CA2027738A1 - 5-{2-[(2-amino-2-oxoethyl) (methyl)amino]ethyl}-2,3-dihydro-3-hydroxy-2-(4-methoxyphen yl)-1,5(5h)-benzothiazepin-4-one derivatives, their preparation and their application in therapy - Google Patents
5-{2-[(2-amino-2-oxoethyl) (methyl)amino]ethyl}-2,3-dihydro-3-hydroxy-2-(4-methoxyphen yl)-1,5(5h)-benzothiazepin-4-one derivatives, their preparation and their application in therapyInfo
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- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
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- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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Abstract
ABSTRACT
A compound, in the form of a pure diastereoisomer or a mixture thereof, of formula (I) (I) in which R1 represents a hydrogen atom or a C2-C4 alkanoyl group, R2 represents a hydrogen atom or a C1-C4 alkyl group, n represents an integer of from 0 to 3, and R3 represents either a phenyl group bearing from 1 to 3 substituents selected from halogen atoms and trifluoromethyl, methyl, C1-C4 alkoxy or alkylthio, nitro, cyano, carbamoyl, acetamido, methanesulphonamido, methoxycarbonyl or phenylcarbonyl groups, or an aromatic heterocyclic group;
or a pharmacologically acceptable acid addition salt thereof.
A compound, in the form of a pure diastereoisomer or a mixture thereof, of formula (I) (I) in which R1 represents a hydrogen atom or a C2-C4 alkanoyl group, R2 represents a hydrogen atom or a C1-C4 alkyl group, n represents an integer of from 0 to 3, and R3 represents either a phenyl group bearing from 1 to 3 substituents selected from halogen atoms and trifluoromethyl, methyl, C1-C4 alkoxy or alkylthio, nitro, cyano, carbamoyl, acetamido, methanesulphonamido, methoxycarbonyl or phenylcarbonyl groups, or an aromatic heterocyclic group;
or a pharmacologically acceptable acid addition salt thereof.
Description
2027~3~ -5-{2-[(2-AMINo-2-OXOETHYL)(METHYL)AMINO]ETHYL}-2,3-DIHyDRo-3-HyDRoxy-2-(4-METHoxypHENyL)-l~5(sH)- ~:
BENZOTHIAZEPIN-4-ONE DERIVATIVES, THEIR PREPARATION AND
THEIR APPLICATION IN THERAPY
The present invention relates to 5-{2-[(2-amino-2-oxoethyl)(methyl)amino]ethyl}-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5(5H)-benzothiazepin-4-one derivatives, to their preparation and to their application in therapy.
The present invention provides a compound, in the ;-form of a pure diastereoisomer or a mixture thereof, of - formula (I): ; .
~OC~)3 ~OR1 .
~ O ~"~"', ~N ~ ~( C~ 2) ~` R3 (I) in which:
Rl represents a hydrogen atom or a C2-C4 alkanoyl group; ; ~ .
.~
R2 represents a hydrogen atom or a C1-C4 alkyl group; -n represents an integer o~ from O to 3; and R3 represents either a phenyl group bearing from 1 to 3 substituents selected from halogen atoms and ~ 202~738 trifluoromethyl, methyl, Cl-c4 alkoxy or alkylthio, nitro, cyano, carbamoyl, acetamido, methanesulphonamido, methoxycarbonyl or phenylcarbonyl groups, or an aromatic heterocyclic group;
or a pharmacologically acceptable acid addition salt thereof.
R1 is preferably a -COCH3 group. R2 is preferably a hydrogen atom or a -CH3 or -CH(CH3)2 group. R3 i8, for example, a pyridyl or imidazolyl group. R3 is preferably a 2-pyridyl, 1-imidazolyl or -C6H3-3,4-(OCH3)2, -C6H4-2- -~
COC6H5, -C6H3-3,4-(0cH3)2, -C6H4-3-OCH3, -C6H3-3-C1, -C6H3-3~4 C12~ -C6H3-3~4-(CH3)2~ -c6H2-3~4~5-(ocH3)3~ -C6H4-4-CH C H -4-CF3 -C6H4-4-F, -C6H4-4-OnC4Hg, C6H4 3 C6H4 4 OCH3~ C6H4-4-CO2CH3, -C6H4-4-Cl~ -C6H4-3-Br-4-CH3, -C6H4-4-CN or -C6H4-4-NO2 group. The substituents on the phenyl group represented by R3 are generally in the 3-and/or 4-positions. When the compound of formula (I) is in the form of a ealt, it may, for example, be in the form of an oxalate or fumarate salt.
Since the carbon atoms at positions 2 and 3 are asymmetric, the compounds of formula (I) can exist in various diastereoisomeric, racemic or optically pure forms.
These various forms form part of the invention.
According to the invention, the compounds of formula (I) may be prepared according to the scheme given below.
2~7738 SCHEME
9(II) ~(CH2)n~R3 OH
~1 ( I I I J
H3C~ ~J~iN~(cH2)n~R3 ~OCi!l3 ~VJ ~OCh3 O (O
H3C J~N~(CH2)~R3 ~-OCH3 R2 - ~:
1~ ~ r~ ~(CN~
(VI) ~NH
; : , ,.
:;` ' '~ '' -` 2~2773~
BENZOTHIAZEPIN-4-ONE DERIVATIVES, THEIR PREPARATION AND
THEIR APPLICATION IN THERAPY
The present invention relates to 5-{2-[(2-amino-2-oxoethyl)(methyl)amino]ethyl}-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5(5H)-benzothiazepin-4-one derivatives, to their preparation and to their application in therapy.
The present invention provides a compound, in the ;-form of a pure diastereoisomer or a mixture thereof, of - formula (I): ; .
~OC~)3 ~OR1 .
~ O ~"~"', ~N ~ ~( C~ 2) ~` R3 (I) in which:
Rl represents a hydrogen atom or a C2-C4 alkanoyl group; ; ~ .
.~
R2 represents a hydrogen atom or a C1-C4 alkyl group; -n represents an integer o~ from O to 3; and R3 represents either a phenyl group bearing from 1 to 3 substituents selected from halogen atoms and ~ 202~738 trifluoromethyl, methyl, Cl-c4 alkoxy or alkylthio, nitro, cyano, carbamoyl, acetamido, methanesulphonamido, methoxycarbonyl or phenylcarbonyl groups, or an aromatic heterocyclic group;
or a pharmacologically acceptable acid addition salt thereof.
R1 is preferably a -COCH3 group. R2 is preferably a hydrogen atom or a -CH3 or -CH(CH3)2 group. R3 i8, for example, a pyridyl or imidazolyl group. R3 is preferably a 2-pyridyl, 1-imidazolyl or -C6H3-3,4-(OCH3)2, -C6H4-2- -~
COC6H5, -C6H3-3,4-(0cH3)2, -C6H4-3-OCH3, -C6H3-3-C1, -C6H3-3~4 C12~ -C6H3-3~4-(CH3)2~ -c6H2-3~4~5-(ocH3)3~ -C6H4-4-CH C H -4-CF3 -C6H4-4-F, -C6H4-4-OnC4Hg, C6H4 3 C6H4 4 OCH3~ C6H4-4-CO2CH3, -C6H4-4-Cl~ -C6H4-3-Br-4-CH3, -C6H4-4-CN or -C6H4-4-NO2 group. The substituents on the phenyl group represented by R3 are generally in the 3-and/or 4-positions. When the compound of formula (I) is in the form of a ealt, it may, for example, be in the form of an oxalate or fumarate salt.
Since the carbon atoms at positions 2 and 3 are asymmetric, the compounds of formula (I) can exist in various diastereoisomeric, racemic or optically pure forms.
These various forms form part of the invention.
According to the invention, the compounds of formula (I) may be prepared according to the scheme given below.
2~7738 SCHEME
9(II) ~(CH2)n~R3 OH
~1 ( I I I J
H3C~ ~J~iN~(cH2)n~R3 ~OCi!l3 ~VJ ~OCh3 O (O
H3C J~N~(CH2)~R3 ~-OCH3 R2 - ~:
1~ ~ r~ ~(CN~
(VI) ~NH
; : , ,.
:;` ' '~ '' -` 2~2773~
A first method consists in reacting a benzothiazepinone of formula (V) (in which R1 is as defined above) with a halogenated amine of general formula (IV) (in which R2 and R3 are as defined above and Y is a halogen S atom such as chlorine or bromine).
The second method consists in reacting a benzothiazepinone of formula (VI) (in which R1 is as defined above) with a halogenated derivative of general formula (II) (in which R2 and R3 are as defined above and Y
is a halogen atom such as chlorine or bromine).
These two reactions, between either a benzothiazepinone (V) or an amine (VI) (in the form of a ~ -free base or of an addition salt) and a halogenated derivative, are conventional, and hence proceed under 15 conditions well known to those skilled in the art, that is -to say, for example, in an aprotic solvent such as acetone, ~-2-butanone or ethyl acetate, at the refluxing temperature, in the presence of a base to bind liberated acid (and, :
where appropriate, to liberate the base from the starting compound), for example potassium carbonate, and optionally in the presence of a phase transfer catalyst such as tetra-n-butylammonium iodide or benzyltriethylammonium chloride.
It is self-evident that a compound of formula (I) in which R1 represents a hydrogen atom may be converted to a compound of formula (I) in which Rl represents an alkanoyl group by an acylation of known type, and that the ^` 202~73~
The second method consists in reacting a benzothiazepinone of formula (VI) (in which R1 is as defined above) with a halogenated derivative of general formula (II) (in which R2 and R3 are as defined above and Y
is a halogen atom such as chlorine or bromine).
These two reactions, between either a benzothiazepinone (V) or an amine (VI) (in the form of a ~ -free base or of an addition salt) and a halogenated derivative, are conventional, and hence proceed under 15 conditions well known to those skilled in the art, that is -to say, for example, in an aprotic solvent such as acetone, ~-2-butanone or ethyl acetate, at the refluxing temperature, in the presence of a base to bind liberated acid (and, :
where appropriate, to liberate the base from the starting compound), for example potassium carbonate, and optionally in the presence of a phase transfer catalyst such as tetra-n-butylammonium iodide or benzyltriethylammonium chloride.
It is self-evident that a compound of formula (I) in which R1 represents a hydrogen atom may be converted to a compound of formula (I) in which Rl represents an alkanoyl group by an acylation of known type, and that the ^` 202~73~
opposite conversion is possible by hydrolysis.
The benzothiazepinones of formula (V) are described in US Patent No. 3,562,257; those of formula (VI) are ~-described in European Patent Applications Nos. 158,339 and 158,340.
The halogenated amine of formula (IV) may be prepared, for example, from the alcohol of formula (III) by the action of a halogenating agent such as thionyl chloride. The amino alcohol of formula (III) can itself be 10 prepared according to any known method, for example from a ~ -~
halogenated derivative of formula (II) and 2-methylaminoethanol. The compounds of formula (II) are ;
accessible from chloroacetyl chloride and amines of general formula RZ-HN-(CH2)n-R3 (in which R2, n and R3 are as ~-15 defined above), which are described in the literature. ~ -The Examples which follow illustrate in detail the ;-preparation of a few compounds according to the invention.
The elemental microanalyses and the IR and NMR spectra ~`~
confirm ths structures of the products obtained. The numbers shown in brackets for each example correspond to those in the table which follows, and which illustrates the structures and physical properties of a few compounds -~
according to the invention. ~ ;
:. .. '' ::.
~`'' .' ' . ' ' ': :~ ', ,~ 2 ~ 2 7 ~ 3 8 Example 1 (Compound No. lL
(+)-cis-(2S,3S)-3-Acetyloxy-2,3-dihydro-5-t2-{[2-(3,4-dimethoxyphenyl)amino-2-oxoethyl](methyl)amino}ethyl]-2-(4-methoxyphenyl)-1,5(5H)-benzothiazepin-4-one.
A mixture of 4 g (9.15 mmol) of (+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-2-(4-methoxyphenyl)-5-(2-methylaminoethyl)-1,5(5H)-benzothiazepin-4-one hydrochloride, 2.4 g (10 mmol) of 1-chloro-N-(3,4-dimethoxyphenyl)acetamide and 9.9 g of potassium carbonate in 50 ml of 2-butanone is heated to reflux for 9 h.
The mixture is filtered, the filtrate is evaporated - and the residue is purified by chromatography on a silica column. 5.3 g of oil are thereby obtained, which oil is taken up with 60 ml of ethanol and treated with 0.81 g of oxalic acid. The precipitate obtained on addition of ether is filtered off and recrystallized in ethanol. 4 g of oxalate are isolated.
M~lting point: 144C t~]20=+59.4 (c=0.5; MeOH).
Example 2 (Compound No. 11) (+)-cis-(2S,3S)-3-Acetyloxy-2,3-dihydro-5-{2-t{2-t(4-methylphenyl)methyl](methyl)amino-2- ;
oxoethyl}(methyl)amino]ethyl}-2-(4-methoxyphenyl)-1,5(5H)-benzothiazepin-4-one.
A mixture of 4 g (9.15 mmol) of (+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-2-(4-methoxyphenyl)-5-(2-methylaminoethyl)-1,5(5H)-benzothiazepin-4-one 2~277~
hydrochloride, 1.85 g (8.73 mmol) of 1-chloro-N-methyl-N-t(4-methylphenyl)m~thyl]acetamide and 6.05 g of potassium carbonate in 50 ml of 2-butanone is heated to reflux for 9 h. The mixture is filtered, the filtrate is evaporated and the residue is purified by chromatography sn a silica column. 3.5 g of oil are thereby obtained, which oil is taken up in ethanol and treated with 1 equivalent of oxalic acid. The precipitate obtained on addition of ether is filtered off and recrystallized in ethanol. 2.5 g of oxalate are isolat4d.
Melting point: 108.3-109.2C [~]20=~71.4 (c=0.3; MeOH).
Exam~le 3 (Com~ound No. 18).
(+)-cis-(2S,3S)-3-Acetyloxy-2,3-dihydro-5-{2-[{2-[2-(3,4-,: :.. ,, ...,~
dimethoxyphenyl)ethyl](methyl)amino-2-oxoethyl}(methyl)amino]ethyl}-2-(4-methoxyphenyl)-1,5(5H)-benzothiazepin-4-one.
A mixture of 3 g (6.7 mmol) of (+)-cis-(2S,3S)-3- --acetyloxy-2,3-dihydro-2-(4-methoxyphenyl)-5-(2-20 methylaminoethyl)-1,5(5H)-benzothiazepin-4-one ---hydrochloride, 2.4 g (8.9 mmol) of 1-chloro-N-methyl-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide and 7 g of potassium carbonate in 50 ml of 2-butanone is heated to reflux for ;
8 h. The mixture is filtered, the filtrate is evaporated ~
25 and the residue is purified by chromatography on a silica ; -column. An oil is obtained, which oil is taken up in ethanol and treated with 1 equivalent of oxalic acid. The `- 2027738 precipitate obtained on addition of ether is filtered off and recrystallized in ethanol. 2 g of oxalate are isolated.
Melting point: 90C [~]20=+52.8 (c=0.5; MeOH).
Exam~le 4 (Compound No. 20).
(+)-cis-(2S,3S)-3-Acetyloxy-2,3-dihydro-5-~2-[{2-t3-(1-imidazolyl)propyl]amino-2-oxoethyl}(methyl)amino~ethyl}-2-(4-methoxyphenyl)-1,5(5H)-benzothiazepin-4-one.
A mixture of 4 g (9.15 mmol) of (+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-2-(4-methoxyphenyl)-5-{2-methylaminoethyl)-1,5(5H)-benzothiazepin-4-one hydrochloride, 4 g (19.8 mmol) of 1-chloro-N-t3-(1-imidazolyl)propyl]acetamide and 3.6 g of potassium carbonate in 60 ml of 2-butanone is heated to reflux for 10 h.
The mixture is filtered, the filtrate is evaporated and the residue is purified by chromatography on a silica column. 2 g of oil are thereby obtained, which oil is taken up with 12 ml of ethanol and treated with 0.32 g of oxalic acid. The precipitate obtained on addition of ether is filtered off and recrystallized in ethanol. 1.1 g of oxalate are isolated.
! Melting point: 55C [~]20=+51.3 (c=0.5; MeOH).
D
.
` 2027~3~
g Table ~( ~OR1 O ( I ) H3C ' ~ Z R3 N R 1 F~2 n R3 ¦Salt I ~ ~ D2 0 M . P . (' C ) c(%),MeOH . ..
_ ._ _ _ _ '.'''' '' ''" ' ''' ' 1 1 ~COCH IH ¦D ~ C6H3 4- (OCH3)2 ~03 1 03 ~1 4 ~
~ ~
COCH3 H 0 C6H4- 2 -COc6H5 ox . ~ 9 0 ,1 2 8 5 ¦ 3¦COCH ICH 1 ¦ bH3-3l4-(OC 3)2 lo 1 04 ~1 0 I ~ ¦COC8 ¦N l~j C 3 3 4-(OCH3 2 13 1~34 5 COCH3 CH3 1 C6H4-3-OCH3 ox . ( 0, 3 ) 106 ¦ 6 ¦COCN3¦CN3 ¦~ CbN3-3-cl lox 1 73 ¦ S
7 COCN3 CN~ i C6H3-3 4-(OCH3~2 OX 69 ~ 115 202 ~73~
1 o --Table ( continued ) N 31 R2 n R3 ~ t I ~ 2D M P SOC) 8 COCH3 CH3 1 C6H3-3 4-C12 OX (0 5) 125 9 COCH3 CH3 1 C6H3- 3, 4-(CH3)2 OX (0695)8 92-95 5 11 COCN3 CN3 1 C6N7-3 4-5-lOCN3 3~0 67 5 143 4-1:q,6' 11 COCH3 ICR3 ¦ ~ C6Hq~4~CH3 ;ox. 71; lOH,3-109,2, 12 COCH3 CH3 1 C6H4-4-CF3 OX (O692) 126 2-128 3 13 COCH3 CH3 1 C6N4-4-F OX ~72 8 B6-88 14 COCH3 CH3 1 C6H4-4-OnC4H9 OX (0 2) 87 5-91 5 115 ¦COCH3¦CH3 1 I C6N -q-SCN3 OX ¦-55 l1 B,S 129,5¦
16 COCN3 CH3 2 C6H4- 3-OCH3 OX ~80 4 85 ~ ~ ;
17 COCH3 CH3 2 2-pyridyl ox (0S) B5 15 COCN3 CN3 2 C6H3-3,4-(0CH3)2 CX 52 H90 90 ;
Table (con~luded) -~-~; ~ R2 n R3 Salt [~D20 IM P tc) _ _ c ( % ), MeOH ¦ . - . -9~COC 3 CN3 C6N2-3,4,5-(ocN3 3~ .~65,4 ~I
20 COCH3 H 3 1-imidazolylox. ~51,3 ¦55 21 COCH3 I CH31 C6H4- 4 - OCH3 OX ~ 68 4 i 9 0 5 ~ ~ ( 0 2 ) `
22 COCH3 CHICH ~2 1C6H~-4-CH3 fwn ~91,N 1 1-l23 23 COC 3 CH3 C6N~-4-CO2CH3~f ~ 72,5 129-131 :~
4 COC 3 CH3 C6H~-4-Clf 3n -35 129-130 25 COCH3 CH3 1C6H4-3-~r-4-CH3 ox. (0,2) 119-122 ~:
126lCCN31CH3 ¦~ ¦ C6N4-4-CN ¦fw3¦-73,5 19 27 COCN3 CN3 _ C6H~-4-NO2 f w3 ~76,2 110 1l2 Legends in the "salt" column, ox. denotes an oxalate and fum denotes a fumarate. -202~38 ,~
The compounds of the invention were subjected to a series of pharmacological tests which demonstrated their value as therapeutic substances for the cardiovascular system.
Their activity as calcium antagonists was shown by means of a test on isolated rabbit aorta. The experimental protocol used is a variant of that used by Godfraind and Kaba (1969), (Blockade or reversal of the contraction induced by calcium and adrenaline in depolarized arterial smooth muscle, Br. J.Pharmac., 36, 549-560). The details of the test are described in European Patent No. 0,103,500.
The molar concentration produGing a 50 % relaxation of the response to calcium (EC50), or alternatively its antilogarithm (pEC50), is calculated.
The pEC50 values of the compounds of the invention range from 4.5 to 6.6.
The compounds of the invention were also subjected to a test of binding of [3H]nitrendipine to whole rat ;
cortex. - ~
The details of the test are described in European ~ -Patent Application No. 0,300,865.
.
The IC50 concentrations of the compounds of the . . . -.
invention (concentrations which inhibit 50 % of the ~-specific binding of ~3H]nitrendipine) lie betwesn 0.001 and 10 ~M.
The compounds of the invention were also subjected to a test of inhibition of the specific binding of "PAF", -- ~027~3~ ~
-blood platelet-activating factor, the protocol of which test is described in European Patent Application No.
0,320,362.
The IC50 values (concentrations which inhibit the specific binding by 50 %) of the compounds of the invention in this test lie between 0.5 and 5 ~m.
Finally, the compounds of the invention were subjected to a test of inhibition of blood platelet aggregation induced by "PAF-acether" (1-0-(C16-C18 alkyl)- ~ -2-acetyl-sn-glyceryl-3-phosphorylcholine), the protocol of which test is also described in European Patent Application No. 0,320,362.
The aggregation-inhibitory action of the compounds is expressed by the IC50 concentration, the concentration which inhibits by 50 % the aggregation produced by PAF-acether.
The IC50 values of the compounds of the invention in this test lie between 2 and 20 ~M.
The results of the tests show that the compounds of -20 the invention are calcium antagonists and can, on these -~
grounds, be used for the treatment of various conditions for which this type of agent is indicated.
Thus, in particular, they may be used in cardiovascular medicine for the treatment of conditions requiring modulators of transmembrane and intracellular movements of calcium, most especially hypertension, angina and cardiac arrhythmia.
2 0 2 ~ .~ 3 8 They are, in addition, capable of exhibiting antiatherogenic, cardiac anti-ischaemic, cerebral anti-ischaemic, antimigraine, antiepileptic, antiasthmatic and antiulcerative effects.
In the cardiovascular field, they may be used alone or in combination with other known active substances such as diuretics, B-blockers, angiotensin-converting enzyme inhibitors and ~1-receptor antagonists.
They may also be indicated for boosting the effect 10 or decreasing the toxicity of agents used in the treatment : -of cancer or in organ transplants.
The compounds of the invention may be presented in all forms suitable for oral or parenteral administration, in combination with known excipients, for example in the form of tablets, hard gelatin capsules, dragees, capsules, and solutions or suspensions to be taken by mouth or :;~
injected.
The present invention therefore also provides a -pharmaceutical composition which comprises a compound of formula (I) or a pharmacologically acceptable acid addition salt thereof and a pharamceutical excipient.
The present invention furthermore provides a compound of formula (I) or a pharmacologically acceptable acid addition salt thereof for use in a method of treatment of the human or animal body by therapy, especially for use in a method of treatment of hypertension, angina or cardiac arrhythmia or for treatment of a condition requiring an - ;
'': '''~`
2~ 73~
antiatherogenic, cardiac anti-ischaemic, cerebral anti- .
ischaemic, antimigraine, antiepileptic, antiasthmatic or :
antiulcerative effect or for boosting the effect or ~- .
decreasing the toxicity of agents used in the treatment of cancer or in organ transplants.
The daily dosage can range, for example, from 30 to 300 mg orally and from 25 to 100 mg parenterally.
: ' "
The benzothiazepinones of formula (V) are described in US Patent No. 3,562,257; those of formula (VI) are ~-described in European Patent Applications Nos. 158,339 and 158,340.
The halogenated amine of formula (IV) may be prepared, for example, from the alcohol of formula (III) by the action of a halogenating agent such as thionyl chloride. The amino alcohol of formula (III) can itself be 10 prepared according to any known method, for example from a ~ -~
halogenated derivative of formula (II) and 2-methylaminoethanol. The compounds of formula (II) are ;
accessible from chloroacetyl chloride and amines of general formula RZ-HN-(CH2)n-R3 (in which R2, n and R3 are as ~-15 defined above), which are described in the literature. ~ -The Examples which follow illustrate in detail the ;-preparation of a few compounds according to the invention.
The elemental microanalyses and the IR and NMR spectra ~`~
confirm ths structures of the products obtained. The numbers shown in brackets for each example correspond to those in the table which follows, and which illustrates the structures and physical properties of a few compounds -~
according to the invention. ~ ;
:. .. '' ::.
~`'' .' ' . ' ' ': :~ ', ,~ 2 ~ 2 7 ~ 3 8 Example 1 (Compound No. lL
(+)-cis-(2S,3S)-3-Acetyloxy-2,3-dihydro-5-t2-{[2-(3,4-dimethoxyphenyl)amino-2-oxoethyl](methyl)amino}ethyl]-2-(4-methoxyphenyl)-1,5(5H)-benzothiazepin-4-one.
A mixture of 4 g (9.15 mmol) of (+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-2-(4-methoxyphenyl)-5-(2-methylaminoethyl)-1,5(5H)-benzothiazepin-4-one hydrochloride, 2.4 g (10 mmol) of 1-chloro-N-(3,4-dimethoxyphenyl)acetamide and 9.9 g of potassium carbonate in 50 ml of 2-butanone is heated to reflux for 9 h.
The mixture is filtered, the filtrate is evaporated - and the residue is purified by chromatography on a silica column. 5.3 g of oil are thereby obtained, which oil is taken up with 60 ml of ethanol and treated with 0.81 g of oxalic acid. The precipitate obtained on addition of ether is filtered off and recrystallized in ethanol. 4 g of oxalate are isolated.
M~lting point: 144C t~]20=+59.4 (c=0.5; MeOH).
Example 2 (Compound No. 11) (+)-cis-(2S,3S)-3-Acetyloxy-2,3-dihydro-5-{2-t{2-t(4-methylphenyl)methyl](methyl)amino-2- ;
oxoethyl}(methyl)amino]ethyl}-2-(4-methoxyphenyl)-1,5(5H)-benzothiazepin-4-one.
A mixture of 4 g (9.15 mmol) of (+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-2-(4-methoxyphenyl)-5-(2-methylaminoethyl)-1,5(5H)-benzothiazepin-4-one 2~277~
hydrochloride, 1.85 g (8.73 mmol) of 1-chloro-N-methyl-N-t(4-methylphenyl)m~thyl]acetamide and 6.05 g of potassium carbonate in 50 ml of 2-butanone is heated to reflux for 9 h. The mixture is filtered, the filtrate is evaporated and the residue is purified by chromatography sn a silica column. 3.5 g of oil are thereby obtained, which oil is taken up in ethanol and treated with 1 equivalent of oxalic acid. The precipitate obtained on addition of ether is filtered off and recrystallized in ethanol. 2.5 g of oxalate are isolat4d.
Melting point: 108.3-109.2C [~]20=~71.4 (c=0.3; MeOH).
Exam~le 3 (Com~ound No. 18).
(+)-cis-(2S,3S)-3-Acetyloxy-2,3-dihydro-5-{2-[{2-[2-(3,4-,: :.. ,, ...,~
dimethoxyphenyl)ethyl](methyl)amino-2-oxoethyl}(methyl)amino]ethyl}-2-(4-methoxyphenyl)-1,5(5H)-benzothiazepin-4-one.
A mixture of 3 g (6.7 mmol) of (+)-cis-(2S,3S)-3- --acetyloxy-2,3-dihydro-2-(4-methoxyphenyl)-5-(2-20 methylaminoethyl)-1,5(5H)-benzothiazepin-4-one ---hydrochloride, 2.4 g (8.9 mmol) of 1-chloro-N-methyl-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide and 7 g of potassium carbonate in 50 ml of 2-butanone is heated to reflux for ;
8 h. The mixture is filtered, the filtrate is evaporated ~
25 and the residue is purified by chromatography on a silica ; -column. An oil is obtained, which oil is taken up in ethanol and treated with 1 equivalent of oxalic acid. The `- 2027738 precipitate obtained on addition of ether is filtered off and recrystallized in ethanol. 2 g of oxalate are isolated.
Melting point: 90C [~]20=+52.8 (c=0.5; MeOH).
Exam~le 4 (Compound No. 20).
(+)-cis-(2S,3S)-3-Acetyloxy-2,3-dihydro-5-~2-[{2-t3-(1-imidazolyl)propyl]amino-2-oxoethyl}(methyl)amino~ethyl}-2-(4-methoxyphenyl)-1,5(5H)-benzothiazepin-4-one.
A mixture of 4 g (9.15 mmol) of (+)-cis-(2S,3S)-3-acetyloxy-2,3-dihydro-2-(4-methoxyphenyl)-5-{2-methylaminoethyl)-1,5(5H)-benzothiazepin-4-one hydrochloride, 4 g (19.8 mmol) of 1-chloro-N-t3-(1-imidazolyl)propyl]acetamide and 3.6 g of potassium carbonate in 60 ml of 2-butanone is heated to reflux for 10 h.
The mixture is filtered, the filtrate is evaporated and the residue is purified by chromatography on a silica column. 2 g of oil are thereby obtained, which oil is taken up with 12 ml of ethanol and treated with 0.32 g of oxalic acid. The precipitate obtained on addition of ether is filtered off and recrystallized in ethanol. 1.1 g of oxalate are isolated.
! Melting point: 55C [~]20=+51.3 (c=0.5; MeOH).
D
.
` 2027~3~
g Table ~( ~OR1 O ( I ) H3C ' ~ Z R3 N R 1 F~2 n R3 ¦Salt I ~ ~ D2 0 M . P . (' C ) c(%),MeOH . ..
_ ._ _ _ _ '.'''' '' ''" ' ''' ' 1 1 ~COCH IH ¦D ~ C6H3 4- (OCH3)2 ~03 1 03 ~1 4 ~
~ ~
COCH3 H 0 C6H4- 2 -COc6H5 ox . ~ 9 0 ,1 2 8 5 ¦ 3¦COCH ICH 1 ¦ bH3-3l4-(OC 3)2 lo 1 04 ~1 0 I ~ ¦COC8 ¦N l~j C 3 3 4-(OCH3 2 13 1~34 5 COCH3 CH3 1 C6H4-3-OCH3 ox . ( 0, 3 ) 106 ¦ 6 ¦COCN3¦CN3 ¦~ CbN3-3-cl lox 1 73 ¦ S
7 COCN3 CN~ i C6H3-3 4-(OCH3~2 OX 69 ~ 115 202 ~73~
1 o --Table ( continued ) N 31 R2 n R3 ~ t I ~ 2D M P SOC) 8 COCH3 CH3 1 C6H3-3 4-C12 OX (0 5) 125 9 COCH3 CH3 1 C6H3- 3, 4-(CH3)2 OX (0695)8 92-95 5 11 COCN3 CN3 1 C6N7-3 4-5-lOCN3 3~0 67 5 143 4-1:q,6' 11 COCH3 ICR3 ¦ ~ C6Hq~4~CH3 ;ox. 71; lOH,3-109,2, 12 COCH3 CH3 1 C6H4-4-CF3 OX (O692) 126 2-128 3 13 COCH3 CH3 1 C6N4-4-F OX ~72 8 B6-88 14 COCH3 CH3 1 C6H4-4-OnC4H9 OX (0 2) 87 5-91 5 115 ¦COCH3¦CH3 1 I C6N -q-SCN3 OX ¦-55 l1 B,S 129,5¦
16 COCN3 CH3 2 C6H4- 3-OCH3 OX ~80 4 85 ~ ~ ;
17 COCH3 CH3 2 2-pyridyl ox (0S) B5 15 COCN3 CN3 2 C6H3-3,4-(0CH3)2 CX 52 H90 90 ;
Table (con~luded) -~-~; ~ R2 n R3 Salt [~D20 IM P tc) _ _ c ( % ), MeOH ¦ . - . -9~COC 3 CN3 C6N2-3,4,5-(ocN3 3~ .~65,4 ~I
20 COCH3 H 3 1-imidazolylox. ~51,3 ¦55 21 COCH3 I CH31 C6H4- 4 - OCH3 OX ~ 68 4 i 9 0 5 ~ ~ ( 0 2 ) `
22 COCH3 CHICH ~2 1C6H~-4-CH3 fwn ~91,N 1 1-l23 23 COC 3 CH3 C6N~-4-CO2CH3~f ~ 72,5 129-131 :~
4 COC 3 CH3 C6H~-4-Clf 3n -35 129-130 25 COCH3 CH3 1C6H4-3-~r-4-CH3 ox. (0,2) 119-122 ~:
126lCCN31CH3 ¦~ ¦ C6N4-4-CN ¦fw3¦-73,5 19 27 COCN3 CN3 _ C6H~-4-NO2 f w3 ~76,2 110 1l2 Legends in the "salt" column, ox. denotes an oxalate and fum denotes a fumarate. -202~38 ,~
The compounds of the invention were subjected to a series of pharmacological tests which demonstrated their value as therapeutic substances for the cardiovascular system.
Their activity as calcium antagonists was shown by means of a test on isolated rabbit aorta. The experimental protocol used is a variant of that used by Godfraind and Kaba (1969), (Blockade or reversal of the contraction induced by calcium and adrenaline in depolarized arterial smooth muscle, Br. J.Pharmac., 36, 549-560). The details of the test are described in European Patent No. 0,103,500.
The molar concentration produGing a 50 % relaxation of the response to calcium (EC50), or alternatively its antilogarithm (pEC50), is calculated.
The pEC50 values of the compounds of the invention range from 4.5 to 6.6.
The compounds of the invention were also subjected to a test of binding of [3H]nitrendipine to whole rat ;
cortex. - ~
The details of the test are described in European ~ -Patent Application No. 0,300,865.
.
The IC50 concentrations of the compounds of the . . . -.
invention (concentrations which inhibit 50 % of the ~-specific binding of ~3H]nitrendipine) lie betwesn 0.001 and 10 ~M.
The compounds of the invention were also subjected to a test of inhibition of the specific binding of "PAF", -- ~027~3~ ~
-blood platelet-activating factor, the protocol of which test is described in European Patent Application No.
0,320,362.
The IC50 values (concentrations which inhibit the specific binding by 50 %) of the compounds of the invention in this test lie between 0.5 and 5 ~m.
Finally, the compounds of the invention were subjected to a test of inhibition of blood platelet aggregation induced by "PAF-acether" (1-0-(C16-C18 alkyl)- ~ -2-acetyl-sn-glyceryl-3-phosphorylcholine), the protocol of which test is also described in European Patent Application No. 0,320,362.
The aggregation-inhibitory action of the compounds is expressed by the IC50 concentration, the concentration which inhibits by 50 % the aggregation produced by PAF-acether.
The IC50 values of the compounds of the invention in this test lie between 2 and 20 ~M.
The results of the tests show that the compounds of -20 the invention are calcium antagonists and can, on these -~
grounds, be used for the treatment of various conditions for which this type of agent is indicated.
Thus, in particular, they may be used in cardiovascular medicine for the treatment of conditions requiring modulators of transmembrane and intracellular movements of calcium, most especially hypertension, angina and cardiac arrhythmia.
2 0 2 ~ .~ 3 8 They are, in addition, capable of exhibiting antiatherogenic, cardiac anti-ischaemic, cerebral anti-ischaemic, antimigraine, antiepileptic, antiasthmatic and antiulcerative effects.
In the cardiovascular field, they may be used alone or in combination with other known active substances such as diuretics, B-blockers, angiotensin-converting enzyme inhibitors and ~1-receptor antagonists.
They may also be indicated for boosting the effect 10 or decreasing the toxicity of agents used in the treatment : -of cancer or in organ transplants.
The compounds of the invention may be presented in all forms suitable for oral or parenteral administration, in combination with known excipients, for example in the form of tablets, hard gelatin capsules, dragees, capsules, and solutions or suspensions to be taken by mouth or :;~
injected.
The present invention therefore also provides a -pharmaceutical composition which comprises a compound of formula (I) or a pharmacologically acceptable acid addition salt thereof and a pharamceutical excipient.
The present invention furthermore provides a compound of formula (I) or a pharmacologically acceptable acid addition salt thereof for use in a method of treatment of the human or animal body by therapy, especially for use in a method of treatment of hypertension, angina or cardiac arrhythmia or for treatment of a condition requiring an - ;
'': '''~`
2~ 73~
antiatherogenic, cardiac anti-ischaemic, cerebral anti- .
ischaemic, antimigraine, antiepileptic, antiasthmatic or :
antiulcerative effect or for boosting the effect or ~- .
decreasing the toxicity of agents used in the treatment of cancer or in organ transplants.
The daily dosage can range, for example, from 30 to 300 mg orally and from 25 to 100 mg parenterally.
: ' "
Claims (13)
1. A compound, in the form of a pure diastereoisomer or a mixture thereof, of formula (I) (I) in which R1 represents a hydrogen atom or a C2-C4 alkanoyl group, R2 represents a hydrogen atom or a C1-C4 alkyl group, n represents an integer of from 0 to 3; and R3 represents either a phenyl group bearing from 1 to 3 substituents selected from halogen atoms and trifluoromethyl, methyl, C1-C4 alkoxy or alkylthio, nitro, cyano, carbamoyl, acetamido, methanesulphonamido, methoxycarbonyl or phenylcarbonyl groups, or an aromatic heterocyclic group;
or a pharmacologically acceptable acid addition salt thereof.
or a pharmacologically acceptable acid addition salt thereof.
2. A compound according to claim 1 in which R1 is a -COCH3 group.
3. A compound according to claim 1 in which R2 is a hydrogen atom or a -CH3 or -CH(CH3)2 group.
4. A compound according to claim 1 in which R3 is a pyridyl or imidazolyl group.
5. A compound according to claim 1 in which R3 is a 2-pyridyl, 1-imidazolyl or -C6H3-3,4-(OCH3)2, -C6H4-2-COC6H5, -C6H3-3,4-(OCH3)2, -C6H4-3-OCH3, -C6H3-3-Cl, -C6H3-3,4-Cl2, -C6H3-3,4-(CH3)2, -C6H2-3,4,5-(OCH3)3, -C6H4-4-CH3, -C6H4-4-CF3, -C6H4-4-F, -C6H4-4-OnC4H9, - C6H4-4-SCH3, -C6H4-4-OCH3, -C6H4-4-CO2CH3, -C6H4-4-Cl, -C6H4-3-Br-4-CH3, -C6H4-4-CN or -C6H4-4-NO2 group.
6. A compound according to claim 1 which is in the form of an oxalate or fumarate salt.
7. A compound according to claim 1 specifically identified herein.
8. A process for preparing a compound as defined in claim 1 wherein a benzothiazepinone of formula (VI) (VI) in which R1 is as defined in claim 1 is reacted with a compound of formula (II) (II) in which R2 and R3 are as defined in claim 1 and Y
represents a halogen atom.
represents a halogen atom.
9. A process for the preparation of a compound as defined in claim 1 substantially as described in any one of the Examples.
10. A pharmaceutical composition which comprises a compound as defined in claim 1 and a pharmaceutical excipient.
11. A compound as defined in claim 1 for use in a method of treatment of the human or animal body by therapy.
12. A compound as defined in claim 1 for use in a method of treatment of hypertension, angina or cardiac arrhythmia or for treatment of a condition requiring an antiatherogenic, cardiac anti-ischaemic, cerebral anti-ischaemic, antimigraine, antiepileptic, antiasthmatic or antiulcerative effect or for boosting the effect or decreasing the toxicity of agents used in the treatment of cancer or in organ transplants.
13. Use of a compound as defined in claim 1 in the manufacture of a medicament for the treatment of hypertension, angina or cardiac arrhythmia or for treatment of a condition requiring an antiatherogenic, cardiac anti-ischaemic, cerebral anti-ischaemic, antimigraine, antiepileptic, antiasthmatic or antiulcerative effect or for boosting the effect or decreasing the toxicity of agents used in the treatment of cancer or in organ transplants.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR89.13540 | 1989-10-17 | ||
| FR8913540A FR2653122B1 (en) | 1989-10-17 | 1989-10-17 | DERIVATIVES OF 5- [2 - [[2-AMINO-2-OXOETHYL] METHYLAMINO] ETHYL] -2,3-DIHYDRO-3-HYDROXY-2- (4-METHOXYPHENYL) -1.5 (5H) -BENZOTHIAZEPINE-4 -ONE, THEIR PREPARATION AND THEIR APPLICATION IN THERAPEUTICS. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2027738A1 true CA2027738A1 (en) | 1991-04-18 |
Family
ID=9386468
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002027738A Abandoned CA2027738A1 (en) | 1989-10-17 | 1990-10-16 | 5-{2-[(2-amino-2-oxoethyl) (methyl)amino]ethyl}-2,3-dihydro-3-hydroxy-2-(4-methoxyphen yl)-1,5(5h)-benzothiazepin-4-one derivatives, their preparation and their application in therapy |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0424214A1 (en) |
| JP (1) | JPH03133970A (en) |
| KR (1) | KR910007901A (en) |
| AU (1) | AU6479690A (en) |
| CA (1) | CA2027738A1 (en) |
| FI (1) | FI905089A0 (en) |
| FR (1) | FR2653122B1 (en) |
| HU (1) | HUT57754A (en) |
| IE (1) | IE903720A1 (en) |
| IL (1) | IL95931A0 (en) |
| NO (1) | NO904470L (en) |
| NZ (1) | NZ235717A (en) |
| PT (1) | PT95606A (en) |
| ZA (1) | ZA908267B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69411387T2 (en) * | 1994-09-16 | 1999-02-25 | Orion Corp. FERMION, Espoo | Process for the preparation of pharmaceutically active benzothiazepine derivatives. |
| WO2005035505A2 (en) * | 2003-09-30 | 2005-04-21 | Artesian Therapeutics, Inc. | Compounds with phosphodiesterase inhibiting and calcium channel blocking activities |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH538492A (en) * | 1970-10-07 | 1973-06-30 | Hoffmann La Roche | Process for the preparation of benzodiazepine derivatives |
| FR2624117B1 (en) * | 1987-12-08 | 1991-02-22 | Synthelabo | HYDROXY-3 (METHOXY-4 PHENYL) -2 (METHYLAMINO-2 ETHYL) -5 DIHYDRO-2,3 5H-BENZOTHIAZEPINE-1,5 ONE-4 DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| FR2630109B1 (en) * | 1988-04-19 | 1991-11-29 | Synthelabo | DERIVATIVES OF ((N- (2-AMINO-2 OXO-2 ETHYL) METHYLAMINO) -2 ETHYL) -5 HYDROXY-3 (METHOXY-4 PHENYL) -2 DIHYDRO-2,3 5H-BENZOTHIAZEPINE-1,5 ONE-4, THEIR PREPARATION AND THEIR APPLICATION IN THERAPEUTICS |
-
1989
- 1989-10-17 FR FR8913540A patent/FR2653122B1/en not_active Expired - Fee Related
-
1990
- 1990-10-10 EP EP90402820A patent/EP0424214A1/en not_active Withdrawn
- 1990-10-16 NZ NZ235717A patent/NZ235717A/en unknown
- 1990-10-16 IE IE372090A patent/IE903720A1/en unknown
- 1990-10-16 JP JP2278828A patent/JPH03133970A/en active Pending
- 1990-10-16 KR KR1019900016471A patent/KR910007901A/en not_active Application Discontinuation
- 1990-10-16 ZA ZA908267A patent/ZA908267B/en unknown
- 1990-10-16 PT PT95606A patent/PT95606A/en not_active Application Discontinuation
- 1990-10-16 IL IL95931A patent/IL95931A0/en unknown
- 1990-10-16 CA CA002027738A patent/CA2027738A1/en not_active Abandoned
- 1990-10-16 NO NO90904470A patent/NO904470L/en unknown
- 1990-10-16 HU HU906466A patent/HUT57754A/en unknown
- 1990-10-16 AU AU64796/90A patent/AU6479690A/en not_active Abandoned
- 1990-10-16 FI FI905089A patent/FI905089A0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| IL95931A0 (en) | 1991-07-18 |
| NO904470L (en) | 1991-04-18 |
| NO904470D0 (en) | 1990-10-16 |
| FR2653122A1 (en) | 1991-04-19 |
| JPH03133970A (en) | 1991-06-07 |
| HUT57754A (en) | 1991-12-30 |
| EP0424214A1 (en) | 1991-04-24 |
| AU6479690A (en) | 1991-07-11 |
| HU906466D0 (en) | 1991-04-29 |
| FR2653122B1 (en) | 1994-04-15 |
| FI905089A0 (en) | 1990-10-16 |
| ZA908267B (en) | 1991-08-28 |
| PT95606A (en) | 1991-09-13 |
| IE903720A1 (en) | 1991-04-24 |
| NZ235717A (en) | 1991-12-23 |
| KR910007901A (en) | 1991-05-30 |
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