CA1267897A - Processes for preparing benzothiazine derivatives - Google Patents
Processes for preparing benzothiazine derivativesInfo
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- CA1267897A CA1267897A CA000488136A CA488136A CA1267897A CA 1267897 A CA1267897 A CA 1267897A CA 000488136 A CA000488136 A CA 000488136A CA 488136 A CA488136 A CA 488136A CA 1267897 A CA1267897 A CA 1267897A
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Abstract
TITLE OF THE INVENTION
PROCESS FOR PREPARING NOVEL BENZOTHIAZINE DERIVATIVE
ABSTRACT
This invention relates to processes for preparing novel benzothiazine derivatives represented by the formula [I].
[I]
The compounds prepared by the processes of this invention are useful for treatment of cardiovascular diseases.
PROCESS FOR PREPARING NOVEL BENZOTHIAZINE DERIVATIVE
ABSTRACT
This invention relates to processes for preparing novel benzothiazine derivatives represented by the formula [I].
[I]
The compounds prepared by the processes of this invention are useful for treatment of cardiovascular diseases.
Description
~789~ 67845-15 DETAILED DESCRIPTION OF THE INVENTION
This invention relates to processes for preparing novel benzothiazine derivatives of the formula [I] and salts thereof, Rl ~<
~ ~ O-A-N / ~ R3 [I]
wherein Rl is one or more groups selected from the group con-sisting of hydrogen, lower alkyl, halogen, nitro, hydroxy, lower alkoxy, lower alkanoyloxy, amino, lower alkylamino and lower alkoxycarbonyloxy;
R2 is hydrogen, lower alkyl or IC3 - C6~cycloalkyl;
R3 is one or more groups selected from the group con-sisting of hydrogen, lower alkyl, hydroxy, lower alkoxy, halogen, nitro, lower alkylenedioxy, lower alkanoyloxy, lower alkanoyl, / amino, lower alkylamino, lower alkanoylamino and lower alkoxy-carbonyloxy;
R4 is hydrogen or~lower alkyl;
A and B are same or dlfferent, and are lower alkylene having 1 to 6 carbon atoms.
The same shall be applied hereinafter.
The groups defined above are explained below in more detail:
~2~7~ 67845-15 Lower alkyl is alkyl groups having l to 6 carbon atoms exemplified by methyl, ethyl, propyl and hexyl; halogen is exemplified by fluorine, chlorine and bromine; lower alkoxy is alkoxy groups having l to 6 carbon atoms exemplified by methoxy, ethoxy, propoxy and hexyloxy; lower alkanoyloxy is al~anoyl groups having l to 6 carbon atoms exemplified by acetyloxy, propionyloxy and hexanoyloxy; (C3 - C6)cycloalkyl is cycloalkyl groups having 3 to 6 carbon atoms exemplified by cyclopropyl and cyclohexyl;
lower alkylenedioxy is the ~roups which have (Cl - C6)alkylene between two oxygen atoms exemplified by methylenedioxy and ethy-lenedioxy; lower alkanoyl is aIkanoyl groups having 1 to 6 carbon atoms exemplified by acetyl, propionyl and hexanoyl.
The compounds prepared by the processes of this invention are novel benzothiazine derivatives which have excellent platelet anti-aggregatory activity and calcium-antagonistic activ-ity, and they are useful for treatment for cardiovascular diseases.
There are only few reports on benzothiazine deri-vatives which are useful for therapy.
Especially, benzothiazine derivatives, which are useful for treat~
ment of cardiovascular diseases, are disclosed only in one publication, that is Japanese ~nexamined Patent Publication 148771/84 filed by the same inventors of this app}lcation. The characteristic of the chemical structure of -the compounds of this invention is that phenyl group substituted at 2~position of benzo-thiazine rlng has a side chain which has a substituted or unsub-stituted phenyloxy group. The characteristic structure of the
This invention relates to processes for preparing novel benzothiazine derivatives of the formula [I] and salts thereof, Rl ~<
~ ~ O-A-N / ~ R3 [I]
wherein Rl is one or more groups selected from the group con-sisting of hydrogen, lower alkyl, halogen, nitro, hydroxy, lower alkoxy, lower alkanoyloxy, amino, lower alkylamino and lower alkoxycarbonyloxy;
R2 is hydrogen, lower alkyl or IC3 - C6~cycloalkyl;
R3 is one or more groups selected from the group con-sisting of hydrogen, lower alkyl, hydroxy, lower alkoxy, halogen, nitro, lower alkylenedioxy, lower alkanoyloxy, lower alkanoyl, / amino, lower alkylamino, lower alkanoylamino and lower alkoxy-carbonyloxy;
R4 is hydrogen or~lower alkyl;
A and B are same or dlfferent, and are lower alkylene having 1 to 6 carbon atoms.
The same shall be applied hereinafter.
The groups defined above are explained below in more detail:
~2~7~ 67845-15 Lower alkyl is alkyl groups having l to 6 carbon atoms exemplified by methyl, ethyl, propyl and hexyl; halogen is exemplified by fluorine, chlorine and bromine; lower alkoxy is alkoxy groups having l to 6 carbon atoms exemplified by methoxy, ethoxy, propoxy and hexyloxy; lower alkanoyloxy is al~anoyl groups having l to 6 carbon atoms exemplified by acetyloxy, propionyloxy and hexanoyloxy; (C3 - C6)cycloalkyl is cycloalkyl groups having 3 to 6 carbon atoms exemplified by cyclopropyl and cyclohexyl;
lower alkylenedioxy is the ~roups which have (Cl - C6)alkylene between two oxygen atoms exemplified by methylenedioxy and ethy-lenedioxy; lower alkanoyl is aIkanoyl groups having 1 to 6 carbon atoms exemplified by acetyl, propionyl and hexanoyl.
The compounds prepared by the processes of this invention are novel benzothiazine derivatives which have excellent platelet anti-aggregatory activity and calcium-antagonistic activ-ity, and they are useful for treatment for cardiovascular diseases.
There are only few reports on benzothiazine deri-vatives which are useful for therapy.
Especially, benzothiazine derivatives, which are useful for treat~
ment of cardiovascular diseases, are disclosed only in one publication, that is Japanese ~nexamined Patent Publication 148771/84 filed by the same inventors of this app}lcation. The characteristic of the chemical structure of -the compounds of this invention is that phenyl group substituted at 2~position of benzo-thiazine rlng has a side chain which has a substituted or unsub-stituted phenyloxy group. The characteristic structure of the
- 2 -~2~7~3~7 compound of this invention is not disclosed in the above Japanese Unexamined Patent Publication.
Other benzothiazine derivatives were reported by J. Krapcho (Uni-ted States Pat. No. 316554), Stearns et al.
(United States Pat. No. 3555156) and Stanley O. et al (Canadian Pat. No. 717979). The chemical structures of the compounds disclosed in the publications are quite different from the com-pounds of this invention. The object of them are also different from this invention. J. Krapcho desired to obtain compounds which are useful for treatment of Parkinsonism, Stearns et al. desired to obtain herbicides, and Stanley et al. desired to obtain com-pounds having anticholinergic activity and antihistaminic activity.
The compounds of this invention represented by the formula [I] can be prepared by the following methods.
1) A reaction of a compound of the formula [II] with an amine derivative of the formula [III] under basic conditions.
~0 -X E~N\
[II] [III]
wherein X is halogen or methanesulfonyloxy.
The same shall be applied hereinafter.
2~ A reaction of a compund of the formula [IV] with a compound of the formula [V].
Other benzothiazine derivatives were reported by J. Krapcho (Uni-ted States Pat. No. 316554), Stearns et al.
(United States Pat. No. 3555156) and Stanley O. et al (Canadian Pat. No. 717979). The chemical structures of the compounds disclosed in the publications are quite different from the com-pounds of this invention. The object of them are also different from this invention. J. Krapcho desired to obtain compounds which are useful for treatment of Parkinsonism, Stearns et al. desired to obtain herbicides, and Stanley et al. desired to obtain com-pounds having anticholinergic activity and antihistaminic activity.
The compounds of this invention represented by the formula [I] can be prepared by the following methods.
1) A reaction of a compound of the formula [II] with an amine derivative of the formula [III] under basic conditions.
~0 -X E~N\
[II] [III]
wherein X is halogen or methanesulfonyloxy.
The same shall be applied hereinafter.
2~ A reaction of a compund of the formula [IV] with a compound of the formula [V].
3 _ i,l , ,, .i 7~
~7~45-15 R
S ~ ~ { ~ R2 ~ [I]
R OH + X-A-N ~ R3 [IV] [V]
3) A reaction of a compound of the formula ~VI] with a compound of the formula [VII].
ll.-NH-13- O~ R3 ~ X-R2 ~ I I 3 [VI] : ~VII]
; The above reactions are usually carried out under the basic condition.: A preferable base used in the reactions is in-organic or organic base such as sodium hydride, potassium carbon-ate, sodium carbonatej sodium hydroxide, sodium alcoholate, triethylamine, pyridine or N,N-dimethylaniline~ The reactions can be carried out using the exaess amount of amine reactant with-out adding a base.
The other;conditions such as solvent an~ reaction temperature are unlimited and can be selected depending on a kind of base, solubility of a reactant, etc.
: The compounds of this invention can be converted to :
pharmaceutically acceptable salts such as~hydrochloric acid salt, : sulfuric acid salt, phosphoric~acld salt, lactiF~acid salt, maleic :
~G7a9~
~7~ 15 acid salt, fumaric acid salt, oxalic acid salt, methanesulfonic acid salt and p-toluenesulfonic acid salt.
The compounds of this invention have stereoisomers, and these isomers are included in the scope of this invention~
The compounds can be administered either orally or parenterally. The dosage forms are tablet, capsule, granule, pow-der, suppository, injection, etc. The dose is adjusted depending on symptoms, dosage form, etc., but usual daily dosage is 1 to 5,000 mg, preferably 10 to 1,000 mg, in one or a fe~ divided doses.
The compounds of this invention have excellent platelet anti-aggregatory activity and calcium-antagonistic activity, and they are useful for treatment of cardiovascular diseases such as hypertenslon, thrombosis and arrhythmia.
The following pharmacological test proved that the compounds of this invention have an excellent calcium-antagonistic activity.
As a preferable compound of this invention, 3,4-dihydro-2-~5-methoxy-2-~4-[N-methyl-2-[(3,4-methylenedioxy)phenoxyJethyl-amino]butoxy]phenyl]~4-methyl--3-oxo-2H-1,4-benzothiazine oxalate ~Compound A) was tested.
As a reference compound, 3,4-dihydro-2-[5-methoxy-2 [4-[N-methyl-(3,4-dlmethoxy)phenytylamino]butoxy]phenyl]-4-methyl]-~
3-oxo-2H-1,4-benzothiazine oxalate (mp 145-147 C) was used~ The structure of the reEerence compound resembles to the comp~ound of this invention. But, the reference cmpound has not the~character-istic structure, namely phenyloxy group in the~ slde chain, o~
::
~2G789~7 the compound of this invention.
Pharmacological ~est (Method for measurement of calcium-antagonistic activity) Isolated guinea-pig teania coli was suspended in a 20ml organ bath with ~rebs solution at 32C and bubbled with 5~
carbon dioxide in oxygen. After equilibration, the muscule was washed with Ca +-free Krebs solution, and when the muscule had relaxed tc basal level, it was suspended in Ca++-free-high-K Krebs solution. The muscule was exposed to test compounds for 5 minutes before an addition of CaCl2, and the contraction evoked by CaCl2(3xlO 4M) was recorded isotonicallyO The calc-um-antagonistic activity was represented by the concentration of test compound which elicited 50% inhibition of Ca +-evoked contraction (IC50).
(Result) Compound IC50 (M) Compound A 3.2 x 10 7 Reference Compound 3.2 x lO 6 _ _ ~
EXAMPLES
Example 1 3,4-Dihydro-2-[5-methoxy-2-[4-~N-methyl-2-~(3,4-methylenedioxy)phenoxylethylamino]butoxy]phenyl]-4-methyl-3-oxo-2H-lr4-benzothiazine oxalate To a suspension of 50% sodium hydride (0.15g) in anhydrous dimethylformamide (Sml), a solution of 3,4-dihydro-2-~ 7 ~7845-~5 (2-hydroxy-5-methoxyphenyl)-3-oxo-2H-l,A-benzothiazine (0.9g) in anhydrous dimethylformamide (lOml) was added aropwise with stir-ring.
After the addition, the mixture was stirred additionally for 15 minutes. To the mixture, a solution o 4-~N-methyl-2-[(3,4-methylenedioxy)phenoxy]ethylamino]butoxy bromide (1.2g) in anhydrous dimethylformamide (lOml) was added dropwise with stir-ring.
After the addition, the mixture was stirred for 2 hours at 50C. The reaction mixture was poured into a mixture of chloroform (50ml) and 2N hydrochloric acid (50 m]). The organic lay~er was concentrated in vacua and the~residue was dis-solved in ethyl acetate. The solution was washed with N sodium hydroxide and saturated sodium chloride solutlon. The organic layer was dried over anhydrous sodium sulfate and~concentrated in vacuo. The resulting residue was purified by silica gel column chromatography and oily product was dissolved in ethyl acetate.
To the solution, a solution of oxalic acid in ethyl acetate was added and resulting crystals were filtered to giVe 14g (73%) of the titled compaund.
mp 160-162C (ethanol - water) IR (KBr, cm 1) : 1655, 1584, 1499, 1475, 1400, 1356, 1277, 1238, 1205, 1185, 1132, 1034 Following compounds were prepared by the similar method as in Exampl- 1 ~4;'78~7 3,4-Dihydro~2-[5-rnethoxy-2-[3-[N-methyl-2-[(3,4-methylenedioxy)phenoxy]ethylamino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR (KBr, cm 1) : 1655 (C=O) 3,4-Dihydro-2-[5-methoxy-2-[4-[N-methyl-2-[(3,4-dimethoxy)phenoxy]ethylamino]butoxy]phenyl]-3-oxo-2H-1,4-benzo-thiazine hydrochloride IR (KBr, cm 1~ : 1653 (C=O) 2-[4-[4-[N-[2-(2-Chlorophenoxy)ethyl]-N-ethylamino]
butoxy]phenyl]-3,4-dihydro-~~methyl-3-oxo-2H-1,4-benzothiaZine : hydrochloride IR (KBr, cm 1) : 1655 (C=O) 3,4-Di.hydro-2-[S-methoxy-2-~4-[N-methyl-~(3/4-methy-lenedioxy)phenoxy]methylamino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR (KBr, cm ) : 1654 (C=O) Example 2 3,4-Dihydro-2-[5-methoxy-2- E 4-[N-methyl-2-[(3,4-methylenedioxy)ph~noxy]ethylamino]butoxyJphenyl]-4-methyl~3-oxo~
. 20 2H-1,4-benzothiazine oxalate To a stirred solution of 2-[2-(4-bromobutoxy)-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine : - (1.2g) and sodium carbonate (0.4g) in dlmethylformamide:(5ml~, N- ~
methyl-2-[(3,4-methylenedioxy)phenoxy]ethylamine (0.8g)~was added ::
and the mixture was stirred for 2 hours at 80C. The reaction mixture was poured into a mixture of chloroform (50ml) and 2N
:
.,.
.~;
~67~7 67~45-15 hydrochloric acid (50ml). Following treatments were carried out by the similar procedures as in Example 1 to give the titled compound.
~ he melting point and IR data of the compound were identified with the data of the crystals prepared in Example 1.
Following compounds were prepared by the similar method as in Example 2.
3,4-Dihydro-2-[5-methoxy-2-[4-[N-methyl-2-(phenoxy) ethylamino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR (KBr, cm ) : 1655 (C=O) 3,4-Dihydro-2-[5-methoxy-2-[5-[N-methyl-2-~(3,4,5-trimethoxy)phenoxy]ethylamino]pentyloxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR (KBr, cm 1) : 1655 (C=O) 3,4-Dihydro-2-[5-methoxy-2-[4-[N-methyl 2-[(3,4-methylenedioxy)phenoxy]ethylamino]butoxy]phenyl]-3-oxo-2H-1,4-benzothiazine hydrochloride IR (KBr, cm 1) : 16S5 (C=O) 3,4-Dihydro-2-[5-chloro-2-[3-[N-methyl-2-[(3,4-dimethoxy)phenoxy]ethylamino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR (KBr, cm 1) : 1655 (C=O) ~ ~ 3,4-D1hydro-2-[5-methoxy-2-[3-[N-methyl-2~(4-methoxy-: phenoxy)ethylamino]propoxy]phenyl]-3-oxo~2H-1,4-berlzothiazine fumarate _ g _ '78~
67~45-15 IR (KBr, cm ) : 1656 (C=O) 3,4-Dihydro-2~[2~[3-EN-[2-(2-fluorophenoxy)ethyl-N-methylamino]propoxy~-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR ~KBr, cm ) : 1656 (C=O) 2-[4-[4-[N-Cyclopropyl-2-(4-nitrophenoxy)ethylamino]
butoxy~phenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR ~KBr, cm ) : 1656 (C=O) 3,4-Dihydro-2-[S-methoxy-2-[3-[N-methyl-2-[(3,4-dimethoxy)phenoxy]ethylamino]propoxy]-4-nitrophenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR (KBr, cm 1) : 1654 (C=O) 3~4-Dihydro-2-[2-[4-[N-ethyl-2-[(2,3,4-trimethoxy) phenoxy]ethylamino]butoxy]-5-methoxyphenyl]-4-methyl-3-oxo-2~-1,4-benzothazine oxalate IR (KBr, cm 1) : 1653 (C=O) 3,4-Dihydro-2-[5-me-thoxy-2-[3-[2-[(3,4-methylenedioxy) phenoxy]ethylamino]propoxy]phenyl]-4-methyl-3-oxo-2H-:L,4-benzo thiazine hydrochloride IR ~KBr, cm ) : 1656 (C=O) 2-[2-[4-[N-[2-(4-Chlorophenoxy)ethyl]-N-cyclohexyl-amino]butoxy]-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR (KBr, cm ) : 1655 (c=o 8~7 67~5-].5 3,4-Dihydro-4-methyl-2-[4-[3-[2-[(3,4,5-trimethoxy) phenoxy]ethylamino]propoxy]phenyl]-3-oxo-2H-1,4-benzothiazine hydrochloride IR (KBr, cm 1) : 1657 (C=O) 2-[4-[5-[N-Cyclohexyl-N-l2-(4-methylphenoxy)ethyl]
amino]pentyloxy]phenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR (KBr, cm ) : 1658 (C=O) 3,4-Dihydro-2-[4-[5-[N-methyl-[(2,3,4-trimethoxy) phenoxy]methylamino]pentyloxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochIoride IR (KBr, cm ) : 1655 (C=o) Example 3 3,4-Dihydro-2-[5-methoxy-2-14-[N-methyl-2-[(3,4-methylenedioxy~phenoxy]ethylamino]butoxy]phenyl]~4-methyl-3-oxo-2H-1,4-benzothiazine oxalate To a solution of 3,4-dihydro-2-[5-methoxy-2-[4-(methyl-amino)butoxy]phenyl]-4-methyl-3-oxo~2H-1,4-benzothiazine (1.2gj and triethylamine (0.4g) in ethanol (10 ml), 2-[(3,4-methylenc-dioxy)phenoxy]ethyl methanesulonate (l.Og) was added and the mixture was refluxed for 2 hours. The reaction mixture was concen-trated in vacuo and the residue was poured lnto a mixture of chloroform (50ml) and 2N hydrochloric acid (50ml).
: : :
~ Following treatments were carried out by the similar procedures in Example 1 to give 1.3g (65%) of the titled compound.
The~melting point and IR data of the compound were - 1 1 - : ~
~' ;
67~5-15 identified with the crystals prepared in Example 1.
Following compounds were prepared by the similar method as in Example 3.
3,4-Dihydro-4-methyl-2-[4-[4-[N-methyl-2-[(3,4-methylenedioxy)phenoxy]ethylamino]butoxy]phenyl]-3-oxo-2H-1,4-benzothiazine oxalate IR (KBr, cm ) : 1654 (C=O) 3,4-Dihydro-2-[4-[4-[2-(2-fluorophenoxy)ethylamino]
butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride ., IR (KBr, cm ) : 1660 (C-O) 3,4-Dihydro-2-[4-~4-[N-methyl-2-(2-chlorophenoxy)ethyl-amino]butoxy]phenyl]-3-oxo-2H-1,4-benzothiazine fumarate IR (KBr, cm ) : 1662 (C=O) 3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-[(3,4-dimethoxy) phenoxy]methylamino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzo-thiazine hydrochloride IR (KBr, cm 1) : 1658 (C=O) Example 4 3,4-~ihydro-2-[5-methoxy-2-[4-[N-methyl-2-~(3~4,5-trimethoxy)phenoxy]ethylamino~butoxy]phenyl]-4-methyl-3-oxo-2H
1,4-benzothiazine oxalate To a solution of 2-~2-~4-bromobutoxy)-5-methoxyphenyl]-3,4-dihydro-4~methyl-3-oxo-2H-1,4-benzothiazine (1.3g) and triethylamine (0.4g) in ethanol (lOml), N-methyl-2-~(3,4,5-tri-methoxy)phenoxy]ethylamine (0.9g~ was added and the mixture was refluxed for 2 hours. The reaction mixture was concentrated 67845-~5 in vacuo and the residue was poured into a mixture of chloroform ~50ml~ and 2N hydrochloric acid (50ml). Following -treatments were carried out by the similar procedures as in Example 1 to give 1.5g (73%) of the titled compound.
IR (KBr, cm ) : 1654 (C=O) : - 13 -
~7~45-15 R
S ~ ~ { ~ R2 ~ [I]
R OH + X-A-N ~ R3 [IV] [V]
3) A reaction of a compound of the formula ~VI] with a compound of the formula [VII].
ll.-NH-13- O~ R3 ~ X-R2 ~ I I 3 [VI] : ~VII]
; The above reactions are usually carried out under the basic condition.: A preferable base used in the reactions is in-organic or organic base such as sodium hydride, potassium carbon-ate, sodium carbonatej sodium hydroxide, sodium alcoholate, triethylamine, pyridine or N,N-dimethylaniline~ The reactions can be carried out using the exaess amount of amine reactant with-out adding a base.
The other;conditions such as solvent an~ reaction temperature are unlimited and can be selected depending on a kind of base, solubility of a reactant, etc.
: The compounds of this invention can be converted to :
pharmaceutically acceptable salts such as~hydrochloric acid salt, : sulfuric acid salt, phosphoric~acld salt, lactiF~acid salt, maleic :
~G7a9~
~7~ 15 acid salt, fumaric acid salt, oxalic acid salt, methanesulfonic acid salt and p-toluenesulfonic acid salt.
The compounds of this invention have stereoisomers, and these isomers are included in the scope of this invention~
The compounds can be administered either orally or parenterally. The dosage forms are tablet, capsule, granule, pow-der, suppository, injection, etc. The dose is adjusted depending on symptoms, dosage form, etc., but usual daily dosage is 1 to 5,000 mg, preferably 10 to 1,000 mg, in one or a fe~ divided doses.
The compounds of this invention have excellent platelet anti-aggregatory activity and calcium-antagonistic activity, and they are useful for treatment of cardiovascular diseases such as hypertenslon, thrombosis and arrhythmia.
The following pharmacological test proved that the compounds of this invention have an excellent calcium-antagonistic activity.
As a preferable compound of this invention, 3,4-dihydro-2-~5-methoxy-2-~4-[N-methyl-2-[(3,4-methylenedioxy)phenoxyJethyl-amino]butoxy]phenyl]~4-methyl--3-oxo-2H-1,4-benzothiazine oxalate ~Compound A) was tested.
As a reference compound, 3,4-dihydro-2-[5-methoxy-2 [4-[N-methyl-(3,4-dlmethoxy)phenytylamino]butoxy]phenyl]-4-methyl]-~
3-oxo-2H-1,4-benzothiazine oxalate (mp 145-147 C) was used~ The structure of the reEerence compound resembles to the comp~ound of this invention. But, the reference cmpound has not the~character-istic structure, namely phenyloxy group in the~ slde chain, o~
::
~2G789~7 the compound of this invention.
Pharmacological ~est (Method for measurement of calcium-antagonistic activity) Isolated guinea-pig teania coli was suspended in a 20ml organ bath with ~rebs solution at 32C and bubbled with 5~
carbon dioxide in oxygen. After equilibration, the muscule was washed with Ca +-free Krebs solution, and when the muscule had relaxed tc basal level, it was suspended in Ca++-free-high-K Krebs solution. The muscule was exposed to test compounds for 5 minutes before an addition of CaCl2, and the contraction evoked by CaCl2(3xlO 4M) was recorded isotonicallyO The calc-um-antagonistic activity was represented by the concentration of test compound which elicited 50% inhibition of Ca +-evoked contraction (IC50).
(Result) Compound IC50 (M) Compound A 3.2 x 10 7 Reference Compound 3.2 x lO 6 _ _ ~
EXAMPLES
Example 1 3,4-Dihydro-2-[5-methoxy-2-[4-~N-methyl-2-~(3,4-methylenedioxy)phenoxylethylamino]butoxy]phenyl]-4-methyl-3-oxo-2H-lr4-benzothiazine oxalate To a suspension of 50% sodium hydride (0.15g) in anhydrous dimethylformamide (Sml), a solution of 3,4-dihydro-2-~ 7 ~7845-~5 (2-hydroxy-5-methoxyphenyl)-3-oxo-2H-l,A-benzothiazine (0.9g) in anhydrous dimethylformamide (lOml) was added aropwise with stir-ring.
After the addition, the mixture was stirred additionally for 15 minutes. To the mixture, a solution o 4-~N-methyl-2-[(3,4-methylenedioxy)phenoxy]ethylamino]butoxy bromide (1.2g) in anhydrous dimethylformamide (lOml) was added dropwise with stir-ring.
After the addition, the mixture was stirred for 2 hours at 50C. The reaction mixture was poured into a mixture of chloroform (50ml) and 2N hydrochloric acid (50 m]). The organic lay~er was concentrated in vacua and the~residue was dis-solved in ethyl acetate. The solution was washed with N sodium hydroxide and saturated sodium chloride solutlon. The organic layer was dried over anhydrous sodium sulfate and~concentrated in vacuo. The resulting residue was purified by silica gel column chromatography and oily product was dissolved in ethyl acetate.
To the solution, a solution of oxalic acid in ethyl acetate was added and resulting crystals were filtered to giVe 14g (73%) of the titled compaund.
mp 160-162C (ethanol - water) IR (KBr, cm 1) : 1655, 1584, 1499, 1475, 1400, 1356, 1277, 1238, 1205, 1185, 1132, 1034 Following compounds were prepared by the similar method as in Exampl- 1 ~4;'78~7 3,4-Dihydro~2-[5-rnethoxy-2-[3-[N-methyl-2-[(3,4-methylenedioxy)phenoxy]ethylamino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR (KBr, cm 1) : 1655 (C=O) 3,4-Dihydro-2-[5-methoxy-2-[4-[N-methyl-2-[(3,4-dimethoxy)phenoxy]ethylamino]butoxy]phenyl]-3-oxo-2H-1,4-benzo-thiazine hydrochloride IR (KBr, cm 1~ : 1653 (C=O) 2-[4-[4-[N-[2-(2-Chlorophenoxy)ethyl]-N-ethylamino]
butoxy]phenyl]-3,4-dihydro-~~methyl-3-oxo-2H-1,4-benzothiaZine : hydrochloride IR (KBr, cm 1) : 1655 (C=O) 3,4-Di.hydro-2-[S-methoxy-2-~4-[N-methyl-~(3/4-methy-lenedioxy)phenoxy]methylamino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR (KBr, cm ) : 1654 (C=O) Example 2 3,4-Dihydro-2-[5-methoxy-2- E 4-[N-methyl-2-[(3,4-methylenedioxy)ph~noxy]ethylamino]butoxyJphenyl]-4-methyl~3-oxo~
. 20 2H-1,4-benzothiazine oxalate To a stirred solution of 2-[2-(4-bromobutoxy)-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine : - (1.2g) and sodium carbonate (0.4g) in dlmethylformamide:(5ml~, N- ~
methyl-2-[(3,4-methylenedioxy)phenoxy]ethylamine (0.8g)~was added ::
and the mixture was stirred for 2 hours at 80C. The reaction mixture was poured into a mixture of chloroform (50ml) and 2N
:
.,.
.~;
~67~7 67~45-15 hydrochloric acid (50ml). Following treatments were carried out by the similar procedures as in Example 1 to give the titled compound.
~ he melting point and IR data of the compound were identified with the data of the crystals prepared in Example 1.
Following compounds were prepared by the similar method as in Example 2.
3,4-Dihydro-2-[5-methoxy-2-[4-[N-methyl-2-(phenoxy) ethylamino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR (KBr, cm ) : 1655 (C=O) 3,4-Dihydro-2-[5-methoxy-2-[5-[N-methyl-2-~(3,4,5-trimethoxy)phenoxy]ethylamino]pentyloxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR (KBr, cm 1) : 1655 (C=O) 3,4-Dihydro-2-[5-methoxy-2-[4-[N-methyl 2-[(3,4-methylenedioxy)phenoxy]ethylamino]butoxy]phenyl]-3-oxo-2H-1,4-benzothiazine hydrochloride IR (KBr, cm 1) : 16S5 (C=O) 3,4-Dihydro-2-[5-chloro-2-[3-[N-methyl-2-[(3,4-dimethoxy)phenoxy]ethylamino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR (KBr, cm 1) : 1655 (C=O) ~ ~ 3,4-D1hydro-2-[5-methoxy-2-[3-[N-methyl-2~(4-methoxy-: phenoxy)ethylamino]propoxy]phenyl]-3-oxo~2H-1,4-berlzothiazine fumarate _ g _ '78~
67~45-15 IR (KBr, cm ) : 1656 (C=O) 3,4-Dihydro-2~[2~[3-EN-[2-(2-fluorophenoxy)ethyl-N-methylamino]propoxy~-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR ~KBr, cm ) : 1656 (C=O) 2-[4-[4-[N-Cyclopropyl-2-(4-nitrophenoxy)ethylamino]
butoxy~phenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR ~KBr, cm ) : 1656 (C=O) 3,4-Dihydro-2-[S-methoxy-2-[3-[N-methyl-2-[(3,4-dimethoxy)phenoxy]ethylamino]propoxy]-4-nitrophenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR (KBr, cm 1) : 1654 (C=O) 3~4-Dihydro-2-[2-[4-[N-ethyl-2-[(2,3,4-trimethoxy) phenoxy]ethylamino]butoxy]-5-methoxyphenyl]-4-methyl-3-oxo-2~-1,4-benzothazine oxalate IR (KBr, cm 1) : 1653 (C=O) 3,4-Dihydro-2-[5-me-thoxy-2-[3-[2-[(3,4-methylenedioxy) phenoxy]ethylamino]propoxy]phenyl]-4-methyl-3-oxo-2H-:L,4-benzo thiazine hydrochloride IR ~KBr, cm ) : 1656 (C=O) 2-[2-[4-[N-[2-(4-Chlorophenoxy)ethyl]-N-cyclohexyl-amino]butoxy]-5-methoxyphenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate IR (KBr, cm ) : 1655 (c=o 8~7 67~5-].5 3,4-Dihydro-4-methyl-2-[4-[3-[2-[(3,4,5-trimethoxy) phenoxy]ethylamino]propoxy]phenyl]-3-oxo-2H-1,4-benzothiazine hydrochloride IR (KBr, cm 1) : 1657 (C=O) 2-[4-[5-[N-Cyclohexyl-N-l2-(4-methylphenoxy)ethyl]
amino]pentyloxy]phenyl]-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride IR (KBr, cm ) : 1658 (C=O) 3,4-Dihydro-2-[4-[5-[N-methyl-[(2,3,4-trimethoxy) phenoxy]methylamino]pentyloxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochIoride IR (KBr, cm ) : 1655 (C=o) Example 3 3,4-Dihydro-2-[5-methoxy-2-14-[N-methyl-2-[(3,4-methylenedioxy~phenoxy]ethylamino]butoxy]phenyl]~4-methyl-3-oxo-2H-1,4-benzothiazine oxalate To a solution of 3,4-dihydro-2-[5-methoxy-2-[4-(methyl-amino)butoxy]phenyl]-4-methyl-3-oxo~2H-1,4-benzothiazine (1.2gj and triethylamine (0.4g) in ethanol (10 ml), 2-[(3,4-methylenc-dioxy)phenoxy]ethyl methanesulonate (l.Og) was added and the mixture was refluxed for 2 hours. The reaction mixture was concen-trated in vacuo and the residue was poured lnto a mixture of chloroform (50ml) and 2N hydrochloric acid (50ml).
: : :
~ Following treatments were carried out by the similar procedures in Example 1 to give 1.3g (65%) of the titled compound.
The~melting point and IR data of the compound were - 1 1 - : ~
~' ;
67~5-15 identified with the crystals prepared in Example 1.
Following compounds were prepared by the similar method as in Example 3.
3,4-Dihydro-4-methyl-2-[4-[4-[N-methyl-2-[(3,4-methylenedioxy)phenoxy]ethylamino]butoxy]phenyl]-3-oxo-2H-1,4-benzothiazine oxalate IR (KBr, cm ) : 1654 (C=O) 3,4-Dihydro-2-[4-[4-[2-(2-fluorophenoxy)ethylamino]
butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine hydrochloride ., IR (KBr, cm ) : 1660 (C-O) 3,4-Dihydro-2-[4-~4-[N-methyl-2-(2-chlorophenoxy)ethyl-amino]butoxy]phenyl]-3-oxo-2H-1,4-benzothiazine fumarate IR (KBr, cm ) : 1662 (C=O) 3,4-Dihydro-2-[5-methoxy-2-[3-[N-methyl-[(3,4-dimethoxy) phenoxy]methylamino]propoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzo-thiazine hydrochloride IR (KBr, cm 1) : 1658 (C=O) Example 4 3,4-~ihydro-2-[5-methoxy-2-[4-[N-methyl-2-~(3~4,5-trimethoxy)phenoxy]ethylamino~butoxy]phenyl]-4-methyl-3-oxo-2H
1,4-benzothiazine oxalate To a solution of 2-~2-~4-bromobutoxy)-5-methoxyphenyl]-3,4-dihydro-4~methyl-3-oxo-2H-1,4-benzothiazine (1.3g) and triethylamine (0.4g) in ethanol (lOml), N-methyl-2-~(3,4,5-tri-methoxy)phenoxy]ethylamine (0.9g~ was added and the mixture was refluxed for 2 hours. The reaction mixture was concentrated 67845-~5 in vacuo and the residue was poured into a mixture of chloroform ~50ml~ and 2N hydrochloric acid (50ml). Following -treatments were carried out by the similar procedures as in Example 1 to give 1.5g (73%) of the titled compound.
IR (KBr, cm ) : 1654 (C=O) : - 13 -
Claims (17)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for prep~ring a compound of the formula [I] or a salt thereof, [I]
wherein R1 is one or more groups selected from the group consisting of hydrogen, lower alkyl, halogen, nitro, hydroxy, lower alkoxy, lower alkanoyloxy, amino, lower alkylamino and lower alkoxycar-bonyloxy;
R2 is hydrogen, lower alkyl or (C3-C6)cycloalkyl;
R3 is one or more groups selected from the group consisting of hydrogen, lower alkyl, hydroxy, lower alkoxy, halogen, nitro, lower alkylenedioxy, lower alkanoyloxy, lower alkanoyl, amino, lower alkylamino, lower alkanoylamino and lower alkoxycarbonyloxy;
R4 is hydrogen or lower alkyl; and A and B are the same or different and are lower alkylene having 1 to 6 carbon atoms, which comprises a reaction of a compound of the formula [II] with a compound of the formula [III], [I]
[II] [III]
wherein X is halogen or methanesulfonyloxy, a reaction of a com-pound of the formula EIV] with a compound of the formula [V], + [I]
[IV] [V]
wherein X is as defined above, or a reaction of a compound of the formula [VI] with a compound of the formula [VII], + [I]
[VI]
[VII]
wherein X is as defined above, and, where required, forming a salt thereof.
wherein R1 is one or more groups selected from the group consisting of hydrogen, lower alkyl, halogen, nitro, hydroxy, lower alkoxy, lower alkanoyloxy, amino, lower alkylamino and lower alkoxycar-bonyloxy;
R2 is hydrogen, lower alkyl or (C3-C6)cycloalkyl;
R3 is one or more groups selected from the group consisting of hydrogen, lower alkyl, hydroxy, lower alkoxy, halogen, nitro, lower alkylenedioxy, lower alkanoyloxy, lower alkanoyl, amino, lower alkylamino, lower alkanoylamino and lower alkoxycarbonyloxy;
R4 is hydrogen or lower alkyl; and A and B are the same or different and are lower alkylene having 1 to 6 carbon atoms, which comprises a reaction of a compound of the formula [II] with a compound of the formula [III], [I]
[II] [III]
wherein X is halogen or methanesulfonyloxy, a reaction of a com-pound of the formula EIV] with a compound of the formula [V], + [I]
[IV] [V]
wherein X is as defined above, or a reaction of a compound of the formula [VI] with a compound of the formula [VII], + [I]
[VI]
[VII]
wherein X is as defined above, and, where required, forming a salt thereof.
2. A process as claimed in claim 1, wherein R1 is hydrogen or methoxy.
3. A process as claimed in claim 1, wherein R3 is methoxy or lower alkylenedioxy.
4. A process according to claim 1, wherein in the starting materials R1 is 5-methoxy, R2 is methyl, R3 is 3,4-methylenedioxy, R4 is methyl, A is butylene and B is ethylene.
5. A process according to claim 4, wherein the salt is an oxalate.
6. A process according to claim 1, wherein R1 is hydrogen or methoxy and R3 is methoxy or lower alkylenedioxy.
7. A process according to claim 1, 4 or 6, wherein the salt is a hydrochloric, sulfuric, phosphoric, lactic, maleic, fumaric, oxalic, methanesulfonic or p-toluenesulfonic acid salt.
8. A compound of the formula I as defined in claim 1, or a salt thereof.
9. A compound of the formula I as defined in claim 1, wherein R1 is hydrogen or methoxy and R3 is methoxy or lower alkylenedioxy.
10. A compound of the formula I as defined in claim 1 or a hydrochloric, sulfuric, phosphoric, lactic, maleic, fumaric, oxalic, methanesulfonic or p-toluenesulfonic acid salt thereof.
11. The compound 3,4-dihydro-2-[5-methoxy-2-[4-tN methyl-2-[(3,4-methylenedioxy)phenoxy]-ethylamino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine.
12. An oxalate salt of a compound according to claim 11.
13. A pharmaceutical composition comprising an active ingre-dient in admixture with a pharmaceutically acceptable diluent or carrier wherein the active ingredient is a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof.
14. A composition according to claim 13, wherein in the com-pound of formula I R1 is hydrogen or methoxy and R3 is methoxy or lower alkylenedioxy.
15. A composition according to claim 13 or 14, wherein the pharmaceutically acceptable salt is a hydrochloric, sulfuric, phos-phoric, lactic, maleic, fumaric, oxalic, methanesulfonic or p-to-luenesulfonic acid salt.
16. A composition according to claim 13, wherein the active ingredient is 3,4-dihydro-2-[5-methoxy-2-[4-[N-methyl-2-[(3,4-methylenedioxy)phenoxy]-ethylamino]butoxy]phenyl]-4-methyl-3 oxo-2H-1,4-benzothiazine.
17. A composition according to claim 16, wherein the active ingredient is 3,4-dihydro-2-[5-methoxy-2-[4-[N-methyl-2-[(3,4-methylenedioxy)phenoxy]-ethylamino]butoxy]phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine oxalate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000488136A CA1267897A (en) | 1985-08-06 | 1985-08-06 | Processes for preparing benzothiazine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000488136A CA1267897A (en) | 1985-08-06 | 1985-08-06 | Processes for preparing benzothiazine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1267897A true CA1267897A (en) | 1990-04-17 |
Family
ID=4131119
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000488136A Expired CA1267897A (en) | 1985-08-06 | 1985-08-06 | Processes for preparing benzothiazine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1267897A (en) |
-
1985
- 1985-08-06 CA CA000488136A patent/CA1267897A/en not_active Expired
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