CA2025005A1 - Condensed diazepinones, process for preparing them and pharmaceutical compositions containing these compounds - Google Patents
Condensed diazepinones, process for preparing them and pharmaceutical compositions containing these compoundsInfo
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- CA2025005A1 CA2025005A1 CA002025005A CA2025005A CA2025005A1 CA 2025005 A1 CA2025005 A1 CA 2025005A1 CA 002025005 A CA002025005 A CA 002025005A CA 2025005 A CA2025005 A CA 2025005A CA 2025005 A1 CA2025005 A1 CA 2025005A1
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- Prior art keywords
- methyl
- diazaspiro
- dihydro
- benzodiazepin
- pyrido
- Prior art date
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- 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
- C07D471/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- 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
- C07D487/10—Spiro-condensed systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Urology & Nephrology (AREA)
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- Reproductive Health (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Abstract Condensed diazepinones Condensed diazepinones of formula I
(I) (wherein ] ? represents one of the divalent groups (s) (r) (u) (v) X represents a =CH- group or a nitrogen atom; R
represents a lower alkyl group optionally substituted by a phenyl group itself optionally substituted by halogen, methyl or methoxy; R4 and R5 represent hydrogen, halogen or lower alkyl; R6 represents hydrogen, chlorine or methyl; R7 and R8 represent hydrogen or lower alkyl and R8 may also represent halogen; m, n, o and p each represents the number 1 or 2 with the proviso that the sum of m+n+o+p must be no greater than 6) and their isomers and salts are suitable for the treatment of cholinergically induced spasms and motility disorders in the gastrointestinal tract and in the region of the outward leading bile ducts, for the symptomatic treatment of cystitis and spasms in urelithiasis, for the treatment of relative incontinence, for the symptomatic treatment of bronchial asthma and bronchitis and for the treatment of ischaemic heart disease. The compounds have a high degree of selectivity.
(I) (wherein ] ? represents one of the divalent groups (s) (r) (u) (v) X represents a =CH- group or a nitrogen atom; R
represents a lower alkyl group optionally substituted by a phenyl group itself optionally substituted by halogen, methyl or methoxy; R4 and R5 represent hydrogen, halogen or lower alkyl; R6 represents hydrogen, chlorine or methyl; R7 and R8 represent hydrogen or lower alkyl and R8 may also represent halogen; m, n, o and p each represents the number 1 or 2 with the proviso that the sum of m+n+o+p must be no greater than 6) and their isomers and salts are suitable for the treatment of cholinergically induced spasms and motility disorders in the gastrointestinal tract and in the region of the outward leading bile ducts, for the symptomatic treatment of cystitis and spasms in urelithiasis, for the treatment of relative incontinence, for the symptomatic treatment of bronchial asthma and bronchitis and for the treatment of ischaemic heart disease. The compounds have a high degree of selectivity.
Description
2~2~ 3 55-915.523 Condensed D.iazepinones The invention relates to new condensed diazepinones, processes for preparing them and pharmaceutical compositions containing these compounds.
Condensed diazepinones with antiulcerative properties and inhibitory effects on gastric acid secretion are already known from EP-A-39519, EP-A-57428 US - A-3660380, US-A-3691159, US - A-4213984, US-A-4213985, US-A - 4210648, US - A - 4410527, US-A-4424225, US-A-4424222 and US-A-4424226.
EP-~-156191 (US Patent 4550107) says, of condensed diazepinones, that by introducing new aminoacyl groups, compared with the compounds in the above mentioned publications it is possible to produce compounds having totally different and useful pharmacological properties.
Compared with the diazepinones disclosed in these various patent publications as having antiulcerative or antibradycardiac effects, certain novel condensed diazepinones, despite being structurally similar surprisingly have been found to possess another different pharmacological activity. In particular the new compounds are suitable for the treatment of cholinergically induced spasms and motility disorders in the gastrointestinal tract and in the region of the outward-leading bile ducts, for the symptomatic treatment of cystitis and spasms in urelithiasis by lowering the pathologically raised tone of the hollow organs, for the treatment of relative incontinence based on a disordered correlation between sphincter and detrusor tone, for the symptomatic therapy of bronchial asthma and bronchitis by suppressing the muscariniclv mediated part of the bronchoconstriction, and for the treatment of ischaemic heart diseases by lowering heart 2 ~02~
rate whilst simultaneously suppressing parasympathetically induced coronary spasm and lowering the basal coronary tone. The new condensed diazepinones show the effects described with a high selectivity and are free from tachycardiac side effects, particularly in the therapeutically useful dosage range.
Viewed fron~ one aspect therefore the present invention provides compounds of formula I
o H\
--N
X ~ '.
~=0 ( I ) ~N
~ ~n ~N ~o R
(wherein ] ~ represents one of the groups ( S ) ( ~
X represents a =CH- group or a nitrogen atom;
R represents a straight chained or branched C14 alkyl group optionally substituted by a phenyl group itself optionally mono or disubstituted by chlorine, bromine, fluorine, methyl or methoxy;
~2~0~
Condensed diazepinones with antiulcerative properties and inhibitory effects on gastric acid secretion are already known from EP-A-39519, EP-A-57428 US - A-3660380, US-A-3691159, US - A-4213984, US-A-4213985, US-A - 4210648, US - A - 4410527, US-A-4424225, US-A-4424222 and US-A-4424226.
EP-~-156191 (US Patent 4550107) says, of condensed diazepinones, that by introducing new aminoacyl groups, compared with the compounds in the above mentioned publications it is possible to produce compounds having totally different and useful pharmacological properties.
Compared with the diazepinones disclosed in these various patent publications as having antiulcerative or antibradycardiac effects, certain novel condensed diazepinones, despite being structurally similar surprisingly have been found to possess another different pharmacological activity. In particular the new compounds are suitable for the treatment of cholinergically induced spasms and motility disorders in the gastrointestinal tract and in the region of the outward-leading bile ducts, for the symptomatic treatment of cystitis and spasms in urelithiasis by lowering the pathologically raised tone of the hollow organs, for the treatment of relative incontinence based on a disordered correlation between sphincter and detrusor tone, for the symptomatic therapy of bronchial asthma and bronchitis by suppressing the muscariniclv mediated part of the bronchoconstriction, and for the treatment of ischaemic heart diseases by lowering heart 2 ~02~
rate whilst simultaneously suppressing parasympathetically induced coronary spasm and lowering the basal coronary tone. The new condensed diazepinones show the effects described with a high selectivity and are free from tachycardiac side effects, particularly in the therapeutically useful dosage range.
Viewed fron~ one aspect therefore the present invention provides compounds of formula I
o H\
--N
X ~ '.
~=0 ( I ) ~N
~ ~n ~N ~o R
(wherein ] ~ represents one of the groups ( S ) ( ~
X represents a =CH- group or a nitrogen atom;
R represents a straight chained or branched C14 alkyl group optionally substituted by a phenyl group itself optionally mono or disubstituted by chlorine, bromine, fluorine, methyl or methoxy;
~2~0~
R4 and Rs, which may be the same or different, eachrepresents a hydrogen, fluorine, chlorine or bromine atom or a C14 alkyl group;
R6 represents a hydrogen or chlorine atom or a methyl ~roup;
R7 and R8, which may be the same or different, each represents a hydrogen atom or C14 alkyl group, and R8 may also represent a halogen atom, m, n, ~ and p each independently represents the number l or 2 with the proviso that the sum of m+n+o+p must be no greater than 6) and the isomers and acid addition salts thereof.
Preferred compounds according to the invention include compounds of formula I wherein:
either X represents a nitrogen atom and ] ~ represents a group (S) or X represents a =C~- group and ] ~ represents the group (V);
R represents a methyl group, R4 and Rs, which may be the same or different, each represents a hydrogen, fluorine or chlorine atom or a methyl or ethyl group; and m and p each represents the number l and n and o each represents the number l or 2, and the isomers and salts thereof.
~ 9 2 .~
Particularly preferred compounds according to the invention include 5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6~-pyrido[2,3-b][1,4]benzodiazepin-6-one;
5,11-dihydro-8-methyl-11-[[7-methyl-2,7-diazaspiro-[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one;
5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-6~-pyrido[2,3-b][1,4]benzodiazepin-6-one;
5,11-dihydro-8-ethyl-11-[[6-methyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one; and 5,11-dihydro-8-methyl-11-[[2-methyl-2,6-diazaspiro[3,4]-oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one;
and the isomers and salts thereof.
The compounds of formula I may occur in the form of their acid addition salts. While physiologically acceptable salts are of course preferred, other salts may be useful as intermediates in the preparation of the free bases or of physiologically acceptable salts.
Organic and inorganic acids which have proved suitable for the preparation of physiologically acceptable salts include, for example, hydrochloric, hydrobromic, sulphuric, methylsulphuric, phosphoric, tartaric, fumaric, citric, maleic, succinic, yluconic, malic, p-toluenesulfonic, methanesulphonic and amidosulphonic acids.
To illustrate the invention further the following compounds are mentioned by way of example:
(+)-5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]-carbonyl]-6H-pyrido[2~3-b][l~4]benzodiazepin-6-one R-5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one S-5,11-dihydro-11-[C7-methyl-2,7-diazaspiro[4,4]non-2-yl]-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (+)-9-chloro-5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 8-Chloro-5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 8-bromo-5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4~benzodiazepin-6-one 5,11-dihydro-8-ethyl-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one -5,11-dihydro-9-methyl-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-ll-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4~benzodiazepin-6-one 5,11-dihydro-8-methyl-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[7-ethyl]-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 9-chloro-5,11-dihydro-11-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-8-ethyl-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H pyrido[2,3-b][1,4]benzodiazepin-6-one 5-11-dihydro-8-methyl-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-9-methyl-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 9-chloro-5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5,11-dihydro-8,9-dimethyl~ll-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5~11-dihydro-11-[[2-methyl-2~6-diazaspiro[3~4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one ~2~
5,11-dihydro-11-[[6-(phenylmethyl)-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-8-methyl-11-[[2-methyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5,11-dihydro-8-ethyl-11-[[2-methyl-2~6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5,11-dihydro-9-methyl~ [2-methyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 9-chloro-11-[[2-methyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 8-chloro-11-[[2-methyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl~-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-8-methyl-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5,11-dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4~oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-9-methyl-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 9-chloro-5,11-dihydro-11-[[6-ethyl-2,6-diazaspiro[3~4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 8 2~2~
5-11-dihydro-8-ethyl~ [[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5,11-dihydro-11-[[6-propyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-6H-pyrido[2,3-b][l,~]benzodiazepin-6-one 5,11-dihydro-8-methyl-11-[[6-propyl-2,6-diazaspiro[3,4~oct-2-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one ~3-chloro-5,11-dihydro-11-[[6-propyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-9-methyl-11-[[6-propyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5,11-dihydro-8-ethyl-11-~[6-propyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5,11-dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-9-methyl-6H-pyrido[2,3-b]tl,4]benzodiazepin-6-one 9-chloro-5,11-dihydro-11-[~2-ethyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[6-(2-methylpropyl)-2,6-diazaspiro~3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-8-methyl-11-[[6-(2-methylpropyl)-2,6-diaza-spiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one 5,11-dihydro-9-methyl-11-[[6-~2-methylpropyl)-2,6-diaza-spiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one 9-chloro~5,11-dihydro~ll-[[6-(2-methylpropyl)-2,6-diaza-spiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5,11-dihydro-11-[[6~methyl-2,6-diazaspiro[3,3]hept-2-yl]-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-8-methyl-11-[[6-methyl-2,6-diazaspiro[3,3]hept-2-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5,11-dihydro-9-methyl-11-[[6-methyl-2,6-diazaspiro[3,3]hept-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[7-methyl 2,7-diazaspiro[3,5]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-8-methyl-11-[[7-methyl-2,7~
diazaspiro[3,5]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 9-chloro-5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[3,5]non-2-yl]carbonyl-6H-pyrido[2,3-b][l,4]benzodiazepin-6 one 5,11-dihydro-11-[[2-methyl-2,7-diazaspiro[3,5]non-7-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-9-methyl-11-[[2-methyl-2,7-diazaspiro[3,5]non-7-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 8-chloro-5,11-dihydro-11-[[2-methyl-2,7-diazaspiro[3,5]non-7-yl]carbonyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 8-bromo-5,11-dihydro-ll-[[2-methyl-2,7-diazaspiro[3,5]non-7-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (+)-6,11-dihydro-11~[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one R-6,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl~-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one S-6,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one (+)-6,11-dihydro-11-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one 6,11-dihydro-11-[[2-methyl-2,6-diazaspiro[3,4]oct-6-yl]-carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one 6,11-dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-5H-pyrido[2l3-b][ll5]benzodiazepin-5-one 6,11-dihydro-11-[[6-propyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one 6,11-dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4]oct-6-yl]-carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one 6,11-dihydro-11-[[6-(2-methylpropyl)-2,6-diazaspiro[3,4]-oct-2-yl]-carbonyl]-SH-pyrido[2,3-b][1,5]benzodiazepin-5-one 6,11-dihydro-lI-[[6-methyl-2,6-diazaspiro[3,3]hept-2-yl]-carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one 6,11-dihydro-11-[[7-methyl-2,7-diazaspiro[3,5]non-2-yl]-carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one 6,11-dihydro-11-[[2-methyl-2,7-diazaspiro[3,5]non-7-yl]-carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one (+)-5,10-dihydro-5-L[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-llH-dibenzo[b,e][1,4]diazepin-11-one 5,10-dihydro-5-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-llH-dibenzo[b,e][1,4]diazepin-11-one (+)-4,9-dihydro-3-methyl-4-~[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one (~)-4,9-dihydro-4-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]-carbonyl]-3-methyl-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one 4,9-dihydro-3-methyl-4-[[6-methyl-2,6-diazaspiro[3,4]-oct-6-yl]carbonyl]-lOH-thieno[3,4~b][1,5]benzodiazepin-10-one 4,9-dihydro-3-methyl-4-[[2-methyl-2,6-diazaspiro[3,4]-oct-6-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one :
4,9-dihydro-4-[[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-3-methyl-lOH-thieno[3,4-b][1,5]benzo~iazepin-10-one :.
4,9-dihydro-3-methyl-4-[[6-propyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-lOH-thieno[3,4-b]tl,5]benzodiazepin-10-one 4,9-dihydro-4-[[2-ethyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-3-methyl-lOH-thieno[3,4-b][l,5]benzodiazepin-10-one 4,9-dihydro-3-methyl-4-[[6-(2-methylpropyl)-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin 10-one 4,9-dihydro-3-methyl-4-[[6-methyl-2,6-diazaspiro[3,3]-hept-2-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one 4,9-dihydro-4-[[6-methyl-2,6-diazaspiro[3,3]hept-2-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one 4,9-dihydro-3-methyl-4-[[7-methyl-2,7-diazaspiro[3,5]-non-2-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one 4,9-dihydro-3-methyl-4-[[2-methyl-2,7-diazaspiro[3,5]-non-7-yl]carbonyl]-loH-thieno[3~4-b][l~5~benzodiazepin 10-one (+)-3-chloro-1-methyl-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one (+3-1-methyl~4-~[7-methyl-2,7-diazaspiro~4,4]non-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzo-diazepin-10-one 3-chloro-1-methyl-4-[[6-propyl-2,~-diazaspiro[3,4~oct-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo~3,2-b]~1,5]benzodiazepin-10-one 3-chloro-1-methyl-4-[[6-(2-methylpropyl)-2,6-diazaspiro[3~4~oct-2-yl]carbonyl]-l/4~9~lo-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one 3-chloro-1-methyl-4-~[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][l,5]benzodiazepin-10-one and 3-chloro-1-methyl-4-[t6-methyl-2,6-diazaspiro[3,3]hept-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one.
Viewed from another aspect the invention also 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 base-substituted condensed diazepinones of formula Ia \N~
~N)~ .
X
:; ( l a n R
- 14 - ~ ~2~
(wherein X, R, m, n, o and p are as hereinbefore defined and ] ~ represents one of the groups (S), (U) or (V) : as hereinbefore defined or a group (T') ~CH3 ~/> ( T
wherein R4, R5, R7 and R8 are as hereinbefore defined and R6 represents a chlorine atom or a methyl group)) reacting a carbonic acid derivative of formula II
Y~
o (wherein ] ~ and X are as hereinbefore defined and Y
represents a halogen atom, preferably bromine or ~ chlorine, or a group ORI1 where R11 represents an : optionally halogen substituted C15 alkyl group, a phenyl :~ group optionally substituted by halogen atoms or nitro ~ 2 ~
groups or a C715 aralkyl group) with a compound of formula III
/
( t~--N
(1~ ~ )n (I ~ I) /Nt ) o R
(wherein R, m, n, o, and p are as hereinbefore defined) or a metal compound of formula IIIa /
( -~1 (~)n (Illa) /N
:~ R
(wherein R,m,n,o and p are as hereinbefore defined and M
represents an alkali metal atom or 1 equivalerlt of an alkaline earth metal atom);
b) (to prepare base substituted condensed diazepinones of formula Ia) reacting a tricyclic compound of formula IV
' 16 2 ~ 2 ~
, H
~ ~0 H
(wherein X and ] ~ are as hereinbefore defined) with a :: chlorocarbonic acid derivative of formula V
i O
~CI
: ( ~N
(V) N
(wherein R, m, n, o and p are as hereinbefore defined);
c) ~to prepare pyrrolo-condensed diazepinones of formula Ib H~ U C H
N ~N
~N
X ~ ( I b~
~N
tJ 3"
~N )~
:~- R
(wherein X, R, m, n, o and p are as hereinbefore defined)~ hydrogenolysing a compound of formula Ia wherein R6 represents a chlorine atom;
d) separating a compound of formula I thus obtained into its isomers; and e) converting a compound of formula I into an acid addition salt thereof or an acid addition salt of a compound of formula I into the free base.
The reaction of step (a) is carried out without or preferably in the presence of a solvent such as water or toluene or an alcohol such as methanol, ethanol or isopropanol, but particularly preferably in the presence of an aprotic polar solvent, e.g. tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric acid triamide, or mixtures thereof and at temperatures between -1~C
and the boiling point of the reaction mixture, preferably between 40 and lOO~C. It has proved convenient to use additional organic or inorganic bases, e.g. alkali metal or alkaline earth metal hydroxides, alkoxides or carbonates (e.g. sodium hydroxide, sodium methoxide, potassium tert butoxide, sodium carbonate and potassium carbonate), tertiary amines (e.g.
triethylamine, ethyldiisopropylamine and N,N-dimethylaniline), pyridine or 4-(dimethylamino~pyridine, and to carry out the reaction in the presence of an excess of a compound of formula III.
If the spirodiamines of formula III and the carbonic acid derivatives of formula II are used in equimolar quantities, the hydrohalic acid salts of the desired compounds of formula Ia are obtained directly (provided that Y represents a halogen atom).
Metal compounds of formula IIIa can readily be pr~pared in situ from compounds of formula III by reacting with alkali or alkaline earth metals, e.g. with sodium, potassium or barium, or with alkali metal or alkaline earth metal hydrides, e.y. with sodium, potassium or calcium hydride, or by reaction with alkali metal or alkaline earth metal organometallic compounds, e.g. with n-butyllithium or phenyllithium.
The reaction of step (b) is preferably carried out in an inert organic solvent, e.g. in an aromatic hydrocarbon such as toluene or xylene, in an ether such as diisopropyl ether, tetrahydrofuran or dioxane, in a ketone such as 3-pentanone, in a chlorinated aliphatic hydrocarbon, such as 1,2-dichloroethane or in another solvent, such as acetonitrile or dimethylformamide, or in mixtures thereof, optionally in the presence of a tertiary organic base such as pyridine, and at temperatures up to the boiling point of the reaction mixture, preferably at temperatures between +30 and +100 C .
The hydrogenolysis of step (c) is conveniently carried out in the presence of a catalyst based on a metal of the VIIIth subgroup of the Periodic Table of the elements, for example palladium on animal charcoal, palladium on barium sulfate, Raney nickel or Raney cobalt and at hydrogen pressures of 1 to 300 bar and temperatures of 0C to 130C, in the presence of solvents, e.g. alcohols (such as methanol and ethanol), ethers (such as dioxane and tetrahydrofuran), carboxylic acids (e.g. acetic acid) or tertiary amines (e.g.
triethylamine). If the work is done in the absence of additional hydrogen chloride acceptors, e.g. sodium carbonate, potassium hydrogen carbonate, triethylamine or sodium acetate, the hydrochlorides of the desired compounds are produced directly and may be isolated after removal of the catalyst by evaporation of the reaction solution. If, in place of hydrogen,formic acid is used in the hydrogenolysis reaction described above, the reaction will theoretically succeed even under pressureless conditions. In this variant, it has proved particularly useful to carry out the reaction with formic acid in the presence of dimethylformamide as solvent and palladium on charcoal as catalyst at temperatures between 70 and 110C, and to carry out the reduction with triethylammoniumformate in the presence of excess triethylamine and palladium on animal charcoal or palladium acetate and triarylphosphines, such as triphenylphosphines, tris(o-tolyl) phosphines and tris-(2,5-diisopropylphenyl)-phosphines, at temperatures between 40 and 110C.
Bases of formula I thus obtained can subsequently be converted into the acid addition salts thereof or, if acid addition salts are obtained, they may be converted into the free bases or other pharmacologically acceptable acid addition salts.
If in the aminocarbonylated condensed diazepinones of formula I according to the invention m and o each represent 1, and n and p each represent 2, these compounds are chiral because they have an asymmetric carbon atom in the side chain. These compounds can therefore occur as enantomeric (+) and (-) forms. The invention includes the individual isomers as well as the racemates.
Any racemates of the compounds of formula I may be resolved by known methods, for example using an optically active acid such as (+l or (-)tartaric acid or -a derivative thereof such as (+~ or (-)diacetyltartaric acid, (+) or (-~monomethyltartrate or (+)camphorsulfonic acid.
According to a conventional method of isomer separation the racemate of a compound of formula I may be reacted with one of the above mentioned optically active acids in equimolar quantities in a solvent and the crystalline diasteromeric salts obtained are separated on the basis of their different solubilities.
This reaction may be carried out in any type of solvent provided that it has a sufficiently different solubility for the salts. Methanol, ethanol or mixtures thereof are preferred, e.~. in a ratio by volume of 50:50. Then - 20 - 2~ 3 each of the diastereomeric salts is 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.
only one enantiomer is obtained if the methods of synthesis described above are carried out with only one enantiomer of formula III, IIIa or V.
The preparation of the carbonic acid derivatives of formula II used as starting products is described in detail in DE-A-3726908.
Compounds of formula III, which are generally new and have not yet been described, can be obtained for example by the following methods:
i) 2-Substituted 2,7-diazaspiro[4,4]nonanes of formula III may be obtained following the procedures described by Warner-Lambert Comp., in AU-A-83/18698 (see Derwent 107 300).
ii) 6-Substituted 2,6-diazaspiro[3,4]octanes of formula III may be prepared for example starting from 1,1,2-ethanetricarboxylic acid esters which, when reacted with suitable 1,3,5-trisubstituted hexahydro-1,3,5-triazines in the presence of catalytic quantities of trifluoroacetic acid, yield 1-substituted 2-pyrrolidinone-4,4-dicarboxylic acid esters in a high yield. Reduction with lithium aluminium hydride leads to 1-substituted 3,3-bis-hydroxymethyl-pyrrolidines which can be reacted with concentrated aqueous hydrombromic acid in a bomb-type tube to obtain the corresponding bis-bromomethyl-pyrrolidine-hydrobromides without difficulty. These react with p-toluenesulfonic acid amides in the presence of concentrated potassium hydroxide solution and using dioxane or dimethylform-amide as solvents to obtain in a high yield 6 substituted 2-(4-methylbenzenesulfonyl~-2,~-diazaspiro[3,4]octanes, which can }:e detosylated, for example, with sodium-bis-t2-methoxyethoxy~-2~2~
aluminiumhydride (RED-Al~ ), preferably in toluene solution, to obtain the desired 6-substituted 2,6-diazaspiro[3,4]octanes.
Alternatively, two cyanosuccinic acid esters may be used for the raaction with the 1,3,5-trisubstituted hexahydro-s-triazines instead of the 1,1,2-ethanetricarboxylic esters. This results in 1-substituted 4-cyano-4-carbalkoxy-2-pyrrolidinones, which yield 1-substituted 3 aminomethyl-3-hydroxymethyl-pyrrolidines when reduced with lithium aluminium hydride. Reaction with concentrated aqueous hydrobromic acid produces a good yield of 1-substituted 3-(aminomethyl)-3-(bromomethyl)-pyrrolidines, which can readily be cyclised, when treated with concentrated sodium or potassium hydroxide solution in the presence of water-miscible solvents, e.g. dioxane, ethanol, methanol or dimethylformamide, to obtain the desired 6-substituted 2,6-diazaspiro[3,4]octanes.
iii) 2-Substituted 2,6-diazaspiro[3,4~octanes of formula III may, according to one of the variants given in (ii) above, be obtained from readily accessible 6-(phenylmethyl)-2,6-diazaspiro[3,4]octane by alkylating in the 2-position in a conventional manner for example by reacting with a suitable acylating agent followed by reduction with lithium aluminium hydride, with the benzyl group subsequently being removed by hydrogenolysis.
iv) 2-Substituted 2,6-diazaspiro[3,3]heptanes of formula III can be prepared in a conventional ~anner from unsubstituted 2,6-diazaspiro[3,3]heptane which is a known compound (see A. Litherland and F.G. Mann, J.
Chem. Soc. [London] 1938, 15~8; F. Govaert and M.
Beyaert. Bull. Soc. Chim. Belg. 55: 106, 112 [1946];
F.G. Mann and A. Litherland, Nature 141: 789-7gO
[1938]), for example by monoacylation and subsequent \
careful re~uction with lithium aluminium hydride in diethylether.
v) 7~Substituted 2,7-diazaspiro[3,5]nonanes of formula III may be prepared from the 1-substituted 4-cyano-4-piperidinecarboxylic acid esters which are obtainable analagously to the procedures described by L. Ciszewski, Pol. J. Chem. 62: 451-455 [1988]. For example, the 1-substituted 4-cyano-4-piperidinecarboxylic acid esters are catalytically hydrogenated in glacial acetic acid and in the presence of platinum~IV)oxide and concentrated sulphuric acid to obtain the corresponding ~-alanine esters. These may then be cyclised with Grignard reagents, for example with ethyl magnesium bromide, in ether and at O to 5C to obtain 7-substituted 2,7-diazaspiro[3,5]nonan-1-ones which when reduced with lithium aluminium hydride in ether are converted into the desired 7-substituted 2,7-diazaspiro[3,5]nonanes. Alternatively, the 7-substituted 2,7-diazaspiro[3,5]non-1-ones may also be obtained by saponifying the above mentioned ~-alanine esters to obtain the corresponding ~-alanines and then closing the azetidinone ring in a theoretically known manner, e.g. by the action of triphenylphosphine and tetrachloromethane or N-bromosuccinimide, ethyldichlorophosphate, phenyldichlorophosphate or phenylphosphonic acid dichloride, in the presence of triethylamine and using acetonitrile as solvent.
vi) 2-Substituted 2,7-diazaspiro[3,5]-nonanes of formula III may also be prepared from 7-(phenylmethyl)-2,7-diazaspiro[3,5]nonane synthesised according to (v~
above, without any significant problems using the reaction sequence specified in (iii) above.
The tricyclic compounds of formula IV are known from patent literature or may be synthesised following published methods from available starting materials.
- 23 ~
Chlorocarbonic acid derivatives of formula V may be prepared in accordance with current methods from spirodiamines of formula II and phosgene.
The condensed diazepinones of formula I and the acid addition salts thereof have valuable properties; as already mentioned, they exhibit selective spasmolytic properties on peripheral organs, particularly the ileum and bladder, and in view of the absence of any effect of increasing heart rate, inhibiting gastric acid secretion, inhibiting saliva or affecting the accommodating powers of the eye in the therapeutic dosage range they are suitable for use in human and veterinary medicine for the treatment of cholinergically induced spasms and motility disorders in the gastrointestinal tract and in the region of the outward-leading bile ducts, for the symptomatic treatment of cystitis and spasm in urelithiasis by lowering the pathologically raised tone of the hollow organs, for the treatment of relative incontinence based on an incongruity of sphincter and detrusor tone, for the symptomatic treatment of bronchial asthma and bronchitis by suppressing the muscarincally mediated part of the bronchoconstriction, and for the treatment of ischaemic heart disease by lowering heart rate and at the same time suppressing parasympathetically induced coronary spasm and lowering the basal coronary tone.
Thus viewed from a further aspect the present invention provides a method of treatment of the human or non-human ~preferably mammalian) body to combat cholinergically induced spasm and motility disorders in the gastrointestinal tract and in the region of the outward leading bile ducts, to combat cystitis and spasm in urelithIasis, to combat relative incontinence, to combat bronchial asthma and bronchitis and to combat ischaemic heart disease, said method comprising administering a compound of formula I or a physiologically acceptable acid addition salt thereof to said body.
- 24 ~
Viewed from a further aspect the invention provides the use of a compound of formula I or a physiologically acceptable acid addition salt thereof for the manufacture of a therapeutic agent for use in a method of treatment to combat cholinergically induced spasm and motility disorders in the gastrointestinal tract and in the region of the outward leading bile ducts, to combat cystitis and spasm in urelithiasis, to combat relative incontinence, to combat bronchial asthma and bronchitis and to combat ischaemic heart disease, Viewed from a still further aspect the invention provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient.
For this purpose the compounds of formula I or salts thereof may be incorporated, in a conventional manner into conventional pharmaceutical forms, e.g. solutions, suppositories, plain or coated tablets, capsules or infusions. For oral administration the daily dose is generally between 0.01 and 10 mg/kg, preferably from 0.02 to 5 mg/kg, more particularly 0.05 to 2.5 mgJkg of body weight, optionally administered in the form of several, preferably one to three doses, to achieve the desired results.
A favourable correlation between spasmolitic effects on the one hand and the undesirable effects on heart rate, pupil size, and the secretion of tears, saliva and gastric acid, on the other hand, which occurs with therapeutic agents having an anticholinergic activity component is of particular importance to the therapeutic use of the substances. The following experiments show that the compounds according to the invention show particularly favourable correlations in this respect.
A. Investi~ation of functional selectivity of the antimuscarinic effect Substances with antimuscarinic properties inhibit the effects of exogenously supplied agonists or of acetylcholine released from cholinergic nerve endings.
The following is a description of methods which are suitable for determining spasmolitically effective antimuscarinics.
"In vitro" OrgLan Preparations Dissociation constants (KB-values) were determined in vitro on the ileum and spontaneQusly beating atrium of the guinea pig. The ileum was removed and incubated in Krebs-~enseleit solution in an organ bath. Contractions were induced by increasing concentrations of methacholine (M) so that full concentration/activity curves could be recorded. Then the M was washed out, the test substance was added and left in contact for 30 minutes and another concentration/activity curve was recorded with M.
The dosage ratio (DR), i.e. the extent of displacement of the concentration/activity curve, made it possible to calculate the dissociation constant according to ~runlakshana and Schild ~Brit. J.
Pharmacol~ 14, 48, 1959).
In an isolated, spontaneously beating right atrium, M reduced the heart rate~ as a function of the concentration. By adding an antimuscarinic agent this effect was cancelled again. Dissociation constants for the muscarinic receptors of th~ atrium were obtained in the manner described above. ~ comparison of the dissociation constants obtained in two tissues made it possible to identify substances ~ith a selective spasmolitic effect. The results are shown in Table III.
"In vivo" Methods The methods used had the purpose of confirming the selectivity of the antimuscarinic effect. Those ~ - 26 - 2~2~
substances which had been selected on the basis of in vitro tests were investigated for 1. Selectivity of the bronchospasmolitic activity in guinea pigs.
2. The saliva-secretion inhibiting effect in the rat and 3. In situ spasmolitic activity in guinea pigs.
1. Effect on M-receptors of the bronchii, heart and bladder of anaethetised auinea pias Method , .
Male and female guinea pigs (body weight 550-600 g) were anaethetised with urethane (1.4 g/kg, i.p.). A
cannula was inserted into the jugular vein for the purpose of injecting the active substance. 220 I.U./kg of heparin were injected intravenously. A cannula was inserted in the trachea; the animals were artificially respirated with oxygen-rich air using a positive pressure pump (Braun-Melsungen~ at a rate of 80 beats per minute. One branch of the tracheal cannula was connected to a water manometer 10 cm high. The respiration volume was adjusted so that the maximum intratracheal pressure during respiration just reached the pressure of a 10 cm water column.
~ part from a few modifications, the effect of the active substances on bronchial tone was measured by the method described by Konzett and Rossler (1940~. The volume of respiration gas mixture produced by broncho-constriction (overflow) which flowed through the water manometer was measured by means of a tube-type pneumatic tachometer (Fleisch, model 1000), connected to an SP
2040D differential pressure transducer tHSE). The results were recorded with an IFD recorder. Before the test the trachea was clamped for a short time to produce 2~2~
the maximum possible degree of bronchoconstriction for calibration purposes. A cannula was inserted in the left carotid artery; the arterial blood pressure was measured using a pressure transducer (Bell and Howell, 4-327 I) in conjunction with an IFD recorder. The heart rate was measured with a heart rate meter triggered by arterial pulse waves.
A small median abdominal cut was made and the bladder was connected to a power transducer under a resting tension of l gram.
The active substances to be tested were injected through the jugular vein and 5 minutes later the increase in the tension of the bladder (in grams) the bronchial resistance (in %) and the decrease in heart rate (beats per minute) after the administration of acetylcholine (50 ~g/kg i.v. and i.a.) were measured.
Dosage-dependent curves were plotted by giving the percentage inhibition of bronchoconstriction, bradycardia and the increase in the tension of the bladder against the logarithm of the dose (mol/kg) of the active substances to be tested. The results are given as averages (for 4 to 6 animals). For the results see Table I.
':
2. Salivation-inhibiting effect in the rat Male THOM rats anaethetised with 1.2 g/kg urethane were given increasing doses of the substance i.v. in accordance with Lavy and Mulder (~rch. int. Pharmacodyn.
178, 437-445, (1969)). The salivation was initiated by the subcutaneous administration o~ 2 mg/kg of pilocarpine. The saliva was mopped up with blotting paper and the area it occupied was determined by planimetry every 5 minutes. The dosage o~ substance which reduced the volume of saliva by 50% was determined graphically. For the results see Table II.
3. In-situ spasmolytic effect on quinea pias - 28 - 2~2~
Male guinea pigs (500 to 600 g body weight) were anaethetised with urethane t1.2 g/kg, i.p.); cannulas were inserted in the trachea, jugular vein and left carotid artery. The animals were artificially respirated with oxygen-rich air using a positive pressure pump at a beat rate of 80 per minute. An abdominal incision 3 to 4 cm long was made and about 15 cm of a movable loop of the small intestine (ileum) was tied off at the distal end whilst the circulation of the blood was maintained~ The proximal part was filled with a Krebs-Ringer solution and a pressure meter with a Millar micro-tip catheter (PC-450, 5F) was inserted into the intestine. A glass tube was placed vertically in the abdomen and fixed to the surrounding abdominal wall so that when the glass tube was filled with Krebs-Ringer solution the animal acted as his own organ bath.
The glass tube was filled with Krebs-Ringer solution until the entire lower abdomen was immersed. The active substances being tested were injected through the jugular vein; 5 minutes later, contractions were produced using methacholine (20 ~g/~g i.a.). By recording the percentage suppression of the methacholine-induced contractions against the logarithm of the dosage (mol/kg) of the test substance, dosage/activity curves were obtained.
The results were given as averages (for 4 to 8 animals~ (see Table II).
The following compounds, by way of example, were tested using the above methods:
A = 5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b]~1,4]benzodiazepin-6-one B = 5,11-dihydro-8-methyl-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one ~2~
C = 5,11-dihydro-11-[[6-methyl-2,6-diazaspiro~3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one D = 5,11-dihydro-8-ethyl-11-[[6-methyl~2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6~-pyrido[2,3-b][1,4]benzodiazepin-6-one E = 5,11--dihydro-8-methyl-11-[[2-methyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one and as comparison substances X = 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (c.f. US Patent 4 550 107) ;
Y = 5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (Pirenzepine, see US Patent No. 3 660 380) and ; Z = Atropine.
- 30 - 2~2~
:~ Table I
Selectivity of the bronchospasmolytic activity in the guinea pigo Acetylcholine - Antagonism _ _ = .. _ . ~ ¦ Tost Bronchii Bladdor Hoart Ratio o~
¦ Substanco - log ED,jo - log ED50 - log ED50 influ~nco o~
,~ l (mol kg'1) (mol kg~1) (mol kg 1) br~dycardia to l i.v. i.v. i.v. bronchoconstriction I
, ¦ A 6.44 5.48 5.10 22 '~' .__ . .. _.___ ¦ B 6.65 6.29 5.45 16 C 7.30 6.79 5.88 26 ~~ .. __.
D 6.97 6.82 6.01 9 ., _ __ E 7.27 6.98 5.76 32 ` -=.- -... _ .. __ X 5.58 4.93 5.84 0.5 Y 6.57 5.84 5.90 5 Z 8.09 7.28 7.57 3 . _ ~ .. ~ ..
-.
Table II
Selectivity of the in situ spasmolytic activity in relation to the salivation inhibiting effect.
Tost In silu spasmolysis S li~vatlon inhibition Ratio ot salivation .
Subst~tnco guinoa plg ilcum rat il~hibition to Ih~
- log ED60 -109 ED spasmolylic activity . ~ . _... (mol kg~1) (mol kg'1) ¦ . _ 6.05 _ ~ 5.46 4 697 _~---~-- 637 Z
¦ - .... _ _ 5.4B . 5 . _ __ 3 Y 6.08 6.42 0.5 I _ l _ 7.2B 7.60 0.5 .
~2~
;: - 32 -Table III
Dissociation constants (KR values) on the ileum and spontaneously beating attrium of the guinea pig.
. _ T~st H~art llourn Soloc~ivity Substanc~ KB Imol/l~ KB [mol/ll KB Hoart to _ ____ _ A 1.23 X 10-6 2.69 X 10-7 4.~
: ~ B 2.51 X 10 7 5.89 X 10 B ._ . _ 3.39 X 10 7 7.24 X 10-8 4 7 __ D 1 1 X 10-7 2.24 X 10 8 4 9 . ~ E 4.68 X 10-7 6.46 X ~0-8 7.2 . ___ .
¦ X 1 05 10-7 6.17X 10 7 0.17 ¦ Y 1 23 X 10-7 1.94 X 10 7 0.63 Z 1.41 X 10 9 8.13 X 10-~ 1.7 ~ ..
Discussion of the results The compounds of the invention, in low doses, inhibit the effects of exogenously supplied acetylcholine or methacholine on the smooth muscle of bronchii, bladder or small intestine, without this agonistic effect altering the heart rate (Tables I and II). For example, substances C and E show a very marked selectivity for the smooth muscle; 26- and 32- times lower doses are needed in order to inhibit the acetylcholine induced broncho-constriction, compared with the acetylcholine-induced bradycardia (Table I). The compounds of the invention not only show selectivity for the smooth muscle compared with effects which are initiated by cardiac muscarine receptors, but also higher doses are - 33 - ~2 needed in order to inhibit the pilocarpine~induced salivation (Table II).
The in vivo selectivity of these compounds for the smooth muscle observed agrees with the in vitro tests.
The substances have a higher affinity for muscarine receptors in the ileum than for cardiac muscarine receptors (Table III).
The data show that the compounds of the invention inhibit the effects of muscarine agonists on the smooth muscle e.g. bronchii, bladder and ileum, at doses which have no effect on heart rate or salivation. The comparison substances Y (pirenzepine) and Z (atropine~
show no selectivity and influence all the above mentioned effects in the same dosage range. Comparison substance X shows a higher level of effect on cardiac muscarine receptors.
All the compounds of the invention are characterised by excellent stability to hydrolysis. It is therefore possible to prepare solutions for parenteral administration which will have a long shelf life.
The following non-limiting examples are intended to illustrate the invention:
Mp denotes melting point, D denotes decomposition.
There are satisfactory elementary analyses, IR-, UV-, 1H-NMR-spectra and frequently mass spectra for all the compounds. Unless otherwise expressly mentioned, the percentages, parts and ratios given are always by weight.
Example 1 5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-Yllcarbonyl]-6H-pvrido r 2,3-bl[1,41benzodiaze~in-6-one A mixture of 9.0 g (0.033 mol) of 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b] r 1,4]benzodiazepin-6-one, 4,3 g (0.041 mol) of '3~
anhydrous sodium carbonate, 5.6 g (0.04 mol) of 2-methyl-2,6-diazaspiro[4,4]nonane and 100 ml of acetonitrile were stirred for 30 minutes at a reaction temperature of 50C. The solvent was then distilled off in vacuo, the remaining highly viscous residue was taken up in 30 ml of water, made alkaline with sodium hydroxide and exhaustively extracted with dichloromethane. The combined dichloromethane phases were dried over sodium sulphate and evaporated down and the residue was purified by chromatography on silica gel (35-70 mesh) using dichloromethane/ethylacetate/
cyclohexane/methanol/conc. ammonia 50/11/9/9/1, v/v/v/v/v, as eluent. The residue remaining after evaporation of the suitable eluates was recrystallised from watertmethanol 1/9 (v/v). 5.9 g (48 96 theory) oî
colourless crystal were obtained, Mp. 271-274C.
C2lH23Ns2 ~377-45)-Calculated: C 66.83 H 6.14 N 18.55 Found: 67.00 6.35 18.85 Example 2 9-Chloro-5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yI]carbonyl]-6H-pyrido[2,3-b~[l,4lbenzodiazepin-6-one Prepared analagously to Example l from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,7-diazaspiro[4,4]nonane in a yield of 41 g6 of theory.
Colourless crystals Mp. 257-259C (dimethylacetamide).
C21H22N52 (411-90)-Calculated: C 61.24 H 5.38 C1 8.61 N 17.00 Found: 61.50 5.67 8.59 17.10 Example 3 - 35 - 2 ~ 2 ~
5,11-Dihydro-8-methyl-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiaepin-6-one . . _ Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,7-diazaspiro[4,4]nonane in a yield of 71 % of theory.
Colourless crystals Mp. 212-214C (acetonitrile using activated charcoal).
CzzHzsNsOz (391.48).
Calculated: C 67.50 H 6.44 N 17.89 Found: 67.89 6.20 18.00 Exam~le 4 8-Chloro-5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][l~4]benzodiazepin-6-one Prepared analagously to Example 1 from 8-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one and 2-methyl-2,7-diazaspiro[4,4~nonane in a yield of 47 % of theory.
Colourless crystals Mp. 214-215C (acetonitrile).
Cz1HzzClN50z (411.90).
Calculated: C 61.24 H 5.38 Cl 8.61 N 17.00 Found: 61.00 5.38 8.72 17.10 Example 5 5,11-Dihydro-8-ethyl-ll-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1~4]benzodiazepin-6-one 2~ 3 Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-ethyl-6H-pyrido[2,3-b][1,4]benzodiazepin 6-one and 2-methyl-2,7-diazaspiro~4,4]nonane in a yield of 57 % of theory.
Colourless crystals Mp. 216-217C (from acetonitrile using activated charcoal).
C23H27NsO2 (405-50)-Calculated: C 68.13 H 6.71 N 17.27 Found: 68.30 6.81 17.30 Example 6 5,11-Dihydro-9-methyl-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][l 4~benzodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,7-diazaspiro[4,4]nonane in a yield of 9 % of theory.
Colourless crystals Mp. 253-255C (acetonitrile).
C2ZH2sNso2 (391-48)-Calculated: C 67.50 H 6.44 N 17.89Found: 66.99 6Y4`7 17.62 Example 7 8-Bromo-5,11-Dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b~[l,4]benzodiazepin-6-one Prepared analagously to Example 1 from 8-bromo-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,7-diazaspiro[4,4~nonane in a yield of 64 % of theory.
Colourless crystals Mp. 227-229C (D.) (from acetonitrile/ethanol 1/1 V/V).
C21H22BrN5O2 (456.36).
Calculated: C 55.27 H 4.86 Br 17.51 N 15.35 Found: 55.60 5.10 17.35 15.13 Example 8 5,11-Dihydro-11-[~7-ethyl-2,7-diazaspiro[4,4]non-2-yllcarbonY11-6H-pyrido~2,3-b]~1,4~benzodiazepin-6-one Prepared analagously to E~ample 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one and 2-ethyl-2,7-diazaspiro[4,4]nonane in a yield of 85 % of theory.
Colourless crystals Mp. 214-215C (acetonitrile).
C22H25Nso2 (391-48)-Calculated: C 67.50 H 6.44 N 17.89 Found: 67.44 6.70 18.10 Example 9 5,11-Dihydro-11-[[7-ethyl-2,7-diazaspiro[4,43non-2-yl]carbonyl]-8 methyl-6H-pyrido[2,3-b~ 41benzodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8~methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-ethyl-2,7-diazaspiro[4,4]nonane in a yield of 74 % of theory.
Colourless crystals Mp. 178-180C (aGetonitrile~.
C23H27N502 (405 50~
Calculated: C 68.13 H 6.71 N 17.27 Found: 67.94 6.70 17.57 Exam~le 10 5,11-Dihydro-11-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-9-methyl-6H-pyrido[2,3-bl r 1.4lbenzodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-ethyl-2,7-diazaspiro[4,4]nonane in a yield of 85 % of theory.
Colourless crystals Mp. 244-246C (acetonitrile).
C23Hz7NsO2 (405-50)-Calculated: C 68.13 H 6.71 N 17.27Found: 67.83 6.92 17.17 Example ll 9-Chloro-5,11-Dihydro-11-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1.4lbenzodiazepin-6-one Prepared analagously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one and 2-ethyl-2,7-diazaspiro[4r4]nonane in a yield o~ 75 % of theory.
Colourless crystals Mp. 224.0-225.5C (acetonitrile).
C22H24ClN5o2 (425.93), Calculated: C 62.04 H 5.68 Cl 8.32 N 16.44 Found: 61.89 5.65 8.35 16.34 Example 12 5,11-Dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbon~l]-6H-pyrido[2,3-b] r 1 F 4~benzodiazepin-6-one ~ ~2 ~
a) 4,4-Bis-(ethox~carbonyl)-l-methyl-2-pvrrolidinone A mixture of 221.6 g (0.90 mol) of triethyl 1,1,2-ethanetricarboxylate, 116.3 g (0.90 mol) of 1,3,5-trimethylhexahydro-1,3,5-tria~ine and 20.6 g (0.18 mol) of trifluoroacetic acid was stirred for 20 hours at a reaction temperature of 100C. ~fter cooling, the mixture was diluted with l litre of toluene and then extracted three times with 100 ml of 10% aqueous hydrochloric acid. The aqueous hydrochloric acid extracts were combined and extracted once with lOo ml of ethylacetate. The organic phases obtained were combined, shaken once with 200 ml of a saturated aqueous sodium hydrogen carbonate solution and then washed three times with 300 ml of water, dried over sodium sulphate and evaporated down in vacuo. The colourless oil obtained (yield 220 g, i.e. 91 ~ of theory) was used without further purification in the following step.
b) 3,3 Bis-(hydroxymethyl~-1-methylpyrrolidine To a suspension of 75.0 g (1.976 mol) of lithium aluminium hydride in 1 litre of anhydrous tetrahydrofuran, a solution of 160.0 g (0.658 mol) of 4,4-bis-(ethoxycarbonyl)-l-methyl-2 pyrrolidinone in 700 ml of dry tetrahydrofuran was added dropwise in such a way that the reaction could be kept under control and the tetrahydrofuran boiled gently. After the addition had ended the mixture was refluxed for a further 4 hours with stirring. It was then left to cool and 75 ml of water, 75 ml of 15% sodium hydroxide solution and 215 ml of water were added dropwise one after the other, with stirring and external cooling with ice water. The precipitate obtained was suction filtered, expended once more with tetrahydrofuran and boiled, then suction filtered again. The filtrates obtained were combined, carefully dried over sodium sulphate and evaporated down in vacuo. The colourless, viscous oil obtained in a 2~2~
yield of 71.4 g (75% of theory) was further processed in tha next step without any more purification.
c) 3,3-Bis-lbromomethyl)-l-methylpyrrolidine A mixture of 28.0 g (0.139 mol) of the above mentioned compound and 250 ml of 63% aqueous hydrobromic acid was heated in a bomb-type tube for 24 hours to 180C. A~ter cooling, the mixture was evaporated to dryness in vacuo, the residue,-which dissolved with relative difficulty in water, was taken up in 400 ml of water and treated with excess potassium carbonate. ~he suspension obtained was extracted exhaustively with ethyl acetate, the extracts were combined and dried over sodium sulphate. The residue remaining after evaporation of the solvent (yield: 49.0 g, i.e. 94 % of theory), a colourless oil, was used in the next step without any further purification. RF . 9 (MaChereY_ Nagel, Polygram~R)SIL G/UV2s4, pre-coated plastic sheets for TLC; ~luent: ethylacetate/methanol/conc. ammonia 100/30/3, v/v/v)O
d) 6-Methyl-2-[(4-methylphenyl)sulfonyl]-2,6-diazaspiro- r 3,41Octane To a solution of 51.3 g (0.3 mol) of p-toluenesulfonamide and 33.6 g (0.6 mol) of potassium hydroxide in 160 ml of water was added a solution of 80.0 g (0.295 mol? of 3,3-bis-(bromomethyl) 1-methyl-pyrrolidine in 4.8 litres of dioxane and the resulting mixture was refluxed. After 17 hours and then a further 24 hours, 10.0 g (0.0584 mol) of p-toluenesulfonamide and 6.7 g (0.12 mol) of potassium hydroxide dissolved in 30 ml of water were again added and the mixture again refluxed for 24 hours. The resulting reaction mixture was evaporated down in vacuo, the residue remaining was distributed between water and ethylacetate, the organic layer was washed once with water, dried over sodium .
sulphate and evaporated in vacuo using a rotary evaporator. The residue remaining (64.0 g) was stirred with diisopropylether and suction filtered, the suction filter residue remaining was finally recrystallised from hot cyclohexane using activated charcoal. 50.5 g (61 %
of theory) of colourless crystals were obtained, Mp. 83-85C.
c14H20N22s (280-39) Calculated: C 59.67 H 7.1~ N 9.99 S 11.43 Found: 56.66 7.16 10.30 11.51 e) 6-Methyl-2~6-diazaspiro r 3~4]octane A mixture of 48.5 g (0.173 mol) of 6-methyl-2-[(4-methyl-phenyl)-sulfonyl]-2,6-diazaspiro[3,4]octane, 199 ml (about 0.7 mol) of an approx. 3.5 molar solution of sodium-bis-(2-methoxy-ethoxy)dihydroaluminate in toluene and 300 ml of dry toluene were heated to 60C for 15 hours with stirring and to 80C for 6 hours. After the reaction had ended, 20 % aqueous sodium hydroxide solution was care~ully added dropwise, whilst external cooling was carried out with ice water, until the development of hydrogen had ceased, the toluene phase was separated off, dried over sodium sulphate and evaporated carefully using a Vigreux column at a pressure of 50 mmHg. The desired compound had a boiling point 22 ~Hg 8~-85C and proved to be a colourless, readily mobile liquid smelling like an amine. Yield:
7.5 g (34 % of theory).
f) 5,11-Dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl-6H-pyrido[2 3-b]~1 4~benzodiaze~in-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 6-methyl-2,6-, f~ ~ ~
diazaspiro[3,4]octane in a yield of 26 % of theory Colourless crystals Mp. 225.5-227.0C (acetonitrile).
C20H21Ns2 (363-42)-Calculated: C 66.10 H 5.82 N 19.27 Found: 66.185.82 19.17 Example 13 5,11-Dihydro-8-ethyl~ [[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl-6H-pyrido[2,3-bl~l,4]be_zodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-ethyl-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one and 6-methyl-2,6-diazaspiro[3,4]octane in a yield of 47 % of theory.
Colourless crystals Mp. 215-217C (acetonitrile).
C22H25N502 (391-48)-Calculated: C 67.50 ~ 6.44 N 17.89 Found: 67.27 6.41 17.88 Example 14 5,11-Dihydro-8-methyl-11-[[6-methyl-2,6-diazaspiro[3~4]oct-2-yl]carbonyl-6H-pyrido[2 r 3~
b]~1 4~benzodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 6-methyl-2,6-diazaspiro[3,4]octane in a yield of 34 % of theory Colourless crystals Mp. 220-223C (acetonitrile).
C21H23Nso2 t377 45) Calculated: C 66.83 H 6.14 N 18.55 Found: 66.59 6.12 18.41 2 ~
Example 15 5,11-Dihydro-9-methyl-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one and 6-methyl-2,6-diazaspiro[3,4]octane in a yield of 41 % of theory Colourless crystals Mp. 242-245C ~after re-crystallisation twice from acetonitrile).
C21H23N50z (377-45)-.
Calculated~ C 66.83 H 6.14 N 18.55 Found: 66.57 6.23 18.41 .Example 16 9-Chloro-5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one Prepared analagously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 6-methyl-2,6-diazaspiro[3,4]octane in a yield of 37 ~ of theory Colourless crystals Mp. 229-230C (acetonitrile).
C20H20ClNsO2 (397,87).
.~ .
Calculated: C 60.38 H 5.07 8.91 N 17.60 Found: 60.21 5.01 8.90 17.~4 xample 17 5,11-Dihydro-11-[[2-methyl-2,6-diazaspiro[3,4]oct-6-yl]-carbonyl-6H-pyrido r 2,3-b][1,4]benzodiazepin-6-one ~- %~2~
a) 4,4-Bis-(ethoxycarbonyl)-1-(phenylmethyl)-2-pyrrolidinone Prepared analagously to Example 12a from triethyl 1,1,2-ethanetricarboxylate and 1,3,5-tris (phenylmethyl)-hexahydro-1,3,5-triazine in the presence of trifluoroacetic acid in a yield of 90 % of theory.
Colourless, viscous oil which was used in the next stage without any further purification.
b) 3 3-Bis-(hydroxymethyl)-l-(phenylmethYl)-pyrrolidine Prepared analagously to Example 12b from 4,4-bis-(ethoxycarbonyl)-l-(phenylmethyl)-2-pyrrolidinone and lithium aluminium hydride in a yield of 78% of theory.
Colourless, highly viscous oil which after being left to stand for one week at ambient temperature crystallised out and was used without further processing in the next step.
c) 3,3-Bis-(bromomethyl)-l-(phenylmethyl)-pyrrolidine-hydrobromide A mixture of 22.0 g (0.1 mol) of 3,3-bis-(hydroxymethyl)-l-(phenylmethyl)-pyrrolidine and 130 ml of 63 % aqueous hydrobromic acid was heated to 180C in a bomb-type tube for 24 hours. After cooling, the mixture was evaporated to dryness in vacuo, the crystalline residue was stirred with 100 ml of cold water and then suction filtered. It was re-crystallised from boiling water and 35.0 g (82 % of theory) of colourless crystals were obtained, Mp. 222-225CC.
C13Hl7Br2N x HBr (428.0) Calculated: C 36.48 H 4024 Br 56.01 N 3.27 Found: 36.56 4.10 55.73 3.02 ~ J
d) 6-(Phenylmethyl)-2-[(4-methylphenyl)sulfonyl]-2,6-di-azaspiro[3,4]octane Prepared analagously to Example 12d from 3,3-bis-(bromomethyl)-l-(phenylmethyl)-pyrrolidine-hydrobromide, potassium hydroxide and p-toluenesulfonamide in a yield of 60 % of theory. The crystalline substance obtained was further processed directly without re-crystallisation or other purification.
e) 6-(Phenylmethyl)-2 6-diazaspiro r 3 4]octane Prepared analagously to Example 12e from 6-(phenylmethyl)-2-[(4-methylphenyl)sulfonyl~-2,6-diazaspiro[3,4]octane and sodium-bis-(2-methoxyethoxy)-dihydroaluminate in a yield of 41 % of theory.
Colourless liquid, Bp 18 mmHg 161-17~C and RF - 25 (Macherey-Nagel, Polygram ~R) SIL G/UV254, pre-coated plastic sheets for TLC; eluent dichloromethane/methanol/conc.aqueous ammonia 68/15/15/2, v/v/v/v).
f) 2-Methyl-6-(phenylmethyl)-2 6-diazaspiro[3 4]octane 10.8 g (0.0534 mol) of 6-(phenylmethyl)-2,6-diazaspiro[3,4]octane were dissolved in 300 ml of ethanol, mixed with 5 ml (about 0.062 mol) of a 37 %
aqueous formalin solution and refluxed for 50 minutes.
The mixture was allowed to cool, 5.0 g of Raney nickel were added and the mixture was hydrogenated for 5 hours at ambient temperature under 4 bar of hydrogen pressure.
The catalyst was filtered off, the filtrate was evaporated down in vacuo, the residue remaining was purified on silica gel by HPLC and using dichloromethane/methanol/cyclohexane/conc.aqueous ammonia 68/15/15/2 as eluent. Evaporation of suitable fractions yielded the desired compound in the form of a colourless viscous oil. Yield 6.1 g t53 ~ of theory).
- 46 ~
RF 0-54 (Macherey-Nagel, Polygram(R) SIL G/UV254, pre-coated plastic sheets for TLC; eluent dichloromethane/methanol/cyclohexane/conc.aqueous ammonia 68/15/15/2, V/V/V/V).
q) 2-Methyl-2,6-diazaspiro[3,4~octane 4.0 g of 10 % palladium/animal charcoal catalyst were added to a solution of 6.1 g (0. 0282 mol) of 2-methyl-6-(phenylmethyl)-2, 6-diazaspiro[3,4]octane in 60 ml of ethanol and the mixture was then hydrogenated for 5 hours a~ ambient temperature under a hydrogen pressure of 5 bar. It was filtered, the filtrate was evaporated under reduced pressure (100 mmHg) and a colourless oil, RF 0.1 was obtained as residue (Macherey-Nagel, Polygram(R) SIL G/UV254, pre-coated plastic sheets for TLC;
eluent dichloromethane/methanol/cyclohexane/conc.aqueous ammonia 68/20/10/5, V/V/V/V).
Yield: 3. 2 g (90 ~ of theory).
h) 5,11-Dihydro-11-[[2-methyl-2,6-diazaspiro[3,4]oct-2-yl~carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][l,4]benzodiaæepin-6-one and 2-methyl-2,6-diazaspiro[3,4]octane in a yield of 46 ~ of theory.
Colourless crystals Mp. 273-275C (acetonitrile).
C20H2~N502 (363.42).
Calculated: C 66.10 H 5.82 N 19.27 Found: 66.25 5. 89 18.90 Example 18 5,11-Dihydro-11-[[6-(phenylmethyl)-2,6-diazaspiro[3,4~oct-2-yl]carbonyl]-SH-pyridoi2,3-b]rl,4]benzodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 6-(phenylmethyl)-2,6-diazaspiro[3,4]octane in a yield of 20 % of theory.
Colourless crystals Mp. 193-195C (diisopropylether).
C26H2sN52 (439-52)-Calculated: C 71.05 ~ 5.73 N 15.93 Found: 70.75 5.91 15.76 Example 19 5~11-Dihydro-8-methyl-11-[[2-methyl-2~6-diazaspiro[3,4]oct-2-yl~carbonyl]-6H-pyrido[2,3-b][l ~]benzodiazepin-6-one Prepaxed analagously to Example 1 rom 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,6-diazaspiro[3,4]octane in a yield of 43 % of theory.
Colourless crystals Mp. 184.0-184.5C (acetonitrile).
C21Hz3NsO2 (377 45) Calculated: C 66.83 H 6.14 N 18.55 Found: 66.79 6.43 18.65 Example 20 5,11-Dihydro-8-ethyl-11-[[2-m~thyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][l 4lbenzodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-ethyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,6-diazaspiro[3,4]octane in a yield of 34 % of theory.
Colourless crystals Mp. 245-~46C (acetonitrile) C22H25Nso2 (391-48)-` 2 ~ J~
Calculated: C 67.50 H 6.44 N 17.89 Found: 67.30 6.33 17.88 Example 21 5,11-Dihydro-9-methyl-11-[[2-methyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-blCl~ J~enzodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,6-diazaspiro[3,4]octane in a yield of 41 % of theory.
Colourless crystals Mp. 284-285C (acetonitrile).
C2~H23N5O2 (377-45)-Calculated: C 66.83 H 6.14 N 18.55Found: 67.08 6.12 18.85 Example 22 9-Chloro-5,11-dihydro-11-[[2-methyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-bl[1,4]benzodiazepin-6-one Prepared analagously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-SH-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,6-diazaspiro[3,4]octane in a yield of 18 % of theory.
Colourless crystals Mp. 276-277C (after re-crystallisation twice from acetonitrile).
C20H20ClNsO2 (397,87)-Calculated: C 60.38 H 5.07 Cl 8.91 N 17.50 Found: 60.74 4.92 ~.91 17.77 Example 23 2 ~
8-Chloro-5,11-dihydro-ll-[[2-methyl-2r6-diazaspiro[3,4~oct-6-yl~carbonyl]-6H-pyrido[2,3-bl~l,41benzodiazepin-6-one Prepared analagously to Example 1 from 8-chloro-11-tchlorocarbonyl)-5,11-dihydro-6H-pyrido~2,3-b][l,~]benzodiazepin-6-one and 2-methyl-2,6-diazaspiro[3,4]octane in a yield of 50 % of theory.
Colourless crystals Mp. 231-232C (acetonitrile).
C20H20ClNsO2 (397.87).
Calculated: C 60.3~ H 5.07 Cl 8.91 N 17.60 Found: 60.62 5.20 8.61 17.54 Example 24 5,11-Dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one a) 4-Cvano-4-(ethoxycarbonyl)-1-ethyl-2-pyrrolidinone Prepared analogously to Example 12a) from diethyl 2-cyanosuccinate and 1,3,5-triethyl-hexahydro-1,3,5-triazine in the presence of trifluoroacetic acid in a yield of 89% of theory. Colourless oil, which was further processed as a crude product without purification.
b) 3-(Aminomethyl)-3-(hydroxymethyl)-1-ethylpyrrolidone Prepared analogously to Example 12b) from ~-cyano-4-(ethoxycarbonyl)-l-ethyl-2-pyrrolidinone and lithium aluminium hydride in tetrahydrofuran in a yield of 74%
of theory. Colourless oil, RF . 25 (Macherey-Nagel, Polygram~ SIL G/UV2s4, pre-coated pIastic sheets for TLC;
eluant: ethyl acetate/methanol/cyclohexane/conc. aqueous ammonia 68/15/15/2, v/v/v/v).
c) 3-(Aminomethyl)-3-~bromomethyl)-1-ethylpyrrolidine-dihydrobromide __ _ Prepared analogously to Example 12c) from 3-(aminomethyl)-3-(hydroxymethyl)-1-ethylpyrrolidine and 63% aqueous hydrobromic acid in a yield o~ 94% of theory. The crude, brownish salt was subjected to the following reaction of cyclisation without any further purification.
d) 6-Ethyl-2,6-diazaspiro~3 4]octane The solution of 149.4 g (0.39 mol) of 3-(aminomethyl)-3-(bromomethyl)-1-ethylpyrrolidine in 2 litres of dioxane was carefully mixed with a mixture of 130 g (3.25 mol) of sodium hydroxide and 120 ml of water and then heated to boiling for 8 hours with stirring and refluxing. After cooling, it was filtered, the aqueous phase was removed from the filtrate and discarded, the organic phase was freed from sol~ent under slightly reduced pressure (100 mmHg) and using a Vigreux column.
The residue remaining yielded 15.8 g (29% of theory~ of a colourless oil, bP.20 ~Hg 83-87C, which was identified as the desired compound by MS, IR and 1H-NMR spectra, after distillation in a water jet vacuum.
e) 5,11-Dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-8-methyl-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one _ , Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one and 6-ethyl-2,6-diazaspiro[3,4]octane in a yield of 27~ of theory.
Colourless crystals m.p. 216-217nC (acetonitrile).
3 ~
C22H2sNs2 (391- 48)-Calc.: C 67. 50 H 6.44N 17.89 Found: 67.39 6.2017.60 Example 25 5,11-Dihydro-11-[[6 ethyl-2,6-diazaspiro[3,4]oc~-2-yl]carbonyl]-6H-pyrido~2 3-b][1 4]benzodiazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 6-ethyl-2,6-diazaspiro[3,4]octane in a yield of 15% of theory.
Colourless crystals m.p. 221-223C (acetonitrile).
C21H23Nso2 (377 45) Calc.: C 66.83 H 6.14 N 18.55 Found: 66.77 6.32 18.32 Example 26 5,11-Dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11~dihydro-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 6-ethyl-2,6-diazaspiro[3,4]octane in a yield of 26~ of theory.
Colourless crystals m.p. 1~9-171C (acetonitrile).
C22H25N52 ( 391.48).
Calc.: C 67.50 H 6.44 N 17.89 Found: 67.46 6.09 17.49 Example 27 9-Chloro-5,11-dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-, 2~2,~
one Prepared analogously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-ben~odiazepin-6-one and 6-ethyl-2,6-diazaspiro[3,4]octane in a yield of 19% of theory.
Colourless crystals, m.p. 158-160~C (acetonitrile) and RF
0.63 (~acherey-Nagel, Polygram~ SIL G/UVz54~ pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/methanol/cyclo-hexane/conc. aqueous ammonia 62/16.7/10/10/1.3, v/v/v/v/v).
C21H22ClN5~2 (411.90).
Calc.: C 61.24 H 5.38 Cl ~.61 N 17.00 Found: 61.25 5.36 8.63 17.08 5,11-Dihydro-11-[[6-propyl-2,6-diazaspiro[3,4]oct-2-yllcarbonyl]-6H-pyrido r 2 3-b][1 41benzodiazepin-6-one a) 4-Cyano-4-(ethoxycarbonyl)-1-propyl-2-pyrrolidinone Prepared analogously to Example 12a) from diethyl cyanosuccinate and 1,3,5-tripropyl-hexahydro-1,3,5-triazine in the presence of trifluoroacetic acid in a yield of 6~% of theory. Colourless liquid, RF . 72 (Macherey-Nagel, Polygram9 SIL G/~V2~4, pre-coated plastic sheets for TLC; eluant: ethyl acetate/petroleum ether 1/1, v/v).
b) 3-(Aminomethyl)-3-(hydroxymethyl)-1-propylpyrrolidine Prepared analogously to Example 12b~ from 4-cyano-4-(ethoxycarbonyl)-l-propyl-2-pyrrolidinone and lithium aluminium hydride in a yield of 28% of theory.
Colourless viscous oil, used in the next step without further purification.
c) 3-(Aminomethyl)-3-(bromomethyl)-1-propylpyrrolidine-dihydrobromide Prepared analogously to Example 12c) from 3-(aminomethyl)-3-(hydroxymethyl)-1-propylpyrrolidine and 63% aqueous hydrobromic acid in a yield of 91% of theory. The brownish coloured salt was reacted without further purification in the next step.
d) 6-Propyl-2,6-diazaspiro[3.4]octane 3-(Aminomethyl)-3-(bromomethyl)-1-propylpyrrolidine was reacted with caustic soda, water and dioxan as described in E~ample 24d). The crude product obtained after processing, RF . 5 (Macherey-Nagel, Polygram3 SIL
G/UV254, pre-coated plastic sheets for TLC; eluant:
dichloromethane/methanol/cyclohexane/conc. a~ueous ammonia 68/20/10/5, v/v/v/v) was purified by column chromatography on silica gel using the eluant described above. The title compound was obtained in a yield of 47% of theory - based on 3-(aminomethyl)-3-(hydroxymethyl)-l-propylpyrrolidine - and identified as the desired compound by MS and 1H-NMR spectrum.
e) 5,11-Dihydro-11-[[6-propyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6 one and 6-propyl-2,6-diazaspiro[3,4]octane in a yield of 74~ of theory.
Colourless crys~als m.p. 208-209C (acetonitrile).
CzH2sN502 (391-48) Calc.: C 67.50 H 6.44 N 17.89 - ` -- 54 - ~JJq7 Found: 67.~Lo 6.39 17.60 Example 29 5,11-Dihydro-8-methyl-11-[[6-propyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b]C1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6H-pyrido[2,3-b]-[1,4]benzodiazepin-6-one and 6-propyl-2,6-diazaspiro[3,4]octane in a yield of 60% of theory.
Colourless crystals m.p. 219-221C (acetonitrile).
C23H27N502 (405.50) Calc.~ C 68.13 H 6.71 N 17.27 Found: 68.02 6.74 17.00 Example 30 8-Chloro-5,11-dihydro-11-[[6-propyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 8-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 6-propyl-2,6-diazaspiro[3,43Octane in a yield of 44% of theory.
Colourless crystals m.p. 210-212C (from diisopropylether and acetonitrile).
C22H24ClN502 (425-93) Calc.: C 62.04 H 5.68 Cl 8.32 N 16.44 Found: 61.85 5.68 8.39 16.38 Example 31 ~ ~ 2 ~
5,11-Dihydro-8-ethyl-11-[[6-ethyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl~-5,11-dihydro-8-ethyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 6-ethyl-2,6-diazaspiro[3,4]octane in a yield of 12% of theory.
Colourless crystals m.p. 190-191C (acetonitrile) and RF
0.65 (Macherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/methanol/cyclohexane/conc. aqueous ammonia 62/16.7/10/10/3, v/v/v/v/v).
C23H27NsO2 (405-50) Calc.: C 68.13 H 6.71 N 17.27 Found: 67.92 6.64 17.44 Example 32 5,11-Dihydro-9-methyl-11-[[6-propyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one - -Prepared analogously to ExampIe 1 from 11-(chlorocarbonyl)-5,11-dihydro~9-methyl-6H-pyrido[2,3-b]-~1,4]benzodiazepin-6-one and 6-propyl-2,6-diazaspiro[3,4]octane in a yield of 39~ of theory.
Colourless crystals m.p. 183-184~C (acetonitrile) and RF
0.51 (Macherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/methanol/cyclohexane/conc. aqueous ammonia 63.5/13/11/11/1.5, v/v/v/v/v).
C23H27N502 (405-50) Calc.: C 68.13 H 6.71 N 17.27 Found: 68.00 6.52 17.10 Example 33 2~2~
5,11-Dihydro-8-ethyl-11-[[6-propyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one ~` Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-ethyl-6H-pyrido[2,3-b]-[1,4]benzodiazepin-6-one and 6-propyl-2,6-diazaspiro[3,4]octane in a yield of 55% of theory.
Colourless crystals m.p. 170-172C (acetonitrile) and RF
0.52 (Macherey-Nagel, Polygram~ SIL G/ W2s4, pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/methanol/cyclohexane/conc. aqueous ammonia 63.5/13/11/11/1.5, v/v/v/v/v).
C24H29N5~2 (419.53) Calc.: C 68.71 H 6.9t N 16.69 Found: 68.90 7.18 16.72 Example 34 5,11-Dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4]oct-2-yl~carbonyll-6H-pyrido r 2 3-bl r 1,4]benzodiazepin-6-one a) 2-Acetyl-6-(PhenylmethYl)-2.6-diazasPiro~3.4loctane 37.7 ml (0.4 mol) of acetic anhydride are added dropwise to a solution of 70.8 g (0.35 mol) of 6-(phenylmethyl)-2,6-diazaspiro[3,4]octane in 300 ml of ethanol with vigorous stirring and the resulting mixture is then refluxed for 3 hours. It is concentrated by evaporation in vacuo, made alkaline with 20% aqueous sodium hydroxide solution and extracted exhaustively with diethylether. The combined ether extracts are dried over caustic potash, freed from solvent and the residue remaining is finally distilled in a high vacuum.
The desired compound is obtained as a colourless oil, bP.O 035 ~H9 155-168C in a yield of 69.3 g (81% of theory).
~2~3 ~
b) 2-Ethyl-6-~phenylmethyl)-2 6-diazasPiro r 3 41octane Prepared analogously to Example 12b) from 2-acetyl-6-(phenylmethyl)-2,6-diazaspiro[3,4]octane and lithium aluminium hydride in anhydrous tetrahydrofuran. The desired compound is obtained as a colourless oil bp.o2 ~Hg 91-93C amd RF 0.6 (Macherey-Nagel, Polygram SIL G/UVzs4, precoated plastic sheets for TLC; eluant:
dichloromethane/methanol/cyclohexane/conc. aqueous ammonia 68/15/15/2, v/v/v/v) in a yield of 73% of theory.
c) 2-Ethyl-2, 6-diazaspiro r 3 41octane Prepared analogously to Example 17g) from 2-ethyl-6-(phenylmethyl)-2,6-diazaspiro[3,4]octane by catalytic hydrogenation in the presence of 10% palladium/animal charcoal. The desired compound is obtained as a colourless oil, RF . 45 (Macherey-Nagel, Polygram~ SIL
G/UV2s4, precoated plastic sheets for TLC; eluant:
dichloromethane/methanol/cyclohexane/ethyl acetate/conc.
aqueous ammonia 62/10/10/16.7/1.3, v/v/v/v/v) in a yield of 96% of theory.
d) 5,11-Dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 2-ethyl-2,6-diazaspiro[3,4]octane in a yield of 60% of theory.
Colourless crystals m.p. 251-254C (dioxan) and RF 0 3 (Macherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/methanol/cyclohexane/conc. aqueous ammonia 63.5/13/11/11/1.~, v/v/v/v/v).
C21H23N5Oz (377-45) Calc.: C 66.83 H 6.14 N 18.55 Found: 66.61 6.20 18.40 Example 35 5,ll-Dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4~oct-6-yl]carbonyl]-8-methyl-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-ethyl-2,6-diazaspiro[3,4]octane in a yield o~ 61% of theory.
Colourless crystals m.p. 213-215C (acetonitrile).
C22H2sNsOz (391-48) Calc.: C 67.50 H 6.44 N 17.89 Found: 1 67.19 6.32 18.22 Example 36 5,11-Dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin 6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6H-pyrido[2,3-b]-[1,4]benzodiazepin-6-one and 2-ethyl-2,6-diazaspiro[3,4]octane in a yield of 56% of theory.
Colourless crystals m.p. 251-253C (acetonitrile~.
C22H2sNs2 (391-48) Calc.: C 67.50 H 6.44 N 17.89 Found: 67.32 6.49 18.31 Example 37 9-Chloro-5,11-dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4~-oct-2-yl]carbonyl]-6H-pyrido[2,3-b]~1,4]benzodiazepin-6-one ~
2 ~ 3 Prepared analogously to Example 1 from 9-chloro~
(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 2-ethyl-2,6-diazaspiro[3,4]octane in a yield of 45% of theory.
Colourless crystals m.p. 248-250C (acetonitrile).
CzlH22ClNsO2 (411-9~) Calc.: C 61.24 H 5.38 Cl 8.61 N 17.00 Found: 61.31 5.22 8.90 16.98 Example 38 5,11-Dihydro-11-[[6-(2-methylpropyl)-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyr do[2 3-b]~1 4]benzodiazepin-6-one a) 4-Cyano-4-(ethoxycarbonyl)-1-(2-methylpropyl)-2-pyrrolidinone Prepared analogously to Example 12a) in a yield of 74% of theory from cyanosuccinic acid and hexahydro-1,3,5-tris-(2-m~thylpropyl)triazine using trifluoroacetic acid. Colourless oil, RF . 8 (Macherey-Nagel, Polygram~ SIL G/UV2s4, pre-coated plastic sheets for TLC; eluant: ethyl acetate/petroleum ether 1:1, v/v) .
b) 3-(Aminomethyl)-3-(hydroxymethyl)-1-(2-methylpropyl)-pyrrolidine Prepared analogously to Example 12b) from 4-cyano-4-(ethoxycarbonyl)-1-(2-methylpropyl) 2-pyrrolidinone by reduction with lithium aluminium hydride in a yield of 35% of theory. Colourless oil, RF . 2~ (Macherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets for TLC;
eluant: dichloromethane/methanol/cyclohexane/conc.
aqueous ammonia 68/15/15/2, v/v/v/v).
2~2~
c) 3-(Aminomethyl)-3-(bromomethyl)-1-(2-methylpropyl)-pyrrolidine-dihydrobromide Prepared analogously to E~ample 12c) from 3-(aminomethyl)-3-hydroxymethyl-1-(2-methylpropyl)-pyrrolidine and 63% aqueous hydrobromic acid. The brownish salt is used in the following step without further purification.
d) 6-(2-Methylpro~yl)-2,6 diazaspiro~3l4]octane Prepared analogously to Example 28d) from 3-(aminomethyl)-3-(bromomethyl)-1-(2-methylpropyl)-pyrrolidine-dihydrobromide and caustic soda in the presence of water and dioxan in a yield of 62% of theory. Colourless oil, RF . 45 (Macherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets for TLC;
eluant: dichloromethane/methanol/cyclohexane/conc.
aqueous ammonia 68/20/10/2, v/v/v/v).
e) 5, 11-Dihydro-11-[[6-(2-methylpropyl)-2,6-diazaspiro-[3,4]oct 2-yl]carbonyl3-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b] [1,43-benzodiazepin-6-one and 6-(2-methyl-propyl)-2,6-diazaspiro[3,4]octane in a yield of 49% of theory.
Colourless crystals m.p. 199-~01C (acetonitrile) and RF
0.48 (Macherey-Nagel, Polygram~ SIL G/UVz54~ pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/methanol/cyclohexane/conc. aqueous ammonia 63.5/13/11/11/1.5, v/v/vjv/v).
C23H27NsO2 (405-50) Calc.: C 68.13 H 6.71 N 17.27 Found: 67.96 6.84 17.47 Example 39 - ~2~3~
5,11-Dihydro-8-methyl-11-[[6-(2-methylpropyl)-~,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b]-r 1 4]benzodiazepin-6-one Prepared analogously to Example 1 ~rom 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 6-(2-methylpropyl)-2,6-diazaspiro[3,4]octane in a yield of 52% o~ theory. Colourless crystals m.p. 1~6-188C
(acetonitrile).
C24H29N502 (419.53) Calc.: C 68.71H 6.97N 16.69 Found: 68.67 6.99 16.47 Example 40 5,11-Dihydro-9-methyl-11-[[6-(2-methylpropyl)-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b]-r 1 4]benzodiazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6H-pyrido[2,3-b]-[1,4]benzodiazepin-6-one and 6-(2-methylpropyl)-2,6-diazaspiro[3,4]octane in a yield of 24~ of theory.
Colourless crystals, m.p. 163-165C (acetonitrile).
C24H29N502 (419.53) Calc.: C 68.71 H 6.97 N 16.69 Found: 68.62 6.72 16.67 Example 41 9-Chloro-5,11-dihydro-11-[[6-(2-methylpropyl)-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b]-r 1~4]benzodiaze~in-6-one Prepared analogously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 6-(2-methylpropyl)-2,6-' ~ t'J
diazaspiro[3,4]octane in a yield of 45% of theory.
Colourless crystals, m.p. 177-179C tdiisopropylether).
C23H26ClNsO2 (439.94) Calc.: C 62.79 H 5.96 Cl 8.06 N 15.92 Found: 62.98 6.29 8.07 16.08 Exam~le 42 6,11-Dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]-carbonyll-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one and 2-methyl-2,7-diazaspiro[4,4]nonane in a yield of 84% of theory.
Colourless crystals, m.p. 212-214C (acetonitrile).
C21H23N502 (377-45) Calc.: C 66.83 H6.14 N 18.55 Found: 66.86 6.33 18.73 ~' Example 43 :`;
6,11-Dihydro-11-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]carbonvl]-5H-pyrido[2.3-b][1,5]benzodiazepin-5-one Prepared analogously to Example l from 11-(chlorocarbonyl)-6,11-dihydro-5~-pyrido[2,3-b][1,5]-benzodiazepin-5-one and 2-ethyl~2,7-diazaspiro[4,4]-nonane in a yield of 68% of theory. Colourless crystals, m.p. 151.0-152.5C (acetonitrile1.
C22H2sN502 (391.48) Calc.: C 67.50 H 6.44 N 17.89 Found: 67.65 6.55 18.04 Example 44 6,11-Dihydro~ [[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-5H-pyrido~2 3-b][1,51benzodiazepin-5-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one and 6-methyl-2,6-diazaspiro[3,4]octane in a yield of 38% of theory.
Colourless crystals, m.p. 239-241C (acetonitrile).
C20H21N5O2 (363.42) Calc.: C 66.10 H 5.82 N 19.27 Found: 65.99 5.77 19.17 Example 45 6,11-Dihydro-11-[[2-methyl-2,6-diazaspiro[3,4]oct-6-y~llcarbonyl]-5H-pyrido[2,3-b]~1,51benzodiazepin-5-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one and 2-methyl-2,6-diazaspiro[3,4]-octane in a yield of 50% of theory. Colourless crystals, m.p. 220-221~C (acetonitrile).
CzoH2lNsO2 (363-4~) Calc.: C 66.10 H 5.82 N 19.27 Found: 65.88 6.08 19.00 Example 46 6,11-Dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyll-5H-pyrido~2,3-bl r 1,51benzodiazePin-5-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one and 6-ethyl-2,6-diazaspiro[3,4]octane in a yield of 10% of theory.
Colourless crystals, m.p. 196-200~C (acetonitrile~ and RF
0.62 (~acherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/methanol/cyclo-hexane/conc. aqueous ammonia 62/16.~/10/10/1.3, v/v/v/v/v).
C2~H23NsO2 (377-45) Calc.: C 66.83 H 6.14 N 18.55 Found: 66.26 6.11 18.14 ~m~
6,11-Dihydro-11-[[6-propyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-5H-pyrido[2,3-bl~l.51benzodiazepin-5-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one and 6-propyl-2,6-diazaspiro[3,4]octane in a yield of 51% of theory.
Colourless crystals, m.p. 195-197C (acetonitrile) and RF
~` 0.58 (conditions as in Example 46).
C22H25NsO2 (391.48) Calc.: C 67.50 H 6.44 N 17.89 Found: 67.46 6.36 17.98 Example 48 6,11-Dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4]oct-6-yl]-carbonyl~-5H-pyrido r 2,3-b U1 51benzodiazepin-5-one :`
Prepared analogously to Example 1 but using tetrahydrofuran instead of acetonitrile as solvent, from ll-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[~,3-b]-[1,5]benzodiazepin-5-one and 2-ethyl-2,6-diazaspiro[3,4]-octane in a yield of 61% of theory.
Colourless crystals/ m.p. 186-189C (acetonitrile) and RF
0.32 (Macherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/methanol/cyclo-hexane/conc. aqueous ammonia 63.5/13/11/11/1.5, v/v/v/v/v).
C21H23N5O2 (377 45) Calc.: C 66.83 H 6.14N 18.55 Found: 67.00 6.17 18.73 Exa~nple 49 6,11-Dihydro-11-[[6-(2-methylpropyl)-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-5H-~ Pyridor2,3-b] r1~5lbenzodiazepin-5-one .
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one and 6-(2-methylpropyl)-2,6-diazaspiro[3,4]octane in a yield of 60~ of theory.
Colourless crystals, m.p. 187-189C (acetonitrile).
C23H27NsO2 (~05 50) Calc.: C 68.13 H 6.71 N 17.27 Found: 67.95 6.77 17O47 Example 50 5,10-Dihydro-5-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]-carbonyl]-llH-dibenzo[b,e][1.4]diazepin-11-one Prepared analogously to Example 1 from 5-(chlorocarbonyl)-5,10~dihydro-llH-dibenzo[b,e][1,4]-diazepin-ll-one and 2-methyl-2,7-diazaspiro[4,4]nonane in a yield of 75% of theory. Colourless crystals, m.p.
190C (acetonitrile).
C22H24N4O2 (376.46) Calc.: C 70.19 H 6.43 N14.88 Found: 70.14 6.4314.86 Example 51 ~2~
4,9-Dihydro-3-methyl-4-[[7-methyl-2,7-diazaspiro[4,4]-non- 2-yllcarbonyll-1OH-thienor3 4-b1 rl 51benzodiazepin-10-one Prepared analogously to Example 1, but using dichloromethane instead of acetonitrile, from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-lOH-thieno[3,4-b]-[1,5]benzodiazepin-10-one and 2-methyl-2,7-diazaspiro-[4,4]nonane in a yield of 44% of theory. Colourless crystals, m.p. 213-214C (acetonitrile).
C21H24N42S (396051) Calc.: C 63.61 H 6.10 N 14.13 S 8.09 Found: 63.30 6.19 14.21 7.94 Example 52 4,9-Dihydro-4-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]-carbonyl]-3-methyl-lOH-thieno[3,4-b][1,5]ben20diazepin-10-one Prepared analogously to Example 51 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-lOH-thieno[3,4-b]-[1,5]benzodiazepin-10-one and 2-ethyl-2,7-diazaspiro[4,4]nonane in a yield of 65% of theory.
Colourless crystals, m.p. 215-216C (acetonitrile).
C22H26N42S (410.54) Calc.: C 64.36 H 6.38 N 13.65 S 7.81 Found: 64.28 6.33 13.87 7.91 Exam~le 53 4,9-Dihydro-3-methyl-4-[[6-methyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dih~dro-3-methyl-lOH-thieno~3,4-~]-[1,5]benzodiazepin-lo-one and 6-methyl-2,6-diazaspiro[3,4]octane in a yield of 52% of theory.
Colourless crystals, m.p. 200-203C (acetonitrile).
2S (382.49) Calc.: C 62.80 H 5.80 N 14.65 S 8.38 j Found: 62.51 5.68 14.67 8.40 ExamPle 54 4,9-Dihydro-3-methyl-4-[[2-methyl-2,6-diazaspiro[3,4]-oct-6-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-lOH-thieno-[3,4-b][1,5]benzodiazepin-10-one and 2-methyl-2,6-diazaspiro[3,4]octane in a yield of 28% of theory.
Colourless crystals, m.p. 135-137C [acetonitrile).
C20H22N42S (382.49) Calc.: C 62.80 H 5.80 N 14.65 S 8.38 Found: 62.62 5.81 14.70 8.54 Example 55 4,9-Dihydro-4-[[6-ethyl-2,6-diazaspiro[3,~]oct-2-yl]carbonyl]-3-methyl-lOH-thieno[3,4-b][1,5]benzo-diazepin-10-one Prepared analo~ously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-lOH-thieno-[3,4-b][1,5]benzodiazepin-10-one and 6-ethyl-2,6-diazaspiro[3,4]octane in a yield of 30% of theory.
Colourless crystals, m.p. 208-210C (acetonitrile).
.~
CzlH24N42S (396.51) Calc.: C 63.61 H 6.10 N 14.13 S 8.09 Found: 63.35 6.25 14.32 8.19 Example 56 4,9-Dihydro-3-methyl-4-[[6-propyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-lOH-thieno[3,4-b]-[1,5]benzodiazepin-10-one and 6-propyl-2,6-diazaspiro[3,4]octane in a yield of 44% of theory.
Colourless crystals, m.p. 180-181C (acetonitrile) and RF
0.54 (Macherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/methanol/cyclohexane/conc. a~ueous ammonia 63.5/13/11/11/1.5, v/v/v/v/v).
CzH26N402S (410.54) Calc.: C 64.36 H 6.38N 13.65 S 7.81 Found: 64.26 6.35 13.64 7.71 Example 57 4,9-Dihydro-4-[[2-ethyl-2,6-diazaspiro[3,4]oct-6-ylJ-carbonyl]-3-methyl-lOH-thieno[3,4-b][1,5Jbenzodiazepin-10-one Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-lOH-thieno[3,4-b]-[1,5]benzodiazepin-10-one and 2-ethyl-2,6-diazaspiro[3,4]octane in a yield of 61% of theory.
,J ,~ J~3 Colourless crystals, m~p. 216-217C (acetonitrile) and RF
0.47 (conditions as in Example 56).
C21H24N42S (396.51) Calc.: C 63.61 H 6.10 N 14.13 S 8.09 Found: 63.51 6.10 14.27 8.08 xample 58 4,9-Dihydro-3-methyl-4-[[6-(2-methylpropyl)-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-lOH-thieno[3,4-b]-r 1~5]benzodiaæepin-lo-one Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one and 6-(2-methylpropyl)-2,6-diazaspiro[3,4]octane in a yield of 71% of theory. Colourless crystals, m.p. 186-188C
(acetonitrile).
C23H28N42S (424.56) Calc.: C 65.07 H 6.65N 13.20 S 7.55 Found: 65.07 6.6113.30 7.42 Example 59 3-Chloro-1-methyl-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]-benzodiazepin-lo-one Prepared analogously to Example 1 from 3-chloro-4-(chlorocarbonyl)-l-methyl-1,4,9,10-tetrahydropyrrolo-[3,2-b][1,5]benzodiazepin-10-one and 2-methyl-2,7-diazaspiro[4,4]nonane in a yield of 80% of theory.
Colourless crystals, m.p. 205-206C (acetonitrile).
C21H24ClN502 (413.92) Calc.: C 60.94 H 5.84 Cl 8.57 N 16.92 Found: 61.13 5.56 8.78 17.20 Example 60 1-Methyl-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]-enzodiazepin-10-one 3.5 g (~.46 mmol) of 3-chloro-1-methyl-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2~b][1,5]benzodiazepin-10-one were dissolved in 350 ml of hot ethanol and after the addition of 3 g of palladium on animal charcoal (20~) the mixture was hydrogenated for 2 hours under a hydrogen pressure of 50 bar and at a temperature of 40C. The catalyst was filtered off, the filtrate was evaporated down ln vacuo, the crystalline hydrochloride was taken up in 20 ml of water, the resulting solution was made alkaline with sodium hydroxide solution and extracted exhaustively with dichloromethane. The combined extracts were dried over sodium sulphate and concentrated by evaporation and the residue remaining was recrystallised from n-propanol. 1.1 g (34% of theory) of colourless crystals are obtained, m.p.
223-225OC.
C2l~25N5o2 (379.47) Calc.: C 66.47 H6.64 N 18.46 Found: 66.43 6.84 18.44 Example 61 3-Chloro-1-methyl-4-[[6-propyl-2,6-diazaspiro[3,4~oct-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]-benzodiazepin-10-one Prepared analogously to Example 1 from 3-chloro-4-(chlorocarbonyl)-1-methyl-1,4,9,10 tetrahydropyrrolo-[3,2-b][1,5]benzodiazepin-lo-one and 6-propyl-2,6-diazaspiro[3,4]octane in a yield of 51% of theory.
Colourless crystals, m.p. 164-165C (acetonitrile).
C22H26ClNsO2 (427.94) Calc.: C 61.75 H 6.12 Cl 8.28 N 16.37 ~ ~ 2 ~
Found: 61.48 5.99 8.42 16.37 Example 62 3-Chloro-l-methyl-4-[[6-(2-methylpropyl)-2,6-diazaspiro-[3,4]oct-2~yl]carbonyl]-1,4,9,10-tetrahydropyrrolo-r 3,2-b][1 ~]benzodiazepin-lo-one __ Prepared analogously to Example 1 from 3-chloro-4-(chlorocarbonyl)-l-methyl-1,4,9,10-tetrahydropyrrolo-[3,2-b][1,5]benzodiazepin-10-one and 6-(2-methylpropyl)-2,6-diazaspiro[3,4]octane in a yield o~ 23% of theory.
Colourless crystals, m.p. 163-165C (acetonitrile).
C23H2sClN5Oz (441-96) Calc.: C 62.51 H 6.39 Cl 8.02 N 15.85 Found: 62.47 6.39 8.18 15.89 Example 63 3-Chloro-l-methyl-4-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b]~1,5]-benzodiazepin-10-one Prepared analogously to Example 1 from 3-chloro-4-(chlorocarbonyl)-l-methyl-1,4,9,10-tetrahydropyrrolo-[3,2-b][1,5]benzodiazepin-10-one and 6-methyl-2,6-diazaspiro[3,4]octane in a yield of 61% of theory.
Colourless crystals, m.p. 215-217C (acetonitrile) and RF 0-7 (Macherey-Nagel, Polygram~ SIL G/UV2s4, pre-coated plastic sheets for TLC; eluant:
dichloromethane/methanol/ c~clohexane/conc. aqueous ammonia 68/15/15/2, v/v/v/v).
CzoH22ClNs2 (399-88) Calc.: C 60 . 07 H 5 . 55 C1 8. 87 N 17 . 51 Found: 60.13 5.39 9.02 17.64 Example 64 ~2~
5,11-Dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbon~l]-6H-pyrido r 2 3-bl[1 4]benzodiazePin-6-one 5.36 g (0.0425 mol) of 6-methyl-2,6-diazaspiro-[3,4]octane were added dropwise to a mixture consisting of 22.5 ml of a 20% solution of phosgene in toluene, 100 ml of acetonitrile and 4.75 g (0.045 mol) of anhydrous sodium carbonate, whilst cooling externally with ice. The mixture was stirred for a further 60 minutes at ambient temperature, then 9.0 g (0.0428 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one were added to the reaction mixture and it was then refluxed for 4 hours. The boiling hot mixture was filtered, the precipitate was washed thoroughly three times with 10 ml of hot acetonitrile and the combined filtrates were evaporated down to a total volume of 50 ml in vacuo. They were left to cool and kept occasionally stirred with a glass rod for 2 hours at 0 to 5C, the crystal slurry formed was suction filtered, recrystallised from acetonitrile and colourless crystals were obtained, m.p. 225.5-227.0C which were found to be identical, according to the mixed melting point, IR and 1H-NMR spectrum, to a preparation made according to Example 12.
Yield: 5.4 g (35~ of theory).
The following were obtained in the same way:
~ 5,11-dihydro-11~[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, m.p. 272-274C (acetonitrile);
5,11-dihydro-8-methyl-11-[[7-methyl-2,7-diazaspiro[4,4]-non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin 6-one, m.p. 212-214C (acetonitrile);
J
5,11-dihydro-8-ethyl-11-[[6-methyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, m.p. 215-217C (acetonitrile);
5,11-dihydro-8-methyl-11-[[2~methyl-2,6-diazaspiro[3,4]-oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, m.p. 184.0-184.5C (acetonitrile).
Example 65 5,11-Dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-6H-pyrido r 2.3-b][1,4]benzodiazepin-6-one To a suspension of 2.6 g (9.5 mmol) of 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one in 30 ml of dimethylformamide, a solution of 1.2 g (9.51 mmol) of 6-methyl-2,6-diazaspiro-[3,4]octane in 10 ml of dimethylformamide was added dropwise at ambient temperature and with stirring.
The initially clear solution turns cloudy within a few minutes. After stirring for half an hour at ambient temperature the colourless solid was suction filtered and washed thoroughly with three times 3 ml of ice cold ethanol. The colourless monohydrochloride of the desired compound obtained was dissolved in 10 ml of water, mixed with a saturated aqueous potassium carbonate solution until a clearly alkaline reaction occurred and then filtered. The resulting solid was washed thoroughly with water, then dried in a vacuum drying chamber at 50C and over diphosphorus pentoxide;
then recrystallised from hot acetonitrile and dried ln vacuo once more. 2.35 g (68~ of theory) of colourless crystals were obtained, m.p. 225.5-227.0C, which was found to be identical to a preparation made according to Example 12, judging by the mixed melting point, IR and H-NMR spectra.
Example 66 .
R6 represents a hydrogen or chlorine atom or a methyl ~roup;
R7 and R8, which may be the same or different, each represents a hydrogen atom or C14 alkyl group, and R8 may also represent a halogen atom, m, n, ~ and p each independently represents the number l or 2 with the proviso that the sum of m+n+o+p must be no greater than 6) and the isomers and acid addition salts thereof.
Preferred compounds according to the invention include compounds of formula I wherein:
either X represents a nitrogen atom and ] ~ represents a group (S) or X represents a =C~- group and ] ~ represents the group (V);
R represents a methyl group, R4 and Rs, which may be the same or different, each represents a hydrogen, fluorine or chlorine atom or a methyl or ethyl group; and m and p each represents the number l and n and o each represents the number l or 2, and the isomers and salts thereof.
~ 9 2 .~
Particularly preferred compounds according to the invention include 5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6~-pyrido[2,3-b][1,4]benzodiazepin-6-one;
5,11-dihydro-8-methyl-11-[[7-methyl-2,7-diazaspiro-[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one;
5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-6~-pyrido[2,3-b][1,4]benzodiazepin-6-one;
5,11-dihydro-8-ethyl-11-[[6-methyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one; and 5,11-dihydro-8-methyl-11-[[2-methyl-2,6-diazaspiro[3,4]-oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one;
and the isomers and salts thereof.
The compounds of formula I may occur in the form of their acid addition salts. While physiologically acceptable salts are of course preferred, other salts may be useful as intermediates in the preparation of the free bases or of physiologically acceptable salts.
Organic and inorganic acids which have proved suitable for the preparation of physiologically acceptable salts include, for example, hydrochloric, hydrobromic, sulphuric, methylsulphuric, phosphoric, tartaric, fumaric, citric, maleic, succinic, yluconic, malic, p-toluenesulfonic, methanesulphonic and amidosulphonic acids.
To illustrate the invention further the following compounds are mentioned by way of example:
(+)-5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]-carbonyl]-6H-pyrido[2~3-b][l~4]benzodiazepin-6-one R-5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one S-5,11-dihydro-11-[C7-methyl-2,7-diazaspiro[4,4]non-2-yl]-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (+)-9-chloro-5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 8-Chloro-5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 8-bromo-5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4~benzodiazepin-6-one 5,11-dihydro-8-ethyl-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one -5,11-dihydro-9-methyl-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-ll-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4~benzodiazepin-6-one 5,11-dihydro-8-methyl-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[7-ethyl]-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 9-chloro-5,11-dihydro-11-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-8-ethyl-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H pyrido[2,3-b][1,4]benzodiazepin-6-one 5-11-dihydro-8-methyl-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-9-methyl-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 9-chloro-5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5,11-dihydro-8,9-dimethyl~ll-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5~11-dihydro-11-[[2-methyl-2~6-diazaspiro[3~4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one ~2~
5,11-dihydro-11-[[6-(phenylmethyl)-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-8-methyl-11-[[2-methyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5,11-dihydro-8-ethyl-11-[[2-methyl-2~6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5,11-dihydro-9-methyl~ [2-methyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 9-chloro-11-[[2-methyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 8-chloro-11-[[2-methyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl~-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-8-methyl-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5,11-dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4~oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-9-methyl-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 9-chloro-5,11-dihydro-11-[[6-ethyl-2,6-diazaspiro[3~4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 8 2~2~
5-11-dihydro-8-ethyl~ [[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5,11-dihydro-11-[[6-propyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-6H-pyrido[2,3-b][l,~]benzodiazepin-6-one 5,11-dihydro-8-methyl-11-[[6-propyl-2,6-diazaspiro[3,4~oct-2-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one ~3-chloro-5,11-dihydro-11-[[6-propyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-9-methyl-11-[[6-propyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5,11-dihydro-8-ethyl-11-~[6-propyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5,11-dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-9-methyl-6H-pyrido[2,3-b]tl,4]benzodiazepin-6-one 9-chloro-5,11-dihydro-11-[~2-ethyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[6-(2-methylpropyl)-2,6-diazaspiro~3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-8-methyl-11-[[6-(2-methylpropyl)-2,6-diaza-spiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one 5,11-dihydro-9-methyl-11-[[6-~2-methylpropyl)-2,6-diaza-spiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one 9-chloro~5,11-dihydro~ll-[[6-(2-methylpropyl)-2,6-diaza-spiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5,11-dihydro-11-[[6~methyl-2,6-diazaspiro[3,3]hept-2-yl]-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-8-methyl-11-[[6-methyl-2,6-diazaspiro[3,3]hept-2-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 5,11-dihydro-9-methyl-11-[[6-methyl-2,6-diazaspiro[3,3]hept-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-11-[[7-methyl 2,7-diazaspiro[3,5]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-8-methyl-11-[[7-methyl-2,7~
diazaspiro[3,5]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 9-chloro-5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[3,5]non-2-yl]carbonyl-6H-pyrido[2,3-b][l,4]benzodiazepin-6 one 5,11-dihydro-11-[[2-methyl-2,7-diazaspiro[3,5]non-7-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 5,11-dihydro-9-methyl-11-[[2-methyl-2,7-diazaspiro[3,5]non-7-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 8-chloro-5,11-dihydro-11-[[2-methyl-2,7-diazaspiro[3,5]non-7-yl]carbonyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one 8-bromo-5,11-dihydro-ll-[[2-methyl-2,7-diazaspiro[3,5]non-7-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (+)-6,11-dihydro-11~[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one R-6,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl~-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one S-6,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one (+)-6,11-dihydro-11-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one 6,11-dihydro-11-[[2-methyl-2,6-diazaspiro[3,4]oct-6-yl]-carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one 6,11-dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-5H-pyrido[2l3-b][ll5]benzodiazepin-5-one 6,11-dihydro-11-[[6-propyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one 6,11-dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4]oct-6-yl]-carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one 6,11-dihydro-11-[[6-(2-methylpropyl)-2,6-diazaspiro[3,4]-oct-2-yl]-carbonyl]-SH-pyrido[2,3-b][1,5]benzodiazepin-5-one 6,11-dihydro-lI-[[6-methyl-2,6-diazaspiro[3,3]hept-2-yl]-carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one 6,11-dihydro-11-[[7-methyl-2,7-diazaspiro[3,5]non-2-yl]-carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one 6,11-dihydro-11-[[2-methyl-2,7-diazaspiro[3,5]non-7-yl]-carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one (+)-5,10-dihydro-5-L[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-llH-dibenzo[b,e][1,4]diazepin-11-one 5,10-dihydro-5-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-llH-dibenzo[b,e][1,4]diazepin-11-one (+)-4,9-dihydro-3-methyl-4-~[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one (~)-4,9-dihydro-4-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]-carbonyl]-3-methyl-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one 4,9-dihydro-3-methyl-4-[[6-methyl-2,6-diazaspiro[3,4]-oct-6-yl]carbonyl]-lOH-thieno[3,4~b][1,5]benzodiazepin-10-one 4,9-dihydro-3-methyl-4-[[2-methyl-2,6-diazaspiro[3,4]-oct-6-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one :
4,9-dihydro-4-[[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-3-methyl-lOH-thieno[3,4-b][1,5]benzo~iazepin-10-one :.
4,9-dihydro-3-methyl-4-[[6-propyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-lOH-thieno[3,4-b]tl,5]benzodiazepin-10-one 4,9-dihydro-4-[[2-ethyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-3-methyl-lOH-thieno[3,4-b][l,5]benzodiazepin-10-one 4,9-dihydro-3-methyl-4-[[6-(2-methylpropyl)-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin 10-one 4,9-dihydro-3-methyl-4-[[6-methyl-2,6-diazaspiro[3,3]-hept-2-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one 4,9-dihydro-4-[[6-methyl-2,6-diazaspiro[3,3]hept-2-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one 4,9-dihydro-3-methyl-4-[[7-methyl-2,7-diazaspiro[3,5]-non-2-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one 4,9-dihydro-3-methyl-4-[[2-methyl-2,7-diazaspiro[3,5]-non-7-yl]carbonyl]-loH-thieno[3~4-b][l~5~benzodiazepin 10-one (+)-3-chloro-1-methyl-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one (+3-1-methyl~4-~[7-methyl-2,7-diazaspiro~4,4]non-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzo-diazepin-10-one 3-chloro-1-methyl-4-[[6-propyl-2,~-diazaspiro[3,4~oct-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo~3,2-b]~1,5]benzodiazepin-10-one 3-chloro-1-methyl-4-[[6-(2-methylpropyl)-2,6-diazaspiro[3~4~oct-2-yl]carbonyl]-l/4~9~lo-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one 3-chloro-1-methyl-4-~[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][l,5]benzodiazepin-10-one and 3-chloro-1-methyl-4-[t6-methyl-2,6-diazaspiro[3,3]hept-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one.
Viewed from another aspect the invention also 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 base-substituted condensed diazepinones of formula Ia \N~
~N)~ .
X
:; ( l a n R
- 14 - ~ ~2~
(wherein X, R, m, n, o and p are as hereinbefore defined and ] ~ represents one of the groups (S), (U) or (V) : as hereinbefore defined or a group (T') ~CH3 ~/> ( T
wherein R4, R5, R7 and R8 are as hereinbefore defined and R6 represents a chlorine atom or a methyl group)) reacting a carbonic acid derivative of formula II
Y~
o (wherein ] ~ and X are as hereinbefore defined and Y
represents a halogen atom, preferably bromine or ~ chlorine, or a group ORI1 where R11 represents an : optionally halogen substituted C15 alkyl group, a phenyl :~ group optionally substituted by halogen atoms or nitro ~ 2 ~
groups or a C715 aralkyl group) with a compound of formula III
/
( t~--N
(1~ ~ )n (I ~ I) /Nt ) o R
(wherein R, m, n, o, and p are as hereinbefore defined) or a metal compound of formula IIIa /
( -~1 (~)n (Illa) /N
:~ R
(wherein R,m,n,o and p are as hereinbefore defined and M
represents an alkali metal atom or 1 equivalerlt of an alkaline earth metal atom);
b) (to prepare base substituted condensed diazepinones of formula Ia) reacting a tricyclic compound of formula IV
' 16 2 ~ 2 ~
, H
~ ~0 H
(wherein X and ] ~ are as hereinbefore defined) with a :: chlorocarbonic acid derivative of formula V
i O
~CI
: ( ~N
(V) N
(wherein R, m, n, o and p are as hereinbefore defined);
c) ~to prepare pyrrolo-condensed diazepinones of formula Ib H~ U C H
N ~N
~N
X ~ ( I b~
~N
tJ 3"
~N )~
:~- R
(wherein X, R, m, n, o and p are as hereinbefore defined)~ hydrogenolysing a compound of formula Ia wherein R6 represents a chlorine atom;
d) separating a compound of formula I thus obtained into its isomers; and e) converting a compound of formula I into an acid addition salt thereof or an acid addition salt of a compound of formula I into the free base.
The reaction of step (a) is carried out without or preferably in the presence of a solvent such as water or toluene or an alcohol such as methanol, ethanol or isopropanol, but particularly preferably in the presence of an aprotic polar solvent, e.g. tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric acid triamide, or mixtures thereof and at temperatures between -1~C
and the boiling point of the reaction mixture, preferably between 40 and lOO~C. It has proved convenient to use additional organic or inorganic bases, e.g. alkali metal or alkaline earth metal hydroxides, alkoxides or carbonates (e.g. sodium hydroxide, sodium methoxide, potassium tert butoxide, sodium carbonate and potassium carbonate), tertiary amines (e.g.
triethylamine, ethyldiisopropylamine and N,N-dimethylaniline), pyridine or 4-(dimethylamino~pyridine, and to carry out the reaction in the presence of an excess of a compound of formula III.
If the spirodiamines of formula III and the carbonic acid derivatives of formula II are used in equimolar quantities, the hydrohalic acid salts of the desired compounds of formula Ia are obtained directly (provided that Y represents a halogen atom).
Metal compounds of formula IIIa can readily be pr~pared in situ from compounds of formula III by reacting with alkali or alkaline earth metals, e.g. with sodium, potassium or barium, or with alkali metal or alkaline earth metal hydrides, e.y. with sodium, potassium or calcium hydride, or by reaction with alkali metal or alkaline earth metal organometallic compounds, e.g. with n-butyllithium or phenyllithium.
The reaction of step (b) is preferably carried out in an inert organic solvent, e.g. in an aromatic hydrocarbon such as toluene or xylene, in an ether such as diisopropyl ether, tetrahydrofuran or dioxane, in a ketone such as 3-pentanone, in a chlorinated aliphatic hydrocarbon, such as 1,2-dichloroethane or in another solvent, such as acetonitrile or dimethylformamide, or in mixtures thereof, optionally in the presence of a tertiary organic base such as pyridine, and at temperatures up to the boiling point of the reaction mixture, preferably at temperatures between +30 and +100 C .
The hydrogenolysis of step (c) is conveniently carried out in the presence of a catalyst based on a metal of the VIIIth subgroup of the Periodic Table of the elements, for example palladium on animal charcoal, palladium on barium sulfate, Raney nickel or Raney cobalt and at hydrogen pressures of 1 to 300 bar and temperatures of 0C to 130C, in the presence of solvents, e.g. alcohols (such as methanol and ethanol), ethers (such as dioxane and tetrahydrofuran), carboxylic acids (e.g. acetic acid) or tertiary amines (e.g.
triethylamine). If the work is done in the absence of additional hydrogen chloride acceptors, e.g. sodium carbonate, potassium hydrogen carbonate, triethylamine or sodium acetate, the hydrochlorides of the desired compounds are produced directly and may be isolated after removal of the catalyst by evaporation of the reaction solution. If, in place of hydrogen,formic acid is used in the hydrogenolysis reaction described above, the reaction will theoretically succeed even under pressureless conditions. In this variant, it has proved particularly useful to carry out the reaction with formic acid in the presence of dimethylformamide as solvent and palladium on charcoal as catalyst at temperatures between 70 and 110C, and to carry out the reduction with triethylammoniumformate in the presence of excess triethylamine and palladium on animal charcoal or palladium acetate and triarylphosphines, such as triphenylphosphines, tris(o-tolyl) phosphines and tris-(2,5-diisopropylphenyl)-phosphines, at temperatures between 40 and 110C.
Bases of formula I thus obtained can subsequently be converted into the acid addition salts thereof or, if acid addition salts are obtained, they may be converted into the free bases or other pharmacologically acceptable acid addition salts.
If in the aminocarbonylated condensed diazepinones of formula I according to the invention m and o each represent 1, and n and p each represent 2, these compounds are chiral because they have an asymmetric carbon atom in the side chain. These compounds can therefore occur as enantomeric (+) and (-) forms. The invention includes the individual isomers as well as the racemates.
Any racemates of the compounds of formula I may be resolved by known methods, for example using an optically active acid such as (+l or (-)tartaric acid or -a derivative thereof such as (+~ or (-)diacetyltartaric acid, (+) or (-~monomethyltartrate or (+)camphorsulfonic acid.
According to a conventional method of isomer separation the racemate of a compound of formula I may be reacted with one of the above mentioned optically active acids in equimolar quantities in a solvent and the crystalline diasteromeric salts obtained are separated on the basis of their different solubilities.
This reaction may be carried out in any type of solvent provided that it has a sufficiently different solubility for the salts. Methanol, ethanol or mixtures thereof are preferred, e.~. in a ratio by volume of 50:50. Then - 20 - 2~ 3 each of the diastereomeric salts is 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.
only one enantiomer is obtained if the methods of synthesis described above are carried out with only one enantiomer of formula III, IIIa or V.
The preparation of the carbonic acid derivatives of formula II used as starting products is described in detail in DE-A-3726908.
Compounds of formula III, which are generally new and have not yet been described, can be obtained for example by the following methods:
i) 2-Substituted 2,7-diazaspiro[4,4]nonanes of formula III may be obtained following the procedures described by Warner-Lambert Comp., in AU-A-83/18698 (see Derwent 107 300).
ii) 6-Substituted 2,6-diazaspiro[3,4]octanes of formula III may be prepared for example starting from 1,1,2-ethanetricarboxylic acid esters which, when reacted with suitable 1,3,5-trisubstituted hexahydro-1,3,5-triazines in the presence of catalytic quantities of trifluoroacetic acid, yield 1-substituted 2-pyrrolidinone-4,4-dicarboxylic acid esters in a high yield. Reduction with lithium aluminium hydride leads to 1-substituted 3,3-bis-hydroxymethyl-pyrrolidines which can be reacted with concentrated aqueous hydrombromic acid in a bomb-type tube to obtain the corresponding bis-bromomethyl-pyrrolidine-hydrobromides without difficulty. These react with p-toluenesulfonic acid amides in the presence of concentrated potassium hydroxide solution and using dioxane or dimethylform-amide as solvents to obtain in a high yield 6 substituted 2-(4-methylbenzenesulfonyl~-2,~-diazaspiro[3,4]octanes, which can }:e detosylated, for example, with sodium-bis-t2-methoxyethoxy~-2~2~
aluminiumhydride (RED-Al~ ), preferably in toluene solution, to obtain the desired 6-substituted 2,6-diazaspiro[3,4]octanes.
Alternatively, two cyanosuccinic acid esters may be used for the raaction with the 1,3,5-trisubstituted hexahydro-s-triazines instead of the 1,1,2-ethanetricarboxylic esters. This results in 1-substituted 4-cyano-4-carbalkoxy-2-pyrrolidinones, which yield 1-substituted 3 aminomethyl-3-hydroxymethyl-pyrrolidines when reduced with lithium aluminium hydride. Reaction with concentrated aqueous hydrobromic acid produces a good yield of 1-substituted 3-(aminomethyl)-3-(bromomethyl)-pyrrolidines, which can readily be cyclised, when treated with concentrated sodium or potassium hydroxide solution in the presence of water-miscible solvents, e.g. dioxane, ethanol, methanol or dimethylformamide, to obtain the desired 6-substituted 2,6-diazaspiro[3,4]octanes.
iii) 2-Substituted 2,6-diazaspiro[3,4~octanes of formula III may, according to one of the variants given in (ii) above, be obtained from readily accessible 6-(phenylmethyl)-2,6-diazaspiro[3,4]octane by alkylating in the 2-position in a conventional manner for example by reacting with a suitable acylating agent followed by reduction with lithium aluminium hydride, with the benzyl group subsequently being removed by hydrogenolysis.
iv) 2-Substituted 2,6-diazaspiro[3,3]heptanes of formula III can be prepared in a conventional ~anner from unsubstituted 2,6-diazaspiro[3,3]heptane which is a known compound (see A. Litherland and F.G. Mann, J.
Chem. Soc. [London] 1938, 15~8; F. Govaert and M.
Beyaert. Bull. Soc. Chim. Belg. 55: 106, 112 [1946];
F.G. Mann and A. Litherland, Nature 141: 789-7gO
[1938]), for example by monoacylation and subsequent \
careful re~uction with lithium aluminium hydride in diethylether.
v) 7~Substituted 2,7-diazaspiro[3,5]nonanes of formula III may be prepared from the 1-substituted 4-cyano-4-piperidinecarboxylic acid esters which are obtainable analagously to the procedures described by L. Ciszewski, Pol. J. Chem. 62: 451-455 [1988]. For example, the 1-substituted 4-cyano-4-piperidinecarboxylic acid esters are catalytically hydrogenated in glacial acetic acid and in the presence of platinum~IV)oxide and concentrated sulphuric acid to obtain the corresponding ~-alanine esters. These may then be cyclised with Grignard reagents, for example with ethyl magnesium bromide, in ether and at O to 5C to obtain 7-substituted 2,7-diazaspiro[3,5]nonan-1-ones which when reduced with lithium aluminium hydride in ether are converted into the desired 7-substituted 2,7-diazaspiro[3,5]nonanes. Alternatively, the 7-substituted 2,7-diazaspiro[3,5]non-1-ones may also be obtained by saponifying the above mentioned ~-alanine esters to obtain the corresponding ~-alanines and then closing the azetidinone ring in a theoretically known manner, e.g. by the action of triphenylphosphine and tetrachloromethane or N-bromosuccinimide, ethyldichlorophosphate, phenyldichlorophosphate or phenylphosphonic acid dichloride, in the presence of triethylamine and using acetonitrile as solvent.
vi) 2-Substituted 2,7-diazaspiro[3,5]-nonanes of formula III may also be prepared from 7-(phenylmethyl)-2,7-diazaspiro[3,5]nonane synthesised according to (v~
above, without any significant problems using the reaction sequence specified in (iii) above.
The tricyclic compounds of formula IV are known from patent literature or may be synthesised following published methods from available starting materials.
- 23 ~
Chlorocarbonic acid derivatives of formula V may be prepared in accordance with current methods from spirodiamines of formula II and phosgene.
The condensed diazepinones of formula I and the acid addition salts thereof have valuable properties; as already mentioned, they exhibit selective spasmolytic properties on peripheral organs, particularly the ileum and bladder, and in view of the absence of any effect of increasing heart rate, inhibiting gastric acid secretion, inhibiting saliva or affecting the accommodating powers of the eye in the therapeutic dosage range they are suitable for use in human and veterinary medicine for the treatment of cholinergically induced spasms and motility disorders in the gastrointestinal tract and in the region of the outward-leading bile ducts, for the symptomatic treatment of cystitis and spasm in urelithiasis by lowering the pathologically raised tone of the hollow organs, for the treatment of relative incontinence based on an incongruity of sphincter and detrusor tone, for the symptomatic treatment of bronchial asthma and bronchitis by suppressing the muscarincally mediated part of the bronchoconstriction, and for the treatment of ischaemic heart disease by lowering heart rate and at the same time suppressing parasympathetically induced coronary spasm and lowering the basal coronary tone.
Thus viewed from a further aspect the present invention provides a method of treatment of the human or non-human ~preferably mammalian) body to combat cholinergically induced spasm and motility disorders in the gastrointestinal tract and in the region of the outward leading bile ducts, to combat cystitis and spasm in urelithIasis, to combat relative incontinence, to combat bronchial asthma and bronchitis and to combat ischaemic heart disease, said method comprising administering a compound of formula I or a physiologically acceptable acid addition salt thereof to said body.
- 24 ~
Viewed from a further aspect the invention provides the use of a compound of formula I or a physiologically acceptable acid addition salt thereof for the manufacture of a therapeutic agent for use in a method of treatment to combat cholinergically induced spasm and motility disorders in the gastrointestinal tract and in the region of the outward leading bile ducts, to combat cystitis and spasm in urelithiasis, to combat relative incontinence, to combat bronchial asthma and bronchitis and to combat ischaemic heart disease, Viewed from a still further aspect the invention provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient.
For this purpose the compounds of formula I or salts thereof may be incorporated, in a conventional manner into conventional pharmaceutical forms, e.g. solutions, suppositories, plain or coated tablets, capsules or infusions. For oral administration the daily dose is generally between 0.01 and 10 mg/kg, preferably from 0.02 to 5 mg/kg, more particularly 0.05 to 2.5 mgJkg of body weight, optionally administered in the form of several, preferably one to three doses, to achieve the desired results.
A favourable correlation between spasmolitic effects on the one hand and the undesirable effects on heart rate, pupil size, and the secretion of tears, saliva and gastric acid, on the other hand, which occurs with therapeutic agents having an anticholinergic activity component is of particular importance to the therapeutic use of the substances. The following experiments show that the compounds according to the invention show particularly favourable correlations in this respect.
A. Investi~ation of functional selectivity of the antimuscarinic effect Substances with antimuscarinic properties inhibit the effects of exogenously supplied agonists or of acetylcholine released from cholinergic nerve endings.
The following is a description of methods which are suitable for determining spasmolitically effective antimuscarinics.
"In vitro" OrgLan Preparations Dissociation constants (KB-values) were determined in vitro on the ileum and spontaneQusly beating atrium of the guinea pig. The ileum was removed and incubated in Krebs-~enseleit solution in an organ bath. Contractions were induced by increasing concentrations of methacholine (M) so that full concentration/activity curves could be recorded. Then the M was washed out, the test substance was added and left in contact for 30 minutes and another concentration/activity curve was recorded with M.
The dosage ratio (DR), i.e. the extent of displacement of the concentration/activity curve, made it possible to calculate the dissociation constant according to ~runlakshana and Schild ~Brit. J.
Pharmacol~ 14, 48, 1959).
In an isolated, spontaneously beating right atrium, M reduced the heart rate~ as a function of the concentration. By adding an antimuscarinic agent this effect was cancelled again. Dissociation constants for the muscarinic receptors of th~ atrium were obtained in the manner described above. ~ comparison of the dissociation constants obtained in two tissues made it possible to identify substances ~ith a selective spasmolitic effect. The results are shown in Table III.
"In vivo" Methods The methods used had the purpose of confirming the selectivity of the antimuscarinic effect. Those ~ - 26 - 2~2~
substances which had been selected on the basis of in vitro tests were investigated for 1. Selectivity of the bronchospasmolitic activity in guinea pigs.
2. The saliva-secretion inhibiting effect in the rat and 3. In situ spasmolitic activity in guinea pigs.
1. Effect on M-receptors of the bronchii, heart and bladder of anaethetised auinea pias Method , .
Male and female guinea pigs (body weight 550-600 g) were anaethetised with urethane (1.4 g/kg, i.p.). A
cannula was inserted into the jugular vein for the purpose of injecting the active substance. 220 I.U./kg of heparin were injected intravenously. A cannula was inserted in the trachea; the animals were artificially respirated with oxygen-rich air using a positive pressure pump (Braun-Melsungen~ at a rate of 80 beats per minute. One branch of the tracheal cannula was connected to a water manometer 10 cm high. The respiration volume was adjusted so that the maximum intratracheal pressure during respiration just reached the pressure of a 10 cm water column.
~ part from a few modifications, the effect of the active substances on bronchial tone was measured by the method described by Konzett and Rossler (1940~. The volume of respiration gas mixture produced by broncho-constriction (overflow) which flowed through the water manometer was measured by means of a tube-type pneumatic tachometer (Fleisch, model 1000), connected to an SP
2040D differential pressure transducer tHSE). The results were recorded with an IFD recorder. Before the test the trachea was clamped for a short time to produce 2~2~
the maximum possible degree of bronchoconstriction for calibration purposes. A cannula was inserted in the left carotid artery; the arterial blood pressure was measured using a pressure transducer (Bell and Howell, 4-327 I) in conjunction with an IFD recorder. The heart rate was measured with a heart rate meter triggered by arterial pulse waves.
A small median abdominal cut was made and the bladder was connected to a power transducer under a resting tension of l gram.
The active substances to be tested were injected through the jugular vein and 5 minutes later the increase in the tension of the bladder (in grams) the bronchial resistance (in %) and the decrease in heart rate (beats per minute) after the administration of acetylcholine (50 ~g/kg i.v. and i.a.) were measured.
Dosage-dependent curves were plotted by giving the percentage inhibition of bronchoconstriction, bradycardia and the increase in the tension of the bladder against the logarithm of the dose (mol/kg) of the active substances to be tested. The results are given as averages (for 4 to 6 animals). For the results see Table I.
':
2. Salivation-inhibiting effect in the rat Male THOM rats anaethetised with 1.2 g/kg urethane were given increasing doses of the substance i.v. in accordance with Lavy and Mulder (~rch. int. Pharmacodyn.
178, 437-445, (1969)). The salivation was initiated by the subcutaneous administration o~ 2 mg/kg of pilocarpine. The saliva was mopped up with blotting paper and the area it occupied was determined by planimetry every 5 minutes. The dosage o~ substance which reduced the volume of saliva by 50% was determined graphically. For the results see Table II.
3. In-situ spasmolytic effect on quinea pias - 28 - 2~2~
Male guinea pigs (500 to 600 g body weight) were anaethetised with urethane t1.2 g/kg, i.p.); cannulas were inserted in the trachea, jugular vein and left carotid artery. The animals were artificially respirated with oxygen-rich air using a positive pressure pump at a beat rate of 80 per minute. An abdominal incision 3 to 4 cm long was made and about 15 cm of a movable loop of the small intestine (ileum) was tied off at the distal end whilst the circulation of the blood was maintained~ The proximal part was filled with a Krebs-Ringer solution and a pressure meter with a Millar micro-tip catheter (PC-450, 5F) was inserted into the intestine. A glass tube was placed vertically in the abdomen and fixed to the surrounding abdominal wall so that when the glass tube was filled with Krebs-Ringer solution the animal acted as his own organ bath.
The glass tube was filled with Krebs-Ringer solution until the entire lower abdomen was immersed. The active substances being tested were injected through the jugular vein; 5 minutes later, contractions were produced using methacholine (20 ~g/~g i.a.). By recording the percentage suppression of the methacholine-induced contractions against the logarithm of the dosage (mol/kg) of the test substance, dosage/activity curves were obtained.
The results were given as averages (for 4 to 8 animals~ (see Table II).
The following compounds, by way of example, were tested using the above methods:
A = 5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b]~1,4]benzodiazepin-6-one B = 5,11-dihydro-8-methyl-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one ~2~
C = 5,11-dihydro-11-[[6-methyl-2,6-diazaspiro~3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one D = 5,11-dihydro-8-ethyl-11-[[6-methyl~2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6~-pyrido[2,3-b][1,4]benzodiazepin-6-one E = 5,11--dihydro-8-methyl-11-[[2-methyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one and as comparison substances X = 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (c.f. US Patent 4 550 107) ;
Y = 5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (Pirenzepine, see US Patent No. 3 660 380) and ; Z = Atropine.
- 30 - 2~2~
:~ Table I
Selectivity of the bronchospasmolytic activity in the guinea pigo Acetylcholine - Antagonism _ _ = .. _ . ~ ¦ Tost Bronchii Bladdor Hoart Ratio o~
¦ Substanco - log ED,jo - log ED50 - log ED50 influ~nco o~
,~ l (mol kg'1) (mol kg~1) (mol kg 1) br~dycardia to l i.v. i.v. i.v. bronchoconstriction I
, ¦ A 6.44 5.48 5.10 22 '~' .__ . .. _.___ ¦ B 6.65 6.29 5.45 16 C 7.30 6.79 5.88 26 ~~ .. __.
D 6.97 6.82 6.01 9 ., _ __ E 7.27 6.98 5.76 32 ` -=.- -... _ .. __ X 5.58 4.93 5.84 0.5 Y 6.57 5.84 5.90 5 Z 8.09 7.28 7.57 3 . _ ~ .. ~ ..
-.
Table II
Selectivity of the in situ spasmolytic activity in relation to the salivation inhibiting effect.
Tost In silu spasmolysis S li~vatlon inhibition Ratio ot salivation .
Subst~tnco guinoa plg ilcum rat il~hibition to Ih~
- log ED60 -109 ED spasmolylic activity . ~ . _... (mol kg~1) (mol kg'1) ¦ . _ 6.05 _ ~ 5.46 4 697 _~---~-- 637 Z
¦ - .... _ _ 5.4B . 5 . _ __ 3 Y 6.08 6.42 0.5 I _ l _ 7.2B 7.60 0.5 .
~2~
;: - 32 -Table III
Dissociation constants (KR values) on the ileum and spontaneously beating attrium of the guinea pig.
. _ T~st H~art llourn Soloc~ivity Substanc~ KB Imol/l~ KB [mol/ll KB Hoart to _ ____ _ A 1.23 X 10-6 2.69 X 10-7 4.~
: ~ B 2.51 X 10 7 5.89 X 10 B ._ . _ 3.39 X 10 7 7.24 X 10-8 4 7 __ D 1 1 X 10-7 2.24 X 10 8 4 9 . ~ E 4.68 X 10-7 6.46 X ~0-8 7.2 . ___ .
¦ X 1 05 10-7 6.17X 10 7 0.17 ¦ Y 1 23 X 10-7 1.94 X 10 7 0.63 Z 1.41 X 10 9 8.13 X 10-~ 1.7 ~ ..
Discussion of the results The compounds of the invention, in low doses, inhibit the effects of exogenously supplied acetylcholine or methacholine on the smooth muscle of bronchii, bladder or small intestine, without this agonistic effect altering the heart rate (Tables I and II). For example, substances C and E show a very marked selectivity for the smooth muscle; 26- and 32- times lower doses are needed in order to inhibit the acetylcholine induced broncho-constriction, compared with the acetylcholine-induced bradycardia (Table I). The compounds of the invention not only show selectivity for the smooth muscle compared with effects which are initiated by cardiac muscarine receptors, but also higher doses are - 33 - ~2 needed in order to inhibit the pilocarpine~induced salivation (Table II).
The in vivo selectivity of these compounds for the smooth muscle observed agrees with the in vitro tests.
The substances have a higher affinity for muscarine receptors in the ileum than for cardiac muscarine receptors (Table III).
The data show that the compounds of the invention inhibit the effects of muscarine agonists on the smooth muscle e.g. bronchii, bladder and ileum, at doses which have no effect on heart rate or salivation. The comparison substances Y (pirenzepine) and Z (atropine~
show no selectivity and influence all the above mentioned effects in the same dosage range. Comparison substance X shows a higher level of effect on cardiac muscarine receptors.
All the compounds of the invention are characterised by excellent stability to hydrolysis. It is therefore possible to prepare solutions for parenteral administration which will have a long shelf life.
The following non-limiting examples are intended to illustrate the invention:
Mp denotes melting point, D denotes decomposition.
There are satisfactory elementary analyses, IR-, UV-, 1H-NMR-spectra and frequently mass spectra for all the compounds. Unless otherwise expressly mentioned, the percentages, parts and ratios given are always by weight.
Example 1 5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-Yllcarbonyl]-6H-pvrido r 2,3-bl[1,41benzodiaze~in-6-one A mixture of 9.0 g (0.033 mol) of 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b] r 1,4]benzodiazepin-6-one, 4,3 g (0.041 mol) of '3~
anhydrous sodium carbonate, 5.6 g (0.04 mol) of 2-methyl-2,6-diazaspiro[4,4]nonane and 100 ml of acetonitrile were stirred for 30 minutes at a reaction temperature of 50C. The solvent was then distilled off in vacuo, the remaining highly viscous residue was taken up in 30 ml of water, made alkaline with sodium hydroxide and exhaustively extracted with dichloromethane. The combined dichloromethane phases were dried over sodium sulphate and evaporated down and the residue was purified by chromatography on silica gel (35-70 mesh) using dichloromethane/ethylacetate/
cyclohexane/methanol/conc. ammonia 50/11/9/9/1, v/v/v/v/v, as eluent. The residue remaining after evaporation of the suitable eluates was recrystallised from watertmethanol 1/9 (v/v). 5.9 g (48 96 theory) oî
colourless crystal were obtained, Mp. 271-274C.
C2lH23Ns2 ~377-45)-Calculated: C 66.83 H 6.14 N 18.55 Found: 67.00 6.35 18.85 Example 2 9-Chloro-5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yI]carbonyl]-6H-pyrido[2,3-b~[l,4lbenzodiazepin-6-one Prepared analagously to Example l from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,7-diazaspiro[4,4]nonane in a yield of 41 g6 of theory.
Colourless crystals Mp. 257-259C (dimethylacetamide).
C21H22N52 (411-90)-Calculated: C 61.24 H 5.38 C1 8.61 N 17.00 Found: 61.50 5.67 8.59 17.10 Example 3 - 35 - 2 ~ 2 ~
5,11-Dihydro-8-methyl-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiaepin-6-one . . _ Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,7-diazaspiro[4,4]nonane in a yield of 71 % of theory.
Colourless crystals Mp. 212-214C (acetonitrile using activated charcoal).
CzzHzsNsOz (391.48).
Calculated: C 67.50 H 6.44 N 17.89 Found: 67.89 6.20 18.00 Exam~le 4 8-Chloro-5,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][l~4]benzodiazepin-6-one Prepared analagously to Example 1 from 8-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one and 2-methyl-2,7-diazaspiro[4,4~nonane in a yield of 47 % of theory.
Colourless crystals Mp. 214-215C (acetonitrile).
Cz1HzzClN50z (411.90).
Calculated: C 61.24 H 5.38 Cl 8.61 N 17.00 Found: 61.00 5.38 8.72 17.10 Example 5 5,11-Dihydro-8-ethyl-ll-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1~4]benzodiazepin-6-one 2~ 3 Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-ethyl-6H-pyrido[2,3-b][1,4]benzodiazepin 6-one and 2-methyl-2,7-diazaspiro~4,4]nonane in a yield of 57 % of theory.
Colourless crystals Mp. 216-217C (from acetonitrile using activated charcoal).
C23H27NsO2 (405-50)-Calculated: C 68.13 H 6.71 N 17.27 Found: 68.30 6.81 17.30 Example 6 5,11-Dihydro-9-methyl-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][l 4~benzodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,7-diazaspiro[4,4]nonane in a yield of 9 % of theory.
Colourless crystals Mp. 253-255C (acetonitrile).
C2ZH2sNso2 (391-48)-Calculated: C 67.50 H 6.44 N 17.89Found: 66.99 6Y4`7 17.62 Example 7 8-Bromo-5,11-Dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b~[l,4]benzodiazepin-6-one Prepared analagously to Example 1 from 8-bromo-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,7-diazaspiro[4,4~nonane in a yield of 64 % of theory.
Colourless crystals Mp. 227-229C (D.) (from acetonitrile/ethanol 1/1 V/V).
C21H22BrN5O2 (456.36).
Calculated: C 55.27 H 4.86 Br 17.51 N 15.35 Found: 55.60 5.10 17.35 15.13 Example 8 5,11-Dihydro-11-[~7-ethyl-2,7-diazaspiro[4,4]non-2-yllcarbonY11-6H-pyrido~2,3-b]~1,4~benzodiazepin-6-one Prepared analagously to E~ample 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one and 2-ethyl-2,7-diazaspiro[4,4]nonane in a yield of 85 % of theory.
Colourless crystals Mp. 214-215C (acetonitrile).
C22H25Nso2 (391-48)-Calculated: C 67.50 H 6.44 N 17.89 Found: 67.44 6.70 18.10 Example 9 5,11-Dihydro-11-[[7-ethyl-2,7-diazaspiro[4,43non-2-yl]carbonyl]-8 methyl-6H-pyrido[2,3-b~ 41benzodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8~methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-ethyl-2,7-diazaspiro[4,4]nonane in a yield of 74 % of theory.
Colourless crystals Mp. 178-180C (aGetonitrile~.
C23H27N502 (405 50~
Calculated: C 68.13 H 6.71 N 17.27 Found: 67.94 6.70 17.57 Exam~le 10 5,11-Dihydro-11-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-9-methyl-6H-pyrido[2,3-bl r 1.4lbenzodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-ethyl-2,7-diazaspiro[4,4]nonane in a yield of 85 % of theory.
Colourless crystals Mp. 244-246C (acetonitrile).
C23Hz7NsO2 (405-50)-Calculated: C 68.13 H 6.71 N 17.27Found: 67.83 6.92 17.17 Example ll 9-Chloro-5,11-Dihydro-11-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1.4lbenzodiazepin-6-one Prepared analagously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one and 2-ethyl-2,7-diazaspiro[4r4]nonane in a yield o~ 75 % of theory.
Colourless crystals Mp. 224.0-225.5C (acetonitrile).
C22H24ClN5o2 (425.93), Calculated: C 62.04 H 5.68 Cl 8.32 N 16.44 Found: 61.89 5.65 8.35 16.34 Example 12 5,11-Dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbon~l]-6H-pyrido[2,3-b] r 1 F 4~benzodiazepin-6-one ~ ~2 ~
a) 4,4-Bis-(ethox~carbonyl)-l-methyl-2-pvrrolidinone A mixture of 221.6 g (0.90 mol) of triethyl 1,1,2-ethanetricarboxylate, 116.3 g (0.90 mol) of 1,3,5-trimethylhexahydro-1,3,5-tria~ine and 20.6 g (0.18 mol) of trifluoroacetic acid was stirred for 20 hours at a reaction temperature of 100C. ~fter cooling, the mixture was diluted with l litre of toluene and then extracted three times with 100 ml of 10% aqueous hydrochloric acid. The aqueous hydrochloric acid extracts were combined and extracted once with lOo ml of ethylacetate. The organic phases obtained were combined, shaken once with 200 ml of a saturated aqueous sodium hydrogen carbonate solution and then washed three times with 300 ml of water, dried over sodium sulphate and evaporated down in vacuo. The colourless oil obtained (yield 220 g, i.e. 91 ~ of theory) was used without further purification in the following step.
b) 3,3 Bis-(hydroxymethyl~-1-methylpyrrolidine To a suspension of 75.0 g (1.976 mol) of lithium aluminium hydride in 1 litre of anhydrous tetrahydrofuran, a solution of 160.0 g (0.658 mol) of 4,4-bis-(ethoxycarbonyl)-l-methyl-2 pyrrolidinone in 700 ml of dry tetrahydrofuran was added dropwise in such a way that the reaction could be kept under control and the tetrahydrofuran boiled gently. After the addition had ended the mixture was refluxed for a further 4 hours with stirring. It was then left to cool and 75 ml of water, 75 ml of 15% sodium hydroxide solution and 215 ml of water were added dropwise one after the other, with stirring and external cooling with ice water. The precipitate obtained was suction filtered, expended once more with tetrahydrofuran and boiled, then suction filtered again. The filtrates obtained were combined, carefully dried over sodium sulphate and evaporated down in vacuo. The colourless, viscous oil obtained in a 2~2~
yield of 71.4 g (75% of theory) was further processed in tha next step without any more purification.
c) 3,3-Bis-lbromomethyl)-l-methylpyrrolidine A mixture of 28.0 g (0.139 mol) of the above mentioned compound and 250 ml of 63% aqueous hydrobromic acid was heated in a bomb-type tube for 24 hours to 180C. A~ter cooling, the mixture was evaporated to dryness in vacuo, the residue,-which dissolved with relative difficulty in water, was taken up in 400 ml of water and treated with excess potassium carbonate. ~he suspension obtained was extracted exhaustively with ethyl acetate, the extracts were combined and dried over sodium sulphate. The residue remaining after evaporation of the solvent (yield: 49.0 g, i.e. 94 % of theory), a colourless oil, was used in the next step without any further purification. RF . 9 (MaChereY_ Nagel, Polygram~R)SIL G/UV2s4, pre-coated plastic sheets for TLC; ~luent: ethylacetate/methanol/conc. ammonia 100/30/3, v/v/v)O
d) 6-Methyl-2-[(4-methylphenyl)sulfonyl]-2,6-diazaspiro- r 3,41Octane To a solution of 51.3 g (0.3 mol) of p-toluenesulfonamide and 33.6 g (0.6 mol) of potassium hydroxide in 160 ml of water was added a solution of 80.0 g (0.295 mol? of 3,3-bis-(bromomethyl) 1-methyl-pyrrolidine in 4.8 litres of dioxane and the resulting mixture was refluxed. After 17 hours and then a further 24 hours, 10.0 g (0.0584 mol) of p-toluenesulfonamide and 6.7 g (0.12 mol) of potassium hydroxide dissolved in 30 ml of water were again added and the mixture again refluxed for 24 hours. The resulting reaction mixture was evaporated down in vacuo, the residue remaining was distributed between water and ethylacetate, the organic layer was washed once with water, dried over sodium .
sulphate and evaporated in vacuo using a rotary evaporator. The residue remaining (64.0 g) was stirred with diisopropylether and suction filtered, the suction filter residue remaining was finally recrystallised from hot cyclohexane using activated charcoal. 50.5 g (61 %
of theory) of colourless crystals were obtained, Mp. 83-85C.
c14H20N22s (280-39) Calculated: C 59.67 H 7.1~ N 9.99 S 11.43 Found: 56.66 7.16 10.30 11.51 e) 6-Methyl-2~6-diazaspiro r 3~4]octane A mixture of 48.5 g (0.173 mol) of 6-methyl-2-[(4-methyl-phenyl)-sulfonyl]-2,6-diazaspiro[3,4]octane, 199 ml (about 0.7 mol) of an approx. 3.5 molar solution of sodium-bis-(2-methoxy-ethoxy)dihydroaluminate in toluene and 300 ml of dry toluene were heated to 60C for 15 hours with stirring and to 80C for 6 hours. After the reaction had ended, 20 % aqueous sodium hydroxide solution was care~ully added dropwise, whilst external cooling was carried out with ice water, until the development of hydrogen had ceased, the toluene phase was separated off, dried over sodium sulphate and evaporated carefully using a Vigreux column at a pressure of 50 mmHg. The desired compound had a boiling point 22 ~Hg 8~-85C and proved to be a colourless, readily mobile liquid smelling like an amine. Yield:
7.5 g (34 % of theory).
f) 5,11-Dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl-6H-pyrido[2 3-b]~1 4~benzodiaze~in-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 6-methyl-2,6-, f~ ~ ~
diazaspiro[3,4]octane in a yield of 26 % of theory Colourless crystals Mp. 225.5-227.0C (acetonitrile).
C20H21Ns2 (363-42)-Calculated: C 66.10 H 5.82 N 19.27 Found: 66.185.82 19.17 Example 13 5,11-Dihydro-8-ethyl~ [[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl-6H-pyrido[2,3-bl~l,4]be_zodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-ethyl-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one and 6-methyl-2,6-diazaspiro[3,4]octane in a yield of 47 % of theory.
Colourless crystals Mp. 215-217C (acetonitrile).
C22H25N502 (391-48)-Calculated: C 67.50 ~ 6.44 N 17.89 Found: 67.27 6.41 17.88 Example 14 5,11-Dihydro-8-methyl-11-[[6-methyl-2,6-diazaspiro[3~4]oct-2-yl]carbonyl-6H-pyrido[2 r 3~
b]~1 4~benzodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 6-methyl-2,6-diazaspiro[3,4]octane in a yield of 34 % of theory Colourless crystals Mp. 220-223C (acetonitrile).
C21H23Nso2 t377 45) Calculated: C 66.83 H 6.14 N 18.55 Found: 66.59 6.12 18.41 2 ~
Example 15 5,11-Dihydro-9-methyl-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one and 6-methyl-2,6-diazaspiro[3,4]octane in a yield of 41 % of theory Colourless crystals Mp. 242-245C ~after re-crystallisation twice from acetonitrile).
C21H23N50z (377-45)-.
Calculated~ C 66.83 H 6.14 N 18.55 Found: 66.57 6.23 18.41 .Example 16 9-Chloro-5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one Prepared analagously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 6-methyl-2,6-diazaspiro[3,4]octane in a yield of 37 ~ of theory Colourless crystals Mp. 229-230C (acetonitrile).
C20H20ClNsO2 (397,87).
.~ .
Calculated: C 60.38 H 5.07 8.91 N 17.60 Found: 60.21 5.01 8.90 17.~4 xample 17 5,11-Dihydro-11-[[2-methyl-2,6-diazaspiro[3,4]oct-6-yl]-carbonyl-6H-pyrido r 2,3-b][1,4]benzodiazepin-6-one ~- %~2~
a) 4,4-Bis-(ethoxycarbonyl)-1-(phenylmethyl)-2-pyrrolidinone Prepared analagously to Example 12a from triethyl 1,1,2-ethanetricarboxylate and 1,3,5-tris (phenylmethyl)-hexahydro-1,3,5-triazine in the presence of trifluoroacetic acid in a yield of 90 % of theory.
Colourless, viscous oil which was used in the next stage without any further purification.
b) 3 3-Bis-(hydroxymethyl)-l-(phenylmethYl)-pyrrolidine Prepared analagously to Example 12b from 4,4-bis-(ethoxycarbonyl)-l-(phenylmethyl)-2-pyrrolidinone and lithium aluminium hydride in a yield of 78% of theory.
Colourless, highly viscous oil which after being left to stand for one week at ambient temperature crystallised out and was used without further processing in the next step.
c) 3,3-Bis-(bromomethyl)-l-(phenylmethyl)-pyrrolidine-hydrobromide A mixture of 22.0 g (0.1 mol) of 3,3-bis-(hydroxymethyl)-l-(phenylmethyl)-pyrrolidine and 130 ml of 63 % aqueous hydrobromic acid was heated to 180C in a bomb-type tube for 24 hours. After cooling, the mixture was evaporated to dryness in vacuo, the crystalline residue was stirred with 100 ml of cold water and then suction filtered. It was re-crystallised from boiling water and 35.0 g (82 % of theory) of colourless crystals were obtained, Mp. 222-225CC.
C13Hl7Br2N x HBr (428.0) Calculated: C 36.48 H 4024 Br 56.01 N 3.27 Found: 36.56 4.10 55.73 3.02 ~ J
d) 6-(Phenylmethyl)-2-[(4-methylphenyl)sulfonyl]-2,6-di-azaspiro[3,4]octane Prepared analagously to Example 12d from 3,3-bis-(bromomethyl)-l-(phenylmethyl)-pyrrolidine-hydrobromide, potassium hydroxide and p-toluenesulfonamide in a yield of 60 % of theory. The crystalline substance obtained was further processed directly without re-crystallisation or other purification.
e) 6-(Phenylmethyl)-2 6-diazaspiro r 3 4]octane Prepared analagously to Example 12e from 6-(phenylmethyl)-2-[(4-methylphenyl)sulfonyl~-2,6-diazaspiro[3,4]octane and sodium-bis-(2-methoxyethoxy)-dihydroaluminate in a yield of 41 % of theory.
Colourless liquid, Bp 18 mmHg 161-17~C and RF - 25 (Macherey-Nagel, Polygram ~R) SIL G/UV254, pre-coated plastic sheets for TLC; eluent dichloromethane/methanol/conc.aqueous ammonia 68/15/15/2, v/v/v/v).
f) 2-Methyl-6-(phenylmethyl)-2 6-diazaspiro[3 4]octane 10.8 g (0.0534 mol) of 6-(phenylmethyl)-2,6-diazaspiro[3,4]octane were dissolved in 300 ml of ethanol, mixed with 5 ml (about 0.062 mol) of a 37 %
aqueous formalin solution and refluxed for 50 minutes.
The mixture was allowed to cool, 5.0 g of Raney nickel were added and the mixture was hydrogenated for 5 hours at ambient temperature under 4 bar of hydrogen pressure.
The catalyst was filtered off, the filtrate was evaporated down in vacuo, the residue remaining was purified on silica gel by HPLC and using dichloromethane/methanol/cyclohexane/conc.aqueous ammonia 68/15/15/2 as eluent. Evaporation of suitable fractions yielded the desired compound in the form of a colourless viscous oil. Yield 6.1 g t53 ~ of theory).
- 46 ~
RF 0-54 (Macherey-Nagel, Polygram(R) SIL G/UV254, pre-coated plastic sheets for TLC; eluent dichloromethane/methanol/cyclohexane/conc.aqueous ammonia 68/15/15/2, V/V/V/V).
q) 2-Methyl-2,6-diazaspiro[3,4~octane 4.0 g of 10 % palladium/animal charcoal catalyst were added to a solution of 6.1 g (0. 0282 mol) of 2-methyl-6-(phenylmethyl)-2, 6-diazaspiro[3,4]octane in 60 ml of ethanol and the mixture was then hydrogenated for 5 hours a~ ambient temperature under a hydrogen pressure of 5 bar. It was filtered, the filtrate was evaporated under reduced pressure (100 mmHg) and a colourless oil, RF 0.1 was obtained as residue (Macherey-Nagel, Polygram(R) SIL G/UV254, pre-coated plastic sheets for TLC;
eluent dichloromethane/methanol/cyclohexane/conc.aqueous ammonia 68/20/10/5, V/V/V/V).
Yield: 3. 2 g (90 ~ of theory).
h) 5,11-Dihydro-11-[[2-methyl-2,6-diazaspiro[3,4]oct-2-yl~carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][l,4]benzodiaæepin-6-one and 2-methyl-2,6-diazaspiro[3,4]octane in a yield of 46 ~ of theory.
Colourless crystals Mp. 273-275C (acetonitrile).
C20H2~N502 (363.42).
Calculated: C 66.10 H 5.82 N 19.27 Found: 66.25 5. 89 18.90 Example 18 5,11-Dihydro-11-[[6-(phenylmethyl)-2,6-diazaspiro[3,4~oct-2-yl]carbonyl]-SH-pyridoi2,3-b]rl,4]benzodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 6-(phenylmethyl)-2,6-diazaspiro[3,4]octane in a yield of 20 % of theory.
Colourless crystals Mp. 193-195C (diisopropylether).
C26H2sN52 (439-52)-Calculated: C 71.05 ~ 5.73 N 15.93 Found: 70.75 5.91 15.76 Example 19 5~11-Dihydro-8-methyl-11-[[2-methyl-2~6-diazaspiro[3,4]oct-2-yl~carbonyl]-6H-pyrido[2,3-b][l ~]benzodiazepin-6-one Prepaxed analagously to Example 1 rom 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,6-diazaspiro[3,4]octane in a yield of 43 % of theory.
Colourless crystals Mp. 184.0-184.5C (acetonitrile).
C21Hz3NsO2 (377 45) Calculated: C 66.83 H 6.14 N 18.55 Found: 66.79 6.43 18.65 Example 20 5,11-Dihydro-8-ethyl-11-[[2-m~thyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][l 4lbenzodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-ethyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,6-diazaspiro[3,4]octane in a yield of 34 % of theory.
Colourless crystals Mp. 245-~46C (acetonitrile) C22H25Nso2 (391-48)-` 2 ~ J~
Calculated: C 67.50 H 6.44 N 17.89 Found: 67.30 6.33 17.88 Example 21 5,11-Dihydro-9-methyl-11-[[2-methyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-blCl~ J~enzodiazepin-6-one Prepared analagously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,6-diazaspiro[3,4]octane in a yield of 41 % of theory.
Colourless crystals Mp. 284-285C (acetonitrile).
C2~H23N5O2 (377-45)-Calculated: C 66.83 H 6.14 N 18.55Found: 67.08 6.12 18.85 Example 22 9-Chloro-5,11-dihydro-11-[[2-methyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-bl[1,4]benzodiazepin-6-one Prepared analagously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-SH-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,6-diazaspiro[3,4]octane in a yield of 18 % of theory.
Colourless crystals Mp. 276-277C (after re-crystallisation twice from acetonitrile).
C20H20ClNsO2 (397,87)-Calculated: C 60.38 H 5.07 Cl 8.91 N 17.50 Found: 60.74 4.92 ~.91 17.77 Example 23 2 ~
8-Chloro-5,11-dihydro-ll-[[2-methyl-2r6-diazaspiro[3,4~oct-6-yl~carbonyl]-6H-pyrido[2,3-bl~l,41benzodiazepin-6-one Prepared analagously to Example 1 from 8-chloro-11-tchlorocarbonyl)-5,11-dihydro-6H-pyrido~2,3-b][l,~]benzodiazepin-6-one and 2-methyl-2,6-diazaspiro[3,4]octane in a yield of 50 % of theory.
Colourless crystals Mp. 231-232C (acetonitrile).
C20H20ClNsO2 (397.87).
Calculated: C 60.3~ H 5.07 Cl 8.91 N 17.60 Found: 60.62 5.20 8.61 17.54 Example 24 5,11-Dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one a) 4-Cvano-4-(ethoxycarbonyl)-1-ethyl-2-pyrrolidinone Prepared analogously to Example 12a) from diethyl 2-cyanosuccinate and 1,3,5-triethyl-hexahydro-1,3,5-triazine in the presence of trifluoroacetic acid in a yield of 89% of theory. Colourless oil, which was further processed as a crude product without purification.
b) 3-(Aminomethyl)-3-(hydroxymethyl)-1-ethylpyrrolidone Prepared analogously to Example 12b) from ~-cyano-4-(ethoxycarbonyl)-l-ethyl-2-pyrrolidinone and lithium aluminium hydride in tetrahydrofuran in a yield of 74%
of theory. Colourless oil, RF . 25 (Macherey-Nagel, Polygram~ SIL G/UV2s4, pre-coated pIastic sheets for TLC;
eluant: ethyl acetate/methanol/cyclohexane/conc. aqueous ammonia 68/15/15/2, v/v/v/v).
c) 3-(Aminomethyl)-3-~bromomethyl)-1-ethylpyrrolidine-dihydrobromide __ _ Prepared analogously to Example 12c) from 3-(aminomethyl)-3-(hydroxymethyl)-1-ethylpyrrolidine and 63% aqueous hydrobromic acid in a yield o~ 94% of theory. The crude, brownish salt was subjected to the following reaction of cyclisation without any further purification.
d) 6-Ethyl-2,6-diazaspiro~3 4]octane The solution of 149.4 g (0.39 mol) of 3-(aminomethyl)-3-(bromomethyl)-1-ethylpyrrolidine in 2 litres of dioxane was carefully mixed with a mixture of 130 g (3.25 mol) of sodium hydroxide and 120 ml of water and then heated to boiling for 8 hours with stirring and refluxing. After cooling, it was filtered, the aqueous phase was removed from the filtrate and discarded, the organic phase was freed from sol~ent under slightly reduced pressure (100 mmHg) and using a Vigreux column.
The residue remaining yielded 15.8 g (29% of theory~ of a colourless oil, bP.20 ~Hg 83-87C, which was identified as the desired compound by MS, IR and 1H-NMR spectra, after distillation in a water jet vacuum.
e) 5,11-Dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-8-methyl-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one _ , Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one and 6-ethyl-2,6-diazaspiro[3,4]octane in a yield of 27~ of theory.
Colourless crystals m.p. 216-217nC (acetonitrile).
3 ~
C22H2sNs2 (391- 48)-Calc.: C 67. 50 H 6.44N 17.89 Found: 67.39 6.2017.60 Example 25 5,11-Dihydro-11-[[6 ethyl-2,6-diazaspiro[3,4]oc~-2-yl]carbonyl]-6H-pyrido~2 3-b][1 4]benzodiazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 6-ethyl-2,6-diazaspiro[3,4]octane in a yield of 15% of theory.
Colourless crystals m.p. 221-223C (acetonitrile).
C21H23Nso2 (377 45) Calc.: C 66.83 H 6.14 N 18.55 Found: 66.77 6.32 18.32 Example 26 5,11-Dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11~dihydro-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 6-ethyl-2,6-diazaspiro[3,4]octane in a yield of 26~ of theory.
Colourless crystals m.p. 1~9-171C (acetonitrile).
C22H25N52 ( 391.48).
Calc.: C 67.50 H 6.44 N 17.89 Found: 67.46 6.09 17.49 Example 27 9-Chloro-5,11-dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-, 2~2,~
one Prepared analogously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-ben~odiazepin-6-one and 6-ethyl-2,6-diazaspiro[3,4]octane in a yield of 19% of theory.
Colourless crystals, m.p. 158-160~C (acetonitrile) and RF
0.63 (~acherey-Nagel, Polygram~ SIL G/UVz54~ pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/methanol/cyclo-hexane/conc. aqueous ammonia 62/16.7/10/10/1.3, v/v/v/v/v).
C21H22ClN5~2 (411.90).
Calc.: C 61.24 H 5.38 Cl ~.61 N 17.00 Found: 61.25 5.36 8.63 17.08 5,11-Dihydro-11-[[6-propyl-2,6-diazaspiro[3,4]oct-2-yllcarbonyl]-6H-pyrido r 2 3-b][1 41benzodiazepin-6-one a) 4-Cyano-4-(ethoxycarbonyl)-1-propyl-2-pyrrolidinone Prepared analogously to Example 12a) from diethyl cyanosuccinate and 1,3,5-tripropyl-hexahydro-1,3,5-triazine in the presence of trifluoroacetic acid in a yield of 6~% of theory. Colourless liquid, RF . 72 (Macherey-Nagel, Polygram9 SIL G/~V2~4, pre-coated plastic sheets for TLC; eluant: ethyl acetate/petroleum ether 1/1, v/v).
b) 3-(Aminomethyl)-3-(hydroxymethyl)-1-propylpyrrolidine Prepared analogously to Example 12b~ from 4-cyano-4-(ethoxycarbonyl)-l-propyl-2-pyrrolidinone and lithium aluminium hydride in a yield of 28% of theory.
Colourless viscous oil, used in the next step without further purification.
c) 3-(Aminomethyl)-3-(bromomethyl)-1-propylpyrrolidine-dihydrobromide Prepared analogously to Example 12c) from 3-(aminomethyl)-3-(hydroxymethyl)-1-propylpyrrolidine and 63% aqueous hydrobromic acid in a yield of 91% of theory. The brownish coloured salt was reacted without further purification in the next step.
d) 6-Propyl-2,6-diazaspiro[3.4]octane 3-(Aminomethyl)-3-(bromomethyl)-1-propylpyrrolidine was reacted with caustic soda, water and dioxan as described in E~ample 24d). The crude product obtained after processing, RF . 5 (Macherey-Nagel, Polygram3 SIL
G/UV254, pre-coated plastic sheets for TLC; eluant:
dichloromethane/methanol/cyclohexane/conc. a~ueous ammonia 68/20/10/5, v/v/v/v) was purified by column chromatography on silica gel using the eluant described above. The title compound was obtained in a yield of 47% of theory - based on 3-(aminomethyl)-3-(hydroxymethyl)-l-propylpyrrolidine - and identified as the desired compound by MS and 1H-NMR spectrum.
e) 5,11-Dihydro-11-[[6-propyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6 one and 6-propyl-2,6-diazaspiro[3,4]octane in a yield of 74~ of theory.
Colourless crys~als m.p. 208-209C (acetonitrile).
CzH2sN502 (391-48) Calc.: C 67.50 H 6.44 N 17.89 - ` -- 54 - ~JJq7 Found: 67.~Lo 6.39 17.60 Example 29 5,11-Dihydro-8-methyl-11-[[6-propyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b]C1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6H-pyrido[2,3-b]-[1,4]benzodiazepin-6-one and 6-propyl-2,6-diazaspiro[3,4]octane in a yield of 60% of theory.
Colourless crystals m.p. 219-221C (acetonitrile).
C23H27N502 (405.50) Calc.~ C 68.13 H 6.71 N 17.27 Found: 68.02 6.74 17.00 Example 30 8-Chloro-5,11-dihydro-11-[[6-propyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 8-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 6-propyl-2,6-diazaspiro[3,43Octane in a yield of 44% of theory.
Colourless crystals m.p. 210-212C (from diisopropylether and acetonitrile).
C22H24ClN502 (425-93) Calc.: C 62.04 H 5.68 Cl 8.32 N 16.44 Found: 61.85 5.68 8.39 16.38 Example 31 ~ ~ 2 ~
5,11-Dihydro-8-ethyl-11-[[6-ethyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl~-5,11-dihydro-8-ethyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 6-ethyl-2,6-diazaspiro[3,4]octane in a yield of 12% of theory.
Colourless crystals m.p. 190-191C (acetonitrile) and RF
0.65 (Macherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/methanol/cyclohexane/conc. aqueous ammonia 62/16.7/10/10/3, v/v/v/v/v).
C23H27NsO2 (405-50) Calc.: C 68.13 H 6.71 N 17.27 Found: 67.92 6.64 17.44 Example 32 5,11-Dihydro-9-methyl-11-[[6-propyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one - -Prepared analogously to ExampIe 1 from 11-(chlorocarbonyl)-5,11-dihydro~9-methyl-6H-pyrido[2,3-b]-~1,4]benzodiazepin-6-one and 6-propyl-2,6-diazaspiro[3,4]octane in a yield of 39~ of theory.
Colourless crystals m.p. 183-184~C (acetonitrile) and RF
0.51 (Macherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/methanol/cyclohexane/conc. aqueous ammonia 63.5/13/11/11/1.5, v/v/v/v/v).
C23H27N502 (405-50) Calc.: C 68.13 H 6.71 N 17.27 Found: 68.00 6.52 17.10 Example 33 2~2~
5,11-Dihydro-8-ethyl-11-[[6-propyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one ~` Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-ethyl-6H-pyrido[2,3-b]-[1,4]benzodiazepin-6-one and 6-propyl-2,6-diazaspiro[3,4]octane in a yield of 55% of theory.
Colourless crystals m.p. 170-172C (acetonitrile) and RF
0.52 (Macherey-Nagel, Polygram~ SIL G/ W2s4, pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/methanol/cyclohexane/conc. aqueous ammonia 63.5/13/11/11/1.5, v/v/v/v/v).
C24H29N5~2 (419.53) Calc.: C 68.71 H 6.9t N 16.69 Found: 68.90 7.18 16.72 Example 34 5,11-Dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4]oct-2-yl~carbonyll-6H-pyrido r 2 3-bl r 1,4]benzodiazepin-6-one a) 2-Acetyl-6-(PhenylmethYl)-2.6-diazasPiro~3.4loctane 37.7 ml (0.4 mol) of acetic anhydride are added dropwise to a solution of 70.8 g (0.35 mol) of 6-(phenylmethyl)-2,6-diazaspiro[3,4]octane in 300 ml of ethanol with vigorous stirring and the resulting mixture is then refluxed for 3 hours. It is concentrated by evaporation in vacuo, made alkaline with 20% aqueous sodium hydroxide solution and extracted exhaustively with diethylether. The combined ether extracts are dried over caustic potash, freed from solvent and the residue remaining is finally distilled in a high vacuum.
The desired compound is obtained as a colourless oil, bP.O 035 ~H9 155-168C in a yield of 69.3 g (81% of theory).
~2~3 ~
b) 2-Ethyl-6-~phenylmethyl)-2 6-diazasPiro r 3 41octane Prepared analogously to Example 12b) from 2-acetyl-6-(phenylmethyl)-2,6-diazaspiro[3,4]octane and lithium aluminium hydride in anhydrous tetrahydrofuran. The desired compound is obtained as a colourless oil bp.o2 ~Hg 91-93C amd RF 0.6 (Macherey-Nagel, Polygram SIL G/UVzs4, precoated plastic sheets for TLC; eluant:
dichloromethane/methanol/cyclohexane/conc. aqueous ammonia 68/15/15/2, v/v/v/v) in a yield of 73% of theory.
c) 2-Ethyl-2, 6-diazaspiro r 3 41octane Prepared analogously to Example 17g) from 2-ethyl-6-(phenylmethyl)-2,6-diazaspiro[3,4]octane by catalytic hydrogenation in the presence of 10% palladium/animal charcoal. The desired compound is obtained as a colourless oil, RF . 45 (Macherey-Nagel, Polygram~ SIL
G/UV2s4, precoated plastic sheets for TLC; eluant:
dichloromethane/methanol/cyclohexane/ethyl acetate/conc.
aqueous ammonia 62/10/10/16.7/1.3, v/v/v/v/v) in a yield of 96% of theory.
d) 5,11-Dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 2-ethyl-2,6-diazaspiro[3,4]octane in a yield of 60% of theory.
Colourless crystals m.p. 251-254C (dioxan) and RF 0 3 (Macherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/methanol/cyclohexane/conc. aqueous ammonia 63.5/13/11/11/1.~, v/v/v/v/v).
C21H23N5Oz (377-45) Calc.: C 66.83 H 6.14 N 18.55 Found: 66.61 6.20 18.40 Example 35 5,ll-Dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4~oct-6-yl]carbonyl]-8-methyl-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-ethyl-2,6-diazaspiro[3,4]octane in a yield o~ 61% of theory.
Colourless crystals m.p. 213-215C (acetonitrile).
C22H2sNsOz (391-48) Calc.: C 67.50 H 6.44 N 17.89 Found: 1 67.19 6.32 18.22 Example 36 5,11-Dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-9-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin 6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6H-pyrido[2,3-b]-[1,4]benzodiazepin-6-one and 2-ethyl-2,6-diazaspiro[3,4]octane in a yield of 56% of theory.
Colourless crystals m.p. 251-253C (acetonitrile~.
C22H2sNs2 (391-48) Calc.: C 67.50 H 6.44 N 17.89 Found: 67.32 6.49 18.31 Example 37 9-Chloro-5,11-dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4~-oct-2-yl]carbonyl]-6H-pyrido[2,3-b]~1,4]benzodiazepin-6-one ~
2 ~ 3 Prepared analogously to Example 1 from 9-chloro~
(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 2-ethyl-2,6-diazaspiro[3,4]octane in a yield of 45% of theory.
Colourless crystals m.p. 248-250C (acetonitrile).
CzlH22ClNsO2 (411-9~) Calc.: C 61.24 H 5.38 Cl 8.61 N 17.00 Found: 61.31 5.22 8.90 16.98 Example 38 5,11-Dihydro-11-[[6-(2-methylpropyl)-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyr do[2 3-b]~1 4]benzodiazepin-6-one a) 4-Cyano-4-(ethoxycarbonyl)-1-(2-methylpropyl)-2-pyrrolidinone Prepared analogously to Example 12a) in a yield of 74% of theory from cyanosuccinic acid and hexahydro-1,3,5-tris-(2-m~thylpropyl)triazine using trifluoroacetic acid. Colourless oil, RF . 8 (Macherey-Nagel, Polygram~ SIL G/UV2s4, pre-coated plastic sheets for TLC; eluant: ethyl acetate/petroleum ether 1:1, v/v) .
b) 3-(Aminomethyl)-3-(hydroxymethyl)-1-(2-methylpropyl)-pyrrolidine Prepared analogously to Example 12b) from 4-cyano-4-(ethoxycarbonyl)-1-(2-methylpropyl) 2-pyrrolidinone by reduction with lithium aluminium hydride in a yield of 35% of theory. Colourless oil, RF . 2~ (Macherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets for TLC;
eluant: dichloromethane/methanol/cyclohexane/conc.
aqueous ammonia 68/15/15/2, v/v/v/v).
2~2~
c) 3-(Aminomethyl)-3-(bromomethyl)-1-(2-methylpropyl)-pyrrolidine-dihydrobromide Prepared analogously to E~ample 12c) from 3-(aminomethyl)-3-hydroxymethyl-1-(2-methylpropyl)-pyrrolidine and 63% aqueous hydrobromic acid. The brownish salt is used in the following step without further purification.
d) 6-(2-Methylpro~yl)-2,6 diazaspiro~3l4]octane Prepared analogously to Example 28d) from 3-(aminomethyl)-3-(bromomethyl)-1-(2-methylpropyl)-pyrrolidine-dihydrobromide and caustic soda in the presence of water and dioxan in a yield of 62% of theory. Colourless oil, RF . 45 (Macherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets for TLC;
eluant: dichloromethane/methanol/cyclohexane/conc.
aqueous ammonia 68/20/10/2, v/v/v/v).
e) 5, 11-Dihydro-11-[[6-(2-methylpropyl)-2,6-diazaspiro-[3,4]oct 2-yl]carbonyl3-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b] [1,43-benzodiazepin-6-one and 6-(2-methyl-propyl)-2,6-diazaspiro[3,4]octane in a yield of 49% of theory.
Colourless crystals m.p. 199-~01C (acetonitrile) and RF
0.48 (Macherey-Nagel, Polygram~ SIL G/UVz54~ pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/methanol/cyclohexane/conc. aqueous ammonia 63.5/13/11/11/1.5, v/v/vjv/v).
C23H27NsO2 (405-50) Calc.: C 68.13 H 6.71 N 17.27 Found: 67.96 6.84 17.47 Example 39 - ~2~3~
5,11-Dihydro-8-methyl-11-[[6-(2-methylpropyl)-~,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b]-r 1 4]benzodiazepin-6-one Prepared analogously to Example 1 ~rom 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 6-(2-methylpropyl)-2,6-diazaspiro[3,4]octane in a yield of 52% o~ theory. Colourless crystals m.p. 1~6-188C
(acetonitrile).
C24H29N502 (419.53) Calc.: C 68.71H 6.97N 16.69 Found: 68.67 6.99 16.47 Example 40 5,11-Dihydro-9-methyl-11-[[6-(2-methylpropyl)-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b]-r 1 4]benzodiazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-9-methyl-6H-pyrido[2,3-b]-[1,4]benzodiazepin-6-one and 6-(2-methylpropyl)-2,6-diazaspiro[3,4]octane in a yield of 24~ of theory.
Colourless crystals, m.p. 163-165C (acetonitrile).
C24H29N502 (419.53) Calc.: C 68.71 H 6.97 N 16.69 Found: 68.62 6.72 16.67 Example 41 9-Chloro-5,11-dihydro-11-[[6-(2-methylpropyl)-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b]-r 1~4]benzodiaze~in-6-one Prepared analogously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 6-(2-methylpropyl)-2,6-' ~ t'J
diazaspiro[3,4]octane in a yield of 45% of theory.
Colourless crystals, m.p. 177-179C tdiisopropylether).
C23H26ClNsO2 (439.94) Calc.: C 62.79 H 5.96 Cl 8.06 N 15.92 Found: 62.98 6.29 8.07 16.08 Exam~le 42 6,11-Dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]-carbonyll-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one and 2-methyl-2,7-diazaspiro[4,4]nonane in a yield of 84% of theory.
Colourless crystals, m.p. 212-214C (acetonitrile).
C21H23N502 (377-45) Calc.: C 66.83 H6.14 N 18.55 Found: 66.86 6.33 18.73 ~' Example 43 :`;
6,11-Dihydro-11-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]carbonvl]-5H-pyrido[2.3-b][1,5]benzodiazepin-5-one Prepared analogously to Example l from 11-(chlorocarbonyl)-6,11-dihydro-5~-pyrido[2,3-b][1,5]-benzodiazepin-5-one and 2-ethyl~2,7-diazaspiro[4,4]-nonane in a yield of 68% of theory. Colourless crystals, m.p. 151.0-152.5C (acetonitrile1.
C22H2sN502 (391.48) Calc.: C 67.50 H 6.44 N 17.89 Found: 67.65 6.55 18.04 Example 44 6,11-Dihydro~ [[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-5H-pyrido~2 3-b][1,51benzodiazepin-5-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one and 6-methyl-2,6-diazaspiro[3,4]octane in a yield of 38% of theory.
Colourless crystals, m.p. 239-241C (acetonitrile).
C20H21N5O2 (363.42) Calc.: C 66.10 H 5.82 N 19.27 Found: 65.99 5.77 19.17 Example 45 6,11-Dihydro-11-[[2-methyl-2,6-diazaspiro[3,4]oct-6-y~llcarbonyl]-5H-pyrido[2,3-b]~1,51benzodiazepin-5-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one and 2-methyl-2,6-diazaspiro[3,4]-octane in a yield of 50% of theory. Colourless crystals, m.p. 220-221~C (acetonitrile).
CzoH2lNsO2 (363-4~) Calc.: C 66.10 H 5.82 N 19.27 Found: 65.88 6.08 19.00 Example 46 6,11-Dihydro-11-[[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyll-5H-pyrido~2,3-bl r 1,51benzodiazePin-5-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one and 6-ethyl-2,6-diazaspiro[3,4]octane in a yield of 10% of theory.
Colourless crystals, m.p. 196-200~C (acetonitrile~ and RF
0.62 (~acherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/methanol/cyclo-hexane/conc. aqueous ammonia 62/16.~/10/10/1.3, v/v/v/v/v).
C2~H23NsO2 (377-45) Calc.: C 66.83 H 6.14 N 18.55 Found: 66.26 6.11 18.14 ~m~
6,11-Dihydro-11-[[6-propyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-5H-pyrido[2,3-bl~l.51benzodiazepin-5-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one and 6-propyl-2,6-diazaspiro[3,4]octane in a yield of 51% of theory.
Colourless crystals, m.p. 195-197C (acetonitrile) and RF
~` 0.58 (conditions as in Example 46).
C22H25NsO2 (391.48) Calc.: C 67.50 H 6.44 N 17.89 Found: 67.46 6.36 17.98 Example 48 6,11-Dihydro-11-[[2-ethyl-2,6-diazaspiro[3,4]oct-6-yl]-carbonyl~-5H-pyrido r 2,3-b U1 51benzodiazepin-5-one :`
Prepared analogously to Example 1 but using tetrahydrofuran instead of acetonitrile as solvent, from ll-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[~,3-b]-[1,5]benzodiazepin-5-one and 2-ethyl-2,6-diazaspiro[3,4]-octane in a yield of 61% of theory.
Colourless crystals/ m.p. 186-189C (acetonitrile) and RF
0.32 (Macherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/methanol/cyclo-hexane/conc. aqueous ammonia 63.5/13/11/11/1.5, v/v/v/v/v).
C21H23N5O2 (377 45) Calc.: C 66.83 H 6.14N 18.55 Found: 67.00 6.17 18.73 Exa~nple 49 6,11-Dihydro-11-[[6-(2-methylpropyl)-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-5H-~ Pyridor2,3-b] r1~5lbenzodiazepin-5-one .
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]-benzodiazepin-5-one and 6-(2-methylpropyl)-2,6-diazaspiro[3,4]octane in a yield of 60~ of theory.
Colourless crystals, m.p. 187-189C (acetonitrile).
C23H27NsO2 (~05 50) Calc.: C 68.13 H 6.71 N 17.27 Found: 67.95 6.77 17O47 Example 50 5,10-Dihydro-5-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]-carbonyl]-llH-dibenzo[b,e][1.4]diazepin-11-one Prepared analogously to Example 1 from 5-(chlorocarbonyl)-5,10~dihydro-llH-dibenzo[b,e][1,4]-diazepin-ll-one and 2-methyl-2,7-diazaspiro[4,4]nonane in a yield of 75% of theory. Colourless crystals, m.p.
190C (acetonitrile).
C22H24N4O2 (376.46) Calc.: C 70.19 H 6.43 N14.88 Found: 70.14 6.4314.86 Example 51 ~2~
4,9-Dihydro-3-methyl-4-[[7-methyl-2,7-diazaspiro[4,4]-non- 2-yllcarbonyll-1OH-thienor3 4-b1 rl 51benzodiazepin-10-one Prepared analogously to Example 1, but using dichloromethane instead of acetonitrile, from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-lOH-thieno[3,4-b]-[1,5]benzodiazepin-10-one and 2-methyl-2,7-diazaspiro-[4,4]nonane in a yield of 44% of theory. Colourless crystals, m.p. 213-214C (acetonitrile).
C21H24N42S (396051) Calc.: C 63.61 H 6.10 N 14.13 S 8.09 Found: 63.30 6.19 14.21 7.94 Example 52 4,9-Dihydro-4-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]-carbonyl]-3-methyl-lOH-thieno[3,4-b][1,5]ben20diazepin-10-one Prepared analogously to Example 51 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-lOH-thieno[3,4-b]-[1,5]benzodiazepin-10-one and 2-ethyl-2,7-diazaspiro[4,4]nonane in a yield of 65% of theory.
Colourless crystals, m.p. 215-216C (acetonitrile).
C22H26N42S (410.54) Calc.: C 64.36 H 6.38 N 13.65 S 7.81 Found: 64.28 6.33 13.87 7.91 Exam~le 53 4,9-Dihydro-3-methyl-4-[[6-methyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dih~dro-3-methyl-lOH-thieno~3,4-~]-[1,5]benzodiazepin-lo-one and 6-methyl-2,6-diazaspiro[3,4]octane in a yield of 52% of theory.
Colourless crystals, m.p. 200-203C (acetonitrile).
2S (382.49) Calc.: C 62.80 H 5.80 N 14.65 S 8.38 j Found: 62.51 5.68 14.67 8.40 ExamPle 54 4,9-Dihydro-3-methyl-4-[[2-methyl-2,6-diazaspiro[3,4]-oct-6-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-lOH-thieno-[3,4-b][1,5]benzodiazepin-10-one and 2-methyl-2,6-diazaspiro[3,4]octane in a yield of 28% of theory.
Colourless crystals, m.p. 135-137C [acetonitrile).
C20H22N42S (382.49) Calc.: C 62.80 H 5.80 N 14.65 S 8.38 Found: 62.62 5.81 14.70 8.54 Example 55 4,9-Dihydro-4-[[6-ethyl-2,6-diazaspiro[3,~]oct-2-yl]carbonyl]-3-methyl-lOH-thieno[3,4-b][1,5]benzo-diazepin-10-one Prepared analo~ously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-lOH-thieno-[3,4-b][1,5]benzodiazepin-10-one and 6-ethyl-2,6-diazaspiro[3,4]octane in a yield of 30% of theory.
Colourless crystals, m.p. 208-210C (acetonitrile).
.~
CzlH24N42S (396.51) Calc.: C 63.61 H 6.10 N 14.13 S 8.09 Found: 63.35 6.25 14.32 8.19 Example 56 4,9-Dihydro-3-methyl-4-[[6-propyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-lOH-thieno[3,4-b]-[1,5]benzodiazepin-10-one and 6-propyl-2,6-diazaspiro[3,4]octane in a yield of 44% of theory.
Colourless crystals, m.p. 180-181C (acetonitrile) and RF
0.54 (Macherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/methanol/cyclohexane/conc. a~ueous ammonia 63.5/13/11/11/1.5, v/v/v/v/v).
CzH26N402S (410.54) Calc.: C 64.36 H 6.38N 13.65 S 7.81 Found: 64.26 6.35 13.64 7.71 Example 57 4,9-Dihydro-4-[[2-ethyl-2,6-diazaspiro[3,4]oct-6-ylJ-carbonyl]-3-methyl-lOH-thieno[3,4-b][1,5Jbenzodiazepin-10-one Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-lOH-thieno[3,4-b]-[1,5]benzodiazepin-10-one and 2-ethyl-2,6-diazaspiro[3,4]octane in a yield of 61% of theory.
,J ,~ J~3 Colourless crystals, m~p. 216-217C (acetonitrile) and RF
0.47 (conditions as in Example 56).
C21H24N42S (396.51) Calc.: C 63.61 H 6.10 N 14.13 S 8.09 Found: 63.51 6.10 14.27 8.08 xample 58 4,9-Dihydro-3-methyl-4-[[6-(2-methylpropyl)-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-lOH-thieno[3,4-b]-r 1~5]benzodiaæepin-lo-one Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-lOH-thieno[3,4-b][1,5]benzodiazepin-10-one and 6-(2-methylpropyl)-2,6-diazaspiro[3,4]octane in a yield of 71% of theory. Colourless crystals, m.p. 186-188C
(acetonitrile).
C23H28N42S (424.56) Calc.: C 65.07 H 6.65N 13.20 S 7.55 Found: 65.07 6.6113.30 7.42 Example 59 3-Chloro-1-methyl-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]-benzodiazepin-lo-one Prepared analogously to Example 1 from 3-chloro-4-(chlorocarbonyl)-l-methyl-1,4,9,10-tetrahydropyrrolo-[3,2-b][1,5]benzodiazepin-10-one and 2-methyl-2,7-diazaspiro[4,4]nonane in a yield of 80% of theory.
Colourless crystals, m.p. 205-206C (acetonitrile).
C21H24ClN502 (413.92) Calc.: C 60.94 H 5.84 Cl 8.57 N 16.92 Found: 61.13 5.56 8.78 17.20 Example 60 1-Methyl-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]-enzodiazepin-10-one 3.5 g (~.46 mmol) of 3-chloro-1-methyl-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2~b][1,5]benzodiazepin-10-one were dissolved in 350 ml of hot ethanol and after the addition of 3 g of palladium on animal charcoal (20~) the mixture was hydrogenated for 2 hours under a hydrogen pressure of 50 bar and at a temperature of 40C. The catalyst was filtered off, the filtrate was evaporated down ln vacuo, the crystalline hydrochloride was taken up in 20 ml of water, the resulting solution was made alkaline with sodium hydroxide solution and extracted exhaustively with dichloromethane. The combined extracts were dried over sodium sulphate and concentrated by evaporation and the residue remaining was recrystallised from n-propanol. 1.1 g (34% of theory) of colourless crystals are obtained, m.p.
223-225OC.
C2l~25N5o2 (379.47) Calc.: C 66.47 H6.64 N 18.46 Found: 66.43 6.84 18.44 Example 61 3-Chloro-1-methyl-4-[[6-propyl-2,6-diazaspiro[3,4~oct-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]-benzodiazepin-10-one Prepared analogously to Example 1 from 3-chloro-4-(chlorocarbonyl)-1-methyl-1,4,9,10 tetrahydropyrrolo-[3,2-b][1,5]benzodiazepin-lo-one and 6-propyl-2,6-diazaspiro[3,4]octane in a yield of 51% of theory.
Colourless crystals, m.p. 164-165C (acetonitrile).
C22H26ClNsO2 (427.94) Calc.: C 61.75 H 6.12 Cl 8.28 N 16.37 ~ ~ 2 ~
Found: 61.48 5.99 8.42 16.37 Example 62 3-Chloro-l-methyl-4-[[6-(2-methylpropyl)-2,6-diazaspiro-[3,4]oct-2~yl]carbonyl]-1,4,9,10-tetrahydropyrrolo-r 3,2-b][1 ~]benzodiazepin-lo-one __ Prepared analogously to Example 1 from 3-chloro-4-(chlorocarbonyl)-l-methyl-1,4,9,10-tetrahydropyrrolo-[3,2-b][1,5]benzodiazepin-10-one and 6-(2-methylpropyl)-2,6-diazaspiro[3,4]octane in a yield o~ 23% of theory.
Colourless crystals, m.p. 163-165C (acetonitrile).
C23H2sClN5Oz (441-96) Calc.: C 62.51 H 6.39 Cl 8.02 N 15.85 Found: 62.47 6.39 8.18 15.89 Example 63 3-Chloro-l-methyl-4-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b]~1,5]-benzodiazepin-10-one Prepared analogously to Example 1 from 3-chloro-4-(chlorocarbonyl)-l-methyl-1,4,9,10-tetrahydropyrrolo-[3,2-b][1,5]benzodiazepin-10-one and 6-methyl-2,6-diazaspiro[3,4]octane in a yield of 61% of theory.
Colourless crystals, m.p. 215-217C (acetonitrile) and RF 0-7 (Macherey-Nagel, Polygram~ SIL G/UV2s4, pre-coated plastic sheets for TLC; eluant:
dichloromethane/methanol/ c~clohexane/conc. aqueous ammonia 68/15/15/2, v/v/v/v).
CzoH22ClNs2 (399-88) Calc.: C 60 . 07 H 5 . 55 C1 8. 87 N 17 . 51 Found: 60.13 5.39 9.02 17.64 Example 64 ~2~
5,11-Dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbon~l]-6H-pyrido r 2 3-bl[1 4]benzodiazePin-6-one 5.36 g (0.0425 mol) of 6-methyl-2,6-diazaspiro-[3,4]octane were added dropwise to a mixture consisting of 22.5 ml of a 20% solution of phosgene in toluene, 100 ml of acetonitrile and 4.75 g (0.045 mol) of anhydrous sodium carbonate, whilst cooling externally with ice. The mixture was stirred for a further 60 minutes at ambient temperature, then 9.0 g (0.0428 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one were added to the reaction mixture and it was then refluxed for 4 hours. The boiling hot mixture was filtered, the precipitate was washed thoroughly three times with 10 ml of hot acetonitrile and the combined filtrates were evaporated down to a total volume of 50 ml in vacuo. They were left to cool and kept occasionally stirred with a glass rod for 2 hours at 0 to 5C, the crystal slurry formed was suction filtered, recrystallised from acetonitrile and colourless crystals were obtained, m.p. 225.5-227.0C which were found to be identical, according to the mixed melting point, IR and 1H-NMR spectrum, to a preparation made according to Example 12.
Yield: 5.4 g (35~ of theory).
The following were obtained in the same way:
~ 5,11-dihydro-11~[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, m.p. 272-274C (acetonitrile);
5,11-dihydro-8-methyl-11-[[7-methyl-2,7-diazaspiro[4,4]-non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin 6-one, m.p. 212-214C (acetonitrile);
J
5,11-dihydro-8-ethyl-11-[[6-methyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, m.p. 215-217C (acetonitrile);
5,11-dihydro-8-methyl-11-[[2~methyl-2,6-diazaspiro[3,4]-oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, m.p. 184.0-184.5C (acetonitrile).
Example 65 5,11-Dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-6H-pyrido r 2.3-b][1,4]benzodiazepin-6-one To a suspension of 2.6 g (9.5 mmol) of 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one in 30 ml of dimethylformamide, a solution of 1.2 g (9.51 mmol) of 6-methyl-2,6-diazaspiro-[3,4]octane in 10 ml of dimethylformamide was added dropwise at ambient temperature and with stirring.
The initially clear solution turns cloudy within a few minutes. After stirring for half an hour at ambient temperature the colourless solid was suction filtered and washed thoroughly with three times 3 ml of ice cold ethanol. The colourless monohydrochloride of the desired compound obtained was dissolved in 10 ml of water, mixed with a saturated aqueous potassium carbonate solution until a clearly alkaline reaction occurred and then filtered. The resulting solid was washed thoroughly with water, then dried in a vacuum drying chamber at 50C and over diphosphorus pentoxide;
then recrystallised from hot acetonitrile and dried ln vacuo once more. 2.35 g (68~ of theory) of colourless crystals were obtained, m.p. 225.5-227.0C, which was found to be identical to a preparation made according to Example 12, judging by the mixed melting point, IR and H-NMR spectra.
Example 66 .
- 7~ -1-Methyl-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbQnyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]-benzodiazepin-10-one 4.02 g (9.71 mmol) of 3-chloro-1-methyl-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one were dissolved in a mixture of 5 ml of 85% formic acid and 25 ml of dimethylformamide and refluxed for 3 hours after the addition of 0.5 g of 10% palladium/activated charcoal. 7.0 ml of formic acid were added, the mixture was refluxed for a further 6 hours and, after the addition of a further 4.0 ml of formic acid and 0.8 g of 10% palladium/activated charcoal, the mixture was refluxed for a further 8 hours. It was then filtered while hot, ths filtrate was evaporated down ln vacuo and the residue was purified by column chromatography (silica gel: dichloromethane/ethyl acetate/methanol/conc. ammonia 3.5:1.5:0.46:0.0~, v/v/v/v). 1.14 g (31% of theory) of colourless crystals were obtained, m.p. 223-225C (n-propanol), which was found according to thin layer chromatography, IR, UV and H-NMR spectra, to be identical to a preparation obtained according to Example 60.
Example 67 l-Methyl-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]-carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]-benzodiazepin-1_-one A mixture of 4.14 g (0.01 mol) of 3-chloro-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5~benzodiazepin-10-one, 83.3 mg (0.001 mol) of 2:1 tris(o tolyl)phosphine-palladium acetate catalyst, 2.025 g (0.044 mol) of formic acid and 5.77 g (0.057 mol) of trie~hylamine in 200 ml of tetrahydro~uran were heated to 100C in an 2 ~ 2 ~
autoclave for 40 hours under a nitrogen atmosphere. The mixture was filtered and evaporated down in vacuo, the residue was made alkaline with sodium hydroxide solution and extracted exhaustively with dichloromethane. The dried and concentrated organic phases were purified by column chromatography as in Bxample 66. 1.44 g (38~ of theory) of colourless crystals were obtained, m.p.
223-225C (n-propanol), found to be identical to a preparation obtained in Example 60, according to the thin layer chromatography, mixed melting point and IR
spectrum.
Example 68 5,11-Dihydro-8,9-dimethyl-11-[~6-methyl-2,6-diazaspiro-[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8,9-dimethyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 6-methyl-2,6-diazaspiro[3,4]octane in a yield of 59% of theory.
Colourless crystals, m.p. 247-249C.
C22H2sNso2 (391-48)-Calc.: C 67.50 H 6.44N17.89 Found: 67.25 6.52 18.10 Example 69 5,11-Dihydro-8,9-dimethyl~ [[2-ethyl-2,6-diazaspiro-[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4~benzo-diazepin-6-one hydrochloride 3.01 g (0.00998 mol) of 11-(chlorocarbonyl)~-5,11-dihydro-8,9-dimethyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 1.4 g (0.00998 mol) of 2-ethyl-2,6-diazaspiro[3,4]octane and 100 ml of anhydrous acetonitrile were heated to 60 D C for 2 hours with 2~
stirring. The colourless crystalline deposit precipitated after cooling was suction filtered and recrystallised from dry boiling ethanol. 2.3 g (52% of theory) of colourless crystals were obtained, m.p.
268-270C.
C23H27NsO2xHCl (441.97).
Calc.: C 62.51 H 6.39 Cl 8.02 N 15.85 Found: 62.38 6.34 8.1615.61 Example 70 5,11-Dihydro-8,9-dimethyl-11~[[2-methyl-2,6-diazaspiro-[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8,9-dimethyl-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,6-diazaspiro~3,4]octane in a yield of 30% of theory.
Colourless crystals, m.p. 292-294C.
C22H2sNs2 (391-48)-Calc.: C 67.50 H 6.44 N 17.89 Found: 66.91 6.39 17.71 Example 71 5,11-Dihydro-11-[[6-methyl-2,6-diazaspiro[3,3]hept-2-yl]-carbonyl]-6H-pyrido[2,3-b]~1,4~benzodiazepin-6-one a) 2,2-Bis(bromomethyl)-1 3-propanediamine-dihydrobromide 40.65 g (0.1 mol~ of 2,6-bis-[(4-methylphenyl)-sulphonyl]-2,6-diazaspiro[3,3]heptane and 300 ml of concentrated aqueous hydrobromic acid were heated to 180C in a glass autoclave for 12 hours with shaking.
After cooling, the reaction mixture was diluted to three times the volume and then filtered. The filtrate was evaporated down in a water jet vacuum, the light brown residue remaining was carefully triturated with 2x lO0 ml of absolute ethanol and suction filtered, the crystals obtained were finally recrystallised from a boiling mixture of 3 parts ethanol and one part water (by volume). Colourless crystals, m.p. 283-285C.
Yield: 35.7 ~ (85% of theory).
C5Hl2Br2N2X2HBr (421-80)-Calc.: C 14.24 H 3.35 Br 75.78 N 6.64 Found: 14.39 3.36 75.32 6.36 b) 5 11-Dihydro~ [~6-methyl-2.6-diazaspiro~3 3]hept-2~yl]carbonyll-6~-pyrido[2,3-bl[I 4]benzodiazePin-6-one A suspension of 16.87 g (0.04 mol) of 2,2-bis-(bromomethyl)-1,3-propanediamine-dihydrobromide in 500 ml of acetonitrile was combined, with stirring and at ambient temperature, with a solution of 6.4 g (0.16 mol) of sodium hydroxide in 25 ml of water, added dropwise. After stirring for 4 hours at ambient temperature the mixture was dried with anhydrous sodium carbonate and filtered. 9.0 g (0.033 mol) of ~1-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4.3 g (0.041 mol) of anhydrous sodium carbonate were added to the filtrate and stirred for 30 minutes at a reaction temperature of 50C. The solvent was then distilled off ln vacuo, the highly viscous residue remaining was dissolved in 300 ml of ethanol, mixed with 4 ml (about 0.05 mol) of a 37% aqueous formalin solution and refluxed for 50 minutes. It was left to cool, 5.0 g of Raney nickel were added and the mixture was hydrogenated for 5 hours at ambient temperature under 4 bar of hydrogen pressure. The catalyst was filtered off, the filtrate was evaporated down ln vacuo and the residue remaining was purified by chromatography on silica gel (35-70 mesh) using dichloromethane/ethyl acetate/cyclohexane/methanol/conc. ammonia 50/11/9/9/1 v/v/v/v/v as eluant. The residue remaining after evaporation of the suitable eluates was recrystallised from hot acetonitrile. 3.3 g t29~ of theory) of colourless crystals were obtained, m.p. 226-228~C.
C19H~9N5O2 (349-39)-Calc.: C 65.32 H 5.48 N 20.04 Found: 65.08 5.29 20.31 .
The following compound was obtained analogously:
5,11-dihydro-8,9-dimethyl 11-[[6-methyl-2,6-diazaspiro-[3,3]hept-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one, m.p. 296-298C.
s2 (377-45)-Calc.: C 66.83 H 6.14 N 18.55 Found: 67.05 6.25 18.75 Example 72 5,11-Dihydro-11-[[7-methyl~2,7-diazaspiro[3,5]non-2-yl]-carbonyl]-6H-pyridor2~3-b][l 4]benzodiazepin-6-one :
a) Ethyl-4-(aminomethyl)-1-methyl-4-piperidine - carboxylate 52.0 g (0.265 mol) of ethyl 4-cyano-1-methyl 4-piperidine carboxylate were dissolved in 400 ml of glacial acetic acid and, after the addition of ~0 ml of conc ntrated sulphuric acid, hydrogenated in the presence of 3 g of platinum(IV~oxide at an initial hydrogen pressure of 40 bar up to the end of the hydrogen uptake at ambient temperature. The catalyst was separated off, the filtrate was freed from solvent in vacuo, the residue was mixed with 100 g of ice and, with stirring and good external cooling using a mixture of ice and common salt, concentrated sodium hydroxide solution was added dropwise until the mixture had a pH
of 8. Whilst external cooling was continued, 250 g of anhydrous potassium carbonate was added in batches and the stiff slurry thus formed was exhaustively extracted with ether. The combined ether solutions were dried over potassium carbonate and concentrated by evaporation and the residue remaining was reacted in the following step without further purification. Yield: 40.0 g (75%
of theory) of a colourless oil.
b) 7-Methyl-2L7-diazaspiro[3,5]nonane 37.5 g (0.187 mol~ of ethyl 4-(aminomethyl)-1-methyl-4-piperidine carboxylate in 100 ml of anhydrous diethylether were added slowly dropwise, with stirring, to a Grignard solution, cooled to 0 to 5C, consisting of 13.6 g (0.559 g-atom) of magnesium, 61.1 g (0.561 mol) of bromoethane and 350 ml of diethylether.
The mixture was stirred for a further 2 hours at 0C and for 4 hours at ambient temperature. The mixture, cooled to 0 to 5C again, was then very slowly mixed, with stirring, with 50 ml of 10% aqueous ammonium chloride solution and made clearly ammoniacal with 50 ml of conc.
ammonia. The ether layer was separated off, the aqueous phase was exhaustively extracted with ether, the combined ether extracts were washed twice with 50 ml of water, dried over sodium sulphate and evaporated ln vacuo. The oily residue was taken up in 80 ml of anhydrous diethylether, the resulting solution was added dropwise to a suspension of 5.9 g (0~16 mol) of lithium aluminium hydride in 200 ml of dry diethylether so that the ether boiled only gently. After all had been added, the mixture was stirred for a further 4 hours at ambient temperature and refluxed for 1 hour. It was left to cool and, with stirring and external cooling with ice water, 6 ml of water, 6 ml of 15% sodium hydroxide solution and 18 ml of water were added dropwise. The precipitate obtained was suction filtered, suspended once more with diethylether and boiled, and then suct~on ::--`` 2~
filtered again. The combined filtrates were dried over sodium sulphate and concentrated by evaporation. The colourless oil obtained in a yield of 19.0 g (72% of theory) was further processed in the next step without any further purification~
c) 5,11-Dihydro-11-~[7- eth~l-2.7-diazaspiro[3,5]non-2-yl]carbo_yll-6H-Pyrido r 2,3-bl r 1,4lbenzodiazepin-6-one .
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 7-methyl-2,7-diazaspiro[3,5]-nonane in a yield of 61~ of theory. Colourless crystals, m~p. 201-203C (acetonitrile~.
C21H23NsO2 (377-45)-Calc.: C 66.83 H 6.14 N 18.55 Found: 66.95 6.27 18.80 r~
Example 73 5,11-Dihydro-8,9-dimethyl-11-[[7-methyl-2,7-diazaspiro-[3,5]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzo-diaze~in-6-one _ __ _ Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8,9-dimethyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 7-methyl-2,7-diazaspiro[3,5]nonane in a yield of 46% of theory.
Colourless crystals, m.p. 222-224C (acetonitrile).
C23H27N502 (405 50) Calc.: C 68.13 H 6.71 N 17.27 Found: 67.95 6.80 17.49 Example 74 5,11-Dihydro-11-[[2-methyl-2,7-diazaspiro[3,5]non-7-yl]carbonyl]-6H-pyrido[2 3-b][1 4]benzodiazepin-6-one a) 2-Methyl-7-tphenylmethyl)-2~7-diazaspiror3,5]nonane 11.55 g (0.0534 mol) of 7-(phenylmethyl)-2;7-diazaspiro[3,5]nonane, obtained analogously to Example 72a) and 72b), were dissolved in 300 ml of ethanol, mixed with 5 ml (about 0.062 mol) of a 37% aqueous formalin solution and refluxed for 50 minutes. The mixture was left to cool, 5.0 g of Raney nickel were added and the mixture was hydrogenated for 5 hours at ambient temperature under 4 bar of hydrogen pressure.
The catalyst was filtered off, the filtrate concentrated hy evaporation in vacuo, the residue remaining was purified on silica gel by HPLC using dichloromethane/meth-anol/cyclohexane/conc. aqueous ammonia 68/15/15/2 as eluant. Evaporation of suitable fractions yielded the desired compound in the form of a viscous colourless oil. Yield: 6.7 g (54% of theory).
RF 0.58 (Macherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets for TLC; eluant:
dichloromethane/methanol/cyclohexane/conc. aqueous ammonia 68/15/15/2 v/v/v/v).
b) 2-Methyl-2,7-diazaspiro~3,5]nonane To a solution of 6.5 g (0.0282 mol) of 2-methyl-6-(phenylmethyl)-2,6-diazaspiro[3,4]octane in 60 ml of ethanol, 4.0 g of 10% palladium/animal charcoal catalyst were added and the mixture was then hydrogenated for 5 hours at ambient temperature under a hydrogen pressure of 5 bar. It was filtered, the filtrate was concentrated by evaporation under reduced pressure (100 mmHg) and a colourless oil was obtained as residue, RF . 13 (Macherey-Nagel, Polygram~ SIL G/UV2s4, pre-coated plastic sheets for TLC; eluan~:
dichloromethane/methanol/cyclo-hexane/conc. aqueous ammonia 68/20/10/5, v/v/v/v).
Yield: 3.2 g (81% of theory).
c) 5 11-Dihydro-11-[[2-methyl-2,7-diazaspiro[3,5]non-7-yl]carbonyl]-6H-pyrido r 2,3-b~[1 4]benzodlaze~in-6-one Prepared analogously to Example 1 from I1-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 2-methyl-2,7-diazaspiro[3,5]-nonane in a yield of 59% of theory. Colourless crystals, m.p. 186-188C (diisopropylether).
C21H23NsO2 (377 45) Calc.: C 66.83 H 6.14 N 18.55 Found: 67.05 6.15 18.79 2 0 2 ~ 3 . .
.
Example 75 5,11-Dihydro-8,9-dimethyl-11-[[2-methyl-2,7-diazaspiro-` [3,5]non-7-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one .,.,~
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8,9-dimethyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,7-diazaspiro[3,5]nonane in a yield of 43% of theory.
: Colourless crystals, m.p. 2~5-247C (acetonitrile).
~: C23H27NsO2 (405.50).
Calc.: C 68.13 H 6.71 N 17.27 Found: 68.05 6.86 17.41 2J ~J ~
-~:
The preparation of some pharmaceutical administration forms will now be described by means of some Examples:
Example I
Tablets containing 5 mg of 5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b]-r 1,4~benzodiazepin-6-one Composition:
1 tablet contains-Active substance 5.0 mg Lactose 148.0 mg Potato starch 65.0 mg Magnesium stearate 2.0 mg 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 screen with a mesh size of 1.5 mm. The granules are dried at 45C, rubbed through the same screen again, mixed with magnesium stearate and compressed to form tablets.
Weight of tablet: 220 mg Punch: 9 mm Example II
Coated tablets containing 5 mg of 5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6~-~yrido[2,3-b] r 1.4]benzodiazepin-6-one The tablets prepared in Example I are coated in a conventional manner with a coating consisting essentially of sugar and talc. The finished coated tablets are polished with beeswax.
- ` -; Weight of coated tablet: 300 mg :
Example III
Ampoules containin~ 10 mg of 5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b]-[1 4]benzodiazepin-6-one_ Composition:
1 ampoule contains:
Active substance 10.0 mg 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 filtered sterile and transferred into 1 ml ampoules.
Sterilisation: 20 minutes at 120C.
Example IV
Suppositories containing 20 mg of 5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Composition:
1 suppository contains:
Active substance 20.0 mg Suppository mass (e.g. Witepsol W 45~ 1 680.0 mq 1,700.0 mg The finely powdered active substance is suspended in the molten suppository mass which has been cooled to 40C. At 37C the mass is poured into slightly chilled suppository moulds.
Weight of suppository 1.7 g -- ~ ` 2 ~ 2 ~
Example V
~.
Drops containing 5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b]-r 1.4~benzodiazepin-6-one Composition:
100 ml o~ drops solution contain:
Methyl p-hydroxybenzoate 0.035 g Propyl p-hydroxybenzoate 0.015 g Aniseed oil 0.05 g Menthol 0.06 g Pure ethanol 10.0 g Acti~e 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 to the aqueous solution with stirring. It is then made up to 100 ml with water and filtered to remove any suspended particles.
Example 67 l-Methyl-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]-carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]-benzodiazepin-1_-one A mixture of 4.14 g (0.01 mol) of 3-chloro-4-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5~benzodiazepin-10-one, 83.3 mg (0.001 mol) of 2:1 tris(o tolyl)phosphine-palladium acetate catalyst, 2.025 g (0.044 mol) of formic acid and 5.77 g (0.057 mol) of trie~hylamine in 200 ml of tetrahydro~uran were heated to 100C in an 2 ~ 2 ~
autoclave for 40 hours under a nitrogen atmosphere. The mixture was filtered and evaporated down in vacuo, the residue was made alkaline with sodium hydroxide solution and extracted exhaustively with dichloromethane. The dried and concentrated organic phases were purified by column chromatography as in Bxample 66. 1.44 g (38~ of theory) of colourless crystals were obtained, m.p.
223-225C (n-propanol), found to be identical to a preparation obtained in Example 60, according to the thin layer chromatography, mixed melting point and IR
spectrum.
Example 68 5,11-Dihydro-8,9-dimethyl-11-[~6-methyl-2,6-diazaspiro-[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8,9-dimethyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 6-methyl-2,6-diazaspiro[3,4]octane in a yield of 59% of theory.
Colourless crystals, m.p. 247-249C.
C22H2sNso2 (391-48)-Calc.: C 67.50 H 6.44N17.89 Found: 67.25 6.52 18.10 Example 69 5,11-Dihydro-8,9-dimethyl~ [[2-ethyl-2,6-diazaspiro-[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4~benzo-diazepin-6-one hydrochloride 3.01 g (0.00998 mol) of 11-(chlorocarbonyl)~-5,11-dihydro-8,9-dimethyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 1.4 g (0.00998 mol) of 2-ethyl-2,6-diazaspiro[3,4]octane and 100 ml of anhydrous acetonitrile were heated to 60 D C for 2 hours with 2~
stirring. The colourless crystalline deposit precipitated after cooling was suction filtered and recrystallised from dry boiling ethanol. 2.3 g (52% of theory) of colourless crystals were obtained, m.p.
268-270C.
C23H27NsO2xHCl (441.97).
Calc.: C 62.51 H 6.39 Cl 8.02 N 15.85 Found: 62.38 6.34 8.1615.61 Example 70 5,11-Dihydro-8,9-dimethyl-11~[[2-methyl-2,6-diazaspiro-[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8,9-dimethyl-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,6-diazaspiro~3,4]octane in a yield of 30% of theory.
Colourless crystals, m.p. 292-294C.
C22H2sNs2 (391-48)-Calc.: C 67.50 H 6.44 N 17.89 Found: 66.91 6.39 17.71 Example 71 5,11-Dihydro-11-[[6-methyl-2,6-diazaspiro[3,3]hept-2-yl]-carbonyl]-6H-pyrido[2,3-b]~1,4~benzodiazepin-6-one a) 2,2-Bis(bromomethyl)-1 3-propanediamine-dihydrobromide 40.65 g (0.1 mol~ of 2,6-bis-[(4-methylphenyl)-sulphonyl]-2,6-diazaspiro[3,3]heptane and 300 ml of concentrated aqueous hydrobromic acid were heated to 180C in a glass autoclave for 12 hours with shaking.
After cooling, the reaction mixture was diluted to three times the volume and then filtered. The filtrate was evaporated down in a water jet vacuum, the light brown residue remaining was carefully triturated with 2x lO0 ml of absolute ethanol and suction filtered, the crystals obtained were finally recrystallised from a boiling mixture of 3 parts ethanol and one part water (by volume). Colourless crystals, m.p. 283-285C.
Yield: 35.7 ~ (85% of theory).
C5Hl2Br2N2X2HBr (421-80)-Calc.: C 14.24 H 3.35 Br 75.78 N 6.64 Found: 14.39 3.36 75.32 6.36 b) 5 11-Dihydro~ [~6-methyl-2.6-diazaspiro~3 3]hept-2~yl]carbonyll-6~-pyrido[2,3-bl[I 4]benzodiazePin-6-one A suspension of 16.87 g (0.04 mol) of 2,2-bis-(bromomethyl)-1,3-propanediamine-dihydrobromide in 500 ml of acetonitrile was combined, with stirring and at ambient temperature, with a solution of 6.4 g (0.16 mol) of sodium hydroxide in 25 ml of water, added dropwise. After stirring for 4 hours at ambient temperature the mixture was dried with anhydrous sodium carbonate and filtered. 9.0 g (0.033 mol) of ~1-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4.3 g (0.041 mol) of anhydrous sodium carbonate were added to the filtrate and stirred for 30 minutes at a reaction temperature of 50C. The solvent was then distilled off ln vacuo, the highly viscous residue remaining was dissolved in 300 ml of ethanol, mixed with 4 ml (about 0.05 mol) of a 37% aqueous formalin solution and refluxed for 50 minutes. It was left to cool, 5.0 g of Raney nickel were added and the mixture was hydrogenated for 5 hours at ambient temperature under 4 bar of hydrogen pressure. The catalyst was filtered off, the filtrate was evaporated down ln vacuo and the residue remaining was purified by chromatography on silica gel (35-70 mesh) using dichloromethane/ethyl acetate/cyclohexane/methanol/conc. ammonia 50/11/9/9/1 v/v/v/v/v as eluant. The residue remaining after evaporation of the suitable eluates was recrystallised from hot acetonitrile. 3.3 g t29~ of theory) of colourless crystals were obtained, m.p. 226-228~C.
C19H~9N5O2 (349-39)-Calc.: C 65.32 H 5.48 N 20.04 Found: 65.08 5.29 20.31 .
The following compound was obtained analogously:
5,11-dihydro-8,9-dimethyl 11-[[6-methyl-2,6-diazaspiro-[3,3]hept-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one, m.p. 296-298C.
s2 (377-45)-Calc.: C 66.83 H 6.14 N 18.55 Found: 67.05 6.25 18.75 Example 72 5,11-Dihydro-11-[[7-methyl~2,7-diazaspiro[3,5]non-2-yl]-carbonyl]-6H-pyridor2~3-b][l 4]benzodiazepin-6-one :
a) Ethyl-4-(aminomethyl)-1-methyl-4-piperidine - carboxylate 52.0 g (0.265 mol) of ethyl 4-cyano-1-methyl 4-piperidine carboxylate were dissolved in 400 ml of glacial acetic acid and, after the addition of ~0 ml of conc ntrated sulphuric acid, hydrogenated in the presence of 3 g of platinum(IV~oxide at an initial hydrogen pressure of 40 bar up to the end of the hydrogen uptake at ambient temperature. The catalyst was separated off, the filtrate was freed from solvent in vacuo, the residue was mixed with 100 g of ice and, with stirring and good external cooling using a mixture of ice and common salt, concentrated sodium hydroxide solution was added dropwise until the mixture had a pH
of 8. Whilst external cooling was continued, 250 g of anhydrous potassium carbonate was added in batches and the stiff slurry thus formed was exhaustively extracted with ether. The combined ether solutions were dried over potassium carbonate and concentrated by evaporation and the residue remaining was reacted in the following step without further purification. Yield: 40.0 g (75%
of theory) of a colourless oil.
b) 7-Methyl-2L7-diazaspiro[3,5]nonane 37.5 g (0.187 mol~ of ethyl 4-(aminomethyl)-1-methyl-4-piperidine carboxylate in 100 ml of anhydrous diethylether were added slowly dropwise, with stirring, to a Grignard solution, cooled to 0 to 5C, consisting of 13.6 g (0.559 g-atom) of magnesium, 61.1 g (0.561 mol) of bromoethane and 350 ml of diethylether.
The mixture was stirred for a further 2 hours at 0C and for 4 hours at ambient temperature. The mixture, cooled to 0 to 5C again, was then very slowly mixed, with stirring, with 50 ml of 10% aqueous ammonium chloride solution and made clearly ammoniacal with 50 ml of conc.
ammonia. The ether layer was separated off, the aqueous phase was exhaustively extracted with ether, the combined ether extracts were washed twice with 50 ml of water, dried over sodium sulphate and evaporated ln vacuo. The oily residue was taken up in 80 ml of anhydrous diethylether, the resulting solution was added dropwise to a suspension of 5.9 g (0~16 mol) of lithium aluminium hydride in 200 ml of dry diethylether so that the ether boiled only gently. After all had been added, the mixture was stirred for a further 4 hours at ambient temperature and refluxed for 1 hour. It was left to cool and, with stirring and external cooling with ice water, 6 ml of water, 6 ml of 15% sodium hydroxide solution and 18 ml of water were added dropwise. The precipitate obtained was suction filtered, suspended once more with diethylether and boiled, and then suct~on ::--`` 2~
filtered again. The combined filtrates were dried over sodium sulphate and concentrated by evaporation. The colourless oil obtained in a yield of 19.0 g (72% of theory) was further processed in the next step without any further purification~
c) 5,11-Dihydro-11-~[7- eth~l-2.7-diazaspiro[3,5]non-2-yl]carbo_yll-6H-Pyrido r 2,3-bl r 1,4lbenzodiazepin-6-one .
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 7-methyl-2,7-diazaspiro[3,5]-nonane in a yield of 61~ of theory. Colourless crystals, m~p. 201-203C (acetonitrile~.
C21H23NsO2 (377-45)-Calc.: C 66.83 H 6.14 N 18.55 Found: 66.95 6.27 18.80 r~
Example 73 5,11-Dihydro-8,9-dimethyl-11-[[7-methyl-2,7-diazaspiro-[3,5]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzo-diaze~in-6-one _ __ _ Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8,9-dimethyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 7-methyl-2,7-diazaspiro[3,5]nonane in a yield of 46% of theory.
Colourless crystals, m.p. 222-224C (acetonitrile).
C23H27N502 (405 50) Calc.: C 68.13 H 6.71 N 17.27 Found: 67.95 6.80 17.49 Example 74 5,11-Dihydro-11-[[2-methyl-2,7-diazaspiro[3,5]non-7-yl]carbonyl]-6H-pyrido[2 3-b][1 4]benzodiazepin-6-one a) 2-Methyl-7-tphenylmethyl)-2~7-diazaspiror3,5]nonane 11.55 g (0.0534 mol) of 7-(phenylmethyl)-2;7-diazaspiro[3,5]nonane, obtained analogously to Example 72a) and 72b), were dissolved in 300 ml of ethanol, mixed with 5 ml (about 0.062 mol) of a 37% aqueous formalin solution and refluxed for 50 minutes. The mixture was left to cool, 5.0 g of Raney nickel were added and the mixture was hydrogenated for 5 hours at ambient temperature under 4 bar of hydrogen pressure.
The catalyst was filtered off, the filtrate concentrated hy evaporation in vacuo, the residue remaining was purified on silica gel by HPLC using dichloromethane/meth-anol/cyclohexane/conc. aqueous ammonia 68/15/15/2 as eluant. Evaporation of suitable fractions yielded the desired compound in the form of a viscous colourless oil. Yield: 6.7 g (54% of theory).
RF 0.58 (Macherey-Nagel, Polygram~ SIL G/UV254, pre-coated plastic sheets for TLC; eluant:
dichloromethane/methanol/cyclohexane/conc. aqueous ammonia 68/15/15/2 v/v/v/v).
b) 2-Methyl-2,7-diazaspiro~3,5]nonane To a solution of 6.5 g (0.0282 mol) of 2-methyl-6-(phenylmethyl)-2,6-diazaspiro[3,4]octane in 60 ml of ethanol, 4.0 g of 10% palladium/animal charcoal catalyst were added and the mixture was then hydrogenated for 5 hours at ambient temperature under a hydrogen pressure of 5 bar. It was filtered, the filtrate was concentrated by evaporation under reduced pressure (100 mmHg) and a colourless oil was obtained as residue, RF . 13 (Macherey-Nagel, Polygram~ SIL G/UV2s4, pre-coated plastic sheets for TLC; eluan~:
dichloromethane/methanol/cyclo-hexane/conc. aqueous ammonia 68/20/10/5, v/v/v/v).
Yield: 3.2 g (81% of theory).
c) 5 11-Dihydro-11-[[2-methyl-2,7-diazaspiro[3,5]non-7-yl]carbonyl]-6H-pyrido r 2,3-b~[1 4]benzodlaze~in-6-one Prepared analogously to Example 1 from I1-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 2-methyl-2,7-diazaspiro[3,5]-nonane in a yield of 59% of theory. Colourless crystals, m.p. 186-188C (diisopropylether).
C21H23NsO2 (377 45) Calc.: C 66.83 H 6.14 N 18.55 Found: 67.05 6.15 18.79 2 0 2 ~ 3 . .
.
Example 75 5,11-Dihydro-8,9-dimethyl-11-[[2-methyl-2,7-diazaspiro-` [3,5]non-7-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one .,.,~
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-8,9-dimethyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-methyl-2,7-diazaspiro[3,5]nonane in a yield of 43% of theory.
: Colourless crystals, m.p. 2~5-247C (acetonitrile).
~: C23H27NsO2 (405.50).
Calc.: C 68.13 H 6.71 N 17.27 Found: 68.05 6.86 17.41 2J ~J ~
-~:
The preparation of some pharmaceutical administration forms will now be described by means of some Examples:
Example I
Tablets containing 5 mg of 5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b]-r 1,4~benzodiazepin-6-one Composition:
1 tablet contains-Active substance 5.0 mg Lactose 148.0 mg Potato starch 65.0 mg Magnesium stearate 2.0 mg 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 screen with a mesh size of 1.5 mm. The granules are dried at 45C, rubbed through the same screen again, mixed with magnesium stearate and compressed to form tablets.
Weight of tablet: 220 mg Punch: 9 mm Example II
Coated tablets containing 5 mg of 5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6~-~yrido[2,3-b] r 1.4]benzodiazepin-6-one The tablets prepared in Example I are coated in a conventional manner with a coating consisting essentially of sugar and talc. The finished coated tablets are polished with beeswax.
- ` -; Weight of coated tablet: 300 mg :
Example III
Ampoules containin~ 10 mg of 5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b]-[1 4]benzodiazepin-6-one_ Composition:
1 ampoule contains:
Active substance 10.0 mg 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 filtered sterile and transferred into 1 ml ampoules.
Sterilisation: 20 minutes at 120C.
Example IV
Suppositories containing 20 mg of 5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Composition:
1 suppository contains:
Active substance 20.0 mg Suppository mass (e.g. Witepsol W 45~ 1 680.0 mq 1,700.0 mg The finely powdered active substance is suspended in the molten suppository mass which has been cooled to 40C. At 37C the mass is poured into slightly chilled suppository moulds.
Weight of suppository 1.7 g -- ~ ` 2 ~ 2 ~
Example V
~.
Drops containing 5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b]-r 1.4~benzodiazepin-6-one Composition:
100 ml o~ drops solution contain:
Methyl p-hydroxybenzoate 0.035 g Propyl p-hydroxybenzoate 0.015 g Aniseed oil 0.05 g Menthol 0.06 g Pure ethanol 10.0 g Acti~e 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 to the aqueous solution with stirring. It is then made up to 100 ml with water and filtered to remove any suspended particles.
Claims (13)
1. Compounds of formula I
(I) (wherein ] ? represents one of the groups (S) (T) (U) (V) X represents a =CH- group or a nitrogen atom;
R represents a straight chained or branched C1-4 alkyl group optionally substituted by a phenyl group itself optionally mono- or disubstituted by chlorine, bromine, fluorine, methyl or methoxy;
R4 and R5, which may be the same or different, each represents a hydrogen, fluorine, chlorine or bromine atom or a C1-4 alkyl group;
R6 represents a hydrogen or chlorine atom or a methyl group;
R7 and R8, which may be the same or different, each represents a hydrogen atom or C1-4 alkyl group, and R8 may also represent a halogen atom, m, n, o and p each independently represents the number l or 2 with the proviso that the sum of m+n+o+p must be no greater than 6) and the isomers and acid addition salts thereof.
(I) (wherein ] ? represents one of the groups (S) (T) (U) (V) X represents a =CH- group or a nitrogen atom;
R represents a straight chained or branched C1-4 alkyl group optionally substituted by a phenyl group itself optionally mono- or disubstituted by chlorine, bromine, fluorine, methyl or methoxy;
R4 and R5, which may be the same or different, each represents a hydrogen, fluorine, chlorine or bromine atom or a C1-4 alkyl group;
R6 represents a hydrogen or chlorine atom or a methyl group;
R7 and R8, which may be the same or different, each represents a hydrogen atom or C1-4 alkyl group, and R8 may also represent a halogen atom, m, n, o and p each independently represents the number l or 2 with the proviso that the sum of m+n+o+p must be no greater than 6) and the isomers and acid addition salts thereof.
2. Compounds as claimed in claim l being compounds of formula I wherein:
either X represents a nitrogen atom and ] ? represents a group (S) or either X represents a =CH- group and ] ? represents the group (V), R represents a methyl group, R4 and R5, which may be the same or different, each represents a hydrogen, fluorine or chlorine atom or a methyl or ethyl group, and m and p each represents the number l and n and o each represents the number l or 2, and the isomers and salts thereof.
either X represents a nitrogen atom and ] ? represents a group (S) or either X represents a =CH- group and ] ? represents the group (V), R represents a methyl group, R4 and R5, which may be the same or different, each represents a hydrogen, fluorine or chlorine atom or a methyl or ethyl group, and m and p each represents the number l and n and o each represents the number l or 2, and the isomers and salts thereof.
3. A compound as claimedin claim l 5,ll-dihydro-ll-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one;
5,11-dihydro-8-methyl-11-[[7-methyl-2,7-diazaspiro-
5,11-dihydro-8-methyl-11-[[7-methyl-2,7-diazaspiro-
[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one;
5,11-dihydro-11-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]-carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one;
5,11-dihydro-8-ethyl-11-[[6-methyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one; or 5,11-dihydro-8-methyl-11-[[2-methyl-2,6-diazaspiro[3,4]-oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one;
or an isomer or salt thereof.
4. A pharmaceutical composition comprising a compound of formula I as defined in any one of claims 1 to 3 or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient.
5. A process for the preparation of compounds as claimed in any one of claims 1 to 3, said process comprising at least one of the following steps:
a) (to prepare base-substituted condensed diazepinones of formula Ia (Ia) (wherein X, R, m, n, o and p are as defined in any one of claims 1 to 3 and ] ? represents one of the divalent groups (S), (U) or (V) as defined in any one of claims 1 to 3 or a group (T') (T') wherein R4, R5, R7 and R8 are as defined in any one of claims 1 to 3 and R6' represents a chlorine atom or a methyl group)) reacting a carbonic acid derivative of formula II
(II) (wherein ] ? and X are as hereinbefore defined and Y
represents a halogen atom or a group OR11 where R11 represents an optionally halogen-substituted C1-5 alkyl group, a phenyl group optionally substituted by halogen atoms or nitro groups or a C7-15 aralkyl group) with a compound of formula III
(III) (wherein R, m, n, o, and p are as hereinbefore defined) or a metal compound of formula IIIa (IIIa) (wherein R,m,n,o and p are as defined in any one of claims 1 to 3, and M represents an alkali metal atom or 1 equivalent of an alkaline earth metal atom);
b) (to prepare base substituted condensed diazepinones of formula Ia) reacting a tricyclic compound of formula IV
(IV) (wherein X and ] ? are as hereinbefore defined) with a chlorocarbonic acid derivative of formula V
(V) (wherein R, m, n, o and p are as hereinbefore defined);
c) (to prepare pyrrolo-condensed diazepinones of formula Ib (Ib) (wherein X, R, m, n, o and p are as hereinbefore defined)) hydrogenolysing a compound of formula Ia wherein R6' represents a chlorine atom;
d) separating a compound of formula I thus obtained into its isomers; and e) converting a compound of formula I into an acid addition salt thereof or an acid addition salt of a compound of formula I into the free base.
5,11-dihydro-8-ethyl-11-[[6-methyl-2,6-diazaspiro[3,4]-oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one; or 5,11-dihydro-8-methyl-11-[[2-methyl-2,6-diazaspiro[3,4]-oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one;
or an isomer or salt thereof.
4. A pharmaceutical composition comprising a compound of formula I as defined in any one of claims 1 to 3 or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient.
5. A process for the preparation of compounds as claimed in any one of claims 1 to 3, said process comprising at least one of the following steps:
a) (to prepare base-substituted condensed diazepinones of formula Ia (Ia) (wherein X, R, m, n, o and p are as defined in any one of claims 1 to 3 and ] ? represents one of the divalent groups (S), (U) or (V) as defined in any one of claims 1 to 3 or a group (T') (T') wherein R4, R5, R7 and R8 are as defined in any one of claims 1 to 3 and R6' represents a chlorine atom or a methyl group)) reacting a carbonic acid derivative of formula II
(II) (wherein ] ? and X are as hereinbefore defined and Y
represents a halogen atom or a group OR11 where R11 represents an optionally halogen-substituted C1-5 alkyl group, a phenyl group optionally substituted by halogen atoms or nitro groups or a C7-15 aralkyl group) with a compound of formula III
(III) (wherein R, m, n, o, and p are as hereinbefore defined) or a metal compound of formula IIIa (IIIa) (wherein R,m,n,o and p are as defined in any one of claims 1 to 3, and M represents an alkali metal atom or 1 equivalent of an alkaline earth metal atom);
b) (to prepare base substituted condensed diazepinones of formula Ia) reacting a tricyclic compound of formula IV
(IV) (wherein X and ] ? are as hereinbefore defined) with a chlorocarbonic acid derivative of formula V
(V) (wherein R, m, n, o and p are as hereinbefore defined);
c) (to prepare pyrrolo-condensed diazepinones of formula Ib (Ib) (wherein X, R, m, n, o and p are as hereinbefore defined)) hydrogenolysing a compound of formula Ia wherein R6' represents a chlorine atom;
d) separating a compound of formula I thus obtained into its isomers; and e) converting a compound of formula I into an acid addition salt thereof or an acid addition salt of a compound of formula I into the free base.
6. A process as claimed in claim 5 wherein the reaction of step (a) is effected in the presence of a solvent, at a temperature of between -10°C and the boiling point of the reaction mixture, and optionally in the presence of a base or an excess of said compound of formula III.
7. A process as claimed in claim 5 wherein process step (b) is effected in an inert solvent, optionally in the presence of a base, and at a temperature of between +30 and +100°C.
8. A process as claimed in claim 5 wherein the hydrogenolysis of step (c) is carried out in the presence of a catalyst based on a metal of the VIIIth subgroup of the Periodic Table, at a hydrogen pressure of 1 to 300 bar and a temperature of 0 to 130°C in the presence of a solvent.
9. A process as claimed in claim 5 wherein the hydrogenolysis of step (c) is carried out a) with formic acid and a palladium-on-charcoal catalyst at a temperature of between 70 and 110°C and in the presence of a solvent; or b) with triethylammonium formate in the presence of excess triethylamine and palladium on animal charcoal;
or c) with palladium acetate and a triarylphosphine at a temperature of between 40 and 110°C.
or c) with palladium acetate and a triarylphosphine at a temperature of between 40 and 110°C.
10. The use of a compound of formula I as defined in any one of claims 1 to 3 or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for use in a method of treatment to combat cholinergically induced spasm and motility disorders in the gastrointestinal tract and in the region of the outward leading bile ducts, to combat cystitis and spasm in urelithiasis, to combat relative incontinence, to combat bronchial asthma and bronchitis and to combat ischaemic heart disease.
11. A method of treatment of the human or non-human animal body to combat cholinergically induced spasm and motility disorders in the gastrointestinal tract and in the region of the outward leading bile ducts, to combat cystitis and spasm in urelithiasis, to combat relative incontinence, to combat bronchial asthma and bronchitis or to combat ischaemic heart disease, said method comprising administering to said body a compound of formula I as defined in any one of claims 1 to 3 or a physiologically acceptable salt thereof.
12. Compounds of formula I as defined in claim 1 and salts thereof substantially as herein disclosed in any of the Examples.
13. Each and every novel compound, process, composition, method and use herein disclosed.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3930262.8 | 1989-09-11 | ||
| DE3930262A DE3930262A1 (en) | 1989-09-11 | 1989-09-11 | CONDENSED DIAZEPINONE, METHOD FOR THE PRODUCTION THEREOF AND MEDICAMENT CONTAINING THESE COMPOUNDS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2025005A1 true CA2025005A1 (en) | 1991-03-12 |
Family
ID=6389152
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002025005A Abandoned CA2025005A1 (en) | 1989-09-11 | 1990-09-10 | Condensed diazepinones, process for preparing them and pharmaceutical compositions containing these compounds |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0417631A3 (en) |
| JP (1) | JPH03209382A (en) |
| KR (1) | KR910006286A (en) |
| AU (1) | AU626452B2 (en) |
| CA (1) | CA2025005A1 (en) |
| DD (1) | DD299308A5 (en) |
| DE (1) | DE3930262A1 (en) |
| FI (1) | FI904469A7 (en) |
| HU (1) | HU206882B (en) |
| IL (1) | IL95622A (en) |
| NO (1) | NO903941L (en) |
| NZ (1) | NZ235270A (en) |
| PL (1) | PL165197B1 (en) |
| PT (1) | PT95259A (en) |
| RU (1) | RU2017740C1 (en) |
| YU (1) | YU47372B (en) |
| ZA (1) | ZA907199B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9139593B2 (en) | 2011-11-01 | 2015-09-22 | Hoffmann-La Roche Inc. | Azetidine compounds, compositions and methods of use |
| US20190169202A1 (en) * | 2017-09-05 | 2019-06-06 | Blackthorn Therapeutics, Inc. | Vasopressin receptor antagonists and products and methods related thereto |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3930266A1 (en) * | 1989-09-11 | 1991-03-14 | Thomae Gmbh Dr K | CONDENSED DIAZEPINONE, METHOD FOR THE PRODUCTION THEREOF AND MEDICAMENT CONTAINING THESE COMPOUNDS |
| DK1519939T5 (en) | 2002-07-05 | 2011-01-24 | Targacept Inc | N-Aryl-diazaspirocyclic compounds and processes for their preparation and use |
| SE0202133D0 (en) | 2002-07-08 | 2002-07-08 | Astrazeneca Ab | Novel compounds |
| SE0303090D0 (en) | 2003-11-20 | 2003-11-20 | Astrazeneca Ab | Novel compounds |
| SE0303541D0 (en) | 2003-12-22 | 2003-12-22 | Astrazeneca Ab | New compounds |
| TWI633087B (en) * | 2012-06-13 | 2018-08-21 | 赫孚孟拉羅股份公司 | New diazaspirocycloalkane and azaspirocycloalkane |
| HRP20191937T1 (en) | 2012-09-25 | 2020-01-10 | F. Hoffmann - La Roche Ag | HEXAHYDROPYROLO [3,4-C] PYROL DERIVATIVES AND RELATED COMPOUNDS AS AUTOTAXIN INHIBITORS (ATX) AND AS LYSOPHOSPHATIC ACID (LPA) PRODUCTION INHIBITORS FOR THE TREATMENT OF EXAMPLE. KIDNEY DISEASES |
| AR095079A1 (en) | 2013-03-12 | 2015-09-16 | Hoffmann La Roche | DERIVATIVES OF OCTAHIDRO-PIRROLO [3,4-C] -PIRROL AND PIRIDINA-FENILO |
| JP6496730B2 (en) | 2013-11-26 | 2019-04-03 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | Novel octahydro-cyclobuta [1,2-c; 3,4-c '] dipyrrol-2-yl |
| SG11201607845RA (en) | 2014-03-26 | 2016-10-28 | Hoffmann La Roche | Condensed [1,4]diazepine compounds as autotaxin (atx) and lysophosphatidic acid (lpa) production inhibitors |
| WO2015144605A1 (en) | 2014-03-26 | 2015-10-01 | F. Hoffmann-La Roche Ag | Bicyclic compounds as autotaxin (atx) and lysophosphatidic acid (lpa) production inhibitors |
| MA41898A (en) | 2015-04-10 | 2018-02-13 | Hoffmann La Roche | BICYCLIC QUINAZOLINONE DERIVATIVES |
| CA2992889A1 (en) | 2015-09-04 | 2017-03-09 | F. Hoffmann-La Roche Ag | Phenoxymethyl derivatives |
| WO2017050791A1 (en) | 2015-09-24 | 2017-03-30 | F. Hoffmann-La Roche Ag | New bicyclic compounds as dual atx/ca inhibitors |
| CN107922412B (en) | 2015-09-24 | 2021-02-23 | 豪夫迈·罗氏有限公司 | Bicyclic compounds as ATX inhibitors |
| KR20180053408A (en) | 2015-09-24 | 2018-05-21 | 에프. 호프만-라 로슈 아게 | A novel biocompatible compound as an autoantix (ATX) / carbonic anhydrase (CA) inhibitor |
| CN107635995B (en) | 2015-09-24 | 2022-08-19 | 豪夫迈·罗氏有限公司 | Bicyclic compounds as ATX inhibitors |
| MA49879A (en) | 2017-03-16 | 2020-06-24 | Hoffmann La Roche | USEFUL HETEROCYCLIC COMPOUNDS AS DUAL ATX / CA INHIBITORS |
| WO2018167113A1 (en) | 2017-03-16 | 2018-09-20 | F. Hoffmann-La Roche Ag | New bicyclic compounds as atx inhibitors |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4210648A (en) * | 1977-05-31 | 1980-07-01 | Boehringer Ingelheim Gmbh | II-Aminoacyl-5,11-dihydro-6H-pyrido(2,3-B) (1,4)benzodiazepin-6-ones and salts thereof |
| DE3204153A1 (en) * | 1982-02-06 | 1983-08-11 | Dr. Karl Thomae Gmbh, 7950 Biberach | SUBSTITUTED THIENOBENZODIAZEPINONE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING IT |
| DE3204403A1 (en) * | 1982-02-09 | 1983-08-11 | Dr. Karl Thomae Gmbh, 7950 Biberach | NEW PYRIDOBENZODIAZEPINONE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| IE55898B1 (en) * | 1982-09-09 | 1991-02-14 | Warner Lambert Co | Antibacterial agents |
| DE3726908A1 (en) * | 1987-08-13 | 1989-02-23 | Thomae Gmbh Dr K | NEW CONDENSED DIAZEPINONE, PROCESS FOR THEIR MANUFACTURE AND MEDICAMENTS CONTAINING THESE COMPOUNDS |
| DE3930266A1 (en) * | 1989-09-11 | 1991-03-14 | Thomae Gmbh Dr K | CONDENSED DIAZEPINONE, METHOD FOR THE PRODUCTION THEREOF AND MEDICAMENT CONTAINING THESE COMPOUNDS |
-
1989
- 1989-09-11 DE DE3930262A patent/DE3930262A1/en not_active Withdrawn
-
1990
- 1990-09-05 EP EP19900117078 patent/EP0417631A3/en not_active Withdrawn
- 1990-09-10 IL IL9562290A patent/IL95622A/en not_active IP Right Cessation
- 1990-09-10 CA CA002025005A patent/CA2025005A1/en not_active Abandoned
- 1990-09-10 HU HU905852A patent/HU206882B/en not_active IP Right Cessation
- 1990-09-10 NO NO90903941A patent/NO903941L/en unknown
- 1990-09-10 DD DD90343932A patent/DD299308A5/en not_active IP Right Cessation
- 1990-09-10 YU YU171590A patent/YU47372B/en unknown
- 1990-09-10 PT PT95259A patent/PT95259A/en not_active Application Discontinuation
- 1990-09-11 FI FI904469A patent/FI904469A7/en not_active Application Discontinuation
- 1990-09-11 AU AU62352/90A patent/AU626452B2/en not_active Ceased
- 1990-09-11 ZA ZA907199A patent/ZA907199B/en unknown
- 1990-09-11 KR KR1019900014616A patent/KR910006286A/en not_active Withdrawn
- 1990-09-11 NZ NZ235270A patent/NZ235270A/en unknown
- 1990-09-11 JP JP2241064A patent/JPH03209382A/en active Pending
- 1990-09-11 PL PL90286835A patent/PL165197B1/en unknown
-
1992
- 1992-03-18 RU SU925011116A patent/RU2017740C1/en active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9139593B2 (en) | 2011-11-01 | 2015-09-22 | Hoffmann-La Roche Inc. | Azetidine compounds, compositions and methods of use |
| US20190169202A1 (en) * | 2017-09-05 | 2019-06-06 | Blackthorn Therapeutics, Inc. | Vasopressin receptor antagonists and products and methods related thereto |
| US10538530B2 (en) * | 2017-09-05 | 2020-01-21 | Blackthorn Therapeutics, Inc. | Vasopressin receptor antagonists and products and methods related thereto |
| CN111212842A (en) * | 2017-09-05 | 2020-05-29 | 布莱克索恩治疗公司 | Vasopressin receptor antagonists and products and methods related thereto |
| US12152038B2 (en) | 2017-09-05 | 2024-11-26 | Neumora Therapeutics, Inc. | Vasopressin receptor antagonists and products and methods related thereto |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA907199B (en) | 1992-05-27 |
| NO903941L (en) | 1991-03-12 |
| DD299308A5 (en) | 1992-04-09 |
| FI904469A7 (en) | 1991-03-12 |
| HU905852D0 (en) | 1991-03-28 |
| EP0417631A2 (en) | 1991-03-20 |
| PL286835A1 (en) | 1991-08-26 |
| IL95622A (en) | 1994-04-12 |
| JPH03209382A (en) | 1991-09-12 |
| HU206882B (en) | 1993-01-28 |
| IL95622A0 (en) | 1991-06-30 |
| YU47372B (en) | 1995-01-31 |
| NZ235270A (en) | 1991-11-26 |
| YU171590A (en) | 1993-05-28 |
| HUT55393A (en) | 1991-05-28 |
| KR910006286A (en) | 1991-04-29 |
| AU6235290A (en) | 1991-03-14 |
| PL165197B1 (en) | 1994-11-30 |
| FI904469A0 (en) | 1990-09-11 |
| AU626452B2 (en) | 1992-07-30 |
| DE3930262A1 (en) | 1991-03-21 |
| RU2017740C1 (en) | 1994-08-15 |
| PT95259A (en) | 1991-05-22 |
| NO903941D0 (en) | 1990-09-10 |
| EP0417631A3 (en) | 1991-12-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |