CA1320198C - Condensed diazepinones, processes for preparing them and pharmaceutical compositions containing these compounds - Google Patents
Condensed diazepinones, processes for preparing them and pharmaceutical compositions containing these compoundsInfo
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- CA1320198C CA1320198C CA000601877A CA601877A CA1320198C CA 1320198 C CA1320198 C CA 1320198C CA 000601877 A CA000601877 A CA 000601877A CA 601877 A CA601877 A CA 601877A CA 1320198 C CA1320198 C CA 1320198C
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
Condensed Diazepinones Abstract The invention relates to condensed diazepinones of formula I
(I) wherein represents one of the groups (S) (T) (U) (V) (W) Xl and x2 each represents a methine group or, when represents a group (S),(U) or (W), Xl and X2 may alternatively be nitrogen atoms, A represents a C16 alkylene group, R1 and R2 represent lower alkyl groups or R1 and R2 together with the intervening nitrogen atom also represent a saturated 4- to 7-membered heteroaliphatic ring, R3 represents lower alkyl or hydrogen or chlorine, R4 and R10 each represents a hydrogen atom or a methyl group, R5 and R6 each represents a hydrogen, fluoride, chlorine or bromine .
atom or a lower alkyl group, R7 represents a hydrogen or chlorine atom or a methyl group and R8 and R9 each represents a hydrogen atom or a lower alkyl group and R9 may also represent a halogen atom.
These compounds are suitable for treating bradycardia and bradyarrhythmia.
(I) wherein represents one of the groups (S) (T) (U) (V) (W) Xl and x2 each represents a methine group or, when represents a group (S),(U) or (W), Xl and X2 may alternatively be nitrogen atoms, A represents a C16 alkylene group, R1 and R2 represent lower alkyl groups or R1 and R2 together with the intervening nitrogen atom also represent a saturated 4- to 7-membered heteroaliphatic ring, R3 represents lower alkyl or hydrogen or chlorine, R4 and R10 each represents a hydrogen atom or a methyl group, R5 and R6 each represents a hydrogen, fluoride, chlorine or bromine .
atom or a lower alkyl group, R7 represents a hydrogen or chlorine atom or a methyl group and R8 and R9 each represents a hydrogen atom or a lower alkyl group and R9 may also represent a halogen atom.
These compounds are suitable for treating bradycardia and bradyarrhythmia.
Description
~32~8 Condensed Diazepinones The invention relates to certain new condensed diazepinones, processes for preparing them and pharmaceutical compositions containing these compounds.
Condensed diazepinones with the properties of inhibiting both ulcer formation and the secretion of gastric acid are descrlbed in EP-A-39519, EP-~-57428, US-A-3660330, US-A-3691159, US-A-4213984, US-A-4213985, US-A-4210648, US-A-4410527, US-A-4424225, US-A-4424222 and lo US-A-4424226.
EP-A-156191 describes how the introduction of certain aminoacyl groups may lead to valuable pharmacological properties completely different fxom those of the compounds disclosed in the above-mentioned publications.
We have now found that certain new condensed diazepinones, comparad with the compounds of EP-A-156191, are distinguished by a substantially increased activity and marked resistance to hydrolysis, whilst having comparable or better ~electivity and resorption after oral administration.
Thus, viewed from one aspect the invention provides a compound of formula I
R3 ~l N -4 ~ xi ~ ~ ? (I~
~ 30 f o M
( ~ A N \ 2 ,,lherein ) ~ represents one of the groups (S), (T), (U), (V) and (W) 2 ~ 3 ~ 8 5 ~ ~ R7 ~ lO
(S) (T) (U) (V) (W) X1 and x2 each represents a methi~e group or, where represents a group (S), (U) or (W), both or either o~ X
and x2 may alternatively represan~ a nitrogen atom;
A repres~nts a straight-chained Cl-6 alkylene group;
R1 and R2, which may be the same or different, each represents a Cl6 alkyl group or R1 and R~ together with the intervening nitrogen atom represent a 4- to 7-membered, saturated, monocyclic, heteroaliphatic ringoptionally interrupted by an oxygen atom or by a,N-CH3 group;
R3 represents a C14 alkyl group or a chlorine or hydrogen atom;
R4 represents a hydrogen atom or a methyl group;
R5 and R6, whlch may be the same or different, each :30 represents a hydrogen, fluorine, chlorine or bromine atom or a C~4 alkyl group;
R represents a hydrogen or chlorine atom or a methyl group:; :~
: :
: : R8 represents a hydrogen atom or a C14alkyl group;
: R3 represonts a hydrogen or halogen atom or a C14 al~yl ,, ' .
~3~01~8 group;
Rl represents a hydrogen atom or a methyl group; and Z represents a single bond, an oxygen or sulphur atom or a methylene or 1,2-ethylene group; with the proviso that where ) ~ represents a group (T) and R7 represents a hydrogen atom, then R3 represents a hydrogen atom or a Cl4 alkyl group and Z represents other than a sulphur atom) or an isomer or acid addition salt thereof.
Preferred compounds according to the invention include compounds of formula I wherein:
Xl represents a methine group;
X2 represents a nitrogen atom, ~ ~ represents a group S, R3, R4 and R5 represent hydrogen atoms and R6 represents a hydrogen atom or a chlorine or bromine atom or a methyl or ethyl group in the 8- or 9- position or the tricyclic moiety, or X2 represents a methine group, ~ ~ represents a group (V) or (U), R3 represents a hydrogen atom and R9 represents a methyl group;
A represents an unbranched, saturated Cl5 alkylene group;
Rl and R2, which may be the same or different, each represents a Cl~ alkyl group or Rl and R2 together with ; the intervening nit ogen atom represent a 4- to 7-membered, saturated, monocyclic, heteroaliphatic ring optionally interrupted by an oxygen atom or a N-CH3 : 35 group; and Z represents a single bondj an oxygen atom or a merhylene or 1,2-ethylene group/
' ' -~ . ` ' . ':' '. ~ ' .
4 1 ~ 2 ~ 1 ~ 8 and isomers and salts, especially physiologically acceptable acid addition salts, thereof.
Particularly preferred compounds according to the invention include compounds of formula I wherein:
Xl represents a methine group;
x2 represents a nitrogen atom, ~ ~ represents a divalent group (S), R3, R4 and R5 represent hydrogen atoms and R6 represents a hydrogen atom or a chlorine or bromine atom or a methyl or ethyl group in the 8- or 9-position of the tricyclic moeity;
lS
A represents an unbranched, saturated Cl5 alkylene group;
Rl and R2, which may be the same or different, each represents a Cl5 alkyl yroup or Rl and R2 together with the intervening nitrogen atom represent a 5- to 7-membered, saturated, monocyclic, heteroaliphatic ring optionally interrupted by an oxygen atom or a N-CH3 group; and Z represents a single bond, an oxygen atom or a methylene or 1,2-ethylene group;
and isomers and salts thereof.
The compounds of formula I, after reaction with : inorganic or organic acids, may be converted into their physiologically acceptable salts. Examples of acids which have proved suitable are hydrochloric, hydrobromic, sulphuric, methylsulphuric, phosphoric, tartaric, fumaric, citric, maleic, succinic, gluconic, malic, p~toluenesulphonic, methanesulphonic, amidosulphonic and cyclohexanesulphaminis acids.
,': , ' :
"' ~32019g The follo~ing compounds will be mentioned by way o~
example to illustrate the invention:
~ 4-[2-[(diethylamino)methyl]-1-piperidinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b]~1,4]
benzodiazepin-6-one;
D,L-5,11-dihydro-11-[4-[2-[(dimethylamino)methyl]-1-piperidinyl]-l-oxobutyl]-6H-pyrido[~,3-b][1,4]
benzodiazepin-6-one;
5,11-dihydro-11-[4-[2-[(ethylmethylamino)methyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-bJ[1,4]
benzodiazepinw6-one;
5,11-dihydro-11-[4-[2-[(dipropylamino)methyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
11-[4 [2-[(diethylamino)methyl]-1-pyrrolidinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
11-~4-[2-[(diethylamino)methyl]-1-azetidinyl]-l~
oxobutyl]-5,11-dihydro-6H-pyridoC2,3-b][1,4]
benzodiazepin-6-one;
D,L-11-[4-[2-[2-(diethylamino)ethyl]-1-piperidinyl]-1-oxobutyl]-5,11-dihydro 6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one, D,L-5,11-dihydro-11-[4-[2-[2-(4-morpholinyl)ethyl]-1-piperidinyl]-1-oxobutyl]-6H pyrido[2,3-b][1,4]
benzodiazepin-6-one, 5,11-dlhydro-11 [4-~2-[2-(hexahydro-lH-l-azepinyl)ethyl]-l-piperidinyl]-l-oxobutyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one;
6 ~ 32~19~
5,11-dihydro-11-~4-[2-~2-(dimethylamino)e'chyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
D,L-11-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
D-11-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
L-11-[4-[3-~(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
11-[4-[2-[(diethylamino)mathyl]-1-piperidinyl]-1-oxobutyl]-5,11-dihydro-9-methyl-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
11-[4-[2-[(diethylamino)methyl]-1-piperidinyl]-1-oxobutyl]-5,11 dihydro-8-methyl-6H-pyrido[2,3-b][1,4]
benzodiaæepin-6-one;
11-[4-[3-[tdiethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-8-ethyl-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
9-chloro-11-[4-l3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][1,~]
bPnzodiazepin-6-one;
8-bromo-11-[4-[2-[(diethylamino)methyl]-1-piperidinyl]-1-oxobutyl]-5,11-dihydro~6H-pyrido[2,3-b][l,~]
benzodiazepin-6-one methanesulphonate;
[4-[2-~(1 azetidinyl)methyl]-1-piperidinyl]-1-oxobutyl]-5,11-dihydro-6~-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
11-[4-[4-~3-(diethylamino)propyl]-1-piperidinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b]tl,4]
benæodiazepin-6-one;
5,11-dihydro-11-[4-[2-[(1--pyrrolidinyl)methyl]-1-piperidinyl]-l-oxobutyl]-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
5,11_dihydro-11-[4-[4-[4 (1-pyrrolidinyl)butyl]-1-piperidinyl]-l-oxobutyl]-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
11-[4-~3-[4-(diethylamino)butyl]-1-piperidinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
5,11-dihydro-11-~4-[3-[2-(1-pyrrolidinyl)ethyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido~2,3-b][1,4]
benzodiazepin-6-one, 5,11-dihydro~ [4~[3-[4-(1-pyrrolidinyl)butyl]-1-piperidinyl]-l-oxobutyl]-6H-pyrido[2,3-b][1,4]
banzodiazepin-6-one;
11-[4-[3-[2-(diethylamino)ethyl]-hexahydro-lH-l-azepinyl]-1-oxobutylJ-5,11-dihydro-6H-pyrido~2,3-b][1,4]
benzodiazepin-6-one;
11-[4-[2-~(diethylamino)methyl]-1-piperidinyl]-1-~ oxobutyl]-6 J 11-dihydro-5H-pyrido[2,3-b][1,5]
: benzodiazepin-5-one;
1l-[4-[2-[2-(diethylamino)ethyl]-l-plperidinyl]
oxobutyl]-6,11-dihydro-5H-pyrido[2,3-b][1,5]
benzodiazepin-5-one;
,,. ,., ,, - - :
8 1~2~19~
11-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-6,11-dihydro-5H-pyridoC2,3-b][1,5]
benzodiazepin-5-one;
11-[4-C4-~3-(diethylamino)propyl]-l-piperidinyl]-1-oxobutyl]-6,11-dihydro-5H-pyrido[2,3-b][1,5]
benzodiazepin-5-one;
11~[4-[3-[4-(diethylamino)butyl]-1-piperidinyl]-1-oxobutyl]-6,11-dihydro-5H-pyrido[2,3-b]C1,5]
benzodiazepin-5-one;
5-[4-[3-C2-(diethylamino)ethyl]-hexahydro-lH-l-azepinyl]
-l-oxobutyl]-5,10-dihydro-llH-dibenzo[b,e]C1,4]
diazepin-ll one;
5-[4-C2-[~diethylamino)methyl]-l-piperidinyl]-1-oxobutyl]-5,10-dihydro-llH-dibenzo[b,e][1,4]
diazepin-ll-one;
5-[4-[2-[2-~diethylamino)ethyl]-1-piperidinyl]-1-oxobutyl]-5,10~dihydro-llH-dibenzo[b,e][1,4]diazepin-11-one;
5-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,10-dlhydro-llH-dibenzo[b,e][1,4]diazepin-11-one;
5-[4-t4-[3-(diethylamino)propyl]-1-piperidinyl]-1-oxobutyl]-5,10-dihydro-llH-dibenzo[b,e][1,4]diazepin-11-one;
5-[4-~3-[4-(diethylamino)butyl]-1-piperidinyl]-l-oxobutyl]-5,10-dihydro-llH dibenzo[b,e][l,4]diazepin-11-one;
4,9-dihydro-3-methyl-4-[4-[3-[2-(l~piperidinyl)ethyl-hexahydro~lH-l-azepinyl] l-oxobutyl]-lOH-thieno[3,4 132~198 b][1,5]benzodiazepln-10-one;
4,9-dihydro-3-methyl-4-[4-~2-[(1-piperidinyl)methyl]-1-piperidinyl] l-oxobutyl]-lOH-thieno[3,4-b][1,5~benzo-diazepin-10-one;
4,9-dihydro-3-methyl-4-[4~[2-[2-(1-piperidinyl)ethyl]-1-piperidinyl]-1-oxobutyl]-lOH-thieno[3,4-b][1,5]benzo-diazepin-10-one;
4,9-dihydro-3-methyl-4-[4-[3-[(1-piperidinyl)methyl]-4-morpholinyl]-1-oxobutyl]-lOH-thieno[3,4-b]tl,5]benzo-diazepin-10-one;.
Condensed diazepinones with the properties of inhibiting both ulcer formation and the secretion of gastric acid are descrlbed in EP-A-39519, EP-~-57428, US-A-3660330, US-A-3691159, US-A-4213984, US-A-4213985, US-A-4210648, US-A-4410527, US-A-4424225, US-A-4424222 and lo US-A-4424226.
EP-A-156191 describes how the introduction of certain aminoacyl groups may lead to valuable pharmacological properties completely different fxom those of the compounds disclosed in the above-mentioned publications.
We have now found that certain new condensed diazepinones, comparad with the compounds of EP-A-156191, are distinguished by a substantially increased activity and marked resistance to hydrolysis, whilst having comparable or better ~electivity and resorption after oral administration.
Thus, viewed from one aspect the invention provides a compound of formula I
R3 ~l N -4 ~ xi ~ ~ ? (I~
~ 30 f o M
( ~ A N \ 2 ,,lherein ) ~ represents one of the groups (S), (T), (U), (V) and (W) 2 ~ 3 ~ 8 5 ~ ~ R7 ~ lO
(S) (T) (U) (V) (W) X1 and x2 each represents a methi~e group or, where represents a group (S), (U) or (W), both or either o~ X
and x2 may alternatively represan~ a nitrogen atom;
A repres~nts a straight-chained Cl-6 alkylene group;
R1 and R2, which may be the same or different, each represents a Cl6 alkyl group or R1 and R~ together with the intervening nitrogen atom represent a 4- to 7-membered, saturated, monocyclic, heteroaliphatic ringoptionally interrupted by an oxygen atom or by a,N-CH3 group;
R3 represents a C14 alkyl group or a chlorine or hydrogen atom;
R4 represents a hydrogen atom or a methyl group;
R5 and R6, whlch may be the same or different, each :30 represents a hydrogen, fluorine, chlorine or bromine atom or a C~4 alkyl group;
R represents a hydrogen or chlorine atom or a methyl group:; :~
: :
: : R8 represents a hydrogen atom or a C14alkyl group;
: R3 represonts a hydrogen or halogen atom or a C14 al~yl ,, ' .
~3~01~8 group;
Rl represents a hydrogen atom or a methyl group; and Z represents a single bond, an oxygen or sulphur atom or a methylene or 1,2-ethylene group; with the proviso that where ) ~ represents a group (T) and R7 represents a hydrogen atom, then R3 represents a hydrogen atom or a Cl4 alkyl group and Z represents other than a sulphur atom) or an isomer or acid addition salt thereof.
Preferred compounds according to the invention include compounds of formula I wherein:
Xl represents a methine group;
X2 represents a nitrogen atom, ~ ~ represents a group S, R3, R4 and R5 represent hydrogen atoms and R6 represents a hydrogen atom or a chlorine or bromine atom or a methyl or ethyl group in the 8- or 9- position or the tricyclic moiety, or X2 represents a methine group, ~ ~ represents a group (V) or (U), R3 represents a hydrogen atom and R9 represents a methyl group;
A represents an unbranched, saturated Cl5 alkylene group;
Rl and R2, which may be the same or different, each represents a Cl~ alkyl group or Rl and R2 together with ; the intervening nit ogen atom represent a 4- to 7-membered, saturated, monocyclic, heteroaliphatic ring optionally interrupted by an oxygen atom or a N-CH3 : 35 group; and Z represents a single bondj an oxygen atom or a merhylene or 1,2-ethylene group/
' ' -~ . ` ' . ':' '. ~ ' .
4 1 ~ 2 ~ 1 ~ 8 and isomers and salts, especially physiologically acceptable acid addition salts, thereof.
Particularly preferred compounds according to the invention include compounds of formula I wherein:
Xl represents a methine group;
x2 represents a nitrogen atom, ~ ~ represents a divalent group (S), R3, R4 and R5 represent hydrogen atoms and R6 represents a hydrogen atom or a chlorine or bromine atom or a methyl or ethyl group in the 8- or 9-position of the tricyclic moeity;
lS
A represents an unbranched, saturated Cl5 alkylene group;
Rl and R2, which may be the same or different, each represents a Cl5 alkyl yroup or Rl and R2 together with the intervening nitrogen atom represent a 5- to 7-membered, saturated, monocyclic, heteroaliphatic ring optionally interrupted by an oxygen atom or a N-CH3 group; and Z represents a single bond, an oxygen atom or a methylene or 1,2-ethylene group;
and isomers and salts thereof.
The compounds of formula I, after reaction with : inorganic or organic acids, may be converted into their physiologically acceptable salts. Examples of acids which have proved suitable are hydrochloric, hydrobromic, sulphuric, methylsulphuric, phosphoric, tartaric, fumaric, citric, maleic, succinic, gluconic, malic, p~toluenesulphonic, methanesulphonic, amidosulphonic and cyclohexanesulphaminis acids.
,': , ' :
"' ~32019g The follo~ing compounds will be mentioned by way o~
example to illustrate the invention:
~ 4-[2-[(diethylamino)methyl]-1-piperidinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b]~1,4]
benzodiazepin-6-one;
D,L-5,11-dihydro-11-[4-[2-[(dimethylamino)methyl]-1-piperidinyl]-l-oxobutyl]-6H-pyrido[~,3-b][1,4]
benzodiazepin-6-one;
5,11-dihydro-11-[4-[2-[(ethylmethylamino)methyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-bJ[1,4]
benzodiazepinw6-one;
5,11-dihydro-11-[4-[2-[(dipropylamino)methyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
11-[4 [2-[(diethylamino)methyl]-1-pyrrolidinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
11-~4-[2-[(diethylamino)methyl]-1-azetidinyl]-l~
oxobutyl]-5,11-dihydro-6H-pyridoC2,3-b][1,4]
benzodiazepin-6-one;
D,L-11-[4-[2-[2-(diethylamino)ethyl]-1-piperidinyl]-1-oxobutyl]-5,11-dihydro 6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one, D,L-5,11-dihydro-11-[4-[2-[2-(4-morpholinyl)ethyl]-1-piperidinyl]-1-oxobutyl]-6H pyrido[2,3-b][1,4]
benzodiazepin-6-one, 5,11-dlhydro-11 [4-~2-[2-(hexahydro-lH-l-azepinyl)ethyl]-l-piperidinyl]-l-oxobutyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one;
6 ~ 32~19~
5,11-dihydro-11-~4-[2-~2-(dimethylamino)e'chyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
D,L-11-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
D-11-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
L-11-[4-[3-~(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
11-[4-[2-[(diethylamino)mathyl]-1-piperidinyl]-1-oxobutyl]-5,11-dihydro-9-methyl-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
11-[4-[2-[(diethylamino)methyl]-1-piperidinyl]-1-oxobutyl]-5,11 dihydro-8-methyl-6H-pyrido[2,3-b][1,4]
benzodiaæepin-6-one;
11-[4-[3-[tdiethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-8-ethyl-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
9-chloro-11-[4-l3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][1,~]
bPnzodiazepin-6-one;
8-bromo-11-[4-[2-[(diethylamino)methyl]-1-piperidinyl]-1-oxobutyl]-5,11-dihydro~6H-pyrido[2,3-b][l,~]
benzodiazepin-6-one methanesulphonate;
[4-[2-~(1 azetidinyl)methyl]-1-piperidinyl]-1-oxobutyl]-5,11-dihydro-6~-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
11-[4-[4-~3-(diethylamino)propyl]-1-piperidinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b]tl,4]
benæodiazepin-6-one;
5,11-dihydro-11-[4-[2-[(1--pyrrolidinyl)methyl]-1-piperidinyl]-l-oxobutyl]-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
5,11_dihydro-11-[4-[4-[4 (1-pyrrolidinyl)butyl]-1-piperidinyl]-l-oxobutyl]-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
11-[4-~3-[4-(diethylamino)butyl]-1-piperidinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]
benzodiazepin-6-one;
5,11-dihydro-11-~4-[3-[2-(1-pyrrolidinyl)ethyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido~2,3-b][1,4]
benzodiazepin-6-one, 5,11-dihydro~ [4~[3-[4-(1-pyrrolidinyl)butyl]-1-piperidinyl]-l-oxobutyl]-6H-pyrido[2,3-b][1,4]
banzodiazepin-6-one;
11-[4-[3-[2-(diethylamino)ethyl]-hexahydro-lH-l-azepinyl]-1-oxobutylJ-5,11-dihydro-6H-pyrido~2,3-b][1,4]
benzodiazepin-6-one;
11-[4-[2-~(diethylamino)methyl]-1-piperidinyl]-1-~ oxobutyl]-6 J 11-dihydro-5H-pyrido[2,3-b][1,5]
: benzodiazepin-5-one;
1l-[4-[2-[2-(diethylamino)ethyl]-l-plperidinyl]
oxobutyl]-6,11-dihydro-5H-pyrido[2,3-b][1,5]
benzodiazepin-5-one;
,,. ,., ,, - - :
8 1~2~19~
11-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-6,11-dihydro-5H-pyridoC2,3-b][1,5]
benzodiazepin-5-one;
11-[4-C4-~3-(diethylamino)propyl]-l-piperidinyl]-1-oxobutyl]-6,11-dihydro-5H-pyrido[2,3-b][1,5]
benzodiazepin-5-one;
11~[4-[3-[4-(diethylamino)butyl]-1-piperidinyl]-1-oxobutyl]-6,11-dihydro-5H-pyrido[2,3-b]C1,5]
benzodiazepin-5-one;
5-[4-[3-C2-(diethylamino)ethyl]-hexahydro-lH-l-azepinyl]
-l-oxobutyl]-5,10-dihydro-llH-dibenzo[b,e]C1,4]
diazepin-ll one;
5-[4-C2-[~diethylamino)methyl]-l-piperidinyl]-1-oxobutyl]-5,10-dihydro-llH-dibenzo[b,e][1,4]
diazepin-ll-one;
5-[4-[2-[2-~diethylamino)ethyl]-1-piperidinyl]-1-oxobutyl]-5,10~dihydro-llH-dibenzo[b,e][1,4]diazepin-11-one;
5-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,10-dlhydro-llH-dibenzo[b,e][1,4]diazepin-11-one;
5-[4-t4-[3-(diethylamino)propyl]-1-piperidinyl]-1-oxobutyl]-5,10-dihydro-llH-dibenzo[b,e][1,4]diazepin-11-one;
5-[4-~3-[4-(diethylamino)butyl]-1-piperidinyl]-l-oxobutyl]-5,10-dihydro-llH dibenzo[b,e][l,4]diazepin-11-one;
4,9-dihydro-3-methyl-4-[4-[3-[2-(l~piperidinyl)ethyl-hexahydro~lH-l-azepinyl] l-oxobutyl]-lOH-thieno[3,4 132~198 b][1,5]benzodiazepln-10-one;
4,9-dihydro-3-methyl-4-[4-~2-[(1-piperidinyl)methyl]-1-piperidinyl] l-oxobutyl]-lOH-thieno[3,4-b][1,5~benzo-diazepin-10-one;
4,9-dihydro-3-methyl-4-[4~[2-[2-(1-piperidinyl)ethyl]-1-piperidinyl]-1-oxobutyl]-lOH-thieno[3,4-b][1,5]benzo-diazepin-10-one;
4,9-dihydro-3-methyl-4-[4-[3-[(1-piperidinyl)methyl]-4-morpholinyl]-1-oxobutyl]-lOH-thieno[3,4-b]tl,5]benzo-diazepin-10-one;.
3-chloro-4,9-dihydro~4-[4-[3-~ piperidinyl)methyl]-4-morpholinyl]-l-oxobutyl]-lOH-thieno[3,4b][1,5]benzo-diazepin-10-one;
~,9-dihydro-4-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-1,3-dimethyl-lOH-thieno-[3,4-b][1,5]benzodiazepin-10-one;
~,9-dihydro-4-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-1,3-dimethyl-lOH-thieno-[3,4-b][1,5]benzodiazepin-10-one;
4,9-dihydro-3-methyl-4-~4-[4-[3-(1-piperidinyl)propyl]-l-piperidinyl]-l~oxobutyl]-lOH-thieno[3,4-b][1,5]benzo-diazepin-10-one;
4,9-dihydro-3-methyl-4-[4-[3-[(4-(1-piperidinyl)butyl]-1-piperidinyl]-1-oxobutyl]-lOH-thieno[3,4-b][1,5]benzo-diazepin-10-ona;
1,3~dimethyl-4-[4-[3-~(1-piperidinyl)methyl~-4-morpholinyl]-1-oxobutyl]-1,4,9,10-tetrahydropyrrolo-[3,2-b][1,5]benzodiazepin-10-one;
3-chloro-1-methyl-4-[4-[3 [(1-piperidinyl)methyl]-4-: morpholinyl]-l-o~obutyl]-1,4,9,10-tetrahydropyrrolo-[3,2-b][1,5]benzodiazepin-10-one;
lO ~320198 1-methyl-4-[4-[2-[2-(1-piperidinyl)ethyl]-4-morpholinyl]-1-oxobutyl] 1,4,9,10-tetrahydropyrrolo-[3,2-b~[1,5]benzodiazepin-10-one;
-1-methyl-4-[4-[3-[4-(1-piperidinyl)butyl]-1-piperidinyl]-1-oxobutyl]-1,4,9,10-tetrahydropyrrolo-[3,2-b][1,5]benzodiazepin-10-one;
1,3 dimethyl-4-~4 [3-[(1-piperidinyl)methyl]-4-morpholinyl]-1-oxobutyl]-1,4,9,10-tetrahydropyrazolo-~4,3-b]~1,5]benzodiazepin-10-one;
1 methyl-4-[4-[3-[(1-piperidinyl)methyl~-4-morpholinyl]-1-oxobutyl]-1,4,9,10-tetrahydropyrazolo[4,3-b]~1,5]-benzodiazepin-10-one;
1,3-dimèthyl-4-[4-[3-[4~ piperidinyl)butyl]-1-.
piperidinyl]-1-oxobutyl]-1,4,9,10-tetrahydropyrazolo-[4,3-b][1,5]benzodiazepin-10-one; and 1-methyl-4-[4-[2-[2~ piperidinyl)ethyl]-4-morpholinyl]-l-oxobutyl]-1,4,9,10-tetrahydropyrazolo-[4,3-b][l,S]benzodiazepin-10-one.
Viewed from another aspect, the invention provides a process for the preparation of the compounds according to the invention, said process comprising at least one of the following steps:
_ .
(a) (to prepare compounds of formula Ia R4 ~ ~ N ~ (Ia) ~: r' ~ ~ A - N \ 2 , ~ :
(wherein R1, RZ, R3, R4, Xl, XZ, A and Z are as hereinbe~ore defined and ~ ~ represents a group (S), (U), (V) or ~W) as hereinbefore defined or a group (T') (T') 7' R
wherein R7' represents a chlorine atom or a methyl ~roup)) reacting a compound of formula II
~ } ~ U (II) Hal (wherein R3, R4, ~ ~ , X1 and x2 are as hereinbefore defined and Hal represents a chlorine, bromine or iodine atom) with a compound of formula III
1 Rl ~ ~ A - N - (III) 12 1 3 2 01 ~ 8 (wherein Rl, R2, A and Z are as hereinbefore dPfined);
(b) (to prepare compounds of formula Ia as hereinbefore defined) reacting a compound of formula IV
~ ~ ~ (IV) R
H
(wherein R3, R4, Xl, x2 and ~ ~ are as hereinbefore defined) with a carboxylic acid derivative of formula V
Nu ~ 0 (V) N` / Rl~
L A - N
~ Z~ \ R2.
(wherein Rl, R2, A and Z are as hereinbefore defined and Nu represents a nucleofugic group or a leaving group);
(c) (to prepare compounds of formula Ib, ,~X~
4 X R7 (I~) : ~ O
: ~ R ' : ~ N~
_ _ A - N
~ ~ \ R2~
Z
,' ' ' ' .
~ 13 ~32019~
(wherein Rl, R2, R4, Xl, X~ and A are as hereinbefore defined, Z
represents a single bond, an oxygen atom or a methylene or 1,2-ethylene group, R3' represents a C14 alkyl group or a hydrogen atom, and R7 represents a hydrogen atom)), hydrogenolysing a compound of formula Ib wherein R7 represents a chlorine atom;
td) converting a compound of formula I into an acid addition salt thereof or converting an acid addition salt of a compound of formula 1 into a free base or another salt, e.g. a pharmacologically acceptable acid addition salt;
(e) separating a compound of formula I into the enantiomers and/or diastereomers thereof.
The amination of step (a) is conveniently carried out in an inert solvent, at temperatures of between -10C and the boiling temperature of the solvent, preferably either with at least 2 moles of a secondary amine of formula III per mole of the haloacyl compound of formula II or with 1 to 2 moles of a secondary amine of formula III and an auxiliary base. Examples of suitable solvents include chlorinatad hydrocarbons such as methylene chloride, chloroform and dichloroethane; opPn-chained or cyclic ethers such as diethyl ether, tetrahydrofuran and dioxan; aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and pyridine;
alcohols such as ethanol and isopropanol; ketones such as acetone; acetonitrile, dimathylformamide and 1,3-dimethyl-2-imidazolidinone. Examples of auxiliary bases ,, .
14 1 3 2 0 ~ 9 8 include tertiary organic bases such as triethylamine, N-methyl-piperidine, diethylaniline, pyridine and 4-(dimethylamino)pyridine or inorganic bases such as alkali metal or alkaline earth metal carbonates or hydrogen carbonates, hydroxides or oxides. If necessary, the reaction may be accelerated by the addition of alkali metal iodides. The reaction times will generally range from 15 minutes to 80 hours, depending on the nature and quantity of the amine of formula III used.
The reaction of step (b) of the compound o~ formula IV
with the acid derivative of formula V may be carried out in a conventional manner. The leaving group Nu is conveniently a group which forms a reactive carboxylic acid derivative together with the carbonyl group to which it is bound. Examples of reactive carboxylic acid derivatives include acid halides, esters, anhydrides or mixed anhydrides, such as those formed from salts of the corresponding acids (wherein Nu represents OH) and acid chlorides such as phosphorus oxychloride, diphosphoric acid tetrachloride or chloroformic acid esters or the N-alkyl-2-acyloxypyridinium salts formed when compounds of general formula V (wherein Nu represents OH) are reacted with N-alkyl-2-halopyridinium salts.
The reaction of step (b) is preferably carried out with the mixed anhydrides of strong mineral acids, particularly dichlorophosphoric acid. The reaction is optionally effected in the presence of an acid binding agent (a proton acceptor). Examples of suitable proton acceptors include alkali metal carbonates and hydrogen carbonates such as sodium carbonate and potassium hydrogen carbonate; tertiary oxganic amines such as pyridine, triethylamine, ethyl diisopropylamine, 4-dimethylaminopyridine and sodium hydride.
The reaction of step (b) may conveniently be carried out ~" 15 1320198 at temperatures of between -25C and 130C in an inert solvent. Examples of suitable inert solvents include chlorinated aliphatic hydrocarbons such as methylene chloride and 1,2-dichloroethane; open-chained or cyclic ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxan; aromatic hydrocarbons such as benzene, toluene, xylene or o-dichlorobenzene; polar aprotic solvents such as acetonitrile, dimethylformamide, l,3-dimethyl-2-imidazolidinone and hexamethylphosphoric acid triamide;
or mixtures thereof. The reaction times generally range from 15 minutes to 80 hours, depending on the nature and quantity of the acylating agent of formula V used. It is not necessary to produce the compounds of formula V
in pure form; instead, they can be prepared in situ in the reaction mixture, in a known manner.
The hydrogenolysis of step (c) is conveniently carried out in the presence of catalysts of metals of the VIIIth sub-group of the periodic table, for example palladium on animal charcoal, palladium on barium sulphate, Raney nickel or Raney cobalt, and under hydrogen pressures of from 1 to 300 bar, and at temperatures of from O'C to 130C, in the presence of solvents, for example alcohols such as methanol and ethanol; ethers such as dioxan and tetrahydrofuran; carboxylic acids, e.g. acetic acid; or tertiary amines, for example triethylamine. If the reaction is carried out in the absence of additional hydrogen chloride acceptors, for example sodium carbonate, potassium hydrogen carbonate, triethylamine or sodium acetate, the hydrochlorides of the desired compounds are formed directly and may be isolated after removal of the catalyst by evaporation of the reaction solution. If in the hydrogenolysis reaction the hydrogen is replaced by formic acid, the reaction will in principle be succPssful even under pressureless conditions. In this alternative embodiment, reaction with formic acid in the presence of dimethylformamide as solvent and palladium on charcoal as catalyst at - 16 1 3 2 ~ 1 g8 temperatures of between 70 and 110C, and reduction with triethylammonium formate in the presence of excess triethylamine, and palladium on animal charcoal or palladium acetate and triarylphosphines such as triphenylphosphine, tris-(o-tolyl)-phosphine, tris-(2,5-diisopropylphenyl)-phosphine, at temperatures of between 40 and llO'C, have proved particularly successful.
The compounds of formula I according to the invention contain up to two independently chiral elements, which may include an asymmetric carbon atom in the side chain.
The second chiral element is the acylated tricyclic group itself, which may occur in two mirror-image forms.
It depends on the nature of the tricyclic group whether the energy barrier for ring inversion at this centre is so high that the individual isomers are stable at ambient temperature and capable of isolation. It has baen ~ound that compounds of formula I wherein y,2 is methine group and ~ ~ represents an o-phenylene group always occur in two diastereoisomeric forms which may be separated into the components at ambient temperature.
The individual diastereoisomers are totally stable in the crystalline state but, in solution and at ambient temperature, revert to the original mixture with a half-life of a few days if there are no space-filling substituents in the peri position, such as a chlorine or a methyl group.
In compounds of formula I wherein x2 reprssents a nitrogen atom and ~ ~ represents an o-phenylene group unsubstituted in the peri positions, the activation energy required is so low that at ambient temperature diastereoisomers can no longer be detected (except by complex lH-NMR spectra), let alone preparatively separated.
The compounds of formula I according to the invention thus contain, as a rule, two shiral centres, one of 17 ~32~98 which is not always configurationally stable at ambient temperature. These compounds may therefore occur in t"o diastereoissmeric forms which may in turn be separated into enantiomeric (+) and (-) forms.
The invention includes the individual isomers as well as the mixtures thereof. The diastereomers may be separated on the basis of their different physico-chemical properties, e.gO by fractional recrystallisation from suitable solvents, by high pressure liquid chromatography, column chromatography or gas chromatography.
The separation of any racemates of the compounds of formula I-may be carried out by known methods, for example using an optically active acid such as (~)- or ~ tartaric acid or a derivative thereof such as (+)-or (-)-diacetyltartaric acid, (+)- or (-)-monomethyltartrate or (~)-camphorsulphonic acid.
According to a conventional method of separating isomers, the racemate of a compound of formula I is reacted with one of the optically active acids specified above in equimolar quantities in a solvent and the crystalline diastereoisomeric salts obtained are separated using their different solubilities. This reaction may be carried out in any type of solvent provided that the latter exhibits sufficiently different solubilities ~or the diastereoisomeric salts.
3Q Preferably, methanol, ethanol or mixtures thereof, e.g.
in a 1:1 ratio by volume, are used. Each of the diastereoisomeric salts is then dissolved in water, neutralised with a base such as sodium hydroxide or potassium hydroxide and in this way the corresponding free compound is obtained in the (+) or (-) form.
A single enantiomer or a mixture of two optically active diastereoisomeric compounds covered by formula I may 18 1 ~ 2 0 1 9 8 also be obtained by sarrying out the syntheses described above with only one enantiomer of ~ormulz III or V.
The starting materials of formulae II, III, IV and V
needed to synthesise the condensed diazepinones of formula I are known or may be prepared by methods analogous to known methods - see for example US-A-4550107, EP-A-254955 and DE-A-3643666.
The base-substituted condensed diazepinones of general formula I and the physiologically acceptable acid addition salts thereof have valuable properties; in particular, whilst having excellent stability to hydrolysis, high selectivity and good resorption after oral administration, they have favourable effscts on heart rate and in view of their lack of mydriatic effects or inhibitory effects on the secretion of gastric acid or saliva, they are suitable for use as vagal pacemakers in the treatment of bradycardia and bradyarrhythmia in ~uman as well as veterinary medicine.
Some of the compounds also exhibit spasmolytic properties on peripheral organs, particularly the colon and bladder.
A favourable correlation between, on the one hand, tachycardiac effects and, on the other hand, the undesirable effects on pupil size and the secretion of tears, saliva and gastric acid which occur with therapeutic agents having an anticholinergic component, is of particular importance in the therapeutic use of such substances. The following tests show that the compounds according to the invention exhibit surprisingly favourable correlations in this respect.
19 13~0198 A. Studies of bindlng to muscarinic receptors:
In vitro measurement of the IC50 value The organs were donated by male Sprague-Dawley rats weighing 180-220 g. After the heart, submandibular gland and cerebral cortex had been removed, all other steps were car-ied out in ice cold Hepes HCl buffer (pH 7.4; 100 millimolar NaC1, 10 millimolar MgC12). The whole heart was cut up with scissors. A11 the organs were then homogenised in a Potter apparatus.
For the binding test the homogenised organs were diluted by volume as follows:
Whole heart l: 40Q
Cerebral cortex 1: 3000 Submandibular gland 1: 400 The homogenised organs were incubated at a certain concentration of the radioligand and at a series of concentrations of the non-radioactive test substances in Eppendorf centrifuge tubes at 30C. Incubation lasted 45 minutes. The radioligand used was 0.3 nanomolar 3H-N-methylscopolamine t3H-NMS). Incubation was ended by the addition of ice cold buffer followed by vacuum filtration. The filters were rinsed with cold buffer and their radioactivity was determined. This represents the sum of specific and non-specific binding of 3H-NMS.
The proportion of non-specific ~inding was defined as the radioactivity which was bound in the presence of l micromolar quinuclidinylbenzylate. Each measurement was taken four times. The IC,o values of the non-labelled test substances were determined graphically. They represent that concentration of test substance at which the specific binding of 3H-NMS to the muscarinic receptors in the various organs was inhibited by 50~.
` 20 ~2~1~8 The results are set forth in Table I.
B._Investiqation of functional selectivity of the antimuscarinic effect S
Substances with antimuscarinic properties inhibit the effects of agonists supplied exogenically or of acetylcholine, which is released from cholinergic nerve endings. The following is a description of some method~
that are suitable for the detection of cardioselective antimuscarinic agents.
"In vivo" methods The objective of the methods was to confirm the selectivity of the antimuscarinic effect. Those substances which had been selec~ed on the basis of "in vitro" tests were tested for their 1. M1/M2 selectivlty in the rat, 2. Salivation-inhibiting effect on the rat and 3. Inhibition of the acetylcholine effect on the bladder, bronchi and heart rate in the guinea pig.
1. M~/M2 selectivity in the rat The method used was described by Hammer and Giachetti (~ife Sciences 31, 2991-2998 (1982)). 5 minutes after the intravenous injaction of increasing doses of the substance, either the right vagus was electrically stimulated (frequency: 25 Hz; pulse width: ~ms; duration of stimulus: 30s; voltage: supramaximal~ or 0.3 mg/kg of McN--A-343 were intravenously injected into male THOM
rats. The bradycardia caused by vagus stimulation and the rise in blood pressure caused by McN-A-343 were ~ 21 ~32~1~8 determined. The dosage of the substances which reduced either the vagal bradycardia (M~) or the rise in blood pressure (Ml) by 50% was determined graphically. The results are set forth in Table II.
2. Salivation-inhibitinq effect in the rat Using the method of Lavy and Mulder (Arch. Int.
Pharmacodyn. 178, 437~445, (1969)) male THOM rats anaesthetised with 1.2 g/kg of urethane were given increasing doses of the substance by i.v. route. The secretion of saliva was initiated by subcutaneous administration of 2 mg/kg of pilocarpine. The saliva was absorbed with blotting paper and the surface area covered was measured every 5 minutes by planimetry. Tne dosage of the substance which reduced the volume of saliva by 50% was determined graphically. The results are set forth in Table II.
3. Inhibition of the effect of acetylcholine on the bladder, bronchi and heart rate in quinea Piqs 5 minutes after the administration of the test substance, 1~ microgram/kg of acetylcholine were simultaneously injected intravenously and intra-arterially into anaesthetised guinea pigs. The heart rate was recorded directly by extracorporeal derivation of the ECG, the expiration resistance according to Konzett-Ro~ler and contraction of the exposed bladder.
In order to determine the inhi~ition of the acetylcholine activity on -the organs under investigation, dosage/activity curves were recorded and from them -log ED50 values were determined. The results are set forth in Table III.
The ollowing compounds, by way of example, were investigated according to the procedures set forth above:
, 22 ~32~98 A = 11-[4-[3-[(diethylamino)~ethyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido~2,3-b]tl,4]benzo-diazepin-6-one;
B = ll-[4-[2-[(diethylamino)methyl]-1-piperidinyl]-1~
oxobutyl]-5,11-dihydro-9-methyl-6H-pyrido[2,3-b]-[1,4]benzodiazepin-6-one; and C = 5,11-dihydro-11-[4-[2-[(1-pyrrolidinyl)methyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one;
and as comparison substances D = 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido~2~3-b]cl~4]ben~odiazepin-6-one (see US-A-4550107), E = 5,11-dihydro-11-~(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3~b]~1t4]benzodiazepin-6-one (see US-A-3660380) and F = atropine.
', -. ~ ' :" ,' .
, ': ' Table I
Receptor Binding Tests in vitro ~ 1L_â' Receptor Binding Tests IC50 [nmol 11]
Substance Cortex Heart Submandibular gland (C) (H) (SM) .
_ _ _ -The information shown in Table I above shows that the new compounds of formula I distinguish between muscarinic receptors in different tissues. This is clear from the substantially lower IC50 values when the test substances are investigated on preparations from the hcart compared with those from the cerebral cortex.
.
~, --- ' 24 ~32~98 Table II
M1/M2 selectivity and salivation-inhibiting activity on the rat Besults:
-log ED50 [mol kg1]
Substance Heart Blood pressure Salivation inhibition A 7.29 6.26 5.96 B 7.21 6.30 5.95 _ C 7.33 6.66 5.78 .
D 6.42 5.63 5.00 E 5.60 6.94 6.22 .
F 7.94 7.34 7.60 .
~ 25' ~2~1~8 Table III
Inhibition of acetylcholine activity on the bladder, bronchi and heart rate in the guinea pig Results:
.
-log ED50[mol kg1]
10 Substance Heart Bronchi 81adder .~ 7.~5 7.15 6.00 B 7.15 6.82 6.12 C 7.56 7.2~ 6.50 D 5.84 5.58 4.73 E 5.85 6.57 5.36 F 7.70 7.96 7.03 The pharmacological data in Tables II and III above show - in total agreement with the receptor binding studies - that the heart rate is increased by the above-mentioned compounds even at dosages at which there is no restriction in the secretion of saliva.
Moreover, the pharmacological data in Table III
above indicate a surprisingly high power of distinction between the heart and smooth muscle.
The above-mentioned substances show a substantially improved effectiveness compared with the known compound D. At the same time, their therapeutically useful selectivity is retained. This results in a reduction in the quantity of drug to be administered to the patient 26 ~3201~8 without increasing the risk of muscarinic side effects.
Furthermore, the compounds prepared according to the invention are well tolerated; even in the hi~hest doses administered, no toxic side effects were observed in the pharmacological trials.
For pharmaceutical use the compounds of formula I
or physiologically acceptable salts thereof may be incorporated in a conventional manner in customary - pharmaceutical preparation forms, e.g. solutions, suppositories, plain or coated tablets, capsules and infusions. The daily dosage is generally between 0.02 and 5 mg/kg, preferably between 0.02 and 2.5 mg/kg, in particular between 0.05 and lqO mg/kg of body weight, optionally administered in the form of several, preferably 1 to 3, individual doses in order to achieve the desired results.
Thus, viewed from another aspect, the invention provides a pharmaceutical composition comprising at least one compound of formula I as defined hereinbefore or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient.
Viewed from a further aspect, the invention provides the use of a compound of formula I as defined hereinbefore or a physiologically acceptable acid addition salt thereof for the manufacture o~ a pharmaceutical composition for combatting bradycardia and brady-arrhythmia and optionally spasm in the bladder andcolon.
Viewed from a yet further aspect, the invention provides a method of treatment of the human or non-human animal body for combatting bradycardia, bradyarrhythmia or spasm of the bladder or colon said method comprising administering to said body a compound of formula I as hereinbefore defined or a physiologically acceptable acid addition salts thereof.
., .. ~ , .... .
~320198 The invention also extends to a commercial package containing, as active pharmaceutical ingredient, a compound of the invention, together with instructions for its use in treatment of the human or non-human animal body for combatting bradycardia, bradyarrhythmia or spasm of the bladder or colon.
26a 27 132~1 98 The following non-limiting Examples are intended to illustrate the invenkion, without restricting its scope in any way.
- Satisfactory elemental analyses, IR, W and lH-NMR
spectra are available for the compounds and mass spectra are available for many of them.
All parts, percentages and ratios hereinafter are by weight unless otherwise stated.
10 ExamPle 1 ll- r 4 - r 2-~(Diethylamino)methvl~ piperidinyl]-1-oxobutyl1-5,11-dihvdro-6H-~yrido~2 3-b] r 1,4]benzo-diazepin-6-one A mixture of 9.5 g (0.03 mol) of 11 (4-chloro-1-oxobutyl)-5,11-dihydro-6H-pyrido~2,3-b][1,4]benzo-diazepin-6-one, 100 ml of anhydrous dimethylformamide, 5.6 g (0.033 mol) of 2-[(diethylamino)methyl]piperidine and 0.5 g of sodium iodide was stirred for 7 days at a reaction temperature of 50C. The mixture was evaporated down in a water jet vacuum, the residue was made significantly alkaline with sodium hydroxide and extracted exhaustively with dichloromethane. The dichloromethane extracts were combined, dried over sodium sulphate and evaporated down. The crude product thus obtained (14.0 g) was purified by column chromatography on silica gel as the stationary phase and using dichloromethane/ethyl acetate/cyc~o-haxane/methanol/conc. ammonia 58.5/2S.1/7.7/7.7/1.0 (by volume) as eluant. The concentrated eluates crystallised when triturated with t-butyl methyl ether.
After recrystallisation from ethyl acetate using animal charcoal, 3.8 g (28% of theory) of colourless crystals were obtained, m~p. 143-144C; RF 0-7 (Macherey-Nagel, Polygram~R~ SIL GjUV254, pre-coated plastic sheets for TLC;
eluant: dichloromethane/cyclohexane/methanol/conc.
ammonia 67.6/15.2/15.2/2 by volume)) or RF 0.3 (eluant:
~,.i............
28 ~32~98 dichloromethane/ethyl acetate/cyclohexane/methanol/conc.
ammonia 58.5/25.1/7.7/7.7/1.0 (by volume).
C26H35N502 (449 59) Calculated: C 69.46 H 7.85 N 15.58 Found: 69.69 7.80 15060 ~ml~
5.11_Dihydro~ r4-t2-rtdimethylamino!meth ~l-1-piperidin~ oxobutvl~-6H-pyridor2,3-b] r 1,4lbenzo-diaze~ine-6-one Prepared analogously to Example 1 ~rom 11-(4-chloro-1-oxobutyl)-5,11-dihydro 6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and 2-C(dimethylamino)methyl]piperidine in a yield of 33% of theory. Colourless crys~als, m.p.
157-158C (acetonitrile).
Example 3 1l-[4-r2 r 2-(Diethylamino!ethyll-1-piPeridinYl1-1-oxo butYll-5.11-dihydro-6H-P~rido r 2,3-b~ r 1,4lbenzodiaze~in-6-one Prepared analogously to Example 1 from 11-(4-chloro~
oxobutyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4~benzo-diazepin-6-one and 2-[2-(diethylamino)ethyl]piperidine in a yield of 31% o~ theory. Colourless crystals, m.p.
86~88C; RF 0.55 (Macherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets ~or TLC; eluant:
dichloromethane/cyclohexane/methanol/conc. ammonia 67.6/15.2/15.2/2.0 (by volume)).
C27H37N502 (463.62) Calculated: C 69.95 H 8.04 N 15.11 Found- 6g.9J 7.97 15.00 ;
29 ~3 2 ~ ~ ~ 8 Exam~le 4 5 11-DihYdro~ 4-~2- r 2-(dimethylamino)ethY11-1-i~eridinyl~ oxobutYll-6H-~Yrido r 2,3-blrl.41benzo-diaze~in-6-one Prepared analogously to Example 1 from 11-(4-chloro-1-oxobutyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and 2-[2-(dimethylamino)ethyl]piperidine in a yield o~ 6% of theory. Colourless crystals, m.p.
94-96 (diisopropyl ~ther/cyclohexane 1:1 v/v), soluble in water.
Example 5 1l- r 4-r3-r(Diethylaminolmeth~1~-4-morPholinyl~-1-oxo-k~yll-5~ dihydro-6H-pyridor2~3-blrl~4lbenzo-diazepin 6-one Prepared analogously to Example 1 from 11-(4-chloro-1-oxobutyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 3-[(diethylamino)methyl]-morpholine in a yield of 8% of theory. Colourless crystals, m.p. 108-110C (t-butyl methyl ether), readily 25 soluble in water.
C25H33N502 (451.57) Calculated: C 66.50H 7.37 N 15.51 Found~ 66.65 7.17 15.42 Exam~le 6 1l- r 4~ r 2-rtDiethylamino)methyl~-l-pi~eridinYlL-1-oxobutYll-S,ll-dihydro-9-methYl-6H-~Yridor2~3-b r 1,41benzodiazepin-6-one Prepared analogously to Example 1 from 11-(4-chloro-1-oxobutyl)-5,11-dihydro-9~methyl-6H-pyrido[2,3-b][1,4]-ben~odiazepin-6-one (m.p. 178C [acetonitrile]~ and 2-.
30 ~32~1~8 [(diethylamino)methyl]piperidine in a yield of 53% oftheory. Colourless crystals, m.p. 154-156C
(acetonitrile).
C27H37N50z (463-62) Calculated: C 69.95H 8.04 N 15.11 Found: 70.00 8.14 15.14 Example 7 8-Bromo~ 4- r 2- r (diethvlamino)methvll-1-PiPeridinyll-1-oxobut~1l-5 11-dihvdro-6H-~Yrido r 2 3-bl r 1 4lbenzo-diazepin-6-one Prepared analogously to Example 1 from 8-bromo-11-(4-chloro-1-oxobutyl]-5,11-dihydro-6H-pyrido~2,3-b]tl,4]-benzodiazepin-6-one and 2-[(diethylamino)methyl]-piparidine in a yield of 50% of theory. Colourless, brittle resin, sparingly soluble in water, capable of being triturated with isooctane to produce a sandy product; R~ 0.3 (Macherey-Nagel, Polygram~R~ SIL G/ W254, pre-coated plastic sheets for TLC; eluant: dichloro-methane/ethyl acetate/cyclohexane/methanol/conc. ammonia 58/25/8/8/1 (by volume)).
C2~H34BrNs02 (528.49) Calcùlated: C 59.09 H 6.48Br 15.12 N 13.25 Found: 58.99 6.42 15.30 13.13 Exam~le 8 11- r 4- r 4-~3-L~iethylamino)Propyl~ iperidinyl~
oxobut~l1-5~ dihydro-6H-pYrido r 2 3-bl r 1,4lbenzo-diazepin-6-one Prepared a~alogously to Example 1 from 11-~4-chloro-1-oxobutyl)-5,11-dihydro-6H-pyrido[2,3-b~[1,4]benzo-diazepin-6-one and 4 [3-(diethylamino)propyl]piperidine in a yield of 4.2% of theory. Colourless crystals m.p.
164-165C (ethyl acetate); RF 0 - 4 (Merck, ready-made TLC
~ 32019~
plates, silica gel 60F-254. Eluant:
4,9-dihydro-3-methyl-4-[4-[3-[(4-(1-piperidinyl)butyl]-1-piperidinyl]-1-oxobutyl]-lOH-thieno[3,4-b][1,5]benzo-diazepin-10-ona;
1,3~dimethyl-4-[4-[3-~(1-piperidinyl)methyl~-4-morpholinyl]-1-oxobutyl]-1,4,9,10-tetrahydropyrrolo-[3,2-b][1,5]benzodiazepin-10-one;
3-chloro-1-methyl-4-[4-[3 [(1-piperidinyl)methyl]-4-: morpholinyl]-l-o~obutyl]-1,4,9,10-tetrahydropyrrolo-[3,2-b][1,5]benzodiazepin-10-one;
lO ~320198 1-methyl-4-[4-[2-[2-(1-piperidinyl)ethyl]-4-morpholinyl]-1-oxobutyl] 1,4,9,10-tetrahydropyrrolo-[3,2-b~[1,5]benzodiazepin-10-one;
-1-methyl-4-[4-[3-[4-(1-piperidinyl)butyl]-1-piperidinyl]-1-oxobutyl]-1,4,9,10-tetrahydropyrrolo-[3,2-b][1,5]benzodiazepin-10-one;
1,3 dimethyl-4-~4 [3-[(1-piperidinyl)methyl]-4-morpholinyl]-1-oxobutyl]-1,4,9,10-tetrahydropyrazolo-~4,3-b]~1,5]benzodiazepin-10-one;
1 methyl-4-[4-[3-[(1-piperidinyl)methyl~-4-morpholinyl]-1-oxobutyl]-1,4,9,10-tetrahydropyrazolo[4,3-b]~1,5]-benzodiazepin-10-one;
1,3-dimèthyl-4-[4-[3-[4~ piperidinyl)butyl]-1-.
piperidinyl]-1-oxobutyl]-1,4,9,10-tetrahydropyrazolo-[4,3-b][1,5]benzodiazepin-10-one; and 1-methyl-4-[4-[2-[2~ piperidinyl)ethyl]-4-morpholinyl]-l-oxobutyl]-1,4,9,10-tetrahydropyrazolo-[4,3-b][l,S]benzodiazepin-10-one.
Viewed from another aspect, the invention provides a process for the preparation of the compounds according to the invention, said process comprising at least one of the following steps:
_ .
(a) (to prepare compounds of formula Ia R4 ~ ~ N ~ (Ia) ~: r' ~ ~ A - N \ 2 , ~ :
(wherein R1, RZ, R3, R4, Xl, XZ, A and Z are as hereinbe~ore defined and ~ ~ represents a group (S), (U), (V) or ~W) as hereinbefore defined or a group (T') (T') 7' R
wherein R7' represents a chlorine atom or a methyl ~roup)) reacting a compound of formula II
~ } ~ U (II) Hal (wherein R3, R4, ~ ~ , X1 and x2 are as hereinbefore defined and Hal represents a chlorine, bromine or iodine atom) with a compound of formula III
1 Rl ~ ~ A - N - (III) 12 1 3 2 01 ~ 8 (wherein Rl, R2, A and Z are as hereinbefore dPfined);
(b) (to prepare compounds of formula Ia as hereinbefore defined) reacting a compound of formula IV
~ ~ ~ (IV) R
H
(wherein R3, R4, Xl, x2 and ~ ~ are as hereinbefore defined) with a carboxylic acid derivative of formula V
Nu ~ 0 (V) N` / Rl~
L A - N
~ Z~ \ R2.
(wherein Rl, R2, A and Z are as hereinbefore defined and Nu represents a nucleofugic group or a leaving group);
(c) (to prepare compounds of formula Ib, ,~X~
4 X R7 (I~) : ~ O
: ~ R ' : ~ N~
_ _ A - N
~ ~ \ R2~
Z
,' ' ' ' .
~ 13 ~32019~
(wherein Rl, R2, R4, Xl, X~ and A are as hereinbefore defined, Z
represents a single bond, an oxygen atom or a methylene or 1,2-ethylene group, R3' represents a C14 alkyl group or a hydrogen atom, and R7 represents a hydrogen atom)), hydrogenolysing a compound of formula Ib wherein R7 represents a chlorine atom;
td) converting a compound of formula I into an acid addition salt thereof or converting an acid addition salt of a compound of formula 1 into a free base or another salt, e.g. a pharmacologically acceptable acid addition salt;
(e) separating a compound of formula I into the enantiomers and/or diastereomers thereof.
The amination of step (a) is conveniently carried out in an inert solvent, at temperatures of between -10C and the boiling temperature of the solvent, preferably either with at least 2 moles of a secondary amine of formula III per mole of the haloacyl compound of formula II or with 1 to 2 moles of a secondary amine of formula III and an auxiliary base. Examples of suitable solvents include chlorinatad hydrocarbons such as methylene chloride, chloroform and dichloroethane; opPn-chained or cyclic ethers such as diethyl ether, tetrahydrofuran and dioxan; aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and pyridine;
alcohols such as ethanol and isopropanol; ketones such as acetone; acetonitrile, dimathylformamide and 1,3-dimethyl-2-imidazolidinone. Examples of auxiliary bases ,, .
14 1 3 2 0 ~ 9 8 include tertiary organic bases such as triethylamine, N-methyl-piperidine, diethylaniline, pyridine and 4-(dimethylamino)pyridine or inorganic bases such as alkali metal or alkaline earth metal carbonates or hydrogen carbonates, hydroxides or oxides. If necessary, the reaction may be accelerated by the addition of alkali metal iodides. The reaction times will generally range from 15 minutes to 80 hours, depending on the nature and quantity of the amine of formula III used.
The reaction of step (b) of the compound o~ formula IV
with the acid derivative of formula V may be carried out in a conventional manner. The leaving group Nu is conveniently a group which forms a reactive carboxylic acid derivative together with the carbonyl group to which it is bound. Examples of reactive carboxylic acid derivatives include acid halides, esters, anhydrides or mixed anhydrides, such as those formed from salts of the corresponding acids (wherein Nu represents OH) and acid chlorides such as phosphorus oxychloride, diphosphoric acid tetrachloride or chloroformic acid esters or the N-alkyl-2-acyloxypyridinium salts formed when compounds of general formula V (wherein Nu represents OH) are reacted with N-alkyl-2-halopyridinium salts.
The reaction of step (b) is preferably carried out with the mixed anhydrides of strong mineral acids, particularly dichlorophosphoric acid. The reaction is optionally effected in the presence of an acid binding agent (a proton acceptor). Examples of suitable proton acceptors include alkali metal carbonates and hydrogen carbonates such as sodium carbonate and potassium hydrogen carbonate; tertiary oxganic amines such as pyridine, triethylamine, ethyl diisopropylamine, 4-dimethylaminopyridine and sodium hydride.
The reaction of step (b) may conveniently be carried out ~" 15 1320198 at temperatures of between -25C and 130C in an inert solvent. Examples of suitable inert solvents include chlorinated aliphatic hydrocarbons such as methylene chloride and 1,2-dichloroethane; open-chained or cyclic ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxan; aromatic hydrocarbons such as benzene, toluene, xylene or o-dichlorobenzene; polar aprotic solvents such as acetonitrile, dimethylformamide, l,3-dimethyl-2-imidazolidinone and hexamethylphosphoric acid triamide;
or mixtures thereof. The reaction times generally range from 15 minutes to 80 hours, depending on the nature and quantity of the acylating agent of formula V used. It is not necessary to produce the compounds of formula V
in pure form; instead, they can be prepared in situ in the reaction mixture, in a known manner.
The hydrogenolysis of step (c) is conveniently carried out in the presence of catalysts of metals of the VIIIth sub-group of the periodic table, for example palladium on animal charcoal, palladium on barium sulphate, Raney nickel or Raney cobalt, and under hydrogen pressures of from 1 to 300 bar, and at temperatures of from O'C to 130C, in the presence of solvents, for example alcohols such as methanol and ethanol; ethers such as dioxan and tetrahydrofuran; carboxylic acids, e.g. acetic acid; or tertiary amines, for example triethylamine. If the reaction is carried out in the absence of additional hydrogen chloride acceptors, for example sodium carbonate, potassium hydrogen carbonate, triethylamine or sodium acetate, the hydrochlorides of the desired compounds are formed directly and may be isolated after removal of the catalyst by evaporation of the reaction solution. If in the hydrogenolysis reaction the hydrogen is replaced by formic acid, the reaction will in principle be succPssful even under pressureless conditions. In this alternative embodiment, reaction with formic acid in the presence of dimethylformamide as solvent and palladium on charcoal as catalyst at - 16 1 3 2 ~ 1 g8 temperatures of between 70 and 110C, and reduction with triethylammonium formate in the presence of excess triethylamine, and palladium on animal charcoal or palladium acetate and triarylphosphines such as triphenylphosphine, tris-(o-tolyl)-phosphine, tris-(2,5-diisopropylphenyl)-phosphine, at temperatures of between 40 and llO'C, have proved particularly successful.
The compounds of formula I according to the invention contain up to two independently chiral elements, which may include an asymmetric carbon atom in the side chain.
The second chiral element is the acylated tricyclic group itself, which may occur in two mirror-image forms.
It depends on the nature of the tricyclic group whether the energy barrier for ring inversion at this centre is so high that the individual isomers are stable at ambient temperature and capable of isolation. It has baen ~ound that compounds of formula I wherein y,2 is methine group and ~ ~ represents an o-phenylene group always occur in two diastereoisomeric forms which may be separated into the components at ambient temperature.
The individual diastereoisomers are totally stable in the crystalline state but, in solution and at ambient temperature, revert to the original mixture with a half-life of a few days if there are no space-filling substituents in the peri position, such as a chlorine or a methyl group.
In compounds of formula I wherein x2 reprssents a nitrogen atom and ~ ~ represents an o-phenylene group unsubstituted in the peri positions, the activation energy required is so low that at ambient temperature diastereoisomers can no longer be detected (except by complex lH-NMR spectra), let alone preparatively separated.
The compounds of formula I according to the invention thus contain, as a rule, two shiral centres, one of 17 ~32~98 which is not always configurationally stable at ambient temperature. These compounds may therefore occur in t"o diastereoissmeric forms which may in turn be separated into enantiomeric (+) and (-) forms.
The invention includes the individual isomers as well as the mixtures thereof. The diastereomers may be separated on the basis of their different physico-chemical properties, e.gO by fractional recrystallisation from suitable solvents, by high pressure liquid chromatography, column chromatography or gas chromatography.
The separation of any racemates of the compounds of formula I-may be carried out by known methods, for example using an optically active acid such as (~)- or ~ tartaric acid or a derivative thereof such as (+)-or (-)-diacetyltartaric acid, (+)- or (-)-monomethyltartrate or (~)-camphorsulphonic acid.
According to a conventional method of separating isomers, the racemate of a compound of formula I is reacted with one of the optically active acids specified above in equimolar quantities in a solvent and the crystalline diastereoisomeric salts obtained are separated using their different solubilities. This reaction may be carried out in any type of solvent provided that the latter exhibits sufficiently different solubilities ~or the diastereoisomeric salts.
3Q Preferably, methanol, ethanol or mixtures thereof, e.g.
in a 1:1 ratio by volume, are used. Each of the diastereoisomeric salts is then dissolved in water, neutralised with a base such as sodium hydroxide or potassium hydroxide and in this way the corresponding free compound is obtained in the (+) or (-) form.
A single enantiomer or a mixture of two optically active diastereoisomeric compounds covered by formula I may 18 1 ~ 2 0 1 9 8 also be obtained by sarrying out the syntheses described above with only one enantiomer of ~ormulz III or V.
The starting materials of formulae II, III, IV and V
needed to synthesise the condensed diazepinones of formula I are known or may be prepared by methods analogous to known methods - see for example US-A-4550107, EP-A-254955 and DE-A-3643666.
The base-substituted condensed diazepinones of general formula I and the physiologically acceptable acid addition salts thereof have valuable properties; in particular, whilst having excellent stability to hydrolysis, high selectivity and good resorption after oral administration, they have favourable effscts on heart rate and in view of their lack of mydriatic effects or inhibitory effects on the secretion of gastric acid or saliva, they are suitable for use as vagal pacemakers in the treatment of bradycardia and bradyarrhythmia in ~uman as well as veterinary medicine.
Some of the compounds also exhibit spasmolytic properties on peripheral organs, particularly the colon and bladder.
A favourable correlation between, on the one hand, tachycardiac effects and, on the other hand, the undesirable effects on pupil size and the secretion of tears, saliva and gastric acid which occur with therapeutic agents having an anticholinergic component, is of particular importance in the therapeutic use of such substances. The following tests show that the compounds according to the invention exhibit surprisingly favourable correlations in this respect.
19 13~0198 A. Studies of bindlng to muscarinic receptors:
In vitro measurement of the IC50 value The organs were donated by male Sprague-Dawley rats weighing 180-220 g. After the heart, submandibular gland and cerebral cortex had been removed, all other steps were car-ied out in ice cold Hepes HCl buffer (pH 7.4; 100 millimolar NaC1, 10 millimolar MgC12). The whole heart was cut up with scissors. A11 the organs were then homogenised in a Potter apparatus.
For the binding test the homogenised organs were diluted by volume as follows:
Whole heart l: 40Q
Cerebral cortex 1: 3000 Submandibular gland 1: 400 The homogenised organs were incubated at a certain concentration of the radioligand and at a series of concentrations of the non-radioactive test substances in Eppendorf centrifuge tubes at 30C. Incubation lasted 45 minutes. The radioligand used was 0.3 nanomolar 3H-N-methylscopolamine t3H-NMS). Incubation was ended by the addition of ice cold buffer followed by vacuum filtration. The filters were rinsed with cold buffer and their radioactivity was determined. This represents the sum of specific and non-specific binding of 3H-NMS.
The proportion of non-specific ~inding was defined as the radioactivity which was bound in the presence of l micromolar quinuclidinylbenzylate. Each measurement was taken four times. The IC,o values of the non-labelled test substances were determined graphically. They represent that concentration of test substance at which the specific binding of 3H-NMS to the muscarinic receptors in the various organs was inhibited by 50~.
` 20 ~2~1~8 The results are set forth in Table I.
B._Investiqation of functional selectivity of the antimuscarinic effect S
Substances with antimuscarinic properties inhibit the effects of agonists supplied exogenically or of acetylcholine, which is released from cholinergic nerve endings. The following is a description of some method~
that are suitable for the detection of cardioselective antimuscarinic agents.
"In vivo" methods The objective of the methods was to confirm the selectivity of the antimuscarinic effect. Those substances which had been selec~ed on the basis of "in vitro" tests were tested for their 1. M1/M2 selectivlty in the rat, 2. Salivation-inhibiting effect on the rat and 3. Inhibition of the acetylcholine effect on the bladder, bronchi and heart rate in the guinea pig.
1. M~/M2 selectivity in the rat The method used was described by Hammer and Giachetti (~ife Sciences 31, 2991-2998 (1982)). 5 minutes after the intravenous injaction of increasing doses of the substance, either the right vagus was electrically stimulated (frequency: 25 Hz; pulse width: ~ms; duration of stimulus: 30s; voltage: supramaximal~ or 0.3 mg/kg of McN--A-343 were intravenously injected into male THOM
rats. The bradycardia caused by vagus stimulation and the rise in blood pressure caused by McN-A-343 were ~ 21 ~32~1~8 determined. The dosage of the substances which reduced either the vagal bradycardia (M~) or the rise in blood pressure (Ml) by 50% was determined graphically. The results are set forth in Table II.
2. Salivation-inhibitinq effect in the rat Using the method of Lavy and Mulder (Arch. Int.
Pharmacodyn. 178, 437~445, (1969)) male THOM rats anaesthetised with 1.2 g/kg of urethane were given increasing doses of the substance by i.v. route. The secretion of saliva was initiated by subcutaneous administration of 2 mg/kg of pilocarpine. The saliva was absorbed with blotting paper and the surface area covered was measured every 5 minutes by planimetry. Tne dosage of the substance which reduced the volume of saliva by 50% was determined graphically. The results are set forth in Table II.
3. Inhibition of the effect of acetylcholine on the bladder, bronchi and heart rate in quinea Piqs 5 minutes after the administration of the test substance, 1~ microgram/kg of acetylcholine were simultaneously injected intravenously and intra-arterially into anaesthetised guinea pigs. The heart rate was recorded directly by extracorporeal derivation of the ECG, the expiration resistance according to Konzett-Ro~ler and contraction of the exposed bladder.
In order to determine the inhi~ition of the acetylcholine activity on -the organs under investigation, dosage/activity curves were recorded and from them -log ED50 values were determined. The results are set forth in Table III.
The ollowing compounds, by way of example, were investigated according to the procedures set forth above:
, 22 ~32~98 A = 11-[4-[3-[(diethylamino)~ethyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido~2,3-b]tl,4]benzo-diazepin-6-one;
B = ll-[4-[2-[(diethylamino)methyl]-1-piperidinyl]-1~
oxobutyl]-5,11-dihydro-9-methyl-6H-pyrido[2,3-b]-[1,4]benzodiazepin-6-one; and C = 5,11-dihydro-11-[4-[2-[(1-pyrrolidinyl)methyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one;
and as comparison substances D = 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido~2~3-b]cl~4]ben~odiazepin-6-one (see US-A-4550107), E = 5,11-dihydro-11-~(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3~b]~1t4]benzodiazepin-6-one (see US-A-3660380) and F = atropine.
', -. ~ ' :" ,' .
, ': ' Table I
Receptor Binding Tests in vitro ~ 1L_â' Receptor Binding Tests IC50 [nmol 11]
Substance Cortex Heart Submandibular gland (C) (H) (SM) .
_ _ _ -The information shown in Table I above shows that the new compounds of formula I distinguish between muscarinic receptors in different tissues. This is clear from the substantially lower IC50 values when the test substances are investigated on preparations from the hcart compared with those from the cerebral cortex.
.
~, --- ' 24 ~32~98 Table II
M1/M2 selectivity and salivation-inhibiting activity on the rat Besults:
-log ED50 [mol kg1]
Substance Heart Blood pressure Salivation inhibition A 7.29 6.26 5.96 B 7.21 6.30 5.95 _ C 7.33 6.66 5.78 .
D 6.42 5.63 5.00 E 5.60 6.94 6.22 .
F 7.94 7.34 7.60 .
~ 25' ~2~1~8 Table III
Inhibition of acetylcholine activity on the bladder, bronchi and heart rate in the guinea pig Results:
.
-log ED50[mol kg1]
10 Substance Heart Bronchi 81adder .~ 7.~5 7.15 6.00 B 7.15 6.82 6.12 C 7.56 7.2~ 6.50 D 5.84 5.58 4.73 E 5.85 6.57 5.36 F 7.70 7.96 7.03 The pharmacological data in Tables II and III above show - in total agreement with the receptor binding studies - that the heart rate is increased by the above-mentioned compounds even at dosages at which there is no restriction in the secretion of saliva.
Moreover, the pharmacological data in Table III
above indicate a surprisingly high power of distinction between the heart and smooth muscle.
The above-mentioned substances show a substantially improved effectiveness compared with the known compound D. At the same time, their therapeutically useful selectivity is retained. This results in a reduction in the quantity of drug to be administered to the patient 26 ~3201~8 without increasing the risk of muscarinic side effects.
Furthermore, the compounds prepared according to the invention are well tolerated; even in the hi~hest doses administered, no toxic side effects were observed in the pharmacological trials.
For pharmaceutical use the compounds of formula I
or physiologically acceptable salts thereof may be incorporated in a conventional manner in customary - pharmaceutical preparation forms, e.g. solutions, suppositories, plain or coated tablets, capsules and infusions. The daily dosage is generally between 0.02 and 5 mg/kg, preferably between 0.02 and 2.5 mg/kg, in particular between 0.05 and lqO mg/kg of body weight, optionally administered in the form of several, preferably 1 to 3, individual doses in order to achieve the desired results.
Thus, viewed from another aspect, the invention provides a pharmaceutical composition comprising at least one compound of formula I as defined hereinbefore or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient.
Viewed from a further aspect, the invention provides the use of a compound of formula I as defined hereinbefore or a physiologically acceptable acid addition salt thereof for the manufacture o~ a pharmaceutical composition for combatting bradycardia and brady-arrhythmia and optionally spasm in the bladder andcolon.
Viewed from a yet further aspect, the invention provides a method of treatment of the human or non-human animal body for combatting bradycardia, bradyarrhythmia or spasm of the bladder or colon said method comprising administering to said body a compound of formula I as hereinbefore defined or a physiologically acceptable acid addition salts thereof.
., .. ~ , .... .
~320198 The invention also extends to a commercial package containing, as active pharmaceutical ingredient, a compound of the invention, together with instructions for its use in treatment of the human or non-human animal body for combatting bradycardia, bradyarrhythmia or spasm of the bladder or colon.
26a 27 132~1 98 The following non-limiting Examples are intended to illustrate the invenkion, without restricting its scope in any way.
- Satisfactory elemental analyses, IR, W and lH-NMR
spectra are available for the compounds and mass spectra are available for many of them.
All parts, percentages and ratios hereinafter are by weight unless otherwise stated.
10 ExamPle 1 ll- r 4 - r 2-~(Diethylamino)methvl~ piperidinyl]-1-oxobutyl1-5,11-dihvdro-6H-~yrido~2 3-b] r 1,4]benzo-diazepin-6-one A mixture of 9.5 g (0.03 mol) of 11 (4-chloro-1-oxobutyl)-5,11-dihydro-6H-pyrido~2,3-b][1,4]benzo-diazepin-6-one, 100 ml of anhydrous dimethylformamide, 5.6 g (0.033 mol) of 2-[(diethylamino)methyl]piperidine and 0.5 g of sodium iodide was stirred for 7 days at a reaction temperature of 50C. The mixture was evaporated down in a water jet vacuum, the residue was made significantly alkaline with sodium hydroxide and extracted exhaustively with dichloromethane. The dichloromethane extracts were combined, dried over sodium sulphate and evaporated down. The crude product thus obtained (14.0 g) was purified by column chromatography on silica gel as the stationary phase and using dichloromethane/ethyl acetate/cyc~o-haxane/methanol/conc. ammonia 58.5/2S.1/7.7/7.7/1.0 (by volume) as eluant. The concentrated eluates crystallised when triturated with t-butyl methyl ether.
After recrystallisation from ethyl acetate using animal charcoal, 3.8 g (28% of theory) of colourless crystals were obtained, m~p. 143-144C; RF 0-7 (Macherey-Nagel, Polygram~R~ SIL GjUV254, pre-coated plastic sheets for TLC;
eluant: dichloromethane/cyclohexane/methanol/conc.
ammonia 67.6/15.2/15.2/2 by volume)) or RF 0.3 (eluant:
~,.i............
28 ~32~98 dichloromethane/ethyl acetate/cyclohexane/methanol/conc.
ammonia 58.5/25.1/7.7/7.7/1.0 (by volume).
C26H35N502 (449 59) Calculated: C 69.46 H 7.85 N 15.58 Found: 69.69 7.80 15060 ~ml~
5.11_Dihydro~ r4-t2-rtdimethylamino!meth ~l-1-piperidin~ oxobutvl~-6H-pyridor2,3-b] r 1,4lbenzo-diaze~ine-6-one Prepared analogously to Example 1 ~rom 11-(4-chloro-1-oxobutyl)-5,11-dihydro 6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and 2-C(dimethylamino)methyl]piperidine in a yield of 33% of theory. Colourless crys~als, m.p.
157-158C (acetonitrile).
Example 3 1l-[4-r2 r 2-(Diethylamino!ethyll-1-piPeridinYl1-1-oxo butYll-5.11-dihydro-6H-P~rido r 2,3-b~ r 1,4lbenzodiaze~in-6-one Prepared analogously to Example 1 from 11-(4-chloro~
oxobutyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4~benzo-diazepin-6-one and 2-[2-(diethylamino)ethyl]piperidine in a yield of 31% o~ theory. Colourless crystals, m.p.
86~88C; RF 0.55 (Macherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets ~or TLC; eluant:
dichloromethane/cyclohexane/methanol/conc. ammonia 67.6/15.2/15.2/2.0 (by volume)).
C27H37N502 (463.62) Calculated: C 69.95 H 8.04 N 15.11 Found- 6g.9J 7.97 15.00 ;
29 ~3 2 ~ ~ ~ 8 Exam~le 4 5 11-DihYdro~ 4-~2- r 2-(dimethylamino)ethY11-1-i~eridinyl~ oxobutYll-6H-~Yrido r 2,3-blrl.41benzo-diaze~in-6-one Prepared analogously to Example 1 from 11-(4-chloro-1-oxobutyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and 2-[2-(dimethylamino)ethyl]piperidine in a yield o~ 6% of theory. Colourless crystals, m.p.
94-96 (diisopropyl ~ther/cyclohexane 1:1 v/v), soluble in water.
Example 5 1l- r 4-r3-r(Diethylaminolmeth~1~-4-morPholinyl~-1-oxo-k~yll-5~ dihydro-6H-pyridor2~3-blrl~4lbenzo-diazepin 6-one Prepared analogously to Example 1 from 11-(4-chloro-1-oxobutyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 3-[(diethylamino)methyl]-morpholine in a yield of 8% of theory. Colourless crystals, m.p. 108-110C (t-butyl methyl ether), readily 25 soluble in water.
C25H33N502 (451.57) Calculated: C 66.50H 7.37 N 15.51 Found~ 66.65 7.17 15.42 Exam~le 6 1l- r 4~ r 2-rtDiethylamino)methyl~-l-pi~eridinYlL-1-oxobutYll-S,ll-dihydro-9-methYl-6H-~Yridor2~3-b r 1,41benzodiazepin-6-one Prepared analogously to Example 1 from 11-(4-chloro-1-oxobutyl)-5,11-dihydro-9~methyl-6H-pyrido[2,3-b][1,4]-ben~odiazepin-6-one (m.p. 178C [acetonitrile]~ and 2-.
30 ~32~1~8 [(diethylamino)methyl]piperidine in a yield of 53% oftheory. Colourless crystals, m.p. 154-156C
(acetonitrile).
C27H37N50z (463-62) Calculated: C 69.95H 8.04 N 15.11 Found: 70.00 8.14 15.14 Example 7 8-Bromo~ 4- r 2- r (diethvlamino)methvll-1-PiPeridinyll-1-oxobut~1l-5 11-dihvdro-6H-~Yrido r 2 3-bl r 1 4lbenzo-diazepin-6-one Prepared analogously to Example 1 from 8-bromo-11-(4-chloro-1-oxobutyl]-5,11-dihydro-6H-pyrido~2,3-b]tl,4]-benzodiazepin-6-one and 2-[(diethylamino)methyl]-piparidine in a yield of 50% of theory. Colourless, brittle resin, sparingly soluble in water, capable of being triturated with isooctane to produce a sandy product; R~ 0.3 (Macherey-Nagel, Polygram~R~ SIL G/ W254, pre-coated plastic sheets for TLC; eluant: dichloro-methane/ethyl acetate/cyclohexane/methanol/conc. ammonia 58/25/8/8/1 (by volume)).
C2~H34BrNs02 (528.49) Calcùlated: C 59.09 H 6.48Br 15.12 N 13.25 Found: 58.99 6.42 15.30 13.13 Exam~le 8 11- r 4- r 4-~3-L~iethylamino)Propyl~ iperidinyl~
oxobut~l1-5~ dihydro-6H-pYrido r 2 3-bl r 1,4lbenzo-diazepin-6-one Prepared a~alogously to Example 1 from 11-~4-chloro-1-oxobutyl)-5,11-dihydro-6H-pyrido[2,3-b~[1,4]benzo-diazepin-6-one and 4 [3-(diethylamino)propyl]piperidine in a yield of 4.2% of theory. Colourless crystals m.p.
164-165C (ethyl acetate); RF 0 - 4 (Merck, ready-made TLC
~ 32019~
plates, silica gel 60F-254. Eluant:
7 dichloromethane/methanol/cyclohexane/conc. ammonia 68/15/15/2 (by volume)).
Example 9 1l- r 4-r3- r 3-LDiethylaminol Pro~yl 1 -l-Piperidiny~
oxobutvll-5~ dihydro-6H-pyridor2~3-blrl~41benzo-diaze~in-6-one Prepared analogously to Example 1 from 11-(4-bromo-1-oxobutyl)~5,11-dihydro-6H-pyrido~2,3-b][1,4]benzo-diazepin-6-one (m.p. 175 180~C) and 3-~3-(diethylamino)-propyl]piperidine in a yield of 14% of theory.
Colourless crystals, m.p. 103-105C (acetonitrile).
C29H39N5O2 (477.65) Calculated: C 70.41 H 8.23 N 14.66 Found: 70.26 8.16 14.55 Example 10 5.11-DihydrO-ll-r4~r2-r(l-~vrrolidinYl)methyll-l-Piperidlnyll-l-oxobutyl]-6H-pyrido~2~3-blrl~4lben diaze~in-6-one Prepared analogously to Example 1 from ll-(4-chloro-1-oxobutyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and 2-[(1-pyrrolidinyl)methyl]piperidine in a yield of 4.7% of theory. Colourless crystals, m.p.
144-145'C (acetonitrile).
C25H33N5O2 (447-60) Calculated: C 69.77 H 7.43 N 15.65 Found: 69.93 7.43 15.77 Jra.~ "~
32 13201~8 Example 11 5.11-Dihydro 11- r 4-~4-r4-(1-pyrrolidinYl)butyl~
iperidinyl~-1-oxobutvll-6H-pyridor2 3-b~ r i 4~-nzodiazepin-6-one Prepared analogously to Example 1 from 11-(4-chloro-1-oxobutyl3-5,11-dihydro-6H-pyridot2,3-b][1,4]benzo-diazepin-6-one and 4-~4-(1-pyrrolidinyl)butyl]piperidine in a yield of 36% o~ theory. Colourless crystals, m.p.
152 154C (from acetonitrile using actiYated charcoal).
C29H39N502 (489.66~
Calculated: C 71.14 H 8.03 N 14.30 ~ound: 71.04 8.03 14.46 Example 12 ~ 4-~3- r 4-(Diethylamino)butyl~ pi~eridinyl~
oxobutyll-5.11~dihydro-6H-pyridor2~3-blrl,41benzo-_azePin-6-one Prepared analogously to Example 1 from 11-(4-chloro-1-oxobutyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and 3-[4-(diethylamino)butyl]piperidine in a yield of 4.7% of theory. Colourless crystals, m.p.
106-108C (acetonitrile).
C29H,,lN50z (491.68) Calculated: C 70.84 H 8.40 N 14.24 Found: 70.60 8.14 14.19 Example 13 5,11~Dihydro-ll-c4-r3-r2-~l-Pyrrolidinyl)ethyl~
pi~ridinyl~ oxohutyl~-6H-P~rido r 2 3-bl r 1,41benzo-diazePin-6-one Prepared analogously to Example 1 from 11-(4-chloro-1-oxobutyl~-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzo-` 33 132~198 diazepin-6-one and 3-[2~ pyrrolidinyl)ethyl]piperidine (but using acetonitrile instead of dimethylformamide as solvent) in a yield of 8.5% of theory. Colourless crystals, m.p. 126-128~C (acetonitrile); R~ 0.47 (Macherey-Nagel, Polygram~R~ SIL G/ W254, pre-coated plastic sheets for TLC; eluant: dichloro-methane/methanol/cyclohexane/conc. ammonia 68/15/15/2 (by volume)).
C27H35N502 (461-61) Calculated: C 70.25 H 7.64 N 15.17 Found: 69.95 7.80 15.08 ExamPle 14 5 ll-Dihvdro-11- r 4- r 3- r 4-(1-~yrrolidinyl)butYll-1-piperidinyll-l-oxobutyl]-6H-pyrido r 2.3-blr1.41benzo-diazepin-6-one Prepared analogously to Example 1 from 11-(4-chloro-1-oxobutyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and 3-[4-(1-pyrrolidinyl)butyl]piperidine in a yield of 15.5~ of theory. Colourless crystals, m.p~ llO-112~C (acetonitrile).
C29H39N502 (489-66) Calculated: C 71.14 H 8.03 N 14.30 Found: 70.97 8.08 14.40 Exam~le 15 11 I4- r 3- r ~Diethylamino)methyl]-4-mor~holinvll-1-oxobut~ 5 11-dihydro-6H-pYrido r 2,3-bl r l~benzo-dlaze~in-6-one A mixture of 16.33 g (0.0632 mol) of 3-[(diethylamino)-methyl]-4-morpholinebutanoic acid and 2.0 g o a 75%
sodium hydride dispersion in paraffin oil was heated in 160 ml of anhydrous dimethylformamide at 50-80C until the development of hydrogen had ceased. 13.20 g 34 i320~98 (0.0625 mol) of 5,11-dihydro-6H-pyrido~2,3-b][1,4]benzo-diazepin-6-one were added to the resulting sodium salt of the above acid and at -lO~C 9.9 g (0.0646 mol) of phosphorus oxychloride were added dropwise within 10 S minutes. The resulting mixture was stirred for 4 hours at -10C, for 4 hours at 0C and ~or 20 hours at ambient temperature. The mixture was stirred into 300 g of ice, adjusted to pH 9 with sodium hydroxide solution and extracted exhaustively with dichloromethane. The combined organic phases were washed once with a little ice water, dried over sodium sulphate and concentrated by evaporation. The oily residue was triturated with a few drops of diisopropyl ether, whereupon crystallisation occurred. The precipitate was suction-filtered and recrystallised from t-butyl methyl ether.
6.55 g (23% of theory) of colourless crystals were obtained, m.p. 108-110C, which were found, according to thin layer chromatography, mixed melting point, IR, W
and lH-MMR spectra, to be totally identical to a sample obtained according to Example 5.
132019~
The following non-limiting Examples illustrate the preparation of some pharmaceutical administration forms:
xample I
Tablets containing 5 my o~ 4-r3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido~2,3-b][1,4]benzodiazepin-6-one __ _ 1 tablet contains:
Active substance 5.0 mg Lactose 148.0 mg Potato starch 65.0 mg 15 Magnesium stearate 2.0 mq Total: 220.0 mg A 10% mucilage is prepared from potato starch by heating. The active substance, lactose and remaining potato starch are mixed together and granulated with the above mucilage through a 1.5 mm mesh screen. The granules are dried at 45C, rubbed through the same screen again, mixed with magnesium stearate and compressed with a 9 mm diameter punch to form tablets each weighing 220 mg.
Example II
Coated tablets containing 5 mg of 11-[4-[3-C(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Tablets prepared according to Example I are coated, by a known method, with a coating consisting essentially of sugar and taic. The finished coated tablets are polished with beeswax. The coated tablets each weigh 300 mg.
36 132~198 Example III
Ampoules containing 10 mg of 11-[4-[3-[(diethylamino)-methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one :
1 ampoule contains:
Active substance 10.0 mg 10 Sodium chloride 8.0 mg Distilled water ad 1 ml The active substance and sodium chloride are dissolved in distilled water and then made up to the volume specified. The solution is sterile filtered and trans-ferred into 1 ml ampoules.
Sterilisation: 20 minutes at 120C.
Example IV
Suppositories containing 20 mg of 11-[4-~3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b]~1,4]benzodiazepin-~-one 1 suppository ~ontains:
~ctive substance 20.0 mg Suppository mass (e.g. Witepsol W 45(R)~ 1 680.0 ma Total:1 700.0 mg Finely~powdered active substance is suspended in molten suppository mass which has been cooled to 40OC.
35 The mass is poured at 37C into slightly chilled suppository moulds, to produce suppositories each weighing 1.7 g.
. ' .
``` 37 132~19~
ExamRle V
Drops containing 11-[4-[3-[(diethylamino)methyl]-~-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3~b~-[1,4]benzodiazepin-6-one 190 ml of drops solutlon contain:
10 Methyl p hydroxybenzoate0.035 g Propyl p hydroxybenzoate0.015 g Aniseed oil 0.05 g Menthol 0.06 g Pure sthanol 10.0 g 15 Active substance 0.5 g Sodium cyclamate 1.0 g Glycerol 15.0 g Distilled water ad100.0 ml The active substance and sodium cyclamate are dissolved in about 70 ml of water and glycerol is added. The p-hydroxybenzoates, aniseed oil and menthol are dissolved in ethanol and this solution is added with stirring to the aqueous solution. Finally, the solution is made up to 100 ml with water and filtered to remove any suspended particles.
Example 9 1l- r 4-r3- r 3-LDiethylaminol Pro~yl 1 -l-Piperidiny~
oxobutvll-5~ dihydro-6H-pyridor2~3-blrl~41benzo-diaze~in-6-one Prepared analogously to Example 1 from 11-(4-bromo-1-oxobutyl)~5,11-dihydro-6H-pyrido~2,3-b][1,4]benzo-diazepin-6-one (m.p. 175 180~C) and 3-~3-(diethylamino)-propyl]piperidine in a yield of 14% of theory.
Colourless crystals, m.p. 103-105C (acetonitrile).
C29H39N5O2 (477.65) Calculated: C 70.41 H 8.23 N 14.66 Found: 70.26 8.16 14.55 Example 10 5.11-DihydrO-ll-r4~r2-r(l-~vrrolidinYl)methyll-l-Piperidlnyll-l-oxobutyl]-6H-pyrido~2~3-blrl~4lben diaze~in-6-one Prepared analogously to Example 1 from ll-(4-chloro-1-oxobutyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and 2-[(1-pyrrolidinyl)methyl]piperidine in a yield of 4.7% of theory. Colourless crystals, m.p.
144-145'C (acetonitrile).
C25H33N5O2 (447-60) Calculated: C 69.77 H 7.43 N 15.65 Found: 69.93 7.43 15.77 Jra.~ "~
32 13201~8 Example 11 5.11-Dihydro 11- r 4-~4-r4-(1-pyrrolidinYl)butyl~
iperidinyl~-1-oxobutvll-6H-pyridor2 3-b~ r i 4~-nzodiazepin-6-one Prepared analogously to Example 1 from 11-(4-chloro-1-oxobutyl3-5,11-dihydro-6H-pyridot2,3-b][1,4]benzo-diazepin-6-one and 4-~4-(1-pyrrolidinyl)butyl]piperidine in a yield of 36% o~ theory. Colourless crystals, m.p.
152 154C (from acetonitrile using actiYated charcoal).
C29H39N502 (489.66~
Calculated: C 71.14 H 8.03 N 14.30 ~ound: 71.04 8.03 14.46 Example 12 ~ 4-~3- r 4-(Diethylamino)butyl~ pi~eridinyl~
oxobutyll-5.11~dihydro-6H-pyridor2~3-blrl,41benzo-_azePin-6-one Prepared analogously to Example 1 from 11-(4-chloro-1-oxobutyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and 3-[4-(diethylamino)butyl]piperidine in a yield of 4.7% of theory. Colourless crystals, m.p.
106-108C (acetonitrile).
C29H,,lN50z (491.68) Calculated: C 70.84 H 8.40 N 14.24 Found: 70.60 8.14 14.19 Example 13 5,11~Dihydro-ll-c4-r3-r2-~l-Pyrrolidinyl)ethyl~
pi~ridinyl~ oxohutyl~-6H-P~rido r 2 3-bl r 1,41benzo-diazePin-6-one Prepared analogously to Example 1 from 11-(4-chloro-1-oxobutyl~-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzo-` 33 132~198 diazepin-6-one and 3-[2~ pyrrolidinyl)ethyl]piperidine (but using acetonitrile instead of dimethylformamide as solvent) in a yield of 8.5% of theory. Colourless crystals, m.p. 126-128~C (acetonitrile); R~ 0.47 (Macherey-Nagel, Polygram~R~ SIL G/ W254, pre-coated plastic sheets for TLC; eluant: dichloro-methane/methanol/cyclohexane/conc. ammonia 68/15/15/2 (by volume)).
C27H35N502 (461-61) Calculated: C 70.25 H 7.64 N 15.17 Found: 69.95 7.80 15.08 ExamPle 14 5 ll-Dihvdro-11- r 4- r 3- r 4-(1-~yrrolidinyl)butYll-1-piperidinyll-l-oxobutyl]-6H-pyrido r 2.3-blr1.41benzo-diazepin-6-one Prepared analogously to Example 1 from 11-(4-chloro-1-oxobutyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one and 3-[4-(1-pyrrolidinyl)butyl]piperidine in a yield of 15.5~ of theory. Colourless crystals, m.p~ llO-112~C (acetonitrile).
C29H39N502 (489-66) Calculated: C 71.14 H 8.03 N 14.30 Found: 70.97 8.08 14.40 Exam~le 15 11 I4- r 3- r ~Diethylamino)methyl]-4-mor~holinvll-1-oxobut~ 5 11-dihydro-6H-pYrido r 2,3-bl r l~benzo-dlaze~in-6-one A mixture of 16.33 g (0.0632 mol) of 3-[(diethylamino)-methyl]-4-morpholinebutanoic acid and 2.0 g o a 75%
sodium hydride dispersion in paraffin oil was heated in 160 ml of anhydrous dimethylformamide at 50-80C until the development of hydrogen had ceased. 13.20 g 34 i320~98 (0.0625 mol) of 5,11-dihydro-6H-pyrido~2,3-b][1,4]benzo-diazepin-6-one were added to the resulting sodium salt of the above acid and at -lO~C 9.9 g (0.0646 mol) of phosphorus oxychloride were added dropwise within 10 S minutes. The resulting mixture was stirred for 4 hours at -10C, for 4 hours at 0C and ~or 20 hours at ambient temperature. The mixture was stirred into 300 g of ice, adjusted to pH 9 with sodium hydroxide solution and extracted exhaustively with dichloromethane. The combined organic phases were washed once with a little ice water, dried over sodium sulphate and concentrated by evaporation. The oily residue was triturated with a few drops of diisopropyl ether, whereupon crystallisation occurred. The precipitate was suction-filtered and recrystallised from t-butyl methyl ether.
6.55 g (23% of theory) of colourless crystals were obtained, m.p. 108-110C, which were found, according to thin layer chromatography, mixed melting point, IR, W
and lH-MMR spectra, to be totally identical to a sample obtained according to Example 5.
132019~
The following non-limiting Examples illustrate the preparation of some pharmaceutical administration forms:
xample I
Tablets containing 5 my o~ 4-r3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido~2,3-b][1,4]benzodiazepin-6-one __ _ 1 tablet contains:
Active substance 5.0 mg Lactose 148.0 mg Potato starch 65.0 mg 15 Magnesium stearate 2.0 mq Total: 220.0 mg A 10% mucilage is prepared from potato starch by heating. The active substance, lactose and remaining potato starch are mixed together and granulated with the above mucilage through a 1.5 mm mesh screen. The granules are dried at 45C, rubbed through the same screen again, mixed with magnesium stearate and compressed with a 9 mm diameter punch to form tablets each weighing 220 mg.
Example II
Coated tablets containing 5 mg of 11-[4-[3-C(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Tablets prepared according to Example I are coated, by a known method, with a coating consisting essentially of sugar and taic. The finished coated tablets are polished with beeswax. The coated tablets each weigh 300 mg.
36 132~198 Example III
Ampoules containing 10 mg of 11-[4-[3-[(diethylamino)-methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one :
1 ampoule contains:
Active substance 10.0 mg 10 Sodium chloride 8.0 mg Distilled water ad 1 ml The active substance and sodium chloride are dissolved in distilled water and then made up to the volume specified. The solution is sterile filtered and trans-ferred into 1 ml ampoules.
Sterilisation: 20 minutes at 120C.
Example IV
Suppositories containing 20 mg of 11-[4-~3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-b]~1,4]benzodiazepin-~-one 1 suppository ~ontains:
~ctive substance 20.0 mg Suppository mass (e.g. Witepsol W 45(R)~ 1 680.0 ma Total:1 700.0 mg Finely~powdered active substance is suspended in molten suppository mass which has been cooled to 40OC.
35 The mass is poured at 37C into slightly chilled suppository moulds, to produce suppositories each weighing 1.7 g.
. ' .
``` 37 132~19~
ExamRle V
Drops containing 11-[4-[3-[(diethylamino)methyl]-~-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3~b~-[1,4]benzodiazepin-6-one 190 ml of drops solutlon contain:
10 Methyl p hydroxybenzoate0.035 g Propyl p hydroxybenzoate0.015 g Aniseed oil 0.05 g Menthol 0.06 g Pure sthanol 10.0 g 15 Active substance 0.5 g Sodium cyclamate 1.0 g Glycerol 15.0 g Distilled water ad100.0 ml The active substance and sodium cyclamate are dissolved in about 70 ml of water and glycerol is added. The p-hydroxybenzoates, aniseed oil and menthol are dissolved in ethanol and this solution is added with stirring to the aqueous solution. Finally, the solution is made up to 100 ml with water and filtered to remove any suspended particles.
Claims (19)
1. A compound of formula I
(I) (wherein represents a group (S), (T), (U), (V) or (W) (S) (T) (U) (V) (W) Xl and x2 each represents a methine group or, where represents a group (S), (U) or (W), either or both of Xl and XZ may alternatively represent a nitrogen atom;
A represents a straight-chained saturated C1-6 alkylene group;
R1 and R2, which may be the same or different, each represents a C1-6 alkyl group or R1 and R2 together with the intervening nitrogen atom represent a 4- to 7-membered, saturated, monocyclic, heteroaliphatic ring optionally interrupted by an oxygen atom or a N-CH3 group;
: : :
R3 represents a C1-4 alkyl group or a chlorine or hydrogen atom;
R4 represents a hydrogen atom or a methyl group;
R5 and R8, which may be the same or different, each represents a hydrogen, fluorine, chlorine or bromine atom or a C1-4 alkyl group;
R7 represents a hydrogen or chlorine atom or a methyl group;
R8 represents a hydrogen atom or a C1-4 alkyl group;
R9 represents a hydrogen or halogen atom or a C1-4 alkyl group;
R10 represents a hydrogen atom or a methyl group; and Z represents a single bond, an oxygen or sulphur atom or a methylene or 1,2-ethylene group;
with the proviso that where represents a group (T) and R7 represents a hydrogen atom, then R3 represents a hydrogen atom or a c1-4 alkyl group and Z represents other than a sulphur atom) or an isomer or acid addition salt thereof.
(I) (wherein represents a group (S), (T), (U), (V) or (W) (S) (T) (U) (V) (W) Xl and x2 each represents a methine group or, where represents a group (S), (U) or (W), either or both of Xl and XZ may alternatively represent a nitrogen atom;
A represents a straight-chained saturated C1-6 alkylene group;
R1 and R2, which may be the same or different, each represents a C1-6 alkyl group or R1 and R2 together with the intervening nitrogen atom represent a 4- to 7-membered, saturated, monocyclic, heteroaliphatic ring optionally interrupted by an oxygen atom or a N-CH3 group;
: : :
R3 represents a C1-4 alkyl group or a chlorine or hydrogen atom;
R4 represents a hydrogen atom or a methyl group;
R5 and R8, which may be the same or different, each represents a hydrogen, fluorine, chlorine or bromine atom or a C1-4 alkyl group;
R7 represents a hydrogen or chlorine atom or a methyl group;
R8 represents a hydrogen atom or a C1-4 alkyl group;
R9 represents a hydrogen or halogen atom or a C1-4 alkyl group;
R10 represents a hydrogen atom or a methyl group; and Z represents a single bond, an oxygen or sulphur atom or a methylene or 1,2-ethylene group;
with the proviso that where represents a group (T) and R7 represents a hydrogen atom, then R3 represents a hydrogen atom or a c1-4 alkyl group and Z represents other than a sulphur atom) or an isomer or acid addition salt thereof.
2. A compound of formula I as claimed in claim 1 wherein:
X1 represents a methine group;
X2 represents a nitrogen atom, represents a group (S), R3, R4 and R5 represent hydrogen atoms and R6 represents a hydrogen atom or a chlorine or bromine atom or a methyl or ethyl group in the 8- or 9- position of the tricyclic moiety, or X2 represents a methine group, represents a group (V) or (U), R8 represents a hydrogen atom and R9 represents a methyl group;
A represents an unbranched, saturated C1-5 alkylene group;
R1 and R2, which may be he same or different, each represents a Cl-3 alkyl group or R1 and R2 together with the intervening nitrogen atom represent a 4- to 7-membered, saturated, monocyclic, heteroallphatic ring optionally interrupted by an oxygen atom or group; and Z represents a single bond, an oxygen atom or a methylene or l,2-ethylene group;
or a diastereomer or enantiomer or acid addition salt thereof.
X1 represents a methine group;
X2 represents a nitrogen atom, represents a group (S), R3, R4 and R5 represent hydrogen atoms and R6 represents a hydrogen atom or a chlorine or bromine atom or a methyl or ethyl group in the 8- or 9- position of the tricyclic moiety, or X2 represents a methine group, represents a group (V) or (U), R8 represents a hydrogen atom and R9 represents a methyl group;
A represents an unbranched, saturated C1-5 alkylene group;
R1 and R2, which may be he same or different, each represents a Cl-3 alkyl group or R1 and R2 together with the intervening nitrogen atom represent a 4- to 7-membered, saturated, monocyclic, heteroallphatic ring optionally interrupted by an oxygen atom or group; and Z represents a single bond, an oxygen atom or a methylene or l,2-ethylene group;
or a diastereomer or enantiomer or acid addition salt thereof.
3. A compound of formula I as claimed in claim l wherein:
X1 represents a methine group;
X2 represents a nitrogen atom represents a group (S), R3, R4 and R5 represent hydrogen atoms and R8 represents a hydrogen atom or a chlorine or bromine atom or a methyl or ethyl group in the 8- or position of the tricyclic moiety;
A represents an unbranched, saturated Cl5 alkylene group;
.
R1 and R2, which may be the same or different, each represents a Cl5 alkyl group or R1 and R2 together with the intervening nitrogen atom represent a 5- to 7-membered, saturated, monocyclic, heteroaliphatic ring optionally interrupted by an oxygen atom or a group; and Z represents a single bond, an oxygen atom or a methylene or 1,2-ethylene group; or a diastereomer or enantiomer or acid addition salt thereof.
X1 represents a methine group;
X2 represents a nitrogen atom represents a group (S), R3, R4 and R5 represent hydrogen atoms and R8 represents a hydrogen atom or a chlorine or bromine atom or a methyl or ethyl group in the 8- or position of the tricyclic moiety;
A represents an unbranched, saturated Cl5 alkylene group;
.
R1 and R2, which may be the same or different, each represents a Cl5 alkyl group or R1 and R2 together with the intervening nitrogen atom represent a 5- to 7-membered, saturated, monocyclic, heteroaliphatic ring optionally interrupted by an oxygen atom or a group; and Z represents a single bond, an oxygen atom or a methylene or 1,2-ethylene group; or a diastereomer or enantiomer or acid addition salt thereof.
4. The compound 11-[4-[3-[(diethylamino)methyl]-4-morpholinyl]-1-oxobutyl]-5,11-dihydro-6H-pyrido[2,3-h][1,4]benzo-diazepin-6-one or an acid addition salt thereof.
5. The compound 11-[4-[2-[(diethylamino)methyl]-1-piperidinyl]-1-oxobutyl]-5,11-dihydro-9-methyl-6H-pyriclo[2,3-b]-[1,4]benzodiazepin-6-one or an acid addition salt thereof.
6. The compound 5,11-dihydro-11-[4-[2-[(1-pyrrolidinyl)-methyl]-1-piperidinyl]-1-oxobutyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one or an acid adcdition salt thereof.
7. A compound as claimed in any one of claims 1 to 6 being a physiologically acceptable acicl addition salt of a compound of formula I.
8. A pharmaceutical composition comprising a compound oi iormula I as claimed in any one of claims 1 to 6 or a physiolog-ically acceptable acid addition salt thereof together with a pharmaceutical carrier or excipient.
9. A process for the preparation of compounds as claimed in claim 1, said process comprising at least one of the following steps:
(a) (to prepare compounds of formula Ia (Ia) (wherein R1, R2, R3, R4, X1, X2, A and Z are as defined in claim 1 and represents a group (S), (U), (V) or (W) as defined in claim 1 or a group (T') (T') wherein R7' is a chlorine atom or a methyl group)) reacting a compound of formula II
(II) (wherein R3, R4,, X1 and X2 are as defined in claim 1 and Hal represents a chlorine, bromine or iodine atom) with a compound of formula III
(III) (wherein R1, R2, A and Z are as defined in claim l);
(b) (to prepare compounds of formula Ia as hereinbefore defined) reacting a compound of formula IV
(IV) (wherein R3, R4, Xl and X2 are as defined in claim 1, is as hereinbefore defined) with a carboxylic acid derivative of formula V
(V) (wherein R1, R2, A and Z are as defined in claim 1 and Nu represents a nucleofugic group or leaving group);
.
(c) (to prepare compounds of formula Ib (Ib) (wherein R1, R2, R4, X1, XZ and A are as defined in claim 1, Z
represents a single bond, an oxygen atom or a methylene or 1,2-ethylene group, R3' represents a Cl-4 alkyl group or a hydrogen atom and R7 represents a hydrogen atom)) hydrogenolysing a compound of formula Ib wherein R7 represents a chlorine atom;
(d) converting a compound of formula I into an acid addition salt thereof, or converting an acid addition salt of a compound of formula I into the free base or into another acid addition salt;
(e) separating a compound of formula I into the enantiomers and/or diastereomers thereof.
(a) (to prepare compounds of formula Ia (Ia) (wherein R1, R2, R3, R4, X1, X2, A and Z are as defined in claim 1 and represents a group (S), (U), (V) or (W) as defined in claim 1 or a group (T') (T') wherein R7' is a chlorine atom or a methyl group)) reacting a compound of formula II
(II) (wherein R3, R4,, X1 and X2 are as defined in claim 1 and Hal represents a chlorine, bromine or iodine atom) with a compound of formula III
(III) (wherein R1, R2, A and Z are as defined in claim l);
(b) (to prepare compounds of formula Ia as hereinbefore defined) reacting a compound of formula IV
(IV) (wherein R3, R4, Xl and X2 are as defined in claim 1, is as hereinbefore defined) with a carboxylic acid derivative of formula V
(V) (wherein R1, R2, A and Z are as defined in claim 1 and Nu represents a nucleofugic group or leaving group);
.
(c) (to prepare compounds of formula Ib (Ib) (wherein R1, R2, R4, X1, XZ and A are as defined in claim 1, Z
represents a single bond, an oxygen atom or a methylene or 1,2-ethylene group, R3' represents a Cl-4 alkyl group or a hydrogen atom and R7 represents a hydrogen atom)) hydrogenolysing a compound of formula Ib wherein R7 represents a chlorine atom;
(d) converting a compound of formula I into an acid addition salt thereof, or converting an acid addition salt of a compound of formula I into the free base or into another acid addition salt;
(e) separating a compound of formula I into the enantiomers and/or diastereomers thereof.
10. A process as claimed in claim 9 wherein the reaction of step (a) is carried out in an inert solvent.
11. A process as claimed in claim 10 wherein the reaction of step (a) is carried out in the presence of an auxiliary base or an excess of the amine of formula III, at temperatures of between -10°C and the boiling temperature of the reaction mixture.
.
.
12. A process as claimed in claim 9 wherein the reaction of step (b) is carried out in an inert solvent at temperatures of between -25 and 130°C, optionally in the presence of a proton acceptor.
13. A process as claimed in claim 9 or 12 wherein, in the reaction of step (c), the carboxylic acid derivative of formula V
used is an acid halide, ester, anhydride or mixed acid anhydride.
used is an acid halide, ester, anhydride or mixed acid anhydride.
14. A process as claimed in claim 9 wherein the hydrogenol-ysis of step (c) is carried out in a solvent in the presence of a catalyst comprising a metal of the VIIIth sub-group of the Periodic Table under hydrogen pressures of from 1 to 300 bar and at temperatures of from 0°C to 130°C.
15. A process as claimed in claim 9 wherein the hydrogenol-ysis of step (c) is carried out in a solvent with formic acid in the presence of palladium on charcoal as catalyst at temperatures of between 70 and 110°C.
16. A process as claimed in claim 9 wherein the hydrogenolysis of step (c) is carried out in a solvent with triethylammonium formate in the presence of excess triethylamine and palladium on animal charcoal or palladium acetate and triarylphosphines, at temperatures of between 40 and 110°C.
17. The use of a compound as claimed in any one of claims 1 to 6 or a physiologically acceptable acid addition salt thereof for combatting bradycardia and bradyarrhythmia, or spasm in the bladder and colon.
18. A process for preparing a pharmaceutical composition for treatment of the human or non-human animal body to combat bradycardia, bradyarrhythmia or spasm of the bladder or colon, which process comprises admixing a compound of formula I as claimed in any one of claims 1 to 5 or a physiologically acceptable acid addition salt thereof with a pharmaceutical carrier or excipient.
19. A commercial package containing, as active pharmaceu-tical ingredient, a compound of formula I as claimed in any one of claims 1 to 6, or a physiologically acceptable acid addition salt thereof, together with instructions for its use in treatment of the human or non-human animal body to combat bradycardia, bradyarrhythmia or spasm of the bladder or colon.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3819444.9 | 1988-06-08 | ||
| DE3819444A DE3819444A1 (en) | 1988-06-08 | 1988-06-08 | NEW CONDENSED DIAZEPINONE, PROCESS FOR THEIR MANUFACTURE AND MEDICAMENTS CONTAINING THESE COMPOUNDS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1320198C true CA1320198C (en) | 1993-07-13 |
Family
ID=6356083
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000601877A Expired - Fee Related CA1320198C (en) | 1988-06-08 | 1989-06-06 | Condensed diazepinones, processes for preparing them and pharmaceutical compositions containing these compounds |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0345629B1 (en) |
| JP (1) | JPH0232074A (en) |
| KR (1) | KR900000366A (en) |
| AT (1) | ATE80630T1 (en) |
| AU (1) | AU612851B2 (en) |
| CA (1) | CA1320198C (en) |
| DD (1) | DD284014A5 (en) |
| DE (2) | DE3819444A1 (en) |
| DK (1) | DK277589A (en) |
| GR (1) | GR3006558T3 (en) |
| HU (1) | HU203754B (en) |
| IL (1) | IL90549A0 (en) |
| NZ (1) | NZ229409A (en) |
| ZA (1) | ZA894297B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3818299A1 (en) * | 1988-05-30 | 1989-12-07 | Thomae Gmbh Dr K | NEW CONDENSED DIAZEPINONE, PROCESS FOR THEIR MANUFACTURE AND MEDICAMENTS CONTAINING THESE COMPOUNDS |
| DE3919076A1 (en) * | 1989-06-10 | 1990-12-13 | Thomae Gmbh Dr K | MEANS TO TREAT DISEASES OF THE CENTRAL NERVOUS SYSTEM AND TO PROMOTE CEREBRAL BLOOD |
| WO1996013488A1 (en) * | 1994-10-31 | 1996-05-09 | Yamanouchi Pharmaceutical Co., Ltd. | Novel benzodiazepinone derivative and medicinal composition thereof |
| DE10205219A1 (en) * | 2002-02-08 | 2003-08-21 | Bayer Ag | Quinoxalinones and their use |
| AU2003248122A1 (en) * | 2002-07-25 | 2004-02-16 | Kotobuki Pharmaceutical Co., Ltd. | Sodium channel inhibitor |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3409237A1 (en) * | 1984-03-14 | 1985-09-19 | Dr. Karl Thomae Gmbh, 7950 Biberach | CONDENSED DIAZEPINONE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| DE3726908A1 (en) * | 1987-08-13 | 1989-02-23 | Thomae Gmbh Dr K | NEW CONDENSED DIAZEPINONE, PROCESS FOR THEIR MANUFACTURE AND MEDICAMENTS CONTAINING THESE COMPOUNDS |
| DE3802334A1 (en) * | 1988-01-27 | 1989-08-10 | Thomae Gmbh Dr K | NEW CONDENSED DIAZEPINONE, PROCESS FOR THEIR MANUFACTURE AND MEDICAMENTS CONTAINING THESE COMPOUNDS |
-
1988
- 1988-06-08 DE DE3819444A patent/DE3819444A1/en not_active Withdrawn
-
1989
- 1989-06-01 DE DE8989109892T patent/DE58902273D1/en not_active Expired - Lifetime
- 1989-06-01 AT AT89109892T patent/ATE80630T1/en not_active IP Right Cessation
- 1989-06-01 EP EP89109892A patent/EP0345629B1/en not_active Expired - Lifetime
- 1989-06-06 DD DD89329307A patent/DD284014A5/en not_active IP Right Cessation
- 1989-06-06 CA CA000601877A patent/CA1320198C/en not_active Expired - Fee Related
- 1989-06-06 NZ NZ229409A patent/NZ229409A/en unknown
- 1989-06-07 JP JP1145041A patent/JPH0232074A/en active Pending
- 1989-06-07 IL IL90549A patent/IL90549A0/en not_active IP Right Cessation
- 1989-06-07 KR KR1019890007771A patent/KR900000366A/en not_active Withdrawn
- 1989-06-07 DK DK277589A patent/DK277589A/en not_active Application Discontinuation
- 1989-06-07 HU HU892911A patent/HU203754B/en not_active IP Right Cessation
- 1989-06-07 ZA ZA894297A patent/ZA894297B/en unknown
- 1989-06-08 AU AU36137/89A patent/AU612851B2/en not_active Ceased
-
1992
- 1992-12-16 GR GR920402932T patent/GR3006558T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DD284014A5 (en) | 1990-10-31 |
| HU203754B (en) | 1991-09-30 |
| EP0345629B1 (en) | 1992-09-16 |
| DE3819444A1 (en) | 1989-12-14 |
| IL90549A0 (en) | 1990-01-18 |
| ZA894297B (en) | 1991-02-27 |
| GR3006558T3 (en) | 1993-06-30 |
| DE58902273D1 (en) | 1992-10-22 |
| AU612851B2 (en) | 1991-07-18 |
| HUT50470A (en) | 1990-02-28 |
| KR900000366A (en) | 1990-01-30 |
| EP0345629A3 (en) | 1990-08-16 |
| DK277589D0 (en) | 1989-06-07 |
| JPH0232074A (en) | 1990-02-01 |
| EP0345629A2 (en) | 1989-12-13 |
| NZ229409A (en) | 1990-12-21 |
| ATE80630T1 (en) | 1992-10-15 |
| DK277589A (en) | 1989-12-09 |
| AU3613789A (en) | 1990-02-01 |
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