyridylmethyloxy, naphthylmethyloxy, or thenyloxy. The alkylamino having 1-8 carbon atoms preferably is methylamino, dimethylamino, ethylamino, propylamino, or isobutylamino. The aralkylamino having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms, and which may have nucleus substituents such as halogen, cyano, alkyl, alkoxy, amino, or alkoxycarbonyl) preferably is benzylamino or (4-chlorophenyl)methylamino. The arylamino having 4-10 carbon atoms (which may have nucleus substituents such as halogen, cyano, alkyl, alkoxy, amino, or alkoxycarbonyl) preferably is phenylamino or p-chlorophenylamino. The aliphatic acylamino having 1-8 carbon atom preferably is acetylamino or propionylamino. The alkoxycarbonyl having 2-9 carbon atoms preferably is methoxycarbonyl, ethoxycarbonyl, or propoxycarbonyl. The aralkyloxycarbonyl 64 having 6-15 carbon atoms (its alkyl portion has 1-4 car- 4 )bon atoms) preferably is benzyloxycarbonyl, pyridylmethyloxycarbonyl, naphthylmethyloxycarbonyl, or thenyloxycarbonyl. The aryloxycarbonyl having 5-11 carbon atoms preferably is phenoxycarbonyl, pyridyloxycarbonyl, naphthyloxycarbonyl, or thienyloxycarbonyl. The alkoxysulfonyl having 1-8 carbon atoms preferably is methoxysulfonyl or ethoxysulfonyl. The aralkyloxysulfonyl having 5-14 carbon atoms (its alkyl portion has 1-4 carbon -34atoms) preferably is benzyloxysulfonyl, naphthylmethyloxysulfonyl, or thenyloxysulfonyl. The aryloxysulfonyl having 4-10 carbon atoms preferably is phenoxysulfonyl, naphthyloxysulfonyl, or thienyloxysulfonyl.

Preferred for R 2 is phenyl or thienyl which may have one to five same or different substituents. More preferred is phenyl having no substituents, or phenyl having, as substituent, one to five of alkyl having 1-8 carbon atoms, alkoxy having 1-8 carbon atoms, halogen, or haloalkyl having 1-8 carbon atoms. Particularly preferred is phenyl having no substituents or phenyl having one substituent such as halogen or alkoxy having 1-8 carbon atoms.

In the formula the alkyl having 1-8 carbon atoms which is represented by R 3 or R 4 preferably is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

The aralkyl having 5-14 carbon atoms (its alkyl portion has 1-4 carbon atoms) preferably is benzyl, phenylethyl, or phenylpropyl. The aryl having 4-10 carbon atoms preferably is phenyl, pyridyl, or naphthyl.

The five to seven membered heterocyclic group represented by the formula (II) formed by the combination of

R

3

R

4 and the nitrogen atom to which

R

3 and R 4 are attached preferably is morpholino, piperidino, homomorpholino, l-pyrrolidinyl, thiomorpholino, l-piperazinyl, l-perhydroazepinyl, S-oxythiomorpholino, or S,S-dioxy- S thiomorpholino.

The alkyl having 1-8 carbon atoms which is represented by Rs of the formula (III) for Z of the formula b 30 (II) preferably is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl. The aralkyl having 5-14 carbon atoms (its alkyl has 1-4 carbon atoms) preferably is benzyl, phenylethyl, or phenylpropyl. The alkoxycarbonyl having 2-9 carbon atoms preferably is methoxycarbonyl, ethoxycarbonyl, or propoxycarbonyl. The aralkyloxycarbonyl having 6-15 carbon atoms (its alkyl portion has 1-4 carbon atoms) preferably is benzyloxycarbonyl, pyridylmethyloxycarbonyl, naphthylmethyloxycarbonyl, or thenyloxycarbonyl. The aryloxycarbonyl having 5-11 carbon atoms preferably is phenoxycarbonyl, naphthyloxycarbonyl, or thienyloxycarbonyl.

Among the substituents which may be attached to the five to seven membered heterocyclic group of the formula the alkyl having 1-5 carbon atoms preferably is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

The aralkyl having 5-14 (its alkyl portion has 1-4 carbon atom) Preferably is benzyl, phenylethyl, or phenylpropyl.

The alkoxy having 1-5 carbon atoms preferably is methoxy, ethoxy, or propoxy. The alkoxycarbonyl having 2-6 carbon atoms preferably is methoxycarbonyl, ethoxycarbonyl, or propoxycarbonyl. The aralkyloxycarbonyl having 6-15 carbon atoms (its alkyl portion has 1-4 carbon atoms) preferably is benzyloxycarbonyl, pyridylmethyloxycarbonyl, naphthylmethyloxycarbonyl, or thenyloxycarbonyl. The aryloxycarbonyl having 5-11 carbon atoms preferably is phenoxycarbonyl, naphthyloxycarbonyl, or thienyloxycarbonyl. The aliphatic acyl having 1-8 carbon atoms preferably is formyl, acetyl, or propionyl. The aromatic acyl having 5-11 carbon atoms preferably is benzoyl or phthaloyl. If the two or more substituents are attached, these substituents may be the same or different.

The five to seven membered heterocyclic group represented by the formula (II) preferably is morpholino, S piperidino, homomorpholino, l-pyrrolidinyl, thiomorpholino, 1-piperazinyl, 1-perhydroazepinyi, S-oxythiomorpholino, or S,S-dioxythiomorpholino which may not have M substituents or may have substituents such as alkyl having 1-8 carbon atoms, phenyl, acyl having 1-8 carbon atoms, carbamoyl, or 2 -pyrimidinyl on its carbon and/or nitrogen atom.

In the formula m preferably is 1 or 2, and 1 is most preferred. n preferably is 0, 1, or 2, and 0 is -36most preferred, p preferably is 0, and q preferably is 1, 2 or 3. The alkylenediamine derivative of the formula in which x is 2 and y is 1 corresponds to the alkylenediamine derivative of the formula The alkylenediamine derivative of the formula in which x is 1 and y is 1 corresponds to the alkylenediamine derivative of the formula The alkylenediamine derivative of the formula in which x is 2 and y is 0 corresponds to the alkylenediamine derivative of the formula

(VI).

The alkylenediamine derivative of the formula

(I)

can be prepared by reacting a compound having the formula (VII): (VII) o (RL)

I

i s N E (0) in which m, x and y have the same meanings as defined in the formula

(I)

with a compound having the formula

(VIII):

(VIII)

R3

Q-

4

CH-

(CH

2 n R2 in which

R

2

R

3

R

4 n, p and q have the same meanings as defined in the formula and Q is a releasable group such as halogen, tosyloxy, or mesyloxy.

SIn the above-mentioned preparation process, the compound of the formula (VII) and the compound of the formula (VIII) are caused to react at a temperature from room temperature to the reflux temperature for 1 to hours, in an organic solvent such as acetone, dimethylformamide, methyl ethyl ketone, or isobutyl methyl ke- -37tone, in the presence of a carbonate such as potassium carbonate, sodium carbonate, or cesium carbonate, to prepare the compound of the formula In the reaction, 1 to 2 moles of the compound of the formula

(VIII)

and the 2 to 8 moles of the carbonate are preferably employed per one mole of the compound of the formula (VII). The compound of the formula (VIII) is preferably employed in its stable hydrochloride form.

Alternatively, the alkylenediamine derivative of the formula can be prepared by reacting a compound of the formula

(IX):

(JX)

lot] x in which R, R 2 m, n, p, q, x and y have the same meanings as defined in the formula and Q is a releasable group such as halogen, tosyloxy, or mesyloxy, with a compound having the formula (x) /3 HN

AN

A

L,

\R4 in which R' and R 4 have the same meanings as defined in the formula In the above-mentioned preparation process, the compound of the formula (IX) and the compound of the formula are caused to react at 50 to 150 0 C for 1 to hours, generally, in the absence of a solvent. If necessary, a solvent which does not participate in the reaction can be employed.

The alkylenediamine derivative of the formula

(I)

-38can be Converted into a pharmacologically acceptable salt. Examples of the pharmacologically acceptable salt of the alkylenediamine derivative of the formula include acid-addition salts such as salts with an inorganic acid hydrochloric acid, sulfuric acid, hydrobropic acid, or phosphoric acid), or an organic acid fumaric acid, acetic acid, propionic acid, citric acid, tartaric acid, maleic acid, mnalic acid, oxalic acid, methanesulfonic acid, or p-toluenesulfonic acid).

Examples of the alkylenediamine derivatives represented by the formula are described below: 2- [l-pheny-3-(l-pyrroldfnl)jpoy-,bez isothiazol-3(2H) -one l,1-dioxide 2- lpey--hoopoin~rpl12bnio thiazol.3 (2K)-one 1,i-dioxide 2- 2 -morpholino.phny 1 ethyl-i, 2 -benzisothiazol- 3 (2K) -one 1, 1-dioxide 2-(4mrhlioipeylbtl1 2 -benzisothiazol- 3 (2H) -one 1 1 -dioxide 2- (iPheny1-3-piperidino)Propyll 2 -benzisothiazol- 3(2K) -one i,1i-dioxide 2- (Perhydroazepin1yl)-lpey rpy-,-ez isothiazol.3 (2H) -one l,1-dioxide 2- (4-methyiPieriio) -i-phenyllpropyl-i 2-benzisothi.az0-3 (2H)-one i,l-dioxide 2- (4-carbamoylpiperidino) -1-phenyl] propyl-i, 2benzisothiazol..

3 2 H)-on 1i--dioxide 3 -morpholinophenyl)pl-,bezstiol 3 (2H) -one 1,l1-dioxide 0 (0 beniZsothiazo- 3 -one 1,1-dioxide ONWO (11) 2- (4-acetyl-1..piperazifl) -l-phenylpropy-12benzisothiazol.

3 (2K) -one 1 ,1-dioxide (12) 2- [1-phenyl.> 2 -pyrimidinyl) -l-piperazinyll 1- 35propyl-1, 2 -benzisotiazol..

3 -one l,1-dioxide (13) (4-chi-orophenyl) -J-piperidinolpropyl1,2- -39benizisotiazolj (2W) -one 1, i-dioxide (14) 2- (4-chi-orophenyl) 3 -rflrpholinopropyii1 2 benzisothiazoij (2H) -one 1, i-dioxide 2- [1-(4-rnetbhoxyphenyi) 3 -piperidinojpropyli ,2benzisothiazoij (2H) -one i, i-dioxide (16) 6-chor..2.(-I-pheny1-3piperidno)propyii1 2 -bez isothiazolj (2W) -one i-,l-dioxide (17) G-chloro-2-(3-morpholinoiph 1 ny)ppy-,bez isothiazolj (2H) -one 1, i -dioxide (18) 6-methoy 2 (1-pheny1>3piperidn) rpl1 2 -benTzisoDth-iazol- 3 (2W) -one 1, i-dioxide (19) G-methoxy-2-(3-morphoinolphe 1 y)prpl1 2 -ben-ziSothiazol- 3 (2W) -one i, i-d-ioxiLde 4 -chiocro.2.(3-piperidinoiphny)propii- 2 -bez IS ~isothiazoiJ3( 2 H)-n lu1-dioxide (21) 2- (1-pheny -3-thiomo p o i o p o yl 1 2 b n iohiaz01-3 (2W) -one i, luS-trioxide (22) 2- lpey--hoopoio~rpl12bni(tia zol-j (2W) -one 1,1,SS-tetraoxide (23) 2- 2 -methylthiomorphoinh -i-Phenylpropy-1 2 benzi-sotjiaz 01 j(2W) -one i,1 ixoide (24) 2- 3 -methythioorhoi -i-phenyilpropyii,2 benzisot.huazoi.

3 (2W) -one i, i-dixoide 2- 2 -dimethylthioorhoino) -i-phenyi3 propyl- (26 1, 2 -benzisothiazoi 3 (2W) -one lu1-dioxide 2 ,6-diethythiorhi phenyllpropyli iu 2 -benzisothiazol- 3 2 -one 1,i-dioxide (27) 2- [l-pheny..3-( 2 -phenylthiomohoino)lpyi1 benzisothiazoi 3 (2W) -one i, i-dioxide (28) 2 [i (4ti uoropheny1)3 -ti mrh l nl rp l 1 benzisothiazoij (2W) -one i, i-dioxide (29) 2- 3 -dmethylamnoj-pe 1 y)prp 2 -benzisothiazo...j(2W) -one i, i-dioxide 2- 3 -diethylamiophiny)poy-,-ezsthiazoi3 (2H)-one 1,i-dioxide (31) 2- (3-benzyethylaminoi-heyPrpl12bnio thiazol13 (2K) -one 1, i-dioxide (32) 2- (J-morphoiiopeil-bniohao 3 (2H) -one i-Oxide (33) 2- (3-Piperidinoilphenyl) ProPli12bnio thiazoline 1,1idioxide (34) 2- 3 -mrphol noiphY)Pryl 1 ,2bni thiazoline 1, i-dioxide Representative examplies Of the aikylenediamine deri'vati-ves of the formula according to the invention, are set forth in Tables 3, in which the symbols corresponld to those seen in the formula Tale 3 INqU.

M

-NR3R 4 M T-1 _P q X v 1 K phenl iProidiy 2 K phenyl thiomorpholino 3 K phenyl rnorpholino 4 K phenyl rrorpholino K phenyl Piperidino 6 H phenyl I-perhYdroazepinyi 7 phenyl 4 -methYlpiperiio 8 K phenyl 4 -carbamcyl- 9 H penyl Piperidino 9 K phnyl rorpholino K phenyl 4-ethyli.- Piperazinyl 11 phenyl 4 -acetyii.- Piperaz inyl 12 H phenyl 4-(2-yrmdnl 13 H -chlro_ i-Piperazinyl 13 K 4 -choro~Piperidino fli r~ r~ L 00 221 phenyl -0 022 1 -41- -41- INO. -NR3R4 M n 14 H 4-chdor- morpholino phenyl H 4 -mecho- Piperidino u 221 100221 is 16 6-chloro 17 G-Chloro 18 G -metfio, 19 G-metho-, 4 -cliloro 21

H

phenyl Phen~yl piperidino phenyl Iforpholi~no ~'phenyl Piperidino phenyl morphlmen PhenYl PiperidWno phenyl thiomcrpheoji 0 oxide phenyl thiorphol1i-ncdioxide phenYl 2 -rnethylthio_ tflrphol1inc phenyl 3 -methyltffj 0 mflrpholino phenyl 2,2 -dirnethyl 23

H

24 0221 100 221 10 0221 100 221 100C221 100 2 2 100 221 p enyl 2, G-dimethylphenyl 2 -phenylthio_ ~1 029 31 32 33 34 morpholin H4-f lucre- thiomerphelino phenyl HphenYl dimethyamno H phenyl diethylanminc H phenyl benzyl.ethylamr H- phenylm rorpholino .4 phenYl Piperidino) -i phenyl rrorpholino 1O 4 -brorno phenyl morpholino 1u 0 2 2 1 -42- NO.- R -NR R M mn p q 36 G-bromo phenyl mor-pholino 1 0 0 2 2 1 37 4 -fluoro phenyl morpholino10022 1 38 G-ffluorO phenyl morpholino 1 0 0 2 21 39 4 -methoxy phenyl morpholino 1 0 0 2 21 4 -cyano phenyl morpholrno 1 0 0 2 21 41 4 -methyl phenyl morpholno 1 0 0 2 2 1 42 G-Cyano phenyl morpholino 1 0 0 2 21 43 G-methyl phenYl morpholino 1 0 0 2 2 1 44 4 -hydroxy phenyl morpholino 1 0 0 2 21 G-Phenox phenyl morpholino 1 0 0 2 2 1 46 4 -acety>. phenyl morphoiia 1 0 0 2 2 1 am-ino10022 47 H 2 -thienyl morpholino 1 0 0 2 21 48 4 -chloro 2 -thieriyl morpholino 1 0 0 2 2 1 49 4-bromo 2-thJienyi morpholino 1 0 0 2 2 1 50 4 -fluoro 2 -thienyl morpholino10022 1 51 4 -methoxy 2-thienyl morpholino 1 0 0 2 21 52 H 2 -turyl morpholino 1 0 0 2 21 53 4 -chloro 2 -furyl morpholino 1 0 0 2 21 54 4-bromo 2 -furyl morpholino 1 0 0 2 21 55 4 -fluoro 2-turyl morpholino 1 0 0 2 2 1 56 4 -rethoxy 2 -turyl morpholino 1 0 0 2 2 1 X 57 4 -chloro phenyl Inopoi~ 1 0 0 2 2 1 S58 4-br-ama phenyl thioror~phol~hO 1 0 0 2 2 1 (II 59 4- tluoro phenyl thiomrpho1jn 1 00 2 2 1 60 4-methoxy phenyl thiomorPholi 1 0 0 2 2 1 61 H 2 -thienyl thiomorPhojjn 0 1 0 0 2 2 1 62 H 2frl thiorrorpholino 1 0 0 2 2 1 63 H phenyl morpholino 11 64 H phenyl rrorpholino 1 0 2 0 2 1 65 Hphenyl tho~rhl~ 1 0 1 1 2 1 1' -43- NO.-

R

2

-NR

3 R 4 np 66 H- phenyl thiomorPhOlin 0 1 0 2 0 2 1 67 H phenyl homomorPholin 0 1 0 0 2 2 1 68 4-chioro phenyl homomorpholino 1 0 0 2 2 1 69 4-bromo phenyl homomorpholino 10022 1 4-fluoro ph n l h m m r~ j 0 1 0 0 2 2 1 0 71 4-methoxy phenyl homororpholino 1 0 022 1 72 5,6- phenyl mrhlno2002 2 1 di chioro mrhln 73 5,6- phenyl thiomorpholino 2 0 0 2 21 di-chloro 74 5,6- phenyl Piperidino 2 0 0 2 2 1 dichiloro 5,6- phenyl homomorPholmno 2 0 0 2 21 dichioro 76 5,6- phenyl morphollino 2 0 0 2 21 dime thoxy 77 5,6- phenYl thiornorpholino 2 0 0D 2 21 di~me thoxy 78 5,6- Phen~Yl Piperidino 2 0 0 2 21 dimethoxy 79 5,6- phenyl horomOr-pholino 200221 dime

C(

4-chjoro 4 -chloro- torpholino 1 0 0 2 2 1 pherlyl 81 4 -Chloro 4 -chloro-- thiomorphojjjno 1 0 0 2 2 1 phenyl 82 4 -chlorO 4 -chloro. piperidino 1 0 0 2 2 1 phny 83 4-brono 4 -chloro- mopcln 1 0 0 2 2 1 phenyl.

84 4-brono 4 -chloro- thiomrpolno 1 0 0 2 2 1 phenyl -44- -44-

(P)

-NR 3 R 4 M n n rT 11 4-bramo 4-fluaro- morphol± 0 Phen1Ln] 00 86 4 -ffluoro 4 -chloro- morpholiia 87 4 phenyl 8 -fluOro 4-Chioro- thiorncrpholjio 88 phenyl 88 H 2 ,G-dichloro. morpholj 120 phenyl 89 H 3 ,S-dichlioro- Morpholinro phenyl 100 2 2 10 0221 10 0221 100 2 2 10 0221 0ao 221 is 90 H 2 ,6-dich-loro- thliomorpholin 0 91 92 93 94 96 97 98 99 phenyl H 3 ,S-dichlor... oorhon phenyl 4 -methyl 4 -chloro morpholino 4 -chlIoro 4 -methyl mrpholjjo 5,6- 2 ,-dichloro. Mornhnj-,_ dichloro phenyl 4 -chlOrO 4 -chlorophenyl rorpholino 1 4 -chloro 4 -chlarophenyl morpholino 1 6-i sopropy1 phenyl rrorphoino 1 6-n-butyl phenyl trorpholino 1 H 4 -isopropyl_ trorpholino 1 phenyl e4 30 00 100 4 4 -isoamyl..

morpholino 1 0 0 2 2 101 H 3 -raphthyl mOrPholino 10022 1 102 H 4 -pyridyl morpho1±no 1 0 0 2 2 1 The comp~ound of the invention was evaluated in urinating contraction of bladder byth fll i es mtod. tefloigts eh A male rat (Wistar strain) was fixed on his back under urethane anesthesia (1.5 g/kg, A tracheal cannula was inserted into the rat to respire easily, and its hypogastrium was subjected to median dissection for exposing its bladder. A small opening was made on the top of the bladder to remove urine. To the bladder was inserted a polyethylene cannula. The bladder system was made to closed system by ligating urethra and ureter.

A physiological saline was injected into the bladder of rat at a rate of 0.05 mL/min. using a continuous injector so as to cause periodical urinating contraction.

The intravesical pressure of the bladder was measured by means of a pressure transducer- The measured value was recorded on a pen-writing recorder. The compound to be tested was dissolved in a Physiological saline and admin- istered into the femoral vein using the polyethylene cannula.

Method of Evaluation The action for relieving urinating contraction was evaluated by measuring a period of time during which the rhythimic bladder contraction was inhibited (period of contraction inhibition).

The compounds tested were those obtained in the working examples. The period of contraction inhibition measured on each compound is set forth in Table 4.

C4 Table 4 Compound Mouse LD.0 Dose Number of Period of Con- (mg/kg (mg/kg Samples traction Inhibition(min.) Control 6 1.6 (Physi. Saline) Example 20[A] >120 12 6 9.7 Example 20[3] 140 6 2 0.4 Example 20 180 6 2 Example 24 62 12 8 5.6 Example 24 32 6 2 Example 24[C] 167 6 2 0.7 Example 21 >100 10 1 Example 26 37 4 2 7.3 Example 10 3 8 2 14.5 Example 11 37 8 4 3.9 Example 12 8 2 Example 1 1 3 2.8 Example 14 17 8 3 12.7 Example 15 23 8 3 4.7 Example 3 8 2 2 Example 2 8 2 16 Example 13 8 2 18 Example 16 8 3 Example 31 8 Example 32 8 3 6 Example 34 8 2 3 Example IX 48 5 4 10.7 Example XI 170 17 2 Example II 47 5 10 3.8 Example XXI >200 20 2 The results seen in Table 4 clearly indicate that the compound of the invention is effective in relieving -47urinating contraction. Further, the toxicity of the compound is set forth in Table 4 in terms of LDs (mg/kg) calculated by Probit method.

The alkylenediamine derivative or its pharmacologically acceptable salt according to the invention is useful as an active ingredient for a pharmaceutical for treatment of dysuria.

The pharmaceutical for treatment of dysuria accord- ing to the invention can be used either in a general preparation form for oral administration or in the form for Parenteral adminstration such as injections and sup- Positories. Preparation forms for oral administration may be tablets, capsules, powder, granules, syrup and the like. Preparation forms for parenteral administration may be injections and suppositories and the like. For the formulation of these preparations, excipients, disintegrants, binders, lubricants, pigments, diluents and the like which are commonly employed in the art may be used. The excipients may include glucose, lactose and the like. Starch, carboxymethylcellulose calcium and the like may be used as the disintegrants. Magnesium stearate, talc and the like may be used as the lubricants.

The binders may be hydroxypropylcellulose gelatin, poyvinylpyrrolidone and the like.atin, poly- The dose may usually be about 0.1 mg/day to 10.0 mg/day in the case of an injectable preparation and about mg/day to 500 mg/day in the case of oral administration, both for adult. The dose may be either increased or decreased depending upon the age and conditions of patients.

aThe present invention is further described by the following examples.

2-[3-(4-Phenoxypiperidino)propyl] -2H- 12 -benzothiazin- 4 (3H) -one 1, 1-dioxide hydrochloride -48- 2-( 3 -Chloropropyl) 2 H-1,2-benzothiazin-4 (3H) -one 1,1-dioxide ethylene ketal In 1, 2 -dimethoxyethane (450 mL) was suspended sodium hydride (2.0 g, 502 mmol.), and then 2H-1,2benzothiazin-4(3H)-one 1,1-dioxide ethylene ketal (12.06 g, 50 mmol.) was added to the suspension. The suspension was heated to 100 0 C for 1 hour under stirring. The reaction liquid was cooled to 50°C, and to this was added a solution of l-bromo-3-chloropropane (23.62 g, 150 rnmol.) in 1, 2 -dimethoxyethane (50 mL). The mixture was heated to 100'C for 21 hours under refluxing. The reaction liquid was filtered to remove insolubles and the solvent was evaporated to give a residue. The residue was treated with water and ether, and the organic layer was taken out. The organic solution was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was evaporated to leave the desired compound (8.89 g, yield 56%) as a yellow oil.

'H-NMR (CDC13) 2.0-2.1 (2H, 3.62 (2H, t, J=6Hz), 3.71 (2H, t, J=6Hz), 3.91 (2H, s), 4.1-4.2 (2H, 4.2-4.3 (2H, m), 7.4-7.6 (3H, 7.7-7.8 (1H, m).

2- [3-(4-Phenoxypiperidino)propyl] 2 H-1,2-benzothiazin-4(3H)-one 1,1-dioxide ethylene ketal In dichloromethane (1 mL) were dissolved 2-(3chloropropyl) -2H-1, 2 -benzothiazin-4 (3H)-one 1,1-dioxide ethylene ketal (830 mg, 2.6 mmol.) obtained in and 4phenoxypiperidine (500 mg, 2.6 nmml.). From the solution 0 was distilled off dichloromethane, and the residue was S heated to 110 0 C for 5.5 hours under stirring and in nitrogen atmosphere. To the reaction liquid were added an aqueous saturated sodium hydrogen carbonate solution and ethyl acetate, and the organic layer was taken out. The organic solution was washed with water and an aqueous -49saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off to leave a residue. The residue was treated by silica gel column chromatography (chloroform/methanol=40/1) to obtain the desired compound (700 mg, yield 58%) as a yellow oil.

1H-NMR (CDC13) a: 1.7-1.9 (4H, 1.9-2.1 (2H, m), 2.2-2.3 (2H, 2.4-2.5 (2H, m), 2.7-2.8 (2H, 3.5-3.6 (2H, m), 3.91 (2H, 4.1-4.2 (2H, m), 4.3-4.4 (3H, 6.9-7.0 (3H, m), 7.2-7.3 (2H, 7.5-7.6 (3H, m), 7.75-7.8 (1H, m).

2- (4-Phenoxypiperidino)propyll] 2 H-1,2-benzothiazin-4 (3H) -one 1,1-dioxide hydrochloride In methanol (10 mL) was dissolved 2 3 -(4-phenoxypiperidino)propyl]-2H-, 2 -benzothiazon-4(3H)-one 1,2dioxide ethylene ketal (700 mg, 1.5 mmol.) obtained in To the obtained solution was added 3N hydrochloric acid (10 mL), and the mixture was heated under refluxing for 15 min. The solvent was distilled off from the reaction liquid. To the residue was added water, and the mixture was kept in a cooled place. Crude crystals deposited were collected by filtration, and recrystallized from dichloromethane/methyl ethyl ketone to give the desired compound (440 mg, yield 64%) as a white crystalline product.

SM.P.: 204-207°C IR (KBr) cm-1: S3400, 2500, 1700, 1600, 1590, 1490, 1340, 1240, 1230, 1170, 1120, 1110, 1050, 975, 780, 750, 690, 570.

H-NMR (CDC3) 6: 2.1-2.3 (4H, 2.5-2.7 (2H, m), 3.0-3.2 (4H, 3.3-3.4 (2H, m), 3.4-3.5 (2H, 4.50 (2H, s), 4.6-4.7 (1K, 6.9-7.0 (3H, m), 7.2-7.3 (2H, 7.7-7.9 (3H, m), 8.0-8.1 (1K, m) Exampl e2 2-3-(4-Benzyloxypiperidino)propyl]-2H-1, 2 -benzothiazin- 4(3H)-one l,l-dioxide hydrochloride 2-[3-(4-Benzyloxypiperidino)propyl]- 2 H-1,2-benzothiazin-4(3H)-one l,1-dioxide free base In 1,2-dimethoxyethane (40 mL) was suspended G0%sodium hydride (180 mg, 4.5 mmol.), and then 2H-1,2benzothiazin-4(3H)-one l,l-dioxide ethylene ketal (1.00 g, 4.1 mmol.) was added to the suspension. The suspension was heated for 1 hour under stirring. The reaction liquid was cooled to 50c, and to this was added a solution of 4 -benzyloxy-1-( 3 -chloropropyl)piperidine (1.11 g, 4.1 mmol.) in 1,2-dimethoxyethane (10 mL). The mixture was further heated for 20 hours under refluxing. The reaction liquid was filtered to remove insolubles and the solvent was distilled off to give a residue. To the residue were added aqueous 9% hydrochloric acid (30 mL) min ethanol (30 mL), and the mixture was heated for mn under refluxing The reaction liquid was placed under reduced pressure to distill methanol off. The residue was treated with ice-water, and the deposited oil was extracted with dichloromethane. The dichloromethane portion was washed with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off to leave a residue. The residue was treated by silica gel column chromatography (chloroform/methanol=3 0 1 to give the desired compound (860 Mg, yield 45k) as a red oil.

1H- NMR (CDC1,) 8 1.6-2.8 (12H, 3.2-3.3 (2H, m) 3.4-3.5 (1K, 4.46 (2H, s -51- 4.53 (2H, 7.2-8.1 (9H, m).

2-[3-(4-Benzyloxypiperidino)propy 1 2 H-1,2-benzothiazin-4(3H)-one 1,1-dioxide hydrochloride In methanol (1 mL) was dissolved 2 -[3-(4-benzyloxypiperidino)propylj -2H-1, 2 -benzothiazin-4(3H)-one 1,1dioxide free base (860 mg, 2 mmol.) obtained in To the resulting solution was added aquoeus 9% hydrochloric acid (1 mL), and the mixture was placed under reduced pressure to distill the solvent off. The residue was then treated with water and dried to give the desired compouud (700 mg, yield 36w) as an orange amorphous product.

IR (KBr) cm-: 3400, 2925, 1690, 1580, 1445, 1335, 1270, 1220, 1s 1170, 1120, 1050, 910, 750, 700, 570.

1 H-NMR (CDC1 3 6: 1.7-2.2 (6H, 2.8-3.8 (9H, m), 4.4-4.6 (4H, 7.2-8.0 (9H, m).

Examprle 3 3-[3-(4Benzylpiperidino)propyll-1H-2, 3 -benzothiazin- 4(3H)-one 2 2 -dioxide furarate 3-[3-(4-Benzylpiperidino)propyll-1H-2,3-benzothiazin-4(3)-one 2 2 -dioxide free base In dry ethanol was dissolved metallic sodium (120 mg, 5.1 ninol.)o To the solution was added 1H- 2 ,3-benzothiazin-4(3x)uone 2 2 -dioxide (1.0 g, 5.1 mmol.), and the mixture was heated for one hour under refluxing To the reaction liquid were added 4-benzyl-l- 3 -chloropropyl) piperidine (1.28 g, 5.1 mmol.) and dry ethanol (10 mL), and subsequently the mixture was heated under refluxing for 6 hours. The reaction liquid was placed under reduced pressure to distill the solvent off. The resulting residue was treated with water, and extracted with ethyl acetate. h e extracted with ethyl 35 acetate. The ethyl acetate portion was washed with water and an aqueous saturated sodium chloride solution, and -52dried over anhydrous sodium sulfate. The dried solution was placed under reduced pressure to distill the solvent off, and the resulting resiude was treated by silica gel column chromatography (ethyl acetate/hexane=2/1) to give the desired compound (860 mg, yield 40%) as a yellow oil.

1H-NMR (CDC13) 6: 1.2-1.3 (2H, 1.4-1.7 (3H, m), 1.8-2.0 (4H, 2.3-2.5 (4H, m), 2.89 (2H, d, J=11Hz), 3.9-4.0 (2H, m), 4.58 (2K, 7.0-7.4 (6H, m), 7.5-7.6 (2H, 8.21 (1H, d, J=8Hz).

3-13-(4-Benzylpiperidino)propyll -1H-2,3-benzothiazon-4(3H)-one 2 ,2-dioxide fumarate 3-[3-(4-Benzylpiperidino)propyl] -1H-2,3-benzothiazin-4(3H)-one 2,2-dioxide free base (840 mg, mmol.) obtained in was treated with fumaric acid (240 mg, 2.0 mmol.) in ethanol (10 mL), to give the desired compound (830 mg, yield 77%) as a crystalline powder.

154-155 0

C

IR (KBr) cm- 3400, 2925, 1680, 1600, 1450, 1430, 1350, 1310, 1285, 1195, 1170, 1140, 985, 750, 745, 650.

1H-NMR (DMSO-d 6: 1.2-1.3 (2H, 1.5-1.6 (3H, m), 2.4-2.6 (4H, 3.00 (2H, d, J=11Hz), 3.8-3.9 (2H, 5.22 (2H, s), 6.53 (2H, 7.1-7.3 (5H, m), 7.5-7.8 m, ArH), 8.05 (1H, d, J=8Hz).

E xa0m ale 4 2-(3-Morpholino-1-phenylprpyl) 2 H-1,2-benzothiazin- 3(4H)-one l,l-dioxide fumarate In toluene (7 mL) were suspended 2 H-1,2-benzothiazin-3(4H)-one l,1-dioxide (250 rmg, 1.3 mmol.), 1- -53chloro-3-morpholino-i-phenylpropane (340 mg, 1.4 mmol.), potassium carbonate (250 mg, 1.8 mmnol.) and a catalytic amount of cupper powder. The suspension was heated for 12 hours under refluxing. The reaction liquid was cooled, and the insolubles were filtered off. The solvent was distilled off to leave a residue. To the residue were added water and ethyl acetate, and the organic layer was taken out. The organic solution was washed with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was treated by silica gel column chromatogrpahy (ethyl acetate) to give the free base of the desired compound (180 mg) as an oil. The free base was treated in the conventional manner to convert into the desired fumarate.

1 8 6 -187oC IR (KBr) cm- 1 3400, 1710, 1570, 1450, 1340, 1255, 1185, 1130, 1090, 1070, 990, 925, 875, 750, 720, 690, 620, 570.

'H-NMR (CD30D) 2.4-3.0 (8H, 3.6-3.9 (4H, m), 5.6-5.9 (1H, 6.73 (2H, s), 7.1-7.9 (9H, m).

3-( 3 -Morpholino-1-phenylpropyll -2H-1, 3 -benzothiazin- 4(3H)-one l,l-dioxide fumarate SIn methyl ethyl ketone (5 mL) were suspended 2H-1,3benzothiazin-4(3H) one l,l-dioxide (100 rg, 0.518 nmmol.), S-chloro-3-morpholino-l-phenylpropane (130 mg, 0.54 rmmol.), and potassium carbonate (180 mg, 1.3 mnol.). The suspension was heated overnight under refluxing. The reaction liquid was cooled, and the insolubles were filtered off. The solvent was distilled off to give a residue. To the residue were added water and ethyl acetate, -54and the organic layer was taken out. The organic solution was washed with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was treated by silica gel column chromatography (chloro- 1 to give the free base of the desired compound (70 mg, yield 35%) as an oil.

The free base was treated in the conventional manner to convert into the desired fumarate.

218°C (decomp.) IR (KBr) cm-1: 3400, 1680, 1650, 1440, 1420, 1390, 1320, 1270, 1160, 1125, 1110, 1085, 970, 900, 800, 750, 695, 680, 530.

H-NM

(CD

2 OD) 6 2.3-2.5 (2H, 2.5-3.3 (6H, m), 3.7-3.9 (4H, 4.58 (1H, d, J=16Hz), 4.88 (1H, d, J=16Hz), 6.1-6.3 (1H, m), 6.70 (2H, 7.3-8.4 (9H, m).

Examples 6 and 7 3-(2-Hydroxy-3-morpholinopropyl) -H-2, 3 -benzothiazin- 4 (3H)-one 2 2 -dioxide 1/2 fumarate Example 6 3-( 2 -Ethoxy-3-morpholinopropy)-1H-2,3 -benzothiazin- 4 (3H)-one 2 ,2-dioxide fumarate Example 7 In dry ethanol (10 mL) was dissolved metallic sodium (23 mg, 1 mmol.), and to the solution was added 1H-2,3benzothiazin-4(3H)-one 2 2 -dioxide (197 mg, 1 mol.).

The mixture was stirred at 50 0 C for 30 min. To the reaction solution was added l-chloro-3-morpholino-2-propanol (198 rg, 1.1 nol.). The mixture was then heated for 6 hours under refluxing. The reaction liquid was placed under reduced pressure to distill the solvent off. The resulting residue was treated with 1 N hydrochloric acid and ethyl acetate. The aqueous layer was taken out, and made basic by addition of potassium carbonate. The oil precipitated and was extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous saturatdrous sodium sulfate. The dried ethyl acetate portion was placed under reduced pressure to distill the solvent off. The resulting residue was treated by silica gel column chromatography (chloroform/methanol=40/1) to give 3-( 2 -hydroxy-3 -morpholinopropyl)-1H-2, 3 -benzothiazin- 4(3H)-one 2 2 -dioxide (215 mg, yield 63%) as a colorless oil, and 3-( 2 -ethoxy-3mo r pholinop r op y l)-H-2,3-benzothiazin-4(3H)-one 2 2 -dioxide (70 mg, yield 20%) as an colorless oil.

Hydroxy-3 -morpholinopropyl) -1H-2, 3 -benzothiazin- 4 (3H)-one 2 2 -dioxide IR (KBr) cm-1: 3400, 2950, 2910, 2850, 2810, 1680, 1600, 1450, 1350, 1305, 1280, 1240, 1195, 1160, 1140, 1115, 1010, 865, 750.

iH-NMR (CDC1:) 6: 2.3-2.7 (6H, 3.40 (1H, bs), 3.6-3.8 (4H, 4.0-4.2 (3H, m), 4.64 (1H, d, J=16Hz), 4.69 (1H, d, J=16Hz), 7.33 (IH, d, J=8Hz), 7.5-7.7 (2H, 8.18 1H d, J=8Hz).

3-(2-Ethoxy-3-morphoolinopropyl)-lH-2, 3 -benzothiazin- 4(3H)-one 2 2 -dioxide IR (KBr) cm-1: 302930, 2850, 2800, 1700, 1440, 1405, 1360, 1320, 1295, 1260, 1110, 1070, 1000, 860.

1 H-NMR (CDC1) 1.41 (3H, t, J=7Hz), 2.2-2.6 (6H, m), 2.84 (1H, dd, J=6Hz, 14Hz), 3.04 (1H, dd, J=2Hz, 13Hz), 3.6-3.8 (5H, 4.39 (2H, q, J=7Hz), 4.92 (1H, d, J=13Hz), -56- 4.96 (1H, d, J=13Hz), 7.4-7.5 (1H, m), 7.5-7.6 (2H, 7.98 (1H, d, J=8Hz).

3-( 2 -Hydroxy-3-morpholinroropy1)-1H-2,3-benzothiazin-4(3H)-one 2 2 -dioxide 1/2 fumarate (Exnample 6) To ethanol (4 mL) were added 3 2 -hydroxy-3morpholinopropyl)-1H-2, 3 -benzothiazin-4(3H)-one 2, 2-dioxide (215 mg, 0.63 mmol.) and fumaric acid (73 mg, 0.63 1 mol.) The mixture was heated to give a solution. The Solution was kept at room temperature. Crystals precipitated and were collected by filtration, to give the desired compound (187 mg, yield 75%) as a white crystalline product.

175-1770C IR (KBr) cm-1: 3370, 1690, 1575, 1340, 1285, 1255, 1175, 1135, 980.

'H-NMR (D20) 6: 3.2-3.5 (6H, 3.9-4.2 (6H, m), 4.4-4.5 (1H, 5.07 (2H, s), 6.52 (1H, 7.54 (1H, d, J=8Hz), 7.67 (1K, dd, J=7Hz, 8Hz), 7.79 (1H, dd, J=7Hz, 8Hz), 8.15 (1H, d, J=8Hz).

3-(2-Ethoxy-3-morpholinopropyI)-1H-2, 3 -benzothiazin- 4(3H)-one 2 2 -dioxide 1/2 fumarate (Example 7) To ethanol (2 mL) were added 3 2 -ethoxy-3-morpholinopropyl)-1H-2, 3 -benzothiazin-4(3H)-one 2 ,2-dioxide (73 mg, 0.2 wmol.) and fumaric acid (23 mg, 0.2 nmmol.).

The mixture was heated to give a solution. The solution was kept at room temperature Crystals precipitated and were collected by filtration, to give the desired compound (64 mg, yield 65%) as a white crystalline product.

1 2 8-1290C IR (KBr) cm- -57- 3400, 1710, 1320, 1300, 1265, 1130, 1080, 985, 645.

1H-NMR (CD30D) 6 1.40 (3H, t, J=7Hz), 2.7-3.1 (18H, m), 3.7-3.9 (4H, 3.9-4.0 (1H, m), 4.38 (2H, q, J=7Hz), 4.98 (2H, s), 6.72 (2H, 7.4-7.6 (3H, m), 7.95 (1H, d, J=8Hz).

Example 8 2-( 2 -Hydroxy-3-morpholinopropyl) 2-benzothiazin- 4(3H)-one 1,1-dioxide 1/2 fumarate 2-( 2 -Hydroxy- 3 -morpholinopropyl) -2H-1,2-benzothiazin-4 (3H)-one 1,1-dioxide ethylene ketal A suspension of 2 H-1,2-benzothiazin4 (3H) -one 1,1dioxide ethylene ketal (0.48 g, 2 mmol) and 60% sodium hydride (0.08 g, 2 mmol.) in 1, 2 -dimethoxyethane (20 mL) was heated for one hour under refluxing. The resulting reaction liquid was further heated for 16 hours under refluxing, after addition of l-chloro-3-morphoiino-2propanol (0.36 g, 2 mmol.). The reaction liquid was placed under reduced pressure to distill the solvent off.

The residue was treated with IN hydrochloric acid and S ethyl acetate, and the aqueous layer was taken out. The aquous solution was made basic by addition of potassium carbonate, and the precipitated oil was extracted with ethyl acetate. The extract solution was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried solution was placed under reduced pressure to distill the solvent off.

SThe resulting residue was treated by silica gel column chromatography (ethyl acetate/methan1l=10/l) to give the desired compound (0.54 g, yield 70%) as a colorless oil.

IR (KBr) cm-1: 3420, 2890, 2810, 1440, 1320, 1270, 1240, 1150, 1110, 1050, 1010, 975, 950, 865, 760, 690.

-58- 1H-NMR (CDCl) 6: 2.4-2.7 (6K, m), 3.45 (1H, dd, J=6Hz, 3.6-3.8 (SH, 3.9-4.0 (1H, m) 4.08 (2H, 4.1-4.3 (4H, m), 7.4-7.6 (3H, 7.77 (1H, d, J=8Hz).

2- 2 -HYdroxy-3-orpholinopropyl)-2H-1,2-benzothiazin-4(3)-one 1,1-dioxide a mixture of methanol (4 mL) and 9% hydrochloric acid (4 L) was dissolved 2 2 -hydroxy-3-mrpholinopropyl)-2H-1, 2 -benzothiazin- 4 (3H)-one I-dioxide ethylene ketal (0.38 g, 1 immol.) obtained in The mixture was then heated for 30 min. under refluxing. The reaction liquid was placed under reduced pressure to distill the solvent off. The er ruedue rsuet tl the solvent off. The residue was treated with an aqueous saturated sodium hydrogen carbonate solution and ethyl acetate. The organic layer was taken out. The oranic solution was washed with water and then an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried solution was placed under reduced pressure to distill the solvent off, to obain the desired corrmpound (0.33 g, yield 97%) as a yellow oil.

IR (KBr) cm1- 3400, 2920, 2850, 2800, 1695, 1580, 1440, 1330, 1275, 1230, 1170, 1110, 1065, 1045, 1005, 920, 860, 760.

H-M (CDC1 3 6: 2.3-2.7 (6H, m), 3.13 (1H, dd, J=6Hz, 14Hz), MO 3.3 bs), 3.45 (1H, dd, J=2Hz, 14Hz), 3.6-3.8 (4H, 3.8-4.0 (1H, m), 4.63 (1K, d, J=18Hz), 4.71 d, J 18Hz), 7.7-7.8 (2H, m), 7.85 d, J=8Hz), 8.08 (1H, d, J 8Hz).

-59- 2-( 2 -HYdroxy-3.mrpholinopropyl)-2K-i,2-benzothiazin-4(3)-one l,ldioxide 1/2 fumarate In ethanol (6 mL) were dissolved under heating 2-(2hydroxy-3f-morpholinopropyl) -2H-1, 2 -benzothiazin-4(3H)-one 1,1-dioxide (0.33 g, 0.97 mmcl.) obtained in and fumaric acid (o.11 g, 0.97 mol.). The solution was kept at room temperature. Crystals precipitated and were col- lected by filtration, to give the desired compound (0.34 g, yield 65%) as a white crystalline product.

1 2 8-1290C IR (KBr) cm-* 3550, 3450, 1700, 1580, 1560, 1440, 1340, 1320, 1275, 1175, 1150, 1135, 1110, 980, 915, 780, 760, 655, 580.

IH-NMR (CD3OD) 8: 2.5-2.8 (6K, 3.17 (1H, dd, J=7Kz, 14Hz), 3.6-3.8 (4H, 3 .9-4.i m), 6.71 (1HK, 7.7-8.0 (3K, m), 8.07 (1K, d, J=8Kz).

ExanZ lg 3-(3-Morphoino-3 -phenylpropyl)-iK-2, 3 -benzothiazin- 4(3H)-one 2 2 -dioxide 1/2 furarate 3-( 3 Oxo-3-phenypropyl)-l-2,3-benzothiazin-4(3H)one 2 2 -dioxide 1

H-

2 ,3-3enzothiazin- 4 3 H)-n 2 2 -dioxide (1 g, 5.08 4mol.) was added to a solution of powdery potassium hydroxide (334 mg, 5.08 mci.) in methanol (4 mL). The mixture was then stirred at room temperature for 15 min.

The solution was placed under reduced pressure to distili the solvent off to dryness. To the dried product were added 3 -chloropropiophenone (856 mg, 5.08 rrmol.) and dimethyformamide (8 mL). The mixture was heated to 120 0

C

for 6 hours under stirring. The reaction liquid was placed under reduced pressure to distill the solvent off.

To the resulting residue was added water, and it was extracted with ethyl acetate. The extract solution was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried extract solution was placed under reduced pressure to distill the solvent off. The resulting oil was treated by silica gel column chromatography (chloroform) to give the desired compound (1.13 g, yield 68%) as a white solid.

'H-NMR (CDC13) 6: 3.4-3.6 (2H, 4.4-4.5 (2H, m), 4.63 (2H, 7.3-8.3 (9

H

m).

2- (2 -Hdroxy-3 -phenylpropyl)-1H-2, -benzothiazin- 4 (3H) -one 2 2 -dioxide To a suspension of 3 -(3-oxo-3-phenylpropyl)-H-2,3benzothiazin 4 3 H)-one 2 2 -dioxide (880 mg, 2.67 mmol.) obtained in in methanol (35 mL) was added under cooling with ice-water sodium borohydride (310 m, 8.16 m2mol.) The mixture was stirred for 40 min. under the same cooling. The excessive sodium borohydride in the reaction liquid was decomposed by acetic acid (500 mg), and the liquid was placed under reduced pressure to distill the solvent off. The residue was extracted with ethyl acetate after addition of water. The extract solu- tion was washed with an aqueous saturated sodium chloride solutione and dried over anhydrous sodium sulfate. The dried extract portion was placed under reduced pressure to distill the solvent off, to give the desired compound (1.02 g) as a yellow oil.

'H-NMR (CDC1,) 6: 2.1-2.3 (2H, 4.1-4.3 (2H, m), 4.56 (2H, 4.7-4.9 (1H, m), 7.3-8.3 (9H, m).

2-( 2 Chloro-3-phenylpropyl)- 1 H-2,3-benzothiazin- 4

H

-one 2 2 -dioxide In dichloromethane (2 mL) was dissoloved 3-(3-hy- -61droxy-3-phenylpropyl) -IH-2,3-benzothiazin4 (3H) -one 2,2dioxide (1.02 3.08 mmol.) obtained in To the solution was dropwise added under ice in ol one f hiony chlori (420 e i c e c o o l i ng a solution of thionyl chloride (420 mg, 3.53 mmol.) in dichloromethane (2 mL) The mixture was stirred at room temperature for 15 hours. To th reaction liquid was added under ice-cooling an aqueous saturated sodium hydren carbon d e ate solution, and the mixture was extracted with dichloromethane. The extract ortion was washed with dichloageuous saturated _i on was wa s h e d with an 0 aqeuou saturated sodium chloride solution and dried over anhydrous sodium sulfate. The dried extract portion was placed under reduced pressure tod e x t r a c t illon off. The obtained crude product wa treated by slican gel column chromatography (ethyl acetate/n-hexne=i/ 3 to give the desired compound (690 e/-heo less oil. 'm yield 64%) as a color- LH-NMR (CDC3) 6: 2.5-2.7 (2H, 4.1-4.3 (2H, m), 4.53 (2H, 5.0-5.j (1H, m), 7.3-8.3 (9H, m).

3- 3 -MorPholino-3-phenylpropyl) -1H-2, 3 -benzothizin_ 4(3H)-one 2 ,2-dioxide 1/2 fumarate A mixture of 2- 2 -chloro-3-phenylpropyl)-1H-2,3benzothiazin4 3 H) -one 2, 2 -dioxide (680 mg 1.95 mmol.) obtained in and or 6 hourie (500 mg, 5.75 mmol.) was heated to 110 0 C for 6 hours under stirring. The reaction liquid was extracted with ethyl acetate after addition of an aqueous saturated sodium hydrogen carbonate slution S The extract portion was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium ft sulfate. The dried extract Portion was placed under rem duced pressure to distill the solvent off. Thus obtained crude product was subjected to silica gel column chroma tography (tethyl etate/n-hexane=/) to give the free base of the desired copo 0 und (698 rg, yield The free base was warmed to 50C after addition of fumaric acid (200 rg, 1.74 rmol.) and ethanol (7 mL) to give a homogeneous solution. The solution was then stirred Overnight at room temperature. Crystals precipitated and were collected by filtration. The collected crystals were dried at 50 0 C under reduced pressure to give the desired compound (606 rg, yield 76%) as a white crystalline product.

130 0

C

IR (KBr) cm- 1 3400, 2950, 1670, 1590, 1450, 1330, 1300, 1280, 1235, 1190, 1160, 1155, 1100, 1060, 980, 910, 810, 790, 730, 690, 550.

'H-NMR (CD3OD) 6: 2.2-2-7 (6H, 3.4-3.6 (5H, m), 3.6-4.0 (2H, 4.82 (2H, s), 6.72 (2H, 7.3-8.2 (9H, mn).

In the following Examples 10 to 16, the compounds were prepared essentially in the same manner as in Exam- pie I. The prepared compounds and characteristics thereof are set forth below.

r.Example 0 (4Benzylpiperidin o )propyl] -2H-1, 2-benzothiazin V 5 4( 3 H)-one 1 ,1-dioxide hydrochloride White crystalline product IR (KBr) cm-1: 3455, 2925, 2650, 1700, 1590, 1450, 1340, 1230, 1170, 1160, 1120, 950, 920, 790, 770, 750, 700, 3 0 5 8 0 S'H-NMR (DMSO-d,) 6: 1.6-1.8 (3H, 1.9-2.1 (2H, m), 2.2-2.3 (2H, 2.5-2.7 (4H, m), 3.0-3.6 (6H, 4.49 (2H, s), 7.0-8.1 (9H, mn).

-63- 2-[3-(-3enzl B 3-U £xamie 1_1 2-3- (Nenzy -Nbutylamino)propyij -2H-1, 2 -benzothiazin- 4 (3H) -one 1,dioxide hydrochloride Amorphous product IR cfl 1 3370, 2930, 2850, 1690, 1580, 1450, 1340, 1270, 1220, 1170, 1120, 1040, 760, 740, 690, 570.

'H-IZP- (CIDD) 6: 0.97 (3H, t, J=6z), 1.38 (2H, m), 1.75 (2H, 1.9-2.4 (2H, m), 2.9-3-4 (6w, 4.3-4.6 (4H, i), 7.4-7.7 (5w, 7.7-8.0 (3H, m), 8.07 d, J=8wz).

Exaine 12 2- (4-Dipheny ethl-l -Piperazinyl)propyll -2H-1,2- benzothijazn- 4 -one l,J-dioxide hydrochloride Pale brown poder IR (ICr) cr 1 3510, 2430, 2810, 2420, 1690, 1580, 1445, 1340, 1275, 1170, 1120, 760, 740, 710.

H-NW (CDC1) 6: 1.65 (2w, 2.2-2.4 (2w, m), .7-3-2 3.30 t, J=6Hz), 3-8-08 (2H, 4.38{z 4.48 7.2-7.4 (low, i), 7-7-7.9 O3H, 8.08(1,dJ=1z, CA 12-68 U1H, bs). Ld~57z (4-BenzylpiperjdiQ)ethyl]-2w-1, 2 -benzothiazin 4 (3H)-one l,1dioxide hYdrochloride 1 98 -2010C IR (KBr) cnr'* 3400, 1695, 1580, 1445, 1340, 1270, 1230, 1170, 1120, 1040, 760, 750, 700, 570.

-64- 1 H-NMP. (CD oD) 8: 15-1.6 (2H, 1.8-1.9 (3H, 2.5-2.6 (2H, 2.9-3.0 (2H, i, 3.3-3.4 (2H, 3.5-3.7 (4H, i, 4-5-4.6 4.7-4.8 (11, i), 7.1-7.3 (5H, 7.8-7.9 (3H, i, 8.0-8.1 (IH, m).

4(3H)--Bone p -iperazi-Tylipropyl -2H-1,2- benzcthJai~ 4(3H)- 1,1-(l-loxide hydrochloride 2 3 5-2371C (decomp.) IR (KBr) cm-1: 3400, 2350, 1690, 1580, 1440, 1345, 270, 1230, 1170, 950, 780, 750, 695, 570.

1 KN1V,.

(D

2 0) 6: 2.0-2-1 (2H, 3.2-3.6 (14H, m), 4.35 (2H, 7 .4-8.1 i).

Exr~e 15 2-3- (1,2,3,4-Tet E 2 Lasguill e]royl- benzoth.. 4 (3K) -one 1,1-dioxide hydroch-oride 195-203oC (decop.) IR (KBr) cm- 3400, 2450, 2400, 1690, 1590, 1450, 1240, 1270, 1230, 1170, 1120, 1040, 900, 755, 570.

'H-Nv[

(D

2 O) 6: 2.0-2-2 (2H, 2.9-3.4 (6H, 3.55-3.7 (2K, 4.1-4.6 (2H, m), 4.60 (2H, 7.1-8.0 m).

EflgJLe~ 23C34(-MethxybenZyl)Piperidino prc., -2H-1,2benzthiazin-4(3H)-one 1,1-dioxide hYdrocloride ,"=rphous product IR (KBr) cm-l: 3400, 2925, 2500, 1700, 1610, 1590, 1510, 1445, 1340, 1245, 1170, 1130, 1030, 955, 920, 850, 770, 630, 580.

'H-NMR

(D

2 O) 6 1.65-1.75 1H 1.8-1.9 (2H, m), 2.3-2.4 (2H, 2.56 (2H, d, J=7Hz), 2.56-2.7 (2H, 3.31 (2H, J=6Hz), 3.5-3.6 (2H, 3.78 (3H, s), 4.49 (2H, 6.8-8.1 (8H, m).

In the following Examples 17 to 22, the compounds were prepared essentially in the same manner as in Exmple 2 T ly n the same ranner as in Exam- ple 2. The prepared compounds and characteristics thereof are set forth below.

Exarrle 17 2- 3 -Morpholiopropyl) -2

H

-1,2-benzothiazin4 (3H)-one 1,1dioxide fumarate IR (KBr) cm-1: 3400, 1690, 1540, 1170, 1120, 980, 770, 640, 570.

'H-NMR

(CD

3 OD) 8: 1.9-2.0 (2H, 2.8-3.0 (6H, m), 3.3-3.4 (4H, 3.9-4.0 (4H, m), 6.72 (2H, 7.8-8.1 (4H, m), Example 18 2-(3-Diethylamino-l-phenylpropyl)-2H-1,2-benzothiazin- 4 3 H)-one 1 ,1-dioxide hydrochloride 1 8 9-1910C IR (KBr) cm-1: 3400, 2925, 2600, 2450, 1690, 1590, 1470, 1440, 1400, 1390, 1335, 1275, 1230, 1170, 1135, 1125, 1100, 1075, 1050, 1005, 890, 870, 845, 810, 750, 700, 635, 580, 550.

-66- 1 H-NMR (C7,OD) 8: 1.4-1.5 (6H, 2.2-3.4 (8H, i), 4.35 d, J=19Kz), 4.66 (1H, d, J=19Kz), 5.0-5.2 6.8-7.8 (9H, Example 19 2-(1-Phenyl-3-piperidinopropyl)-2H-1,2 -benzothiazin- 4(3K)-one l,1-dioxide hydrochloride 216-2210C IR (KBr) cm-l: 3400, 2500, 1690, 1350, 1180, 710.

'H-NMR (CC1) 6: 1.5-3.8 (14K, 4.1-4.8 (2K, i, 4.9-5.2 (1K, 6.8-7.8 (9K, m).

Exam~le 2-( 3 M0n olino..phenpy l) -2K-i, 2 -benzothiazin- 4(3K) -one hi-dioxide hydrochloride 220 0

C

IR (Kcr) =rw': 3400, 2425, 1690, 1590, 1445, 1350, 1330, 1280, 1230, 1170, 1130, 1105, 1080, 1040, 1010, 980, 890, 760, 700, 640, 580, 550.

'K-N4p. (CDCl 3 6: 2.4-2.6 (1H, 2.8-3.6 (7H, m), 3.9-4.0 (2K, 4.2-4.3 (2K, m), 4.35 (1K, d, J=19Kz), 4.66 (1K, d, T=19Hz) 6.9-7.8 (9K, m).

(3-MOrPhOlin o1.phenylpropy1- 2 H-1,2-benzo.

thiazin-4(3) -one l,l-dioxide hYdrochloride 2-(3-Morphoino- -phenylpropy)-2H-1, 2-benzothiazin-4(3H)-one 1,1 dioxide hydrochloride (17.48 g, 40.0 mmol.) obtained in was dissolved in an aqueous -67saturated sodium hydro-en carbonate solution (300 mL), and then extracted with ethyl acetate. The ethyl acetate portion was washed with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried portion was placed under reduced pressure to distill the solvent off. To the obtained oil were added methanol (80 mL) and L-(+)-tartaric acid (6.00 g, 40.0 nrol.), and the mixture was warmed to 50'C to give a homogenous solution. The solution was left to stand at room temperature for 5 hours. Crystals precipitated and was recrystallized twice from methanol to give a dia- stereomer (5.27 g, 47%) of an optical purity 93.2% e.e. in the form of a white powder. The product (5.26 g) was added to an aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off. To the residual oil were added ethnaol mL) and then concentrated hydrochloric acid (I mL). The mixture was allowed to stand overnight. Crystals precip- itated and were collected by fitration. The collected crystals were washed with ethanol and placed under re- duced pressure at 400C for 3 hours to dryness. Thus, there was obtained the desired compound (3.50 g, yield as a white crystalline product.

238-240oC 23= 050 (c 0.1, methanol) 3 -Morpholino-l-phenylpropyl) -2H-I, 2-benzothiazin-4(3H) -one I,1-dioxide hydrochloride To the mother liquer remaining after the recrystallization step in was added an aqueous saturated sodium hydrogen carbonate solution" and it was extracted with ethyl acetate (100 mL). The ethyl acetate portion was washed with an aqueous saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and placed -68under reduced pressure to distill the solvent off. To thus obtained amorphous product (12.0 30.0 r tol.) were added methanol (501)2.0) g 3 0 0 mm c were added metanol (50 mL) and D-(-)tartaric acid (4.50 g, 30.0 etol.), and the mixture was warmed to 50 0 C to give a homogenous solution. The solution was allowed to stand overnight at room temperature. Crystals precipitated and were recrystallized twice from methanol to give a diastereomer (7.58 g, 69%) of an optical purity 100% e.e. in the form of a white powder. The product (7.58 g) was added to an aqueous saturated sodium hydrogen carbonate Solution and extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate The drying agent was filtered off. The filtrate was allowed to stand overnight at room temperature after addition of 4N hydrochloric acid gas/ethyl acetate MrL). Crystals precipitated and were collected by fitration. The collected crystals were washed with ethyl acetate, and placed under reduced pressure at 400c for 3 hours to dryness. Thus, there was obtained the desired compound (5.26 g, yield 30%) as a white crystalline product.

242-244"C (c 0. I, methanol) 7 ,_E~tmple 21 2-(lPhenyl-3-thiomorpholinopropyl) 2 H-,2-benzothiazin_ 4(3H) -one 1,1-dioxide hydrochloride 2 2 4-227oC IR (KBr) cm-1: 3410, 2400, 1690, 1340, 1170, 760.

H-NIR (CD30D) 8 2.3-4.0 (12H, 4.4-4.6 (2H, m), 5.0-5.3 (1

H

6.8-7.8 (9H, m).

E

MMa

I

t2a -69- 2- [-Morpholino_ (4-chloropheyl)propyl -2W-i, 2bezothiazin 4 (3H) -one 1,i-dioxide hydrochloride 2541C (decomp.) IR (KBr) cm-1-: 3400, 2375, 1680, 1580, 1340, 1320, 1270, 1230, 1170, 1085, 1005, 890, 815, 740, 585, 550.

1Hi-NMP' (CD301D) 2.5-4.4 (14H, 5.2-5.4 m), 6.9-7.8 (8H, m).

In the following Exanpes 23 to 28, the compounds were prepared essentially in the same manner as in Example 3. The prepared compound ard characteristics there- of are set forth below.

ExinDle 23 3-(l-Phenyl-3-piperidinopropyl)-l-2,3 -benzothiazin- 4(3H)-one 2 2 -dioxide 1/2 fumarate 135-137oC (decorrp.) IR (KBr) cml: 2930, 1670, 1575, 1440, 1350, 1275, 1235, 1190, 1160, 1135, 990, 730.

1HNWM (CDC1 3 6: 1.4-2.0 (6W, 2.6-3.2 (8H, m), 4.99 (2H, 5.6-5.9 (1W, i), G.63 (1H, 6.1-6.7 (8H, m), 6.9-7.1 (11, in).

3-(3-Morpholin-l-phenylpro 1)-1-2,3 -benzothiazin- 4(3W)-one 2 2 -dioxide fumarate 1 4 4-1450C IR (KBr) cm- 1: 3400, 1680, 1450, 1345, 1270, 1170, 1130, 980, 910, 870, 800, 730, 690, 640, 560, 500.

H-NMR

(Q

3 OD) 2.3-3.1 (8H, 3.6-3.9 (4H, m), 4.96 (2H, 5.7-5.9 (1H, m), 6.64 (2H, 7.2-7.7 (8H, m, ArH), 7.9-8.1 (1H, m).

3 -Morpholino-l-phenylpropyl)-lH-2,3-benzothiazin-4(3H)-one 2 2 -dioxide fumarate Water (90 mL) was added to 2 -(3-morpholino-l-phenylpropyl)-lH-2,3-benzo-thiazin-4(3

H

-one 2 2-dioxide fumarate (11.33 g, 28.3 mmol.) obtained in as intermediate and D-(-)-tartaric acid (4.24 g, 28.2 nrol.), and the mixture was warmed to 80C to give a homogenous solution.

The solution was left to stand overnight at room temperature. Crystals precipitated and were recrystallized three times from water to give a diastereomer (3.93 g, 25.2%) of an optical purity 98.7% e.e. in the form of a white powder. To the product (3.93 g) were added water (100 mL) and 28% aqueous amonia (3 mL). The mixture was extracted with two portions of dichloromethane (50 mL).

The dichloromethane extract was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off. To the residual amorphous product (2.34 g, 5.84 mmol.) was added ethnaol (30 mL). To this mixture was further added a solution of fumaric acid (678 5.84 rno in ethnaol (20 mL). The resulting mixture was then stirred overnight. Crystals precipitated and were collected by fitration. The collected crystals were dried at 50 0 C for 20 hour. Thus, there was obtained the desired compound (2.6 g, yield 18%) as a white crystalline product.

160_163oC (c 0.2, methanol) 3 -Morpholino-l-phenylpropy 1 -lH-2,3-benzothiazin-4 (3H)-one 2,2-dioxide fumarate To the mother liquer remaining after the recrystallization step in was added 28% aqueous ammonia, and -71it was extracted with three portions of dichloromethane (100 mL). The dichloromethane extract was washed with an aqueous saturated sodium chloride solution (200 mL), Sdried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off. To thus nder obtained amorphous product (85 21.2 e n t o f f T o wathus L-(+)-tartaric acid (318 g, 22.1 mol.) was addmixture was warmed to 80Ct 22.1 reol.), and the mixture solution warmed to to give a homogenous solution. The 1 0 lution was alowed to stand overnight at room temperature. Crystals precipitated and were recrystallized three times from water to give a diastereomer (3.32 9, 21.3-) of an optical purity 97.3%- e.e. in the form of a white powder. To the product (3.32 g) were added water (100 ML) and 28%- aqueous ammonia (3 mL), and the mixture was extracted with two portions of dichloromethane mL). The dichloromethane extract was washed with an aqueous saturated sodium chloride solution (50 mL), dried ver anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off. To the resulting amorphous product (2-38 g, 5.94 mmol.) was added ethanol (50 mL)ric. T the mixture were further added a solution of fumaric acid (690 rg, 5.94 etmol.) in ethanol (20 mL) The mixture was stirred overnight at room temperat Crystals precipitated and were collected by filtration.

The collected crystals were dried at 50C for 20 hours.

Thus, there was obtained the desired omp und (2.35 h o u r s yield 16%) as a white crystalline product.

M.p. 163-1640C [30 a=+4.3 (c 0.2, methanol) 3-(3-Diethylano-i-p 3 3 -Diethyl am 1 phenYlpropyl)-1H-2,3-benzothiazin- 4(3H)-one 2 ,2-dioxide fumarate 169-1700C IR (KBr) cm-1: 3400, 1680, 1590, 1540, 1440, 1340, 1270, 1230, -72- 1190, 1160, 1140, 980, 800, 740, 720, 690, 640, 550, 500.

1 H-NMR (CDOD) 6: 1.29 t, J=8Hz), 2.6-2.8 (2H, i), 3.0-3.4 (6K, in), 5.10 (2H, s), 5.8-5-9 (1K, 6.70 (2H, s), 7.2-8.1 (9K, m).

Exml e2 6 3-(l-Pheny1...thilororphol -1Koproyl l-2, 3 -benzothiazin- 4(3H)-one 2 2 -dioxide mesylate 2 3 1-233'c (decoup.) IR (Icr) cm--: 1670, 1600, 1350, 1300, 1280, 1235, 1205, 1190, 1165, 1145, 1135, 1025, 960.

'-H-NR (CDcl/CD:,OD) 6: 2.5-4.2 (12K, 2.72 (3H, s), 4.82 (2K, bs), 5.7-5.9 (1K, m), 7.1-7.6 (8H, 7.9-8.1 (1K, mn).

EtinD e 27 3-[3-Morpholino- 1 (4 -chlorophenyl)propyl] -1-2,3-benzothiazn-4 (3H)-One 2 2 -dioxide fumarate 179 0

C

IR (KBr) cm-1: 3425, 1680, 1350, 1270, 1160, 980, 730.

'H-NMP, (aJDoD) 6: 2.4-3.0 (8H, 3.6-3.8 (4K, m), 4.90 (2H, 6.68 (1K, s), 7.2-8.1 i).

3- (3-Morpholin.2.phenylproy1) -1K-2, 3 -benzothiazinl 4(3H)-one 2 2-dioxide fuarate 157-158oC IR (KBr) cm-L.

-73- 3400, 2950, 1680, 1600, 1450, 1340, 1300, 1280, 1235, 1190, 1160, 1130, 1100, 980, 910, 870, 790, 730, 700, 680, 640, 550, 500.

'H-NMR (CD3OD) 6: 2.6-2.8 (4H, 2.9-3.0 (1H, m), 3.0-3.1 mi), 3.5-3.7 (5H, m), 4.0-4.1 (1H, 4.2-4.3 (1H, m), 4.6 (1H, d, J=6Hz), 4.78 (1H, d, J=6Hz), 6.71 (2H, 7.2-8.1 (9H, m).

Example 29 2-( 3 -Morpholino-3-phenyipropyl)-1H-1, 2 -benzothiazin- 4(3H)-one l,1-dioxide hydrochloride The above-mentioned compound was prepared essentially in the same manner as in Example 9.

214-216C (decomp.) IR (KBr) cm-1: 3550, 3380, 2580, 2550, 2470, 1695, 1455, 1340, 1280, 1170, 1125, 760, 700, 575.

1H-NMR

(D

2 0) 8: 2.5-2.7 (2H, 3.1-3.6 (6H, m), 3.8-4.1 (4H, m), 4.45 (1K, dd, J=4Hz, 12Hz), 7.5-7.6 (5H, 7.82 (1H, d, J=8Hz), 7.92 (1H, dd, J=8Hz, 8Hz), 8.01 (1H, d, J=8Hz).

Exa1e 2-( 3 -Chloropropyl)-2H-1,2 -benzothiazin-4(3H)-one l,1-dioxide A mixture of 2-( 3 -chloropropyl)-2H-1,2 -benzothiazin- 4(3H)-one l,l-dioxide ethylene ketal (5.0 g, 15.7 mmol.), 3N aqueous hydrochloric acid (30 mL) and methanol (30 mL) was heated under refluxing for 20 min. Methanol was distilled off under reduced pressure. To the residue was added water (30 mL), and the mixture was extracted with -74ethyl ether. The ethyl ether portion was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off, to give the desired compound (4.19 g, 100%) as a yellow oil.

.H-NMR (CDC13) 6: 2.0-2.1 (2H, 3.36 (2H, t, J=6Hz), 3.65 (2H, t, J=6Hz), 4.46 (2H, s), 7.7-8.1 (4H, m).

Eample 31 2- 2 ,3-Dihydro-lH-benz [del isoquinolin-2-yl)prcpyl] -2H- 1, 2 -benzothiazin-4(3H)-one 1,1-dioxide hydrochloride A mixture of 2-(3-chloropropyl)-2H-1,2-benzothiazin- 4 (3H)-one 1,1-dioxide (324 mg, 1.18 mmol) obtained in Example 30, 3N aqueous hydrouchloric acid (30 mL) and methanol (30 mL) was heated to reflux for 20 min The mixture was then placed under reduced pressure to distill methanol off. To the residue was added water, and the aqueous mixture was subjected to extraction with diethyl ether. The diethyl ether portion was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off. The resulting crude product was subjected to silica gel column chromatography. Its eluate at ethyl acetate/n-hexane cave a red oil (200 mg, The oil was dissolved in methanol (1 mL), made acidic by 3N hydrochloric acid, and placed under reduced pressure to distill methanol off.

The residue was allowed to stand after addition of water, to give the desired compound (133 mg, 61.0%) as an orange solid.

Free base 1H-NMR (CDC13) 6 1.9-2.0 (2H, 2.70 (2H, t, J=7Hz), 3.32 (2H, t, J=7Hz), 3.95 (4H, s), 4.45 (2H, 7.1-8.1 (10H, m).

Hydrochloride (desired compound) 'H-NMR (CDOD) 6: 2.2-2.3 (2H, 3.3-3.4 (2H, m), 3.4-3.5 (2H, 4.6-5.0 (6H, m), 7.5-8.1 (10H, m).

IR (KBr) cm- 1 3350, 1685, 1585, 1430, 1335, 1270, 1250, 1225, 1170, 1120, 1105, 1040, 990, 900, 820, 790, 770, 735, 680, 640, 570.

above 220'C (decomp.) ExaQmle 32 2- (4-Cyano-4-phenylpiperidino propyl]- 2 H-1,2-benzothiazin-4(3H) -one ,1-dioxide fumarate 2- 3 -Chloropropyl)-2H-1,2-benzothiazin-4(3H)-one l,l-dioxide (485 mr, 1.77 mrol.) obtained in Example and 4-cyano-4-phenlpiperidine (330 mg, 77 inol.) were treated essentially in the same manner as in EXample 31 to give a free acid o n th e s a m e manner as Fa Eample 31 to ive a free acid of the desired compound (411 mr, 56.7%) and its fumarate (300 mg, 56.9%).

Free base H-NMR (CDC1) 6: 1.75-1.85 (2H, 2.0-2.2 (4H, m), 2.4-2.6 (4H, 2.9-3.0 (2H, m), 3.29 (2H, t, J=7Hz), 4.47 (2H, s), 7.2-8.1 (9H, s).

Fumarate (desired compound) 1H-NMR (CD30D) 6: 1.7-1.8 (2H, 1.9-2.1 (4H, m), 2.9-3.0 (2H, 3.15-3.25 (2H, m), 4.56 (2H, 6.63 (2H, s), 7.3-8.0 (9H, m).

IR (KBr) cm- 1 3400, 1710, 1690, 1580, 1340, 1295, 1170, 910, -76- 750, 570.

145-150C QQa- e 33 2- (3id-Chloro-1-phenylpropyl)-2H-1, 2 -benzothiazin-4 (3H) -one 1,1ldioxide 2-( 3 -Chloro-l-phenylpropyl)-2H-1, 2 -benzothiazin- 4 3 H)-one lbl-dioxide ethylene ketal (500 mg, 27 mmol.) was obtained essentially in the same manner as in xaPle was suspended in a mixture of ethanol (3 mL) and concentrated hydrochloric acid (1 mL), and heated to reflux for 2 hours. The reaction liquid was placed under reduced pressure to distill ethanol off, and extracted with ethyl acetate after addition of water. The ethyl acetate portion was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off. There was obtained the desired comrpound (380 mg, 85.6%) as an orange oil.

'H-NMR (CDC1 3 400 MHz) 6: 2.3-2.4 (IH, in), 2.5-2.6 m), 3.5-3.7 (2H, 4.13 (lH, d, J=19Hz), 4.60 (1H, d, J=19Hz), 5.4-5.5 (1H, m) 6.9-7.8 (9H, m).

Exainle 34 2-[3-(4-Cyano-4-phenylpiperidino)-l-phenylpropyl -2Hi-1,2benzothiazin-4(3H)-one 1,1-dioxide fumarate 4-Cyano-4-phenylpiperidine (236 r, 1.06 rnoI.) was dissolved in water (3 mL), made alkaline by an aqueous saturated sodium hydrogen carbonate solution, and extracted with dichlorometane. The dichloromethane porwas dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off, to give an oil. The oil and 2 chloro-l1phenylpropyl -2H- -77l, 2 -benzothiazin.4 (3H)-one l,1-djoxide obtained in Exampie 33 were treated essentially in the same manner as in Example 31, to give a free base of the desired compound (160 mg, 30.29.) and its fumarate (37 mg, 18.8-0, orange solid).

Free base 'H-NM. (CDCl 3 400 MHz) a: 2.0-2.2 (6H, mn), 2.5-2.6 (4H, mn), 2.9-3.1 (2H, mn), 4.18 (1K, d, J=l9Hz), 4.58 (1H, d, J=l9Kz), 5.3-5.4 (1H, in), 6.9-7.8 (9H, mn).

Furnarate (desired compound) 1 -MR~ (CDC1 3 400 Miz) a: 2.1-2.3 (6H, mn), 2.5-2.6 in), 2.9-3.1 (2H, in), 3.40 (1H, s), 4.20 5.3-5.4 (1K, in), 7.0-7.8 (9K, m).

3400, 1690,' 1590, 1450, 1335, 1280, 1230, 1170, 1080, 980, 765, 700, 640, 590, 550.

M.P. 188-19011C 2- [l-Phenyl.3 (1-pyrrolidinyl) ]propyl-l, 2 -benzisothiazolp 3 2 H)-one 1 1l-dioxide furnarate 2- tl-Phenyl3<1.proldnl)lprpl12bnio thjiazol.3 (2K) -one 1, 1-dioxide In diethy1formmde (DMF) 8 mL) were suspended

I-

(3 -chloro-3 -phenyl) propyll pyrrolidine hydrochloride (1.04 g, 4.00 mml.), anhydrous potassium~ carbonate (1.11 g, 8.03 rrnmrl.), and saccharin (733 mrg, 4.00 mcil). The suspension was heated under stirring to 100 0 C for 3 hours to carry out a reaction. The reaction liquid was cooled to room temperature, and placed under reduced pressure to distill UAF off. To the residue were added water and ethyl acetate, and the organic layer was taken out. The -78organic portion was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off. The residue was subjected to silica gel column chromatography (chloroform/methanol= 30/1) to obtain 438 rmg of the desired compound (yield 30%) as a pale yellow oil.

IR (KBr) cm 2950, 2780, 1720, 1455, 1330, 1290, 1250, 1180, 750, 695, 670.

1H-NMR (CDCl3) a 1.4-1.2 (4H, 2.2-3.1 (8H, m), 5.39 (1K, t, J=7Hz), 7.1-8.0 (9H, m).

2-[1-Phenyl-3-(1-pyrrolidinyl)]propy1-1,2-benzisothiazol-3(2H)-one 1,1-dioxide fumarate A solution of fumaric acid (128 mg, 1.10 mmol.) in hot ethanol (4 mL) was added to a solution of 2-[1-phenyl-3-(l-pyrrolidinyl)}propyl-1,2-benzisothiazol-3(2H)one 1,1-dioxide (408 mg, 1.10 mmol). The obtained solution was placed under reduced pressure to distill the solvent off. The residue was recrystallized from ethanol/ether, to give 360 mg of the desired compound (yield 67%) as a white crystalline product.

IR (KBr) cm-L: 2910, 2640, 2600, 2560, 2470, 1675, 1595, 1465, 1445, 1380, 1330, 1310, 1220, 960, 750, 690.

'H-NMR (CIDC13/CD30D=6/1) 6: 2.92 (6H, 3.3-3.8 (4H, m), 7.2-7.7, 7.8-8.1 (5H, m).

2-(1-Phenyl-3-thiomorpholino)propyl-1, 2 -benzisothiazol- 3(2H)-one 1,1-dioxide fumarate 1-Bromo-3-chloro--phenylpropane 3 -Chloro-l-phenylpropane (3.09 g, 20 mmol.),

N-

bromosuccinimide (3.56 g, 20 mmol.), benzoyl peroxide -79- (catalytic amount), and carbon tetrachloride (30 mL) were mixed, and the resulting mixture was heated to reflux for in while it was exposed to a light of 100V/10ow, to perform a reaction. Insolubles were filtered off. The reaction liquid was washed with an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off, to give 4.58 g of the desired compound (yield 98%) as an oil.

IH-NMR (CDC13) 6: 2.1-2.9 (2H, 3.3-3.9 (2H, m), 5.16 (1H, dd, J=7Hz, 7.1-7.5 (5H, m).

2- (3-Chloro--phenyl)propyl-1,2-benzisothiazol- 3 (2H) -one 1, 1 -dioxide In DMF(10 mL) were suspended l-bromo-3-chloro- 1 phenylpropane (1.00 g, 4.28 mol.), saccharin (780 mg, 4.3 rmol), and potassium carbonate (600 mg, 4.4 mmol.) The suspension was heated under stirring to 100CC for 3 min. to carry out a reaction. The reaction liquid was placed under reduced pressure to distill DMF off. To the residue were added water and ethyl acetate, and the organic layer was taken out. The organic portion was washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off.

The residue was subjected to silica gel column chromatog- raphy (hexane/ethyl acetate=2/l) to obtain 440 mg of the desired compound (yield 31%) as an oil.

IR (KBr) cm- 1 1720, 1590, 1450, 1390, 1325, 1290, 1250, 1180, 1125, 1060, 1010, 940, 850, 760, 750, 695, 670, 580, 560, 535, 510.

H-NMR (CDC13) a 2.5-3.2 (2H, 3.3-3.8 (2H, m), 5.46 (1H, t, J=8Hz), 7.1-8.0 (9H, m).

2- (-Phenyl-3-thiomorpholino)propyl-1,2-benzisothiazol-3(2)-one 1,1-dioxide 2-(3-Chloro-l-phenyl)propyl-1, 2 -benzisothiazol- 3( 2 H)-one l,l-dioxide (1.01 g, 3 mmol.) and thiomorpholine (0.62 g, 6 nmol.) were mixed with each other.

The mixture was heated to 110 0 C under stirring for 6 hours, to perform a reaction. The reaction liquid was cooled to room temperature. To the cooled liquid were added 2 Nhydrochloric acid and ethyl acetate, and the aqueous layer was taken out. The aqueous portion was made alkaline by addition of an aqueous saturated sodium hydrogen carbonate solution. An oil precipitated which was then extracted with ethyl acetate. The ethyl acetate portion was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off.

The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 420 mg of the desired compound (yield 35-) as a colorless oil.

IR (KBr) cm- 2800, 1720, 1450, 1330, 1285, 1255, 1180, 1130, 750, 700, 580.

1H-NMR (CDC13) 6: 2.3-2.9 (12H, 5.3-5.4 (1H, m), 7.2-7.4 (3H, 7.6-7.7 (2H, m), 7.7-7.8 (2H, m), 7.84 (1H, dd, J=1Hz, 8Hz), 7.94 (1H, dd, J=lHz, 7Hz).

2-(l-Phenyl-3-thiomrpholino)propyl-1,2-benzisothiazol-3(2)-one 1,1-dioxide fumarate A Solution of furnaric acid (120 r, 1 mmol.) in hot ethanol (12 mL) was added to a Solution of 2 -(1-phenyl-3thiomrpholino)propyl-1, 2 -benzisothiazol-3(2H)-one 1,1- dioxide (400 mg, 1 mmol.) in ethanol (20 mL). The mixture was stirred at room temperature. Insolubles precip- -81itated and were collected by filtration and recrystallized from water, to give 325 mr of the desired compound (yield 64%) as a white crytalline powder.

187-189oc IR (KBr) cm- 1 1720, 1335, 1290, 1250, 1175.

1H-NMR (D20) 2.8-4.0 (12H, 5.4-5.6 (1H, m), 6.61 (2H, 7.4-7.5 (3H, m), 7.6-7.7 (2H, 7.9-8.1 (4H, m).

In the following Examples III to XX, the compounds were prepared essentially in the same manner as in Example I. The prepared compounds and characteristics thereof are set forth below.

Example III 2-( 2 -Morpholino--phenyl) ethyl-1,2-benisothiazol-3 (2H) one 1 ,1-dioxide mesylate 240-241°C (decomp.) IR (KBr) cm- 1745, 1325, 1290, 1260, 1220, 1180, 1160, 1040, 555.

'H-NMR (CD0OD) 2.64 3H 3.2-4.2 (8H, m), 3.97 (1H, dd, J=4Hz, 14Hz), 5.91 (1H, dd, J=4Hz, 12Hz), 7.3-7.7 (5H, 7.9-8.2 (4H, m).

Examle 2-( 4 -Morpholino--phenyl)butyl-1, 2 -benzisothiazol-3 (2H)one ,l1-dioxide fumarate 1 7 5-177°C (decomp.) IR (KBr) cm- 1 3450, 1720, 1635, 1330, 1290, 1255, 1180.

'H-NMR (CD.0D) 8 -82- 1.8-2.0 (1H, 2.3-2.5 (1H, m), 2.6-2.8 (1H, 3.0-4.2 (10H, i), 5.45 (1K, dd, J=7Hz, 9Hz), 6.64 (2H, 7.4-7.5 m), 7.6-7.7 (2H, 7.9-8.0 (2H, i), 8.04 d, J=8Hz), 8.07 (1K, d, J=8Hz).

Example

V

2- (l-Phenyl-3-piperidino)propyl- 1 2-benzisothiazol-3 (2H)one lu-dioxide fumarate 182 0

C

IR (KBr) cm-': 3440, 2940, 1730, 1595, 1445, 1390, 1325, 1295, 1255, 1195, 985, 750, 700, 675.

KH-NMR (DMSO-d.) 6: 1.2-1.7 (6K, 2.2-3.0 (8H, i), 5.36 (1K, t, J=8Kz), 6.55 (2H, s), 7.3-8.2 (9H, 10.0 (2H, brs).

Example

VI

2-[3-(Perhydroazepi n -1y l)-l-phenyllpropyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide fumarate IR (K1r) cm- 3410, 2920, 2620, 1720, 1320, 1285, 1250, 1180, 975, 740.

'H-NMR (COD) 6: 1.5-2.1 (8H, 2.4-3.5 i), 5.1-5.5 (1H, 6.67 (2H, s), 7.1-8.1 (9H, m).

4 -Methylpiperidin) -l-phenyllpropyl-1,2-benzisothiazol-3 (2H)-one 1,1-dioxide funarate 177-1780C IR (Klr) cm': 3400, 3000, 2950, 2750, 2550, 1720, 1695, 1630, -83- 1590, 1530, 1450, 1390, 1330, 1290, 1250, 1200, 1180, 1050, 1000, 985, 970, 950, 920, 790, 750, 695, 670, 630, 580, 550, 505.

'H-NMR (CD30D) 86 1.00 (3H, d, J=6Hz), 1.0-2.0 (5H, m), 2.5-3.7 (8H, 5.2-5.4 (1H, m), 7.2-8.1 (9H, m).

Example VIII 2- [3-(4-Carbamoylpiperidino) -l-phenyl]propyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide fumarate 178-1800C IR (KBr) cm-1: 3420, 1725, 1670, 1610, 1325, 1290, 1265, 1180, 980, 750, 640, 580.

IH-NMR (D20) 1.8-2.2, 2.6-3.8 (13H, m), 5.50 (1H, dd, J=7Hz, 9Hz), 6.67 (2H, 7.4-7.5 (3H, m), 7.6-7.7 (2H, 7.9-8.1 (4H, m).

Example IX 2-(3-orphlino- heny)propyl-1,2-benzisothiazol 3 (2H) one 1,1-dioxide fumarate 159 0

C

IR (KBr) cm- 1 3425, 2855, 1720, 1655, 1610, 1495, 1450, 1370, 1330, 1290, 1270, 1250, 1180, 1130, 1095, 1060, 980, 900, 870, 790, 750, 690, 675, 640, 610, 580, 550, 510.

'H-NMR (CD3OD) 2.4-3.0 (8H, 3.6-3.8 (4H, m), 5.2-5.4 (1H, 6.66 (2H, s), 7.2-8.1 (9H, m).

-84- Example

X

2-[3-(4-Ethyl-lpiperazinyl)-l-Phenylpropyl-1,2-benziso thiazol-3 (2H)-one 1,1-dioxide difumarate above 200 0 C (decomp.) IR (Icr) cm-%: 2400, 1720, 1320, 1290, 1250, 1180, 980, 750, 640.

1H-NMR (CDjOD) 1.28 (3H, 2.4-3.2 (14K, 5.2-5.4 (1K, 6.66 (4H, s), 7.3-8.1 (9H, m) 2-[3-(P-Acetyl-l-piperazinyl)- -phenypropyl 1,2-benzisot-hiazol3(2H)-one l,1-dioxide fumarate 129-130oC IR (KBr) cm-r.

3400, 3000, 2950, 2575, 1720, 1640, 1410, 1325, 1290, 1250, 1180, 980, 750, 670, 640, 580, 500.

'H-NMR (CD3OD)6: 2.04 (3K, 2.4-2.9 (8K, m), 3.4-3.7 (4K, 5.2-5.5 (1K, m), 6.68 (2H, 7.2-8.1 (9K, m).

Exarmee

XII

2- £-Pheny1.> 2 -pyriidinyl) -l-piperazinyll Ipropyll, 2 -benzisothiazol.

3 (2K)-one l, 1 -dioxide hydrochloride IR (KBr) cm- 1 3470, 1725, 1620, 1580, 1550, 1440, 1330, 1290, 1250, 1180, 580.

1 K-NMR

(D

2 O) 8 2.8-4.0 (12K, 5.55 (1H, dd, J=7z, 9Kz), 6.87 (1H, t, J=5Hz), 7.4-7.5 m), 7.6-7.7 (2K, 7.9-8.1 (4H, m), 8.44 (2H, d, Exam~le

XIII

2-[1-(4-C-orophenyl) 3 -piperidinojpropyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide fumarate 193-194'c (decoirr.) IR (Xcr) cml: 3400, 2945, 1720, 1650, 1590, 1485, 1455, 1330, 1280, 1240, 1175, 1120, 1085, 1055, 1005, 980, 830, 780, 745, 720, 645, 630, 600, 575, 550, 520, 505.

'H-NMR

(CE

2 OD) 6: 1.4-2.0 (6H, 3.0-3.3 (8H, m), 5.2-5.4 (1K, 6.62 (2H, s), 7.2-8.1 (8H, in).

Examle

XIV

2-[1-(4-Cholorophenyl) 3 -morphoinopropyl-1,2-benziscthiazol-3(2H)-one l,1-dioxide fumarate 189-190 0

C

IR (Icr) cm-1.: 3425, 1725, 1610, 1590, 1490, 1450, 1400, 1325, 1280, 1250, 1170, 1125, 1090, 1060, 1010, 975, 920, 870, 840, 800, 780, 740, 715, 670, 640, 615, 580, 570, 505.

KH-NMR

(CD

3 OD) 8: 2.3-3.0 (8H, 3.5-3.8 (4H, m), 5.2-5.4 (1K, 6.66 (2H, s), 7.2-7.7 (4K, 7.8-8.1 (5K, m).

2-[1-(4-Methoxyphenyl) -3-piperidinolpropyl112benzisothiazol-3(2)-one l,1-dioxide fumarate 173-1761C (decomp.) IR (K1r) cm- 1 3410, 2950, 2510, 1735, 1610, 1510, 1325, 1290, 1245, 1180, 980, 745.

I-H-NMR (CD-30D) 8: 1.4-2.1 (6H, 2.4-3.4 m), 3.79 (3H, 5.0-5.4 (1H, 6.73 (2H, 6.7-7.0, 7.3-8.1 (8H, m) Example

XVI

6-Chloro-2 (l-phenyl-3-piperidin opropyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide fum-arate 212-214'c (decomp.) IR (1cr) cm-1: 3400, 2940, 1730, 1585, 1320, 1260, 1240, 1175, 980.

IH-NMR (DMSO-c 6: 1.1-1.6 (6H, 2.0-2.9 (8H, m), 5.33 (1H, t, J=7Hz), 6.57 (2K, s), 7.1-7.6 (5K, 7.9-8.0 (2H, m), 8.3-8.4 (1K, m) ExamDe

XVII

6-Chloro-2-( 3 -mopholino-l-phenyl)propyl-1,2-benzisothiazol-3(2H)-one 1,1-dioxide fumarate 197-1980C IR (K1r) cm-l- 3425, 1725, 1585, 1490, 1450, 1400, 1390, 1320, 1260, 1240, 1170, 1125, 1090, 975, 865, 830, 800, 750, 690, 655, 630, 580, 520, 450.

'KH-NM

(J

3 DOD) 6: 2.3-3.0 (8H, 3.5-3.8 (4H, i), 5.2-5.4 (1H, 6.66 (2H, s), 7.2-7.7 (5K, 7.9-8.2 (3K, i).

6-Methoxy-2(1-pheny1-3.piperidino)propyl-1,2-benzisothiazol-3 (2H)-one l,1-dioxide fumarate 199-2010C (decomp.) IR (KBr) cn-': 3420, 2950, 1725, 1600, 1580, 1490, 1320, 1265, -87- 1170, 980.

'H-NMR (DMSO-d) 6: 1.1-1.7 (6H, 2.0-2.9 (8H, i), 3.96 (3H, 5.32 (1H, t, J=7z) 6.57 7.2-8.0 Exainle

XIX

6-Methoy2 -morpho iri o -phenyl)propyl-1,2-benzisotM.Pazol.:3 h-dioxide fuinarate 196-198"C (decomp.) IR cm-1: 1725, 1605, 1580, 1490, 1320, 1270, 1170.

1 KH-ZV'

(D

2 O) 6: 2.7-4.3 (12H, 3.97 s), 5.50 dd, J=6z, 9z), 6.59 (2K, 7.4-7.5 (4H, m), 7.6-7.7 (3H, 7.94 (1K, d, J=l-z).

E arl e XX 4 -Th- 1 oro-2- (3-piperidino-l-phenyl)propyl-1 2-benzisothiazol-3(2K)-One 1 ,l-dioxide fumarate 208 0

C

IR (KBr) cm-1: 3425, 3050, 2950, 2675, 2525, 1720, 1570, 1445, 1395, 1340, 1250, 1210, 1180, 1150, 980, 930, 790, 760, 690, 660, 635, 580, 560, 520, 470.

1 H-NMR (CDOD) 6: 1.3-2.1 (6H, 2.5-3.4 m), 5.2-5.5 (1H, 6.64 (2H, s), 7.2-8.0 (3H, n) In the following Examples XXI to XXVIII, the com- Pounds were prepared essentially in the same manner as in Exanrle II. The prepared componds and cbaracteristics thereof are set forth below.

-88- 2- (-Phenyl-3-thOpholino)propyl- 2 -benzisothiazol- 3(2H)-one 1,l,S-trioxide funmarate 1 78 1.80oC (decomp.) IR (KBr) cml: 3420, 1735, 1395, 1320, 1290, 1250, 1180, 1020, 1000, 980, 925, 760, 740, 640, 580.

'K-NIR

(D

2 O) 6: 2.8-3.0 (1H, 3.0-3.4 i), 3.6-3.9 (4K, 5.51 (1H, t, J=8Hz), 6.66 (2K, 7.4-7.5 (3H, m), 7.6-7.7 (2H, 7.8-8.0 (3H, i), 8.02 (1K, d, J=7Kz).

EisBnD e XX 2--Phenyl-3-thiOdrpholino propyl-1,2-benzisothiazol- 3(2K)-one 1,1,S,S-tetraoxide mesylate Amorphous IR cm-1: 3420, 1720, 1320, 1290, 1250, 1180, 1130. 1 K-NMp

(D

2 0) 6: 2.8-3.2 (2K, 2.82 (3K, s), 3-4-3.6 (2K, 3.6-3.8 (4K, i), 3.8-4.1 (4K, i), 5.52 (1K, dd, 7 =7Hz, 9Hz), 7.4-7.6 (3K, 7.6-7.7 (2K, m), 7.8-8.1 (4K, m).

2 -Methyltomorphoino)-l-Phenyllpropyl-1,2benzisotiazo- 3 (2K) -one 1,1-dioxide fumarate 170-178"C IR cm-1: 3400, 1730, 1330, 1290, 1250, 1180, 970, 750.

1H-63 8) 1.12, 1.16 (3H, d, J=8Hz), -89- 2.2-3.2 (11H, 5.2-5.4 (1H, i), 6.72 (2H, 7.2-8.0 (9K, i).

Exanle XX IV -Methylthiomcr-holinP)-l-phenyllpropyl-1,2benzisothiazol-3(2) -one 1,1-dioxide fumarate 175-1770c IR (KBr) cm-1: 3400, 1730, 1450, 1380, 1330, 1290, 1250, 1180, 970, 750, 690, 670, 640, 580, 540, 510.

IH-NR (CD3D) 6: 1.1-1.3 (3H, 2.3-3.7 (11K, m), 5.2-5.4 (1H, 6.68 (2H, s), 7.2-8.1 m).

Exan~l e XXV 2-[3-(2,2-Dimethylthi Omorpholino)-l -phenyl] propyl-1,2benzisothiazol-3(2) -one 1 ,1-dioxide iesylate Amorphous IP (B3r) cm-': 3400, 1730, 1330, 1290, 1240, 1180, 1060, 785, 560, 540.

'-H-NMR (D20) 8: 1.35 (3K, 1.55 (3H, s), 2.8-3.4 (8H, 2.84 (3H, s), 3.5-3.6 (1K, 3.8-3.9 m), 5.4-5.6 (1H, 7.4-7.5 (3K, m), 7.6-7.7 (2H, 7.8-8.1 (4H, m).

iplaeMa 2-[3-(2,6-Dimethyl thiomrpholino)-l -phenyl] propyl-1,2benzisothiazol- 3 (2H)-one 1,l-dioxide funarate 167 0

C

IR (KBr) cm-1: 3400, 1730, 1690, 1555, 1445, 1380, 1320, 1280, 1250, 1180, 1050, 980, 750, 695, 670, 640, 580, 510.

I-NMR 3 OD) 1.12 (3H, dd, J=4Hz, 8Hz), 1.30 dd, J=4Hz, 8Hz), 2.2-3.4 (8H, 5.2-5.5 (1K, 6.66 (2H, 7.2-8.1 (9H, i).

Example

CCVII

2-[1-Phenyl-3-(2-phenlthiomorpholino) jpropyl-1,2benzisothiazol-3 (2H)-one l,l-dioxide iesylate Amorphous IR (KBr) cm-' 3420, 1720, 1450, 1330, 1290, 1250, 1180, 1060, 1035, 750, 695, 580.

KH-NMR

(C

3 DOD) 6: 2.71 (3H, 2.6-3.1 (2H, i), 3.2-3.7 (6H, 3.8-4.0 (2H, 4.3-4.4 (1H, 5.3-5.4 (1H, m), 7.3-7.7 (10K, 7.9-8.1 (4K, m).

E2XIpe

-CVIII

2-[1-(4-Fluorophenyl) -3-thiomorpholinolpropyl-2-benzisothiazol-3(2K) -one l,1-dioxide fumarate 186-1870c IR (KBr) cm-1: 3400, 1720, 1710, 1600, 1505, 1460, 1330, 1300, 1250, 1220, 1180, 1160, 920, 840, 780, 750, 670, 630, 580, 510.

'H-NMP. ((M3OD) 8: 2.5-2.6 (2K, 2.7-3.2 (10H, m), 5.37 (1H, dd, J=6Hz, 9Hz), 6.72 (2K, 7.1-8.1 (8H, i).

In the following Examples XXIX to XXXI, the compounds were prepared essentially in the same manner as in Example I. The prepared compounds and characteristics -91thereof are set forth below.

ExaBple

XXIX

2-( 3 -Dimethylamino-l-phenyl)propyl-1,2-benzisot hiaz 1 3( 2 K)-one l,-dioxide fumarate 170 1731C IR cm-1: 3410, 2940, 2660, 1720, 1680, 1610, 1455, 1325, 1290, 1250, 1180, 980, 745, 640, 580.

'K-NMIR

(CD

3 OD) 6: 2.86 2.4-3.4 (4H, m), 5.2-5.5 (1HK, 6.68 (2H, s), 7.1-8.1 (9K, m).

Examle

OXXX

2-(3-Diethylamino-i -phenyl 2 propyl- -benzisothiazol- 3(2H)-one l,1-dioxide fumarate 1 7 3-1760c IR (KBr) cm-: 3430, 1730, 1330, 1295, 1260, 1185, 990.

1 H-NMR

(D

2 O) 8: 1.27 (6H, t, J=7Hz), 2.6-3.4 (4K, m), 3.26 (4K, q, J=7Kz), 5.50 (1K, t, J=8Fz), 6.65 (2H, 7.4-8.1 (9H, m).

Exar e XXI 2-( 3 -Benzylethylamino-l-phenyl) propyl-, 2 -benzisothiazol 3(2H)-one 1,-dioxide funarate Arorphous IR (K1r) cm-'* 3400, 1720, 1450, 1370, 1330, 1285, 1245, 1180, 970, 740, 690, 580.

IH-NMR (CD:30D) 6: 1.31 (3K, t, J=8Kz), 2.5-3.3 (6H, m), 4.28 (2H, 5.1-5.4 (1K, m), 6.70 (2H, 7.2-7.6 (12K, m, ArK), -92- Exaniole

XXXII

3 Morho7.8-.1(Hem) 2-(3-Morpholino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)one 1-oxide fumarate 2-(3-Morpholino-i-phenyl)propyl-1, 2 -benzisothiazol- 3(2H) -one i-oxide In DMF(2 mL) were Suspended 4 -[(3-chloro-3-phenyl)propyl]morpholine hydrochloride (116 mg, 0.42 mol.), 1, 2 -benzisothiazol-3( 2 H)-one i-oxide (70 mg, 0.42 mmol.), and cesium carbonate (137 mg, 0.42 mmol.). The suspension was stirred at room temperature for 70 hours to carry out a reaction. The reaction liquid was placed under reduced pressure to distill DMF off. To the residue were added water and ethyl acetate, and the organic layer was taken out. The organic portion was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off. The residue was subjected to silica gel column chromatography (chloroform/methanol =100/1) to obtain 19 nmg of the desired compound (yield 12%) as a colorless oil.

1H-NMR

(CDC

3 8: 2.3-2.8 (8H, 3.6-3.8 (4H, m), 5.76 (1H, t, J=8Hz), 7.3-7.4 (3H, m), 7.5-7.6 (2H, 7.7-7.8 (3H, m), 7.97 (1H, dd, J=7Hz, 1Hz).

2-( 3 -Morpholino-1-pheny)propyl-1,2-benzisothiazol- 3(2H)-one 1-oxide funmarate A solution of fumaric acid (6 mg) in hot ethanol (6 mL) was added to a solution of 2 3 -rmorpholino-1-phenyl)propyl-1,2-benzisothiazol-3(2H)-one 1-oxide (19 mg) in ethanol (2 mM'. The mixture was concentrated under reduced pressure to approx. 1 mL, and then allowed to stand two days at room temperature. Insolubles precipitated and were collected by filtration. The collected insolu- -93bles were washed successively with ethanol and hexane, to give 15 mg of the desired compound (yield 61%) as a white crystalline product.

IR (KBr) cm-1: 3420, 1700, 1620, 1460, 1300, 1240, 1120.

'H-NMR (DO2) 6: 2.7-4.2 (12H, 5.72 (1H, t, J=8Hz), 6.65 (2H, 7.4-7.6 (5H, m), 7.8-8.0 (3H, 8.04 (1H, d, J=7Hz).

Example

XXXIII

2-( 3 -Piperidino-1-phenyl)propyl-1, 2 -benzisothiazoline 1,1-dioxide fumarate 2-( 3 -Piperidino-l-phenyl)propyl-1,2-benzisothiazoline 1,1-dioxide In anhydrous ethanol was dissolved sodium (131 mg, 5.7 mmol.). To the obtained solution were added 1,2benzisothiazoline (483 mg, 2.85 nmol.) and [(3-chloro- 3-phenyl)propyllpiperidine hydrochloride (783 mg, 2.85 mmol). The mixture was then heated for 7 hours under refluxing. The reaction liquid was placed under reduced pressure to distill the solvent off. To the residue were added water and ethyl acetate, and the organic layer was taken out. The organic portion was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure.

The residue was subjected to silica gel column chromatography (chloroform/methanol=40/l) to give 890 mg of the desired compound (yield 84%) as a white crystalline product.

117-1180C IR (KBr) cm- 1 2920, 2800, 1450, 1280, 1210, 1170, 1150, 1120, 1060, 1040, 800, 760, 745, 720, 700, 560.

1H-NMR (CDC1,) 1 1.0-1.8 (6H, 1.9-2.6 (8H, m), -94- 3.95 (1H, d, J=14Hz), 4.30 (1H, d, J=14Hz), 4.95 (1H, t, J=7Hz), 7.1-7.9 (9H, m).

2-(3-Piperidino-l-phenyl)propyl-1,2-benzisothiazoline 1,1-dioxide fumarate A solution of fumaric acid (130 mg, 1.12 mmol.) in hot ethanol (13 mL) was added to a solution of 2-(3piperidino-1-phenyl)propyl-1, 2 -benzisothiazoline 1,1dioxide (415 rmg, 1.12 mmol.) in ethanol (20 mL). The mixture was allowed to stand ovenight at room temperature. Insolubles precipitated and were collected by filtration. The collected insolubles were washed successively with ethanol and hexane, to give 430 mg of the desired compound (yield 79% a )s a white crystalline product.

2 05-206°C (decomp.) IR (KBr) cm- 1 3420, 2930, 1720, 1640, 1600, 1450, 1285, 1170, 1160, 1120, 980, 755, 630.

IH-NMR (DMSO-d) 6: 1.2-1.8 (6H, 2.1-2.9 (8H, m), 4.02 (1H, d, J=14Hz), 4.50 (1H, d, J=14Hz), 4.91 (1H, t, J=7Hz), 6.54 (2H, 7.1-7.9 (9H, m).

Example

XXXIV

2-( 3 Morpholino1 -phenyl) propyl-1,2 -benzisothiazoline 1,1-dioxide fumarate This was prepared essentially in the same manner as in Example

XXXCIII.

1 9 1-192oc IR (KBr) cm-1: 3420, 1710, 1450, 1310, 1280, 1170, 1150, 1120, 980, 765, 630.

1H-NMR (DMSO-d) 6 2.0-2.6 (8H, 3.3-3.7 (4H, m), 4.02 (IH, d, 4.47 (1K, d, 4.91 (1H, t, J=7Hz), 6.61 (2H, 7.1-7.9 (9H, m).

Industrial Apnicability The alkylenediamine derivative of the invention and its pharmacologically acceptable salt can relieve urinating contraction which is observed under high intracystic pressure, and can be used for treating nervous dysuria, chronic prostatitis, chronic cystitis, dysuria caused by neurogenic bladder or unstable bladder, incontinence of urine, urgency of micturition, and residual urine, and therefore is of value as an active ingredient of a therapeutic agent for treating dysuria.

Claims (13)

1. An alkylenediamine derivative having the formula R R3 (CH 2 S-(CH2)---N-(CH 2 )m-CH-(CH 2 )n-N (R 1 )k (CH2)z- C-(CH2)y P I 0 0q q (1) in which R 1 represents an atom or a group selected from the group consisting of hydrogen, alkyl having 1-8 carbon atoms, halogen, haloalkyl having 1-4 carbon atoms, hydroxyl, alkoxy having 1-8 carbon atoms, aryloxy having 4-10 carbon atoms, aralkyloxy having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, nitro, amino, cyano, alkylamino having 1-8 carbon atoms, aralkylamino having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, arylamino having 4- carbon atoms, aliphatic acylamino having 1-8 carbon atoms, carboxyl, alkoxycarbonyl having 2-9 carbon atoms, aralkyloxycarbonyl having 6-15 carbon atoms, its alkyl portion having 1-4 carbon atoms, aryloxycarbonyl having 5-11 carbon atoms, carbamoyl, sulfo, alkoxysulfonyl having 1-8 carbon atoms, aralkyloxysulfonyl having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, aryloxysulfonyl haying 4-10 carbon atoms, sulfonamide, and 1H-tetrazol-5-yl; R 2 represents hydrogen, alkyl having 1-8 carbon atoms, alkenyl having 2-9 carbon atoms, alkoxy having 1-8 carbon atoms, or an aryl having 4-10 carbon atoms, aralkyl having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, or aromatic heterocyclic group which may have one to five same or different substituents selected from the group consisting of alkyl having 1-8 carbon atoms, halogen, haloalkyl having 1-4 carbon atoms, hydroxyl, alkoxy having 1-8 carbon atoms, aryloxy having 4-10 carbon atoms, aralkyloxy having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, nitro, amino, cyano, alkylamino having 1-8 carbon atoms, aralkylamino having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, arylamino having 4-10 carbon atoms, aliphatic acylamino having 1-8 carbon atoms, carboxyl, alkoxycarbonyl having 2-9 carbon atoms, aralkyloxycarbonyl having 6-15 carbon atoms, its alkyl portion having 1-4 carbon atoms, aryloxycarbonyl having 5-11 carbon atoms, carbamoyl, sulfo, alkoxysulfonyl having 1-8 carbon atoms, aralkyloxysulfonyl having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, aryloxysulfonyl having 4-10 carbon atoms, sulfonamide and 1F-tetrazol-5-yl; each of R 3 and R 4 independently represents hydrogen, alkyl having 1-8 carbon atoms, aralkyl having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, or aryl having 4-10 carbon atoms, or R 3 and R 4 form in combination with the nitrogen atom to which R 3 and R 4 are attached, a hetero ring which may contain another nitrogen, oxygen or sulfur as the ring- forming atom in addition to the former nitrogen atom and which may have a substituent selected from the group consisting of alkyl having 1-8 carbon atoms which may have one or two aryl having 4-10 carbon atoms, phenyl, hydroxyl, alkoxy having 1-8 carbon atoms which may have one or two aryl having 4-10 carbon atoms, aryloxy having 4-10 carbon atoms, carboxyl and cyano, provided that where R 2 is hydrogen, R 3 and R 4 form in combination with the nitrogen atom to which R 3 and R 4 are attached, a hetero ring which may contain another nitrogen, oxygen or sulfur as the ring-forming atom Zz00077 in addition to the former nitrogen atom and which has a substituent selected from the group consisting of alkyl having 1-8 carbon atoms which has one or two aryl having 4-10 carbon atoms, phenyl, hydroxyl, alkoxy having 1-8 carbon atoms which may have one or two aryl having 4-10 carbon atoms, aryloxy having 4-10 carbon atoms, carboxyl and cyano, and where R 2 is alkyl or phenyl, there is no case wherein R 3 and R 4 are both hydrogens k is an integer of 1 to 4; each of m and n independently represents an integer of 0 to 4, under the condition that the total number of m and n is in the range of -C- II O to 4; p is 0, 1 or 2; q is 0 or 1 wherein when q is 0, is CH 2 each of w, x, y and z independently is an integer of 0 to 2, under the condition that the total number of w, x, y and z is 1 or 2 1o 2. The alkylenediamine derivative of claim 1, which is represented by the formula O.O S0 R 3 SN N (RI)k R4 O (2) in which R 1 R 2 R 3 R 4 k, m, and n are the same as those defined in claim 1.

3. The alkylenediamine derivative of claim 1 which is represented by the formula O (RI)k I R 3 N CH-(CIl 2 )i-N R4 O (3) in which R 1 R 2 R 3 R 4 k, m, and n are the same as those defined in claim 1.

4. An alkylenediamine derivative having the formula S R3 (R 1 )m N-(CH 2 )p--CH-(CH 2 N (O)y R (I) in which R 1 represents an atom or a group selected from the group consisting of hydrogen, alkyl having 1-8 carbon atoms, halogen, haloalkyl having 1-4 carbon atoms, hydroxyl, alkoxy having 1-8 carbon atoms, aryloxy having 4-10 carbon atoms, aralkyloxy having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, nitro, amino, cyano, alkylamino having 1-8 carbon atoms, aralkylamino having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, arylamino having 4- carbon atoms, aliphatic acylamino having 1-8 carbon atoms, carboxyl, alkoxycarbonyl having 2-9 7700077 carbon atoms, aralkyloxycarbonyl having 6-15 carbon atoms, its alkyl portion having 1-4 carbon atoms, aryloxycarbonyl having 5-11 carbon atoms, carbamoyl, sulfo, alkoxysulfonyl having 1-8 carbon atoms, aralkyloxysulfonyl having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, aryloxysulfonyl having 4-10 carbon atoms, sulfonamide, and 1H-tetrazol-5-yl; R 2 represents phenyl, napthamoyl or aromatic heterocyclic group which may have one to five same or different substituents selected from the group consisting of alkyl having 1-8 carbon atoms, halogen, haloalkyl having 1-4 carbon atoms, hydroxyl, alkoxy having 1-8 carbon atoms, aryloxy having 4-10 carbon atoms, aralkyloxy having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, nitro, amino, cyano, alkylamino having 1-8 carbon atoms, aralkylamino having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, arylamino having 4-10 carbon atoms, aliphatic acylamino having 1-8 carbon atoms, carboxyl, alkoxycarbonyl having 2-9 carbon atoms, aralkyloxycarbonyl having 6-15 carbon atoms, its alkyl portion having 1-4 carbon atoms, aryloxycarbonyl having 5-11 carbon atoms, carbamoyl, sulfo, alkoxysulfonyl having 1-8 carbon atoms, aralkyloxysulfonyl having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, aryloxysulfonyl having 4-10 carbon atoms, sulfonamide and yl; each of R 3 and R 4 independently represents hydrogen, alkyl having 1-8 carbon atoms, aralkyl having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, or aryl having 4-10 carbon atoms, or R 3 and R 4 form in combination with the nitrogen atom to which R 3 and R 4 are attached, a five to seven membered hetero ring having the formula (II): -N )t (1I) in which Z is a group of the formula (III): I -N- (Ill) in which R 5 represents hydrogen or a group selected from the group consisting of alkyl having 1-8 carbon atoms, aralkyl having 5-14 carbon atoms, its alkyl portion having 1-4 carbon atoms, phenyl, 2- pyrimidinyl, carboxyl, alkoxycarbonyl having 2-9 carbon atoms, aralkyloxycarbonyl having 6-15 carbon atoms, its alkyl portion having 1-4 carbon atoms, and aryloxycarbonyl having 5-11 carbon atoms, or -SO 2 and t is 0 or 1; in which the five to seven membered hetero ring may have 1 to substituents selected from the group consisting of alkyl having 1-5 carbon atoms, aralkyl having 5-14 carbon atoms, its alkyl having 1-4 carbon atoms, phenyl, hydroxyl, alkoxy having 1-8 carbon atoms, carboxyl, alkoxycarbonyl having 2-9 carbon atoms, aralkyloxycarbonyl having 6-15 carbon atoms, its alkyl having 1-4 carbon atoms, aryloxycarbonyl having 5-11 carbon atoms, aliphatic acyl having 1-8 carbon atoms, aromatic acyl having 5-11 carbon atoms, and carbamoyl, provided that where n is 0 and R 2 is phenyl, there is no case that R 3 and R 4 both are hydrogens; m represents an integer of 1 to 4. and n represents an integer of 0 to 4; each of p and q independently represents an integer of 0 to under the condition that the total number of p and q is in the range of 1 to 5, under the condition that Zz00077 99 the total number of p and q is in the range of 1 to 5; x is 0, 1 or 2; and y is 0 or 1 wherein when y is 0, C- (O)q is CH 2 The alkylenediamine derivative of claim 4 which is represented by the formula (IV): o O 3S R3 (R 1 )m N-(CH 2 )p-CH-(CH 2 N R2 (j R 4 o (IV) in which R 1 R 2 R 3 R 4 m, n, p and q are the same as those defined in claim 4.

6. The alkylenediamine derivative of claim 4 which is represented by the formula o O S /R 3 (R 1 )m N-(CH 2 )p--CH-(CH 2 N N R4 O (V) in which R 1 R 2 R 3 R 4 m, n, p and q are the same as those defined in claim 4.

7. The alkylenediamine derivative of claim 4 which is represented by the formula (VI): o o (R 1 N-(CH 2 )p-CH-(CH 2 N RR 4 (VI) in which R 1 R 2 R 3 R 4 m, n, p and q are the same as those defined in claim 4.

8. A therapeutic agent for treatment of dysuria comprising the alkylenediamine derivative of claim 1.

9. A benzothiazinylalkylamine derivative substantially as hereinbefore described with reference to any one of the examples. A thiaazabenzocycloheptanylalkylamine derivative substantially as hereinbefore described with reference to any one of the examples.

11. A process for the preparation of a benzothiazinylalkylamine derivative substantially as hereinbefore described with reference to any one of the examples.

12. A process for the preparation of a thiaazabenzocycloheptanyalkylamine derivative substantially as hereinbefore described with reference to any one of the examples.

13. A pharmaceutical composition comprising an effective amount of at least one compound according to any one of claims 1 to 7, 9 or 10, together with a pharmaceutically acceptable carrier, diluent or adjuvant therefor. Zz00077

14. A method for the treatment of prophylaxis of dysuria in a mammal requiring said treatment or prophylaxis, which method comprises administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 7, 9 or 10, or of a composition according to claim 13.

15. Use of a compound according to any one of claims 1 to 7, 9 or 10 for the preparation of a medicament for the treatment or prophylaxis of dysuria.

16. A compound according to any one of claims 1 to 7, 9 or 10 when used in the prophylaxis or treatment of dysuria. Dated 18 December, 1998 NIPPON-CHEMIPHAR CO., LTD. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON Zz00077