AU626452B2 - Condensed diazepinones - Google Patents

Condensed diazepinones Download PDF

Info

Publication number
AU626452B2
AU626452B2 AU62352/90A AU6235290A AU626452B2 AU 626452 B2 AU626452 B2 AU 626452B2 AU 62352/90 A AU62352/90 A AU 62352/90A AU 6235290 A AU6235290 A AU 6235290A AU 626452 B2 AU626452 B2 AU 626452B2
Authority
AU
Australia
Prior art keywords
methyl
dihydro
pyrido
diazaspiro
benzodiazepin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
AU62352/90A
Other versions
AU6235290A (en
Inventor
Adrian De Jonge
Henri Doods
Wolfgang Eberlein
Wolfhard Engel
Norbert Mayer
Gerhard Mihm
Gunter Trummlitz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Dr Karl Thomae GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dr Karl Thomae GmbH filed Critical Dr Karl Thomae GmbH
Publication of AU6235290A publication Critical patent/AU6235290A/en
Application granted granted Critical
Publication of AU626452B2 publication Critical patent/AU626452B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • 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
    • A—HUMAN NECESSITIES
    • 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
    • A—HUMAN NECESSITIES
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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
    • 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
    • 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
    • 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

Description

r
AUSTRALIA
Form PATENTS ACT 1952 COMPLETE SPECIFICATION 626452 (ORIGINAL) FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: Complete Specification Lodged: SAccepted: ,,Lapsed: S. Published: SPriority: -Related Art: S4 4 4 TO BE COMPLETED BY APPLICANT Ncme of Applicant: Addlress of Applicant: Actual Inventors: Address for Service: DR KARL THOMAE GmbH a body corporate organized and existing under the laws of the Federal Republic of Germany of D-7950, Biberach an der Riss, Federal Republic of Ge:many Wolfhard ENGEL, Wolfgang EDERLEIN, Gunter TRUMMLITZ, Gerhard MIHM, Henri DOODS, Norbert MAYER and Adrian DE JONGE CALLINAN LAWRIE, 278 High Street, Kew, 3101, Victoria, Australia Complete Specification for the invention entitled: "CONDENSED DIAZEPINONES" The following statement is a full description of this invention, including the best method of performing it known to me:- .i 1 8 ri 1 iA- 55-915.523 Condensed Diazepinones 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 S' US-A-3660380, US-A-3691159, US-A-4213984, C A--4213985, SUS-A-4210648, US-A-4410527, US-A-4424225, US-A-4424222 O and US-A-4424226.
o EP-A-156191 (US Patent 4550107) says, of condensed diazepinones, that by introducing new aminoacyl groups, O 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 0o00 "o antibradycardiac effects, certain novel condensed s 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 o 0 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 muscarinic' mediated part of the bronchoconstriction, and for the treatment of ischaemic heart diseases by lowering heart I I 1* 2 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 from one aspect therefore the present invention provides compounds of formula I rI I I I r*
I
11 t I0 a 0 41 a 4 a
(I)
oao a 0 66000 oo e o a o oa a a t a a (wherein ]Grepresents one of the groups (v) a, 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 d'.substituted by chlorine, bromine, fluorine, methyl or methoxy; g i ii I- i,
M
rIf -i L r
L'
B
F 0 0 0 0 0 S00 044 0 0 0 0 0 00 0 00 0000 a 0 60 00 a 000 00 o I e0 40 3
R
4 and R 5 which may be the same or different, each represents a hydrogen, fluorine, chlorine or bromine atom or a C1.
4 alkyl group;
R
6 represents a hydrogen or chlorine atom or a methyl group;
R
7 and R 8 which may be the same or different, each represents a hydrogen atom or C 1 4 alkyl group, and R 8 may also represent a halogen atom, m, n, o and p each independently represents the number 1 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 or X represents a =CH- group and represents the group R represents a methyl group,
R
4 and R 5 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 1 and n and o each represents the number 1 or 2, and the isomers and salts thereof.
1
L_
i:i f:; j I g: i:ic -4- Particularly preferred compounds according to the invention include 5,11-dihydro-ll-[[7-methyl-2,7-diazaspiro[4,4]non-2yl]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-ll-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one; a 25,11-dihydro-8-ethyl-1l-[[6-methyl-2,6-diazaspiro[3,4]o" oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6- S one; and 11l-dihydro-8-methyl-1- [2-methyl-2,6-diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6one; 0 0 0000 P ::and the isomers and salts thereof.
*0 0The compounds of formula I may occur in the form of P their acid addition salts. While physiologically 000" 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, gluconic, malic, ptoluenesulfonic, methanesulphonic and amidosulphonic acids.
To illustrate the invention further the following compounds are mentioned by way of example: di (±)-5,11-dihydro-i1-[7-Inethyl-2,7-diazaspiroII4,4]lof-2yl]-carbonyl]-6H-pyrido[2 [1,4]benzodiazepin-6-one R-5,11-dihydro-11-[ [7-methyl-2,7-diazaspiro[4,4]lof-2yl]-carbonyl]-6H-pyrido[2, 3-b] [1,4]benzodiazepin-6-ole S-5,11-dihydro-l-[[7-methy-2,7-iazaspiro[4,4]of-2yl]-carbonyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one -9-chloro-5, il-dihydro-il- [17-methyl-2 ,7diazaspiro [4 non-2-yl] carbonyl-6H-pyrido [2,3b] [1,4]benzodiazepin-6-one li-dihydro-li- [[7-rnethyl-2,',- I: diazaspiro [4,41 non-2-yl] -6H-pyrido [2,3- 0 b] [1,4]benzodiazepin-6-one 0000 8-brono-5, li-dihydro-li- [[7-xnethyl-2, 7diazaspiro 4] non-2-yl] carbonyl] -6H-pyrido[2, 3b] [1,4]benzodiazepin-6-one 11-dihydro-8-ethyl-1- [7-Inethyl-2 ,7- 00 diazaspiro[. ,4]non-2-yl]carbonyl]-6H-pyrido[2,3b] [1,4]benzodiazepin-6-one 11-dihydro-9-inethyl-1- [7-methyl-2 ,7diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2, 3b] [1,4]benzodiazepin-6-one 5,11-dihyclro-ll-[[7-ethyl-2,7-diazaspiro[4,4]lof-2yl]carbonyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one 11-dihydro-8-methyl-11-[ [7-methyl-2,7diazaspiro non-2-yl] carbonyl] -6H-pyrido [2,3b] [1,4]benzodiazepin-6-one -6- 5,11-dihydro-l1-[[7-ethyl-2,7-diazaspiro[4,4]non-2yl] carbonyl] -8-miethyl-6H-pyrido [2,3b] [1,4]benzocdiazepin-6-one 5,11-dihydro-ll-[[7-ethyl]-2,7-diazaspiro[4,4]non-2yl ]carbonyl] -9-inethyl-6H-pyrido [2,3b] [1,4]benzodiazepin-6-one il-dihydro-li- [[7-ethyl-2 ,7diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3bj [1,4]benzodiazepin-6-one 00 0 00 o 11-dihydro-il-e[ [6-mel-26-diaaspro 3,42oc-2 y]cabnl-Hprd[,-[1,4]benzodiazepin-6-one 0 5, 11-dihydro-9-ethyl-- [6-methyl-2, 6- 04diazaspiro [3,41 oct-2-yl] carbonyl] -61{-pyrido[2, 3b] [1,4]benzodiazepin-6-one 5-cho511-dihydro-hl--[ [6-inethyl-2, 6diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3- 0 00]ezdizpn--n 0 5, 11-dihydro-89-ethyl-11-l [inetl-2 6diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3b] [1,4]benzodiazepin-6-one 11-dihydro-8, -di2methyl-l-[6-iethyl-2[,4]--6 yl]carbonyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one -7- 5,11-dihydro-ll-[[6-(phenylmethyl)-2,6diazaspiro[3,4]oct-2-yl]carbonyl]--GH,-pyrido[2, 3b] benzodiazepin-6-oie 11-dihydro-8-methyl-11- [[2-methyl-2, 6diazaspiro [3,41 oct-6-yl] carbonyl] -6H-pyrido [2,3b] [1,4]benzodiazepin-6-one 11-dihydro-8-ethyl-1- [2-inethyl-2, 6diazaspiro[3,4]oct-6-yl]carbonyl]-6H-pyridoli2,3b] [1,4]benzodiazepin-6-one 11-dihydro-9-methyl-11-[ [2-methyl-2, 6diazaspiro[3,4]oct-6-yl]carbonyl]"-6H-pyrido[2, 3o b] [1,4]benzodiazepin-6-one 9-chloro-ll-[[2-mlethyl-2,6--diazaspiro[3,4110ct-6yl]carbonyl]-6H-pyrido[2,3-b] [1,4]benzodiazepini-6-one 8-chloro-ll- [[2-inethyl-2, 6-diazaspiro [3 oct-6- 44*0 yl]carbonyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one a yljcarbonyl]-8-methyl-6H-pyrido[2 ,3b] [1,4]benzodiazepin-6-one 5,11-dihydro-ll-[[6-ethyl-2,6-diazaspiro[3,4]oct-2- 4:44; yl]carbonyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one 11-dihydro-il-[ [6-ethyl-2, 6-diazaspiro oct-2yllcarbonyl] -9-mIethyl-6H-pyrido[2 ,3b] [1,4]benzodiazepin-6-one il-dihydro-il- [[6-ethyl-2 ,6diazaspiro oct-2-yl] carbonyl] -6H-pyrido [2,3b] [1,4]benzodiazepin-6-one -8- 5-11-dihydro-8-ethyl-l- [6-ethyl-2, 6diazaspiro[3,43oct-2-yl]carbonyl]-6H-pyrido[2,3b] [1,4]benzodiazepin-6-one 5,11-dihydro-ll-[[6-propyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one 11-dihydro-8-methyl-11-[3[6-propyl-2, 6diazaspiro oct-2-yl] carbonyl] -6H-pyrido [2,3b] [1,4]benzodiazepin-6-one il-dihydro-il- [[6-propyl-2, 6di-azaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3- 0 00 b] 4]benzodiazepin-6-one *0 0 5, 11-dihydro-9-ethyl-ll- [[6-propyl-2, 6diazaspiro[3 oct-2-yl] carbonyl] -6H-pyrido [2,3b] 4]benzodiazepin-6-one .00. 5, 11-dihydro-8l[-ethyl-[ 6-ropyl-2, 6- ]ct-6 dizsio 34 ct2y]carbonyl] -6H-pyrido [2,3-[2,3 b] [1,4]benzodiazepin-6-one 11-dihydro-l1-[ [2-et%-hyl-2, 6-diazaspiro[3 ,4]oct-6yl]cabnl-H-yio23b 1,4]benzodiazepin-6-one 5,9-dihydrQ-,11-iy[ l-[2-ethyl-2,6apr-[,]ot6 dizsio4ot6yl]carbonyl]-9-xethy-61I-pyido[, 3 b] [1,4]benzodiazepin-6-one -9- 5,11-dihydro-ll-[[6-(2-xnethylpropyl)-2,6diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2, 3b] [1,4]benzodiazepin-6-one 5,11-dihydro-8--methyl-11-[ 16-(2-xethylpropyl) 6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one 11-dihydro-9-methyl-1-[[6- (2 -iethyipropyl) 6-diazaspirof3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one 9-chloro-5, 11-dihydro-l1-( [6-(2-methylpropyl) 6-diaza- 4 spiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2, 3b] (1,4]benzodiazepin-6-one O 40 5,11-dihydro-ll-[[6-methyl-2,6-diazaspiro[3,3]hept-2yl]-carbonyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one 11-dihydro-8-methyl-ll-[[6-methyl-2, 6diazaspiro[3 ,3]hept-2-yl]carbonyl]-6H-pyrido[2, 3b] [1,4]benzodiazepin-6-one 4 0 0 0 ~~511-dihydro-9-inethyl-1- [6-methyl-2, 6diazaspiro(3,3]hep-2-yl]carbonyl]-6H-pyrido[2,3b] [1,4]benzocliazepin-6-one 0 5,-dihydro-,11dhd-[[7-methyl-2,7-sio35nn2 diazaspiro[~3,51 non-2-yl] carboriyl I-6H-pyrido [2,3bI [1,4]benzodiazepin-6-one K 5,11-dihydro-l1-[ [2-iethyl-2,7-diazaspiro[3,5]non-7yl]carbonyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one 11-dihydro-9-inethyl-l1- [2-inethyl-2,7diazaspiro [3 non-7-yl] carbonyl] -6H-pyrido 3b] [1,4]benzodiazepin-6-one 11-dihydro-l1-[ [2-methyl-2,7diazaspiro[3 ,5]non-7-yl]carbonyl-6H-pyridof 2,3b] [1,4]benzodiazepin-6-one il-dihydro-il- 2-methyl-2 ,7diaza::spiro non-7-yl] carbonyl] -6H-pyrido [2,3b] [1,4]benzodiazepin-6-one (±)-6,11-dihydro-ll-[f[7-methyl-2,7-diazaspiro[4,4]non-2yl]carbonyl-5H-pyrido[2,3-b] [1,5]benzodiazepin-5-one R-6,11-dihydro-11-[[7-methyl-2,7-diazaspiro[4,4]non-2yl ]carbonyl ]-5H-pyrido C2, 3-b] 1, 5 S-6, 11-dihydro-11-[[7-methyl-2, diazaspiro[(4, 4 ]non-2yl carbonyl -5H--pyrido 3 1, 5 6, 1 1-dihydro-1 [7-ethyl -2 7 -diaz asp iro 4, 4 ]non-2 ycarbonyl]-5H-pyrido[2,3-b] [1,5]benzodiazepin-5-one 6,11-dihydro-ll-[[6-rethy-2,6-diazaspiro[3,:]oct-6-yl]- 6,11-dihydro-11-[ [6-ethyl-2,6--diazaspiro[3,4]oct-2-yl]carbonyl]-5H-pyrido[2,3-b] k-
TI
diazaspiro 3,4 -oct-2-yl -carbonyl -5H-jpyt o[2,3b] [1,5]benzodiazepin-5-one l-dihydro-li- [[6-methyl-2, 6-diazaspiro 3] hept-2yl]-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-cllhydro-ll-[ [2-methyl-2,7-diazaspiro[3,5]non-7-yl]carbonyl]-5H-pyrido[2, 3-b] (±)-5,1O-dihydro-5-[[7-mrethyl-2,7-diazaspiro[4,4]non-2yl]carbonyl]-11H-dibenzo[b,e] [1,4]diazepin-11-one 5,10-dihydro-5-[ [6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-11H-dibenzo[b,e] [1,4]diazepin-11-one (±)-4,9-dihydro-3-methyl-4-[[7-methyl-2,7diazaspiro[4,4]non-2-yl]carbonyl]-10H-thieno[3,4b] [1,5]benzodiazepin-10-one (±)-4,9-dihydro-4-[[7-ethyl-2,7-diazaspiro[4,4]non-2- 46 yl]-carbonyl]-3-methyl-1OH-thieno[3 ,4b] [1,5]benzodiazepin-10-one 4 4,9-dihydro-3-methyl-4-[ [6-methyl-2,6--diazaspiro[3,4]oct-6-yl]carbonyl]-10H-thieno[3,4-b)[1,5]benzodiazepin- 4,9-dihydro-3-methyl-4-[[2-methyl-2,6-diazaspiro[3,4]oct-6--yljcarboriyl]-1OH-thieno[3,4-b] 4,9-dihydro-4-[[6-ethyl-2,6-diazaspiro[3,4]oct-2yl] carbonyl] -3-methyl-1OH-thieno [3,4b] 5]benzodiazepin-10-orie -1.2- 4,9-dihy'dro-3-methyl-4-[ [6-propyl-2, 6-diazaspiro[3 oct-2-yiLlcarbonyl]-10H-thieno[3,4-b] 4, 9-dihydro-4- [[2-ethyl-2, 6-diazaspiro 4] oct-6yl] carbonyl] -3-methyl-1OH-thieno [3 ,4b] 4, 9-dihydro--3-methyl-4-[ (2-iethyipropyl) -2,6- 4 diazaspiro[5,4]oct-2-yl]carbonyl]-10H-thieno[3,4bJ 5]benzodiazepin-10-one 4,9-dihydro-3-niethyi-4-[[6-methy1-2,6-diaza~piro[3,3]hiept-2-yl]carbonyl]-1OH-thieno[3,4-b] 0 4,9-cdihydro-4- [[6-methyl-2, 6-dz-.azaspiro hept-2yl]carbonyl]-IOH-thieno[3,4-b] [1,5]benzodiazepin-10-one 4, 9-dihydro-3-methyl-4-[[7-inethyl-2,7-diazaspiro[3,5]non-2-yl]carbonyl]-1OH-thieno[3,4-b] IC -one 0 0 0 00 4,9-dihydro-3-iethyl-4-[[2-methyl1-2,7-diazaspiro[3,5]non-7-yl]carbonyi]-1OH-thieno[3, 4-b] 0 (±)-3-chloro-l-nethyl-4-I[7-rnethyl-2,7tetrahydropyrrolo[3,2-b] [1,53benzodiazepin-10l-one (±)-l-methyl-4-[ [7-methyl-2,7-diazaspiro[4,4]non-2- 1l]carbonyl]-1,4,9,10-ts'crahydropyrrolo[3 b] [1,5]benzo-diazepin-10-one 3-chloro-1-methyl-4-[ [6-pr.,)py1-2, 6-diazaspiro[3,4]oct-2yl] carbonyl] *-9-tetrahydropyrrolo [3,2b] [1,5]benzodiazepin-10-one -13- 3-chloro-1-methyl-4-[ [6-(2-methylpropyl) -2,6diazaspiro[3,4]oct-2-yl]carbonyl]-1,4,9,10tetrahydropyrrolo[3, 2-b] (1,5]benzodiazepin-1O-one 3-chloro-1-methyl-4-[ [6-methyl-2,6--diazaspiro[3 ,4]oct-2yl] carbonyl] 9, 10-tetrahydropyrrolo (3,2bI [1,5]benzodiazepin-1o-one and 3-chloro-l-methyl-4-[ [6-methyl-2, 6-diazaspiro[3 3]hept- 2-yl] carbonyl]-1, 4,9, 1O-tetrahydropyrrolo[3,2b] [1,5]benzodiazepin-1O-one.
*1 Viewed from another aspect the invention also provides a process for the preparation of the compounds according to the invention, said process comprising at 'PT, t eaLL. one of the following steps: a) (to prepare base-substituted condensed diazepinones of formula Ia 0 coo*H Oba a q a N
.J
rr: 14 S(wherein X, R, m, n, o and p are as hereinbefore defined and represents one of the groups or (V) as hereinbefore defined or a group
CH
3
N
R
6 44 4i Sr 4 t 44 4r* 4 D~ 4: 4q14 4 4 4444 I44 44 t 4 4 r i I ft i wherein R 4
R
5
R
7 and R 8 are as hereinbefore defined and
R
6 represents a chlorine atom or a methyl group)) reacting a carbonic acid derivative of formula II
H
S(IfI) N
Y
(wherein and X are as hereinbefore defined and Y represents a halogen atom, preferably bromine or chlorine, or a group OR" where R 11 represents an optionally halogen-substituted C1-s alkyl group, a phenyl group optionally substituted by halogen atoms or nitro 1;1 a~r 1 i
L
i iii j.
ii A1 a -i i "Al 4i ii 15 groups or a C 7 15 aralkyl group) with a compound of formula III
/"H
R
Ill t tr ot s o 0 I p 4 1 0 *1 (wherein R, m, n, o, and p are as hereinbefore defined) or a metal compound of formula IIIa I I I
/N
C S to (wherein R,m,n,o and represents an alkali alkaline earth metal p are as hereinbefore defined and M metal atom or 1 equivalent of an atom); b) (to prepare base substituted condensed diazepinones of formula Ia) reacting a tricyclic compound of formula
IV
I.
Oa F x: I V) (wherein X and ]B are as hereinbefore defined) with a chlorocarbonic acid derivative of formula V I/p I. (V)
R
(wherein R, m, n, o and p are as hereinbefore defined); c) (to prepare pyrrolo-condensed diazepinones of formula Ib (Ib) fl,1 F B
L
17 (wherein X, R, m, n, o and p are as hereinbefore defined)) hydrogenolysing a compound of formula Ia wherein R 6 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 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 o isopropanol, but particularly preferably in the presence 0 0o of an aprotic polar solvent, e.g. tetrahydrofuran, 1,4dioxane, acetonitrile, N,N-dimethylformamide, 0 dimethylsulfoxide, hexamethylphosphoric acid triamide, 0% 0or mixtures thereof and at temperatures between 9 oand the boiling point of the reaction mixture, 0o00 preferably between 40 and 100"C. It has proved convenient to use additional organic or inorganic bases, e.g. alkali metal or alkaline earth metal hydroxides, o alkoxides or carbonates sodium hydroxide, sodium methoxide, potassium tert butoxide, sodium carbonate and i potassium carbonate), tertiary amines (e.g.
triethylamine, ethyldiisopropylamine and N,Ndimethylaniline), 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 prepared in situ from compounds of formula III by reacting with alkali or alkaline earth metals, e.g. with
L
q 9 di e h l u f xd ,h x m t yl h sh r c ai r ai e 18 sodium, potassium or barium, or with alkali metal or alkaline earth metal hydrides, e.g. 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 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 0 o temperatures up to the boiling point of the reaction mixture, preferably at temperatures between +30 and o 0 +100"C.
SThe hydrogenolysis of step is conveniently 0" S carried out in the presence of a catalyst based on a 0 0 metal of the VIIIth subgroup of the Periodic Table of 0 0 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 0 temperatures of 0°C to 130*C, in the presence of solvents, e.g. alcohols (such as methanol and ethanol), ethers (such as dioxane and tetrhydrofuran), carboxylic acids acetic acid) or tertiary amines (e.g.
0 o 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 19formic acid in the presence of dimethylformamide as solvent and palladium on charcoal as catalyst at temperatures between 70 and 110°C, 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 trisat temperatures between 40 and 110°C.
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 o? represent 1, and n and p each represent 2, these a compounds are chiral because they have an asymmetric 6 carbon atom in the side chain. These compounds can 0 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 ar optically active acid such as or (-)tartaric acid or a derivative thereof such as or (-)diacetyltartaric 9999, 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.g. in a ratio by volume of 50:50. Then i~L 20 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: o i) 2-Substituted 2,7-diazaspiro[4,4]nonanes of formula III may be obtained following the procedures described o a o by Warner-Lambert Comp., in AU-A-83/18698 (see Derwent S107 300).
ii) 6-Substituted 2,6-diazaspiro[3,4]octanes of formula III may be prepared for example starting from 1,1,2ethanetricarboxylic acid esters which, when reacted with suitable 1,3,5-trisubstituted in the presence of catalytic quantities of trifluoroacetic acid, yield 1-substituted 2- S pyrrolidinone-4,4-dicarboxylic acid esters in a high *oO, 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 dimethylformamide as solvents to obtain in a high yield 6substituted 2-(4-methylbenzenesulfonyl) -2,6diazaspiro[3,4]octanes, which can be detosylated, for example, with sodium-bis-(2-methoxyethoxy)- F I L^ 8 6. 21 aluminiumhydride (RED-A1®), preferably in toluene solution, to obtain the desired 6-substituted 2,6diazaspiro[3,4]octanes.
Alternatively, two cyanosuccinic acid esters may be used for the reaction with the 1,3,5-trisubstituted hexahydro-s-triazines instead of the 1,1,2ethanetricarboxylic esters. This results in 1substituted 4-cyano-4-carbalkoxy-2-pyrrolidinones, which yield 1-substituted 3-aminomethyl-3-hydroxymethylpyrrolidines 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 6substituted 2,6-diazaspiro[3,4]octanes.
o 4* o 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 manner 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, 1588; F. Govaert and M.
Beyaert. Bull. Soc. Chim. Belg. 55: 106, 112 [1946]; SF.G. Mann and A. Litherland, Nature 141: 789-790 f! [1938]), for example by monoacylation and subsequent
I
22 careful reduction 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-4piperidinecarboxylic acid esters which are obtainable analagously to the procedures described by L. Ciszewski, Pol. J. Chem. 62: 451-455 [1988]. For example, the 1substituted 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 0 to 5°C to obtain 7substituted 2,7-diazaspiro[3,5]nonan-l-ones which when reduced with lithium aluminium hydride in ether are 0 converted into the desired 7-substituted 2,7diazaspiro[3,5]nonanes. Alternatively, the 7- 4 t .t substituted 2,7-diazaspiro[3,5]non-l-ones may also be obtained by saponifying the above mentioned P-alanine esters to obtain the corresponding p-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.
T vi) 2-Substituted 2,7-diazaspiro[3,5]-nonanes of formula III may also be prepared from 7-(phenylmethyl)- 4 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.
r -i* e~l~r~
F:
23 9 *4 oa 4 490 9 *9 *9 4 4 o 9*a *d 4 9*94 9*09 *99*: o *9 *9*4^ 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 outwardleading 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.
i I Kt a1i :1i 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.
°o For this purpose the compounds of formula I or salts eo othereof may be incorporated, in a conventional manner into conventional pharmaceutical forms, e.g. solutions, o o o suppositories, plain or coated tablets, capsules or o 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 mg/kg of body weight, optionally administered in the form of several, preferably one to three doses, to achieve the i a° desired results. i 000 I A favourable correlation between spasmolitic effects a 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. Investigation of functional selectivity of the antiiuscarinic effect
E~
F:;
7 rr 25 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" Organ Preparations 0 0 0 0 0 a a 0 o 0 Dissociation constants (K)-values) were determined in vitro on the ileum and spontaneously beating atrium of the guinea pig. The ileum was removed and incubated in Krebs-Henseleit solution in an organ bath. Contractions were induced by increasing concentrations of methacholine 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 3 minutes and another concentration/activity curve was recorded with M.
The dosage ratio i.e. the extent of displacement of the concentration/activity curve, made it possible to calculate the dissociation constant according to Arunlakshana 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 the atrium were obtained in the manner described above. A comparison of the dissociation constants obtained in two tissues made it possible to identify substances with 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 t i:l ii g :I-i i .Y Li. I I 1 26 substances which had been selected on the basis of in vitro tests were investigated for 1. Selectivity :f 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 guinea pigs Metaod Male and female guinea pigs (body weight 550-600 g) S, were anaethetised with urethane (1.4 g/kg, A s* cannula was ins( :ted into the jugular vein for the purpose of injecting the active substance. 220 I.U./kg 0, 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 s. connected to a water manometer 10 cm high. The n" Lespiration volume was adjusted so that the maximum «o intratracheal pressure during respiration just reached the pressure of a 10 cm water colun.:..
Apart from a few modifications, the effect of the active substances on bronchial tone was measured by the method described by Konzett and R6ssler (1940). The 1 volume of respiration gas mixture produced by bronchoconstriction (overflow) which flowed through the water manometer was measured by means of a tube-type pneumatic tachometer (Fleisch, model 1000), cnnected to an SP 2040D differential pressure transd (FHE). The results were recorded with an IFD recorder. Before the test the trachea was clamped for a short time to produce 21 27 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 1 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 a acetylcholine (50 g/kg i.v. and 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 i ai 4 Male THOM rcts anaethetised with 1.2 g/kg urethane were given increasing doses of the substance i.v. in accordance with Lavy and Mulder (Arch. int. Pharmacodyn.
178, 437-445, (1969)). The salivation was initiated by the subcutaneous administration of 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 of substance which reduced the volume of saliva by 50% was determined graphically. For the results see Table II.
3. In-situ spasmolytic effect on guinea pigs V M L I ,I ii :c 28 Male guinea pigs (500 to 600 g body weight) were anaethetised with urethane (1.2 g/kg, 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 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 0 a solution the animal acted as his own organ bath.
SThe glass tube was filled with Krebs-Ringer solution O. until the entire lower abdomen was immersed. The active 0 substances being tested were injected through the o o jugular vein; 5 minutes later, contractions were °o produced using methacholine (20 Ag/kg By recording the percentage suppression of the methacholine-induced contractions against the logarithm 0..0 of the dosage (mol/kg) of the test substance, 0o00 .dosage/activitv curves were obtained.
*o The results were given as averages (for 4 to 8 animals) e Table II).
I
Sr The fo .owing compounds, by way of example, were tested usil j the above methods: A 5,11-dihydro-ll-[[7-methyl-2,7-diazaspiro[4,4]non-2yl]carbonyl]-6H-pyrido[2;3-b][l,4]benzodiazepin-6-one B 5,1ll-dihydro-8-methyl-ll-[[7-methyl-2,7diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3b][l,4]benzodiazepin-6-one 1
I
4 29 C 5,11-dihydro-l1-[[6-mnethyl-2,6-diazaspiro[3,4]oct-2yl]carbonyl]-6H-pyrido[2,3-b] [I,4]benzodiazepin-6-one D 5,11-dihydro-8-ethyl-1-[[6-methyl-2,6diazaspiro 13,41 oct-2-yl] carbonyl] -6H-pyrido 3b] 4]benzodia-.'epin-6-one E 5,11-dihydro-8-methyl-l1-[[2-methyl-2,6diazaspiro oct-6-yl] carbonyl] -6H-pyrido 3b] [1,4]benzodiazepin-6-one and as comparison substances X (diethylamino)methyl]-1-piperidinyl]acetylj- 5, 11-dihydro-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one US Patent 4 550 107) Y 5,11-dihydro-11-[ (4-methyl-1-piperazinyl)acetyl]-6Hpyrido[2,3-b] [1,4]benzodiazepin-6--one (Pirenzepine, see US Patent No. 3 660 380) *5 1 a at b as 0 a O4o a 0* 0 a ot a o t 4 0 as O Sa a 0*5* and Z Itropine. 0*05 o a OOsS 000* O a so a 05.8( a a I a. tLI f 4 .1
B
4 4 ii ~Li1 I -t 00 0 O 0 4 o 04 0 00 00 0 000 0 00 00 0 0 0 0 00 0 0 04 0 00 0 00 0 0 0 0040 30 Table I Selectivity of the bronchospasmolytic activity in the guinea pig: Acetylcholine Antagronism Test Bronchii Bladder Heart Ratio of Substance log ED50 log ED50 log ED 50 influence of (mol kg- 1 (mol kg- 1 (mol kg" 1 bradycardia to LV. iv. bronchoconstriction A 6.44 5.48 5.10 22 B 6.65 6.29 5.45 16 o 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 Y 6.57 5.84 5.90 z1 8.09 7,28 17.57 3 0*00 0 0 0000 00 0 05 00 0 0000 0 04 00 4 44445 4(01.41 I 0 n
K'
Al j I' .1 31 Table II Selectivity of the in situ relation to the salivation spasmolytic activity in inhibiting effect.
Test In situ spasmolysis Salivation inhibition Ratio of salivation Substance guinea pig ileum rat inhibition to the log ED50 log ED spasmolytic activity (mol kg) (mol kg-) Lv. 1..
A 6,05 5,46 4 C 7.32 6.37 9 E 6.97 6.60 2 x 5.46 5.0 3 V 6.08 6.42 Z 7.28 17.60 pa ~0 a a~.
Os p 500 0 a 0 0 5 59 0 00 0 95 o so o 5 o 5059 ~055 a asos as as 0 0 op o 0005 0 09 do a 0 000095 a o a JO 000 o s
I
I
I
32 Table lII Dissociation constants (KB values) on the ileum and spontaneously beating attrium of the guinea pig.
Test Heart Ileum Selectivity Substance K 8 [mol/I] KB [mol/I] KB Heart to KB Ileum A 1.23 x 10 6 2,69 x 10 7 4.6 B 2.51 x 10 7 5.89x 10 8 4.3 o 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 10' 8 7.2 X 1.05 x 10 7 6.17 x 10 7 0.17 Y 1.23 x 10 7 1.94 x i0 7 0.63 Z 1.41 x 10 9 8.13 x 10 1 0 1.7 4 4 4~ 4 44 4.4 4 4 64 4 6 44 4 44 04 4,4.4 5.50 O 4 4o~ 4 44 o so .4 4 4.45 44 44 .4 Ia445~ (3U1.51 4 4 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 acetylcholineinduced bradycardia (Table 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 A i 33 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 S'S" by excellent stability to hydrolysis. It is therefore possible to prepare solutions for parenteral Stadministration 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-, i o NMR-spectra and frequently mass spectra for all the 1a compounds. Unless otherwise expressly mentioned, the percentages, parts and ratios given are always by weight.
Example 1 5,11-dihydro-ll-[ 7-methyl-2,7-diazaspiro[4,4]non-2yl 1 carbonyl 1 -6H-pyrido 2, 3-bl 1, 41 benzodiazepin-6-one A mixture of 9.0 g (0.033 mol) of 11ii. (chlorocarbonyl) ll-dihydro-6H-pyrido 2, 3b][l,4]benzodiazepin-6-one, 4,3 g (0.041 mol) of
SI
f 1 r 34 anhydrous sodium carbonate, 5.6 g (0.04 mol) of 2methyl-2,6-diazaspiro[4,4]nonane and 100 ml of acetonitrile were stirred for 30 minutes at a reaction temperature of 50"C. 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 water/methanol 1/9 5.9 g (48 theory) of colourless crystal were obtained, Mp. 271-274°C.
o a S C 21
H
23
N
5 0 2 (377.45).
0O 9 o o 9 o 9 Calculated: C 66.83 H 6.14 N 18.55 Found: 67.00 6.35 18.85 Example 2 oO**o 9-Chloro-5,11-dihydro-ll-[[7-methyl-2 7diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3b]l,4]benzodiazepin-6-one 4 4 Prepared analagously to Example 1 from 9-chloro-ll- (chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3b][1,4]benzodiazepin-6-one and 2-methyl-2,7diazaspiro[4,4]nonane in a yield of 41 of theory.
Colourless crystals Mp. 257-259°C (dimethylacetamide).
C
21
H
22
N
5 0 2 (411.90).
Calculated: C 61.24 H 5.38 Cl 8.61 N 17.00 Found: 61.50 5.67 8.59 17.10 Example 3 J 1 n I1: i: I N 1l-Dihydro-8--methyl-l1-[ [7-methyl-2,7diazaspiro [4,4 non-2-yl] carbonyl] -6H-pyrido [2,3b] 4]benzodiaepin-6-one Prepared analagously to Example 1 from 11- (chiorocarbonyl) ll-dihydro-8-methyl-6H-pyrido [2,3b] [l,4]benzodiazepin-6-one and 2-methyl-2,7diazaspiro[4,4]nonane in a yield of 71 of theory.
Colourless crystals Mp. 212-214*C (acetonitrile using activated charcoal).
C
22
H
25
N
5 0 2 (391.48).
Calculated: C 67.50 H 6.44 N 17.89 Found: 67.89 6.20 18.00 0 0 0 0 ~00 0 0 x m l 0 8-Chloro-5, 11-dihydro-11-[ [7-methyl-2, 7diazaspiro non-2-yl] carbonyl]I-6H-pyrido [2,3bl fl,41benzodiaze-pin-6-one Prepared analagously to Example 1 from 8-chloro-ll- 0 (chlorocarbonyl) 11-dihydro-6H-pyrido[C2,3 04:0 b] [1,4]benzodiazepin-6-one and 2-methyl-2,7- 04 0 diazaspiro[4,4]nonane in a yield of 47 of theory.
a Colourless crystals Mp. 214-215'C (acetonitrile).
C
2 1
H
22 C1N 5 0 2 (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 ll-Dihydro-8-ethyl-ll-[ [7-methyl-2, 7diazaspiro [4,4 non-2-yl] carbonyl] -6H-pyrido [2 ,3bi rl,4lbenzodiazeipin-6-one -36 Prepared analagously to Example 1 from 11- (chlorocarbonyl) ll-dihydro-8-ethyl-6H-pyrido[2, 3b] [1,4]benzodiazepin-6-one and 2-methyl-2,7diazaspiro[4,4]nonane in a yield of 57 of theory.
colourless crystals Mp. 216-217*C (from acetonitrile using activated charcoal).
C
23
H
27
N
5 0 2 (405.50).
Calculated: C 68.13 H 6.71 N 17.27 Found: 68.30 6.81 17.30 Example 6 ll-Dihydro-9--methyl-ll-[ [7-methyl-2, 7diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyridoj2,3bi Fl,41benzodiazepin-6-one 0 b0 0 Prepared analagously to Example 1 from 11- 0 (chlorocarbonyl) 5, ll-dihydro-9-methyl-6H-pyrido[2 ,3- 00 b] [l,4]benzodiazepin-6-one and 2-methyl-2,7diazaspiro[4,4]nonane in a yield of 9 of theory.
Colourless crystals Np. 253-255*C (acetonitrile).
C
22
H
25
N
5 0 2 (391.48).
0.4 Calculated: C 67.50 H 6.44 N 17.89 Found: 66.99 6.47 17.62 Example 7 8-Bromo-5,11-Dihydro-ll-[[7-methyl-2,7diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido(2,3- 0 bi r.41benzodiazepin-6-one Prepared analagously to Example 1 from 8-bromo-1-ll (chlorocarbonyl) ll-dihydro-6H-pyrido(2, 3b] [l,4]benzodiazepin-6-one and 2-methyl-2,7diazaspiro[4,4]nonane in a yield of 64 of theory.
37 Colourless crystals Np. 227-229*C (from acetonitrile/ethanol 1/1 v/v).
C
2 1
H
22 BrN 5
O
2 (456.36).
Calculated: C Found: 55 .27 55. 60 H 4.86 5.10 Br 17.51 17. 35 N 15.35 15. 13 Example 8 5,ll-Dihydro--ll-[[7-ethyl-2,7-diazaspiro[4,4]non-2yllcarbonvll-6H-pvridor2,3-bl rl,41benzodiazepin-6-one Prepared analagously to Example 1 from 11- (chlorocarbonyl) ll-dihydro-6H--pyrido [2,3b] [l,4]benzodiazepin-6-one and 2-ethyl-2 ,7diazaspiro[4,4]nonane in a yield of 85 of theory.
Colourless crystals Np. 214-215*C (acetonitrile).
C
22
H
25
N
5 0 2 (391.48).
I
o t o 55 0 St o 0 000 S 00 5* I 0 5 to o 5 t o St o 55 o t Calculated: C Found: 67. 50 67.44 H 6.44 6.70 N 17.89 18. .5.5 o I *55 0 soot o S S OS S ''St
S
St Example 9 5,11-Dihydro-1l-f47-ethyl-2,7-diazaspiro[4,4]non-2yl] carbonyl 1-8 -methyl-6H-pyrido 3bi rl.41benzodiazepin-6-one Prepared analagously to Example 1 from 11- (chlorocarbonyl) ll-dihydro-8-methyl-6H-pyrido [2,3b] [l,4]benzodiazepin-6-one and 2-ethyl-2,7diazaspiro[4,4]nonane in a yield of 74 of theory.
Colourless crystals Np. 178-180'C (acetonitrile).
C
2 3
H
27
N
5 0 2 (405.50).
Calculated: C Found: 68. 13 67.94 H 6.71 6.70 N 17.27 17 .57
L
-38 Example 5,1l-Dihydro-ll-[[7-ethyl-2,7-diazaspiro[4,4]non-2yl]carbor~yl] -9-methyl-6H-pyrido[2 ,3blfl(1.4benzlodiazepin-6-one Prepared analagously to Example 1 from 11- (chiorocarbonyl) ll-dihydro-9-methyl-6H-pyrido[2 ,3b] [l,4]benzodiazepin-6-one and 2-ethyl-2,7diazaspiro[4,4]nonane in a yield of 85 of theory.
Colourless crystals Mp. 244-246*C (acetonitrile).
C
23
H
2 7
N
5 0 2 (405.50).
Calculated: C 68.13 H 6.71 N 17.27 O Found: 67.83 6.92 17.17 o0 Example 11 000 o 0 0 00 diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3bI rl, lbenzodiazepin-6-one Prepared analagously to Example 1 from 9-chloro-ll- 0000 (chlorocarbonyl) ll-dihydro-6H-pyridoL2, 3b] [1,4]benzodiazepin-6-one and 2-ethyl-2,7diazaspiro[4,4]nonane in a yield of 75 of theory.
Colures crystals Mp. 224.0-225.5'C (acetonitrile).
C
2 2
H
24 C1N 5 0 2 (425.93).
Calculated: C 62.04 H 5.68 Cl 8.32 N 16.44 Found: 61.89 5.65 8.35 16.34 0 Example 12 5,1l-Dihydro-ll-[ [6-methyl-2,6-diazaspiro[3 ,4]oct-2yllcarbonvll-6H-pyridor2 .3-bi rl,41benzodiazepin-6-one 39 a) 4,4-Bis-(ethoxycarbonyl)-l-methyl-2-pvrrolidinone A mixture of 221.6 g (0.90 mol) of triethyl 1,1,2ethanetricarboxylate, 116.3 g (0.90 mol) of 1,3,5and 20.6 g (0.18 mol) of trifluoroacetic acid was stirred for 20 hours at a reaction temperature of 100°C. After cooling, the mixture was diluted with 1 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 100 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 S* and evaporated down in vacuo. The colourless oil o. obtained (yield 220 g, i.e. 91 of theory) was used 00 without further purification in the following step.
0, 0 0 so .o b) 3,3-Bis-(hydroxymethyl) -1-methylprrolidine To a suspension of 75.0 g (1.976 mol) of lithium aluminium hydride in 1 litre of anhydrous o tetrahydrofuran, a solution of 160.0 g (0.658 mol) of a 4 4,4-bis-(ethoxycarbonyl) -l-methyl-2-pyrrolidinone in 700 o 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 i F k;: 40 *g 0t# 4 0*I 4* 40 0 *0 4 O Q 0 0 44 o Q 0i4r yield of 71.4 g (75% oi theory) was further processed in the next step without any more purification.
c) 3,3-BJ Ilr .ucTmethyl) -l-methylpyrrolidine A mixtutre o)f ,8.o g (0.139 mol) of th( above mentioned compound and 250 ml of 63% aqueous hydrobromic acid was heated in a bomb-type tub', for 24 hours to 180"C. After 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. The 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 0.9 (Macherey- Nagel, Polygram(SIL G/UV 254 pre-coated plastic sheets for TLC; eluent: ethylacetate/methanol/conc. ammonia 100/30/3, v/v/v).
d) 6-Methyl-2-[(4-methylphenyl)sulfonyl]-2,6diazaspiro-[3,41octane To a solution of 51.3 g (0.3 mol) of ptoluenesulfonamide 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)-l-methylpyrrolidine 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 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 9 04 0 4 4000 0.04 4, G sl b
Q
e i i 1 ii: 41 sulphate and evaporated in vacuo using a rotary evaporator. The residue remaining (J4.0 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-
C
14
H
20
N
2 0 2 S (280.39) Calculated: C 59.67 H 7.19 N 9.99 S 11.43 Found: 56.66 7.16 10.30 11.51 e) 6-Methyl-2,6-diazaspiro 3 ,4 octane A mixture of 48.5 g (0.173 mol) of 6-methyl-2-[(4- °methyl-phenyl) -sulfon, 1]-2,6-diazaspiro[3,4]octane, 199 l° 0 ml (about 0.7 mol) of an approx. 3.5 molar solution of 8 sodium-bis-(2-methoxy-ethoxy)dihydroaluminate in toluene and 300 ml of dry toluene were heated to 60"C for p hours with stirring and to 80"C for 6 hours. After the Oo reaction had ended, 20 aqueous sodium hydroxide solution was carefully added dropwise, whilst external cooling was carried out with ice water, until the o development of hydrogen had ceased, the toluene phase was separated off, dried over sodium sulphate and o evaporated carefully using a Vigreux column at a a.:o pressure of 50 mmHg. The desired compound had a boiling point 22 mHg 80-85°C and proved to be a colourless, readily mobile liquid smelling like an amine. Yield: g (34 of theory).
f) 5,ll-Dihydro-ll-[[6-methyl-2,6-diazaspiro[3,4]oct-2vll-carbonyl-6H-pyrido 2,3-b [1,41benzodiazepin-6-one Prepared analagously to Example 1 from 11- (chlorocarbonyl)-5,ll-dihydro-6H-pyrido[2,3b][l,4]benzodiazepin-6-one and 6-methyl-2,6- L1 A "I -42diazaspiro(3,4]octane in a yield of 26 %of theory Colourles8 crystals Np. 225.5-227.0*C (acetonitrile).
C
2 0
H
21
N
5 0 2 (363.42).
Calculated: C 66.10 H 5.82 N 19.27 Found: 66.18 5.82 19.17 Example 13 ll-Dihydro--8-ethyl-ll- [[6-methyl-2, 6diazaspiro[3,4]oct-2-yllcarbonyl-6H-pyrido[2 ,3bi ll4benzodiazepin-6-one Prepared analagously to Example 1 from 11- (chlorocarbonyl) ll-dihydro-8-ethyl-6H-pyrido[2, 3b] [l,4]benzodiazepin-6-one and 6-methyl-2, i-- 4 diazaspiro[3,4]octane in a yield of 47 of theory.
Colourless crystals Np. 215-217'C (acetonitrile).
4C 22
H
2 5
N
5 0 2 (391.48).
Calculated: C 67.50 H 6.44 N 17.89 Found: 67.27 6.41 17.88 0 4 44 Example 14 44a5, l1-Dihydro-8-methyl-ll- 6-methyl-2 ,6- '~.diazaspiro oct-2-yl] carbonyl-6H-pyrido 12,3bi rl,41benzodiazepin-6-one Prepared analagously to Example 1 from 11- (chlorocarbonyl) 1l-dihydro-8--methyl-6H-pyrido [2 ,3b] benzodiazepin-6-one and 6-methyl -2,6diazaspiro[3,4]octane in a yield of 34 of theory Colourless crystals Np. 220-223'C (acetonitrile).
C
21
H
23 No (377.45).
Calculated: C 66.83 H 6.14 N 18.55 Found: 66.59 6.12 18.41 -43 Example ll-Dihydro-9-methyl-ll- 6-methyi-2, 6diazaspiro[3 ,4]oct-2-yl]carbonyl-6H-pyrido[2 ,3- WI rl,41benzodiazepin-6-one Prepared analagously to Example 1 from 11- (chiorocarbonyl) ll-dihydro--9-methyl-6H-pyrido [2,3b] [l,4]benzodiazepin-6-one and 6-methyl-2, 6diazaspiro [3,4 ]octane in a yield of 41 of theory Colourless crystals Mp. 242-245*C (after recrystallisation twice from acetonitrile).
C
21
H
23
N
5 0 2 (377.45).
$4 4 4 4 4 4$ 4$, 4$ 4 4 44 4 4 4, $5 4$ 444$ Calculated: C Found: 66.83 66. 57 H 6.14 6.23 N 18.55 18.41 Example 16 9-Chloro-5, Il-dihydro-li- [[6-methyl-2, 6diazaspiro[3, 4]oct-2-yl]carbonyl-6H-pyrido[2, 3bi rl,41benzodiazepin-6-one Prepared analagously to Example 1 from 9-chloro-ll- (chlorocarbonyl) ll-dihydro-6H-pyrido[2, 3b] [l,4]benzodiazepin-6-one and 6-methyl-2, 6diazaspiro[3,4]octane in a yield of 37 of theory Colourless crystals Mp. 229-230' C (acetonitrile).
C
20
H
2 OClN 5 0 2 (397,87).
'44$ 4 4 '44; 4 4$ ~4 44$ 4 I I Calculated: C Found: 60.38 60.21 H 5.07 5.01 8.91 8.90 N 17.60 17.94 Example 17 ll-Dihydro-ll- [[2-methyl-2, 6-diazaspiro[3 oct-6-yl] carbonvl-6H-pvridor2. 3-bi fl,41benzodiazepin-6-one Al 44 a) 4,4-Bis-(ethoxycarbonyl)-l-(phenylmethyl)-2pyrrolidinone Prepared analagously to Example 12a from triethyl 1,1,2-athanetricarboxylate and 1,3,5-trisin 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)-1-(phenvlmethyl)-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.
S'Colourless, highly viscous oil which after being left to fi 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)-pyrrolidinehydrobromide A mixture of 22.0 g (0.1 mol) of 3,3-bis- (hydroxymethyl)-l-(phenylmethyl)-pyrrolidine and 130 ml S'L of 63 aqueous hydrobromic acid was heated to 180°C 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. 222-225'C.
C
13
H
1 Br 2 N x HBr (428.0) Calculated: C 36.48 H 4.24 Br 56.01 N 3.27 Found: 36.56 4.10 55.73 3.02 1 ll-, n ll" 1
"V.
d) 6-(Phenylmethyl) (4-methyiphenyl) sulfonyl]-2,6di-aas::r::3,41 octane Prepredanalagously to Example l2d from 3,3-bis- (bromomethyl) -1-(phenylmethyl) -pyrrolidine-hydrobromide, potassium hydroxide and p-toluenesulfonamide in a yield of 60 of theory. The crystalline substance obtained was further processed directly without recrystallisation or other purification.
e) 6-(Phenvlmethyl) -2,6-diazaspirof3,41octane Prepared analagously to Example 12e from 6- (phenylmethyl)-2-[ (4-methylphenyl)sulfonyl]-2,6diazaspiro[3,4loctane and sodium-bis-(2-methoxyethoxy)dihydroaluminate in a yield of 41 of theory.
Colourless liquid, Bp 18 mmHg 161-170*C and R F 0.25 04(R) j 4 4 t(Macherey-Nagel, Polygram R)SIL G/UV 2 54 1 pre-coated plastic sheets for TLC; eluent dichloromethane/methanol/conc. aqueous ammonia 68/15/15/2, v/v/v/v).
0 f) 2-Methyl-6-(phenvlmethyl) 6-diazaspiror3,.41octane 10.8 g (0.0534 mol) of 6-(phenylwethyl)-2,6- 0 *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 ref luxed 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 sil -qel by HPLC and using dichloromethane/m,- t hanol/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 (3%of theory).
A h -46- R0.54 (Macherey-Nagel, Polygram SIL G/UV 2 54 1 precoated plastic sheets for TLC; eluent dichloromethane/methanol/cyclohexane/conc. aqueous ammonia 68/15/15/2, v/v/v/v).
q) 2-Methvl-2,6-diazaspiro f3,41 octane g of 10 palladium/animal charcoal catalyst were added to a solution of 6.1 g (0.0282 mol) of 2methyl-6-(phenylmethyl)-2,6-diazaspiro[3,4]octane in ml of ethanol and the mixture was then hydrogenated for hours at 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, 0R 0.1 was obtained as residue (Macherey-Nagel, 0PclygramR SIL G/UV 25 4 pre-coated plastic sheets for TLC; eluent dichloromethane/methanol/cyclohexane/conc. aqueous 4 ammonia 68/20/10/5, v/v/v/v).
Yield: 3.2 g (90 of theory).
h) 5,ll-Dihydro-ll-[ [2-methyl-2,6--diazaspiro[3,4]oct-2yllcarbonyll-6H-pyridor2,3-bl fl,41benzodiazepin-6-one .00:4Prepared analagously to Example 1 from 11- 00:0 (chlorocarbonyl) ll-dihydro-6H-pyrido[2 ,3b] Ll,4]benzodiazepin-6-one and 2-methyl-2,6diazaspiro[3,4]octane in a yield of 46 of theory.
Colourless crystals Mp. 273-275'C (acetonitrile).
6~ C 2
H
21 No (363.42) Calculated: C 66.10 H 5.82 N 19.27 Found: 66.25 5.89 18.90 Example 18 ll-Dihydro-ll-[ (phenylmethyl) -2,6diazaspiro[3,4]oCt-2-yl]carbonyl3-6H-pyrido[2,3bi F 141 benzodiazepin-6-one -47 Prepared analagously to Example 1 from 11- (chiorocarbonyl) ll-dihydro-6H-pyrido [2,3b] [l,4]benzodiazepin-6-one and 6-(phenylmethyl) -2,6diazaspiro[3,4]octane in a yield of 20 of theory.
Colourless crystals Mp. 193-195' C (diisopropylether).
C
26
H
25
N
5 0 2 (439.52).
Calculated: C 71.05 H 5.73 N 15.93 Found: 70.75 5.91 15.76 Example 19 ll-Dihydro-8-methyl-ll- [[2-methyl-2 ,6- 0~ 0 0diazaspiro [3,41 oct-2 -yl] carbonyl] -6H-pyrido [2,3- 0,blf 1.41 benzodiazepin-6-one 0 Prepared analagously to Example 1 from 11- (chlorocarbonyl) ll-dihydro-8-methyl-6H-pyrido[2 ,3o b] [l,4]benzodiazepin-6-one and 2-methyl-2,6diazaspiro[3,4]octane in a yield of 43 of theory.
Colourless crystals Mp. 184. 0-184. 5 C (acetonitrile).
C
21
H
23 No (377.45).
ocalculated: C 66.83 H 6.14 N 18.55 Found: 66.79 6.43 18.65 Example 0000* 5, 1l-Dihydro-8-ethyl-ll- II[2-methyl-2,6diazaspiro[3,4]oct-6-y'L]carbonyl]-6H-pyrido[2,3bi fl,41benzodiazepin-6-one Prepared analagously to Example 1 from 11- (chlorocarbonyl) l1-dihydro-8-ethyl-6H-pyrido[2, 3b] [l,4]benzodiazepin-6-one and 2-methyl-2,6diazaspiro[3,4]octane in a yield of 34 of theory.
Colourless crystals Mp. 245-246 0 C (acetonitrile).
C
22 25 N0 (391.48).
4 48 Calculated: C Found: 67.50 67.30 H 6.44 6.33 N 17.89 17.88 Example 21 ll-Dihydro-9-methyl-ll- -methyl-2, 6diazaspiro [3,4 ]oct-6-yl] carbonyl] -6H-pyrido 3bi rl,4benzodiazepin-6-one Prepared analagously to Example 1 from 11- (chiorocarbonyl) 11-dihydro-9-methyl-6H-pyrido[2, 3b] [l,4]benzodiazepin-6-one and 2-methyl-2,6diazaspiro[3,4]octane in a yield of 41 of theory.
Colourless crystals Np. 284-285*C (acetonitrile).
C
2 1
H
2 3
N
5 0 2 (377.45).
0 0 0 0% 0 o, 00 0 00~ 0 00 00 00 0 0 0 00 0 0 0 0 0 00 0 00 00 0 0000 Calculated: C Found: 66.83 67. 08 H 6.14 6. 12 N 18.55 18.85 0000 0 0 0000 0000 0 00 00 0 00,., 0 0 0 00 0 0 0 0 0.0.00.
Example 22 9-Chloro-5, il-dihydro-li- [[2-methyl-2, 6diazaspiro [3 oct-6-yl Icarbonyl] -6H-pyrido 3bi rl.41benzodiazepin-6-one Prepared analagously to Example 1 from 9-chloro-ll- (chlorocarbonyl) 1l-dihydro-6H-pyrido[2 ,3b] [l,4]benzodiazepin-6-one and 2-methyl-2,6diazaspiro[3,4]octane in a yield of 18 of theory.
Colourless crystals Mp. 276-277*C (after recrystallisation twice from acetonitrile).
C
2 0
H
2 OClN 5 0 2 (397,87).
Calculated: C Found: 60. 38 60.74 H 5.07 4.92 Cl 8.91 8.91 N 17.60 17.77 Example 23 L 1~ 49 ll-dihydro-ll-[ [2-methyl-2, 6diazaspiro oct-6-yl] carbonyl] -6H-pyrido 3bi Fl,41benzodiazepin-6-one Prepared analagously to Example 1 from 8-chloro-l1- (chiorocarbonyl) -5 ,ll-dihydro-6H-pyrido [2,3b] [l,4]benzodiazepin-6-one and 2-methyl-2,6diazaspiro[3,4]octane in a yield of 50 of theory.
Colourless crystals Mp. 231-232*C (acetonitrile).
C
20
H
2 OClN 5 0 2 (397.87).
Calculated: C Found: 60.38 60. 62 H 5.07 5.20 Cl 8.91 8.61 N 17.60 17 .54 00 o 1 0 W~ 00 000 1 00 01 0 0 t 0 4 00 4 0 0 0l 0 0? 0 0 0 *00.
Example 24 carbonyl]-8-methyl-6H-pyrido[2 [1,4]benzodiazepin-6one 0 0 04 0 a04 00 a00* a) 4-Cvano-4- (ethoxvcarbonvH -l-ethyl-2-pvrrolidinone Prepared analogously to Example 12a) from diethyl 2cyanosuccinate and 1,3, 5-triethyl-hexahydro-l, 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) (hydroxymethyl) -l-ethylpyrrolidone Prepared analogously to Example 12b) from 4-cyano-4- (ethoxycarbonyl) -l-ethyl-2-pyrrolidinone and lithium aluminium hydride in tetrahydrofuran in a yield of 74% of theory. Colourless oil, RF 0. 25 (Macherey-Nagel, PolygramO SIL G/UV 254 pre-coated plastic sheets for TLC; eluant: ethyl acetate/methanol/cyclohexane/conc. aqueous ammonia 68/15/15/2, v/v/v/v).
c) 3-(Aminomethyl)-3-(bromomethyl)-l-ethylpyrrolidinedihydrobromide Prepared analogously to Example 12c) from 3- (aminomethyl)-3-(hydroxymethyl)-l-ethylpyrrolidine and 63% aqueous hydrobromic acid in a yield of 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)-l-ethylpyrrolidine in 2 litres of dioxane was carefully mixed with a mixture of a,(0 130 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 solvent 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 mHg 83-87'C, which was identified as the desired compound by MS, IR and 1 H-NMR spectra, after distillation in a water jet vacuum.
e) 5,11-Dihydro-ll-[[6-ethyl-2,6-diazaspiro[3,4]oct-2yljcai'bonyl]-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-2,6diazaspiro[3,4]octane in a yield of 27% of theory.
Colourless crystals m.p. 216-217*C (acetonitrile).
S- I )51-iyr-l[6ehy-,-izsio34ot2 e
I;
C
22
H
25
N
5 0 2 (391.48).
Caic.: C 67.50 H 6.44 Found: 67.39 6.20 51 N 17.89 17.60 Example 11-Dihydro-li-[[6-ethyl-2, 6-diazaspiro [3 oct-2 vllcarbonvll-6H-pvridor2,3-bl Fl,41benzodiazepip-6-one Prepared analogously to Example 1 from 11- (chiorocarbonyl) -5,1l-dihydro-6H-pyrido[2 benzodiazepin-6-one and 6-ethyl-2, 6diazaspiro[3,4]octane in a yield of 15% of theory.
Colourless crystals m.p. 221-223*C (acetonitrile).
C
21
H
23 N 5 0 2 (377.45).
Calc.: C 66.83 H 6.14 N 18.55 Found: 66.77 6.32 18.32 0 00 a 00 a0 O a.)q a 04 00 0 0 00 0 U 00 0 Example 26 0000 0 0 0000 0 00 0 0 oo~ 0 00 00 0 0 000000 0 0 04.400 p ll-Dihydro-ll- [[6-ethyl-2, 6-diazaspiro [3 oct-2-yl 1carbonyl]-9-methyl-6H-pyrido[2,3-b] [l,4]benzodiazepin-6one Prepared analogously to Example 1 from 11- (chlorocarbonyl) 1l-dihydro-9-methyl-6Hpyrido[2,3-b] [l,4]benzodiazepin-6-one and 6-ethyl-2,6diazaspiro[3,4]octane in a yield of 26% of theory.
Colourless crystals m.p. 169-171'C (acetonitrile).
C
2 2
H
2 5
N
5 0 2 (391.48).
Cabc.: C 67.50 H 6.44 N 17.89 Found: 67.46 6.09 17.49 Example 27 il-dihydro-il-[ [6-ethyl-2, 6-diazaspiro oct-2-yl]carbonyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6- -i 52 one 0~ I o t o9 o 00 4I Of o cir 0004 Prepared analogously to Example 1 from 9-chioro-il- (chiorocarbonyl)-5,l1-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 6-ethyl-2, 6diazaspiro[3,4]octane in a yield of 19% of theory.
Colourless crystals, m.p. 158-160'C (acetonitrile) and RF 0.63 (Macherey-Nagel, PolygramO SIL G/UV 5 4 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).
C
21
H
22 C1N 5 0 2 (411.90).
Calc.: C 61.24 H 5.38 Cl 8.61 N 17.00 Found: 61.25 5.36 8.63 17.08 Example 28 5,11-Dihydro-il-[[6-propyl-2,6-diazaspiro[3,4]oct-2yllcarbonyll-6H-pyridof2,3-bl l,4ibenzodiazepin-6-one a) 4-Cvano-4-(ethoxycarbonyl)-l-propyl-2-pyrrolidinone Prepared analogously to Example 12a) from diethyl cyanosuccinate and 1,3,5-tripropyl-hexahydro-1,3,5triazine in the presence of trifluoroacetic acid in a yield of 65% of theory. Colourless liquid, RF 0.72 (Macherey-Nagel, PolygramO SIL G/UV 2 5 4 pre-coated plastic sheets for TLC; eluant: ethyl acetate/petroleum ether 1/1, v/v) ci 4 o 00D 00( 4 0004 o 04 4,s b) 3-(Aminomethvyl-3-(hydroxymethyl)-1propylpyrrolidine 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.
t; k- 53 Colourless viscous oil, used in the next step without further purification.
c) 3-(Aminomethyl)-3-(bromomethyl)-1-propylpyrrolidinedihydrobromide 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-diazaspiror3 ,41octane 3-(Aminomethyl)-3-(bromomethyl)-1-propylpyrrolidine was reacted with caustic soda, water and dioxan as described in Example 24d). The crude product obtained *I after processing, RF 0.5 (Macherey-Nagel, PolygramO SIL
G/UV
54 pre-coated plastic sheets for TLC; eluant: dichioromethane/methanol/cyclohexane/conc. aqueous 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 o 47% of theory based on 3-(aminomethyl)-3- (hydroxymethyl)-l-propylpyrrolidine and identified as the desired compound by MS and 1 H-NMR spectrum.
e) 5,11-Dihydro-ll-r[6-propyl-2,6-diazaspiro[3,4]oct-2yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzudiazepin-6one Prepared analogously to Example 1 from 11- (chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 6-propyl-2,6diazaspiro[3,4]octane in a yield of 74% of theory.
Colourless crystals m.p. 208-209*C (acetonitrile).
C
22
H
25
N
5 0 2 (391.48) Calc.: C 67.50 H 6.44 N 17.89
A
-54 Found: 67.40 6.39 17.60 Example 29 ll-Dihydro-8-methyl-ll- El6-propyl-2, 6-diazaspiro [13k4]oct-2-yi] carbonyl]-6H-pyrido 3-b] 4]benzodiazepiri-6one Prepared analcjously tc .cample 1 from 11- (chiorocarbonyl) 1l-dihyuio-8-methyl-6H-pyrido[2, 3-b] [l,4]benzodiazepin-6-one and 6-propyl-2, 6diazaspiro[3,4]octane in a yield of 60% of theory.
Cac: C 81 6.71 17.27' Example il-dihydro-lI-r[6-propyl-2, 6-diazaspiro 4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b] [l,4]benzodiazepin-6- 0 one Prepared analogously to Example 1 from 8-chloro-ll- (chlorocarbonyl)-5,ll-dihydro-6H-pyrido[2,3-b] benzodiazepin-6-one arnd 6-propyl-2 ,6diazaa5piro[3,4]octane in a yield of 44% of theory.
Colourless crystals m.p. 210-2l2*C (from diisopropylether arnd acetonitrile).
C
22
H
24 C1N 5 0 2 (425.93) Calc.: C 62.04 H 5.68 Cl 0. 32 N 16.44 Found: 61.85 5.6r3 8.39 16.38 Example 31 55 llI-Dihydro-8 -ethyl-ll-[ [ii6-et nyl-2, 6-diazaspiro [3 oct-2-yllcarbonyl]-6H-pyrido[2,3-b] [l,4]benzodiazepin-6one Prepared analogously to Example 1 from 11- (chlorocarbonyl) ll-dihydro-8-ethyl-6Hpyrido[2,3-b] [l,4]benzodiazepin-6-one and 6-ethyl-2,6diazaspiro[3,4]octane in a yield of 12% of theory.
Colourless crystals xn.p. l90-191*C (acetonitrile) and R 0.65 (IMacherey-Nagel, PolygramO SIL G/UV 2 5 4 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).
C 23 H 2 7N 5 0 2 (405.50) Calc.: C 68.13 H 6.71 N 17.27 Found: 67.92 6.64 17.44 Example 32 5,ll-Dihydro-9-methyl-ll-[ [6-propyl-2,6-diazaspiro[3,43oc, .2-yl]carbonyl]-6H-pyrido[2,3-b] [l,4]benzodiazepin-6on~e Prepared analogously to Example I from 11- (chlorocarbonyl) ll-dihydro-9-methyl-6H-pyrido 3-b] benzodiazepin-6-Qne and 6-propyl-2, 6diazaspiro [3,4 ]octane in a yield o239% of theory.
Colourless crystals m.p. 183-184O*7 cacetonitrile) andRF 0.51 (Macherey-Nagel, PolygramO SIL G/UV 25 4 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).
C 23
H
2 7
N
5 0 2 (405.50) Calc.: C 68.13 H 6.71 N 17.27 Found: 68.00 6.52 17.10 a 4 t v Example 33 1>: 56 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-6one Prepared analogously to Example 1 from 11- 11-dihydro-8-ethiyl-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one and 6-propyl-2,6diazaspiro[3,4]octane in a yield of 55% of theory.
Colourless crystals m.p. 170-172*C (acetonitrile) and RF 0.52 (Macherey-Nagel, PolygramO SIL G/UV 2 54 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).
C
24
H
29
N
5 0 2 (419.53) Calc.: C 68.71 H 6.97 N 16.69 S' Found: 68.90 7.18 16.72 o or 0 4 Example 34 5,11-Dihydro-11- [2-ethyl-2,6-diazaspiro[3,41oct-2vllcarbonyll-6H-prido[2,3-blrl,41benzodiazepin-6-one a) 2-Acetyl-6-(phenylmethyl)-2,6-diazaspiror3,41octane 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 00041 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.- 0.035 W155-168*C in a yield of 69.3 g (81% of theory).
Ii -57 b) 2-Ethyl-6- (phenvlmethyl) 6-diazaspirof 3,4 1 ctane Prepared analogously to Example 12b) from 2-acetyl- 6- (phenylmethyl) 6-diazaspiro[3,4 ]octane and lithium aluminium hydride in anhydrous tetrahydrofuran. The desired compound is obtained as a colourless oil bp 02 H991-93-C amd R F 0. 6 (Macherey-Nagel, Polygram SIL G/UV 254 precoated plastic sheets for TLC; eluant: dichioromethane/methanol/cyc lohexane/conc. aqueous ammonia 68/15/15/2, v/v/v/v) in a yield of 73% of theory.
c) 2-Ethvl-2 6-diazaspiro r3, 4octane Prepared analogously to Example 17g) from 2-ethyl-6- (phenylmethyl) 6-diazaspiro [3,4 3octane by catalytic A hydrogenation in the presence of 10% palladium/ animal charcoal. The desired compound is obtained as a colourless oil, RF 0.45 (Macherey-Nagel, PolygramO SIL 4 44F G/UV 2 54 precoated plastic sheets for TLC; eluant: dichi oromethane/methanol/cyclohexarie/ ethyl acetate/conc.
aqueous ammonia 62/10/10/16.7/1.3, v/v/v/v/v) in a yield t of 96% of theory.
~4 4 d) 5,ll-Dihydro-ll-[[2-ethyl-2,6-diazasp.-ro[3,4]oct-6o' yl ]carbonyl ]-6H-pyrido 3-b] 4 ]benzodiazepin-6one A Prepared analogously to Example 1 from 11- (chlorocarbonyl) 1 1-dihydro- 6H-pyrido 3 [1,4] benzodiazepin-6-one and 2-ethyl-2, 6diazaspiro[3,4 ]octane in a yield of 60% of theory.
Colourless crystals m.p. 251-254*C (dioxan) and RF 0.3 (Macherey-Nagel, PolygramO SIL G/UV 2 4 pre-coated plastic sheets for TLC; eluant: dichloromethane/ ethyl acetate/methanol/cyclohexane/conc. aqueous ammonia 63.5/13/1/11/1.5, v/v/v/v/v).
C 21
H
23 N 5 0 2 (377.45) -58 Cac.: C 66.83 H 6.14 N 18.55 Found: 66.61 6.20 18.40 Example 5,1l-Dihydro-ll-[ [2-ethyl-2,6-diazaspiro[3,4]oct-6y1]carbonyl]-8-methyl-6H-pyrido[2,3-b] [l,4]benzodiazep in-6-one Prepared analogously to Example 1 from 11- (chiorocarbonyl) 11-dihydro-8-xnethyl-6Hpyrido[2, 3-b] 4]benzodiazepin-6-one and 2-ethyl-2, 6diazaspiro[3,4]octane in a yield of 61% of theory.
1. Colourless crystals m.p. 2l3-2l5*C (acetonitrile).
C
22
H
2 5
N
5 0 2 (391.48) Calc.: C 67.50 H 6.44 N 17.89 *Found: 67.19 6.32 18.22 Example 36 5,1l-Dihydro-ll-[[2-ethyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-9-methyl-6H-pyrido[2, 3-b] 4]benzodiazepin-6flit $sit one i t Prepared analogously to Example 1 from 11- (chlorocarbonyl) 11-dihydro-9-methyl-6H-pyrido benzodiazepin-6-one and 2-ethyl-2, 6diazaspiro[3,4]octane in a yield of 56% of theory.
Colourless crystals m.p. 251-253'C (acetonitrile).
C
22
H
2 No0 (391. 48) Caic.: C 67.50 H 6.44 N 17.89 Found: 67.32 6.49 18.31 Example 37 11-dihydro-ll-[ [2-ethyl-2, 6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2, 3-b] 4]benzodiazepin-6one :I'i i:: ilt' 'r i.: 59 Prepared analogously to Example 1 from 9-chioro-li- (chiorocarbonyl) ll-dihydro-6H-pyrido[2,3-b] benzodiazepin-6-one and 2-ethyl-2,6diazaspiro[3,4]octane in a yield of 45% of theory.
Colourless crystals m.p. 248-250 0 C (acetonitrile).
C
21
H
22 C1N 5 0 2 (411.90) 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-l-[[6-(2-methylpropyl)-2,6diazaspiro[3,4]-oct-2-yl]carbonyl]-6Hpyridor2.3-b]rl,4lbenzodiazepin-6-one o oo Oo 6 o o 66s 6 o 6 4 64 61 6 a) 4-Cyano-4-(ethoxycarbonyl)-l-(2-methylpropyl)-2pyrrol-ldinone Prepared analogously to Example 12a) in a yield of 74% of theory from cyanosuccinic acid and hexahydro- 1,3,5-tris-(2-methylpropyl)triazine using trifluoroacetic acid. Colourless oil, RF 0.8 (Macherey- Nagel, PolygramO SIL G/UV 54 pre-coated plastic sheets for TLC; eluant: ethyl acetate/petroleum ether 1:1, v/v).
b) 3-(Aminomethyl)-3-(hydroxymethyl)-l-(2methylpropyl)-pyrrolidine Preparea analogously to Example 12b) from 4-cyano-4- (ethoxycarbonyl)-l-(2-methylpropyl)-2-pyrrolidinone by reduction with lithium aluminium hydride in a yield of of theory. Colourless oil, RF 0.26 (Macherey-Nagel, PolygramO SIL G/UV 2 54 pre-coated plastic sheets for TLC; eluant: dichloromethane/methanol/cycl ohexane/conc.
aqueous ammonia 68/15/15/2, v/v/v/v).
6 6 6 i
L
k 3- (Aminomethyl) (bromomethyl) -1-(2-methyipropyl) pyrrolidine-dihydrobromide Prepared analogously to Example 12c) from 3- (aminomethyl) -3-hydroxymethyl-l- (2-methyipropyl) pyrrolidine and 63% aqueous hydrobromic acid. The brownish salt is used in the following step without further purification.
d) 6-(2-Methylpropyl)-2,6-diazaspirof3,41octane Prepared analogously to Example 28d) from 3- (aminomethyl) (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 0.45 (Macherey-Nagel, PolygramO SIL G/UV 25 4 pre-coated plastic sheets for TLC; eluant: dichloromethane/methanol/cyclohexane/conc.
aqueous ammonia 68/20/10/2, v/v/v/v).
e) 5,ll-Dihydro-ll-fI[6-(2-methylpropyl)-2,6-diazaspiro- 13 ,4]oct-2-yl]carbonyl]-6H-pyrido[2, 3-b] El,4]benzodiazeipin-6-one Prepar.'d analogously to Example 1 from 11- (chlorocarbonyl)-5,ll-dihydro-6H-pyrido(2,3-b] benzodiazepin-6-one and 6- (2-methyl-propyl) 6diazaspiro[3,4]octane in a yield of 49% of theory.
Colourless crystals m.p. 199-201*C (acetonitrile) andRF .40.48 (Macherey-Nagel, PolygramO SIL G/UV 25 4 1 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).
C 23
H
2 7 N 5 0 2 (405.50) Calc.: C 68.13 H 6.71 N 17.27 Found: 67.96 6.84 17.47 Example 39 -61- 11-Dihydro-8-methyl-1l-[ (2-methylpropyl) -2,6diazaspiro[3,4]oct-2-y]carbolyl]-6H-pyridoI2,3-b]rl,41benzodiazepin-6-one Prepared analogously to Example 1 from 11- (chiorocarbonyl) ll-dihydro-8-methyl-6Hpyrido[2,3-b] [l,4]benzodiazepin-6-one and 6-(2methylpropyl) -2,6-diazaspiro octane in a yield of 52% of theory. Colourless crystals m.p. 186-188*C (acetonitrile).
C
24
H
2 9
N
5 0 2 (419.53) Calc.: C 68.71 H 6.97 N 16.69 Found: 68.67 6.99 16.47 Example 0 5,11-Dihydro-9-methyl-ll-[ [6-(2-methylpropyl)--2,6diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b]- 04 10 000 r 1.41 benzodiazepin-6-one a 0 0 0a 0 p0 0 a Prepared analogously to Example 1 from 11- (chlorocarbonyl) l1-dihydro-9-miethyl-6H-pyrido [2 [l,4]benzodiazepin-6-one and 6-(2-methylpropyl)-2,6diazaspiro[3,4]octane in a yield of 24% of theory.
O Colourless crystals, m.p. 163-165'C (acetonitrile).
0 C 24
H
29
N
5 0 2 (419.53) Calc.: C 68.71 H 6.97 N 16.69 000Found: 68.62 6.72 16.67 Example 41 9-Chloro-5, l1-dihydro-ll-[ [6-(2-methylpropyl) -2,6diazaspiro oct-2-yl] carbonyl] -6H-pyrido 1.,41 benzodiazepin-6-one Prepared analogously to Example 1 from 9-chloro-1l- (chiorocarbonyl) ll-dihydro-6H-pyrido[2,3-b] benzodiazepin-6-one and 6- (2-methylpropyl) -2 ,6- -62 diazaspiro[3,4]octane in a yield of 45% of theory.
Colourless crystals, m.p. 177-179*C (diisopropylether).
C
2 3
H
2 6 C1N 5 0 2 (439.94) Caic.: C 62.79 H 5.96 Cl 8.06 N 15.92 Found: 62.98 6.29 8.07 16.08 Example 42 6,ll1-Dihydro-ll-[ [7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyll-5H-pyridof2,3-bl Fl,51benzodiazepin-5-one Prepared analogously to Example 1 from 11- (chiorocarbonyl) ll-dihydro-5H-pyrido[2, 3-b] and 2-methyl-2 ,7diazaspiro[4,4]nonane in a yield of 84% of theory.
Colourless crystals, m.p. 212-214'C (acetonitrile).
a0 C 2
H
23 No0 (377.45) Caic.: C 66.83 H 6.14 N 18.55 0*Found: 66.86 6.33 18.73 0 .41 Example 43 6,ll-Dihydro-ll-[ [7-ethyl-2,7-diazaspiro[4,4]non-2- 0 yllcarbonyll-5H-pyridor2,3-bl Fl,51benzodiazepin-5-one 0 Prepared analogously to Example 1 from 11- 0 (chlorocarbonyl)-6,ll-dihydro-5H-pyrido[2,3-b] and 2-ethyl-2,7-diazaspiro[4,4]nonane in a yield of 68% of theory. Colourless 4 0 4 4crystals, m.p. 151.0-152.5'C (acetonitrile).
00000C 22
H
25
N
5 0 2 (391.48) Calc.: C 67.50 H 6.44 N 17.89 Found: 67.65 6.55 18.04 Example 44 -63- 6,11-Dihydro~-[ 6-methyl-2, 6-diazaspiro[3,4]oct-2-yl]- Prepared analogously to Example 1 from 11- (chiorocarbonyl) -6,ll-dihydro-5H-pyrido[2 and 6-methyl-2, 6diazaspiro[3, 4]octane in a yield of 38% of theory.
Colourless crystals, m.p. 239-241' C (acetonitrile)
C
20
H
21
N
5 0 2 (363.42) Caic.: C 66.10 TI 5.82 N 19.27 Found: 65.99 5.77 19.17 Example 6,11-Dihydro-ll-[[2-methyl-2,6-diazaspiro[3,4]oct-6yll carbonvll -5H-Pyrido F2, 3-b1 rl,51benzodiazepin-5-one Prepared analogously to Example 1 from 11- (chlorocarbonyl) -6,ll1-dihydro-5H-pyrido 2, 3-b] 1, 4 benzodiazepin-5-one and 2-methyl-2, 6-diazas-)iro[3,4]octane in a yield of 50% of theory. Colourless crystals, m.p. 220-221'C (acetonitrile)
C
20
H
21
N
5 0 2 (363.42) aCalc.: C 66.10 H 5.82 N 19.27 Cal" a Found: 65.88 6.08 19.00 o Example 46 6,11-IDihydro-ll-[[6-ethyl-2,6-diazaspiro[3,4]oct-2-yl]carbonVll-5H-pVridor2,3-bl 1*1,5lbenzodiazepin-5-one Prepared analogously to Example 1 from 11- (chlorocarbonyl) ll-dihydro-5H-pyrido[2, 3-b] and 6-ethyl-2, 6diazaspiro[3,4 ]octane in a yield of 10% of theory.
Colourless crystals, m.p. 196-200*C (acetonitrile) and R 0.62 (Macherey-Nagel, PolygramO SIL G/UV 254 pre-coated -64plastic sheets for TLC; eluant: dichioromethane/ethyl acetate/methanol/cyclo-hexane/conc. :-.ueous ammonia 62/16.7/10/10/1.3, v/v/v/v/v).
C
21
H
23
N
5 0 2 (377.45) Caic.: C 66.83 H 6.14 N 18.55 Found: 66.26 6.11 18.14 Example 47 6,ll-Dihiydro-ll-[ [6-propyl-2,6--diazaspiro[3,4]oct-2vllcarbonyll-5H-pvridof2,3-bl Fl.51benzodiazepin-5-one Prepared analogously to Example 1 from 11- (chiorocarbonyl) ll-dihydro-5H-pyrido[2 and 6-propyl-2, 6- 0 diazaspiro[3,4]octane in a yield of 51% of theory.
Colourless crystals, m.p. 195-197*C (acetonitrile) and RF 0.58 (conditions as in Example 46).
0C 22
H
25
N
5 0 2 (391.48) e Calc. C 67.50 H 6.44 N 17.89 *Found: 67.46 6.36 17.98 o Example 48 6,ll-Dihydro-ll-[ [2-ethyl-2,6-diazaspiro[3,4]oct-6-yl]o 0 carbonyll-5H-pyridor2,3-bl Fl,51benzodiazepin-5-one Prepared analogously to Example 1. but using tetrahydrofuran instead of acetonitrile as solvent, from ll-(chlorocarbonyl) -6,ll-dihydro-5H-pyridol2 [1,5,]benzodiazepin-5-one and 2-ethyl-2 ,6diazaspiro[3,4]-octane in a yield of 61% of theory.
Colourless crystals, m.p. 186-189*C (acetoni4trile) and R 0.32 (Macherey-Nagel, PolygramO SIL G/UV 254 r-cae plastic sheets for TLC; eluant: dichioromethane/ethyl acetate/methanol/cyclo-hexane/conc!. aqueous amm onia 63.5/13/11/11/1.5, v/v/v/v/v).
C
21
H
23
N
5 0 2 (377.45) Caic..* C 66.83 H 6.14 N 18.55 Found: 67.00 6.17 18.73 Example 49 6,li-Dihydro-ll-[ E6-(2-methylpropyl) -2,6diazaspiro 13,4] -oct-2-yl] carbonyl] Pvridg_2 rl,. Prepared analogously to Example 1 from 11- (chiorocarboniyl) ll-dihydro-5H-pyrido[2,3-bl 11,51and 6- (2-methyipropyl) -2,6diazaspir-o[3, 4]octane in a yield of 60% of theory.
Colourcess crystals, m.p. 187-189*C (acetonitrile).
C
23
H
2 N0 (405.50) Caic.:. C 68.13 H 6.73- N 17.27 Found: 67.95 6.77 17.47 Example 3,10-Dihydro-5-[ [7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyll-1lH-dibenzofb~el rl,41diazepin-1l-one Prepared analogously to Example 1 from (chlorocarbohy) 10-dihydro-l1H-dibenzo~b~e] 4]diazepin-l.1-one and 2-methyl-2,7-diazaspiro[4,4]nonane in a yield of 75% of theory. Colourless crystals, m.p.
190'C (acetonitrile).
C
2 2
H?
4 N40 2 (376..46) Calc.: C 70.19 H 6.43 N 14.88 Found: 7).14 6.43 14.86 Example 51 -66 4,9-Dihydro-3-methyl-4-[7[7-methyl-2,7-diazaspiro[4,41non- 2-ylicarbonylii-lOH-thienor3,4-bl fl,51benzodiazepin- Prepared analogously to Example 1, but using dichioromethane instead of acetonitrile, from 4- (chiorocarbonyl) 9-dihydro-3--methyl-10H-thieno[3 5]benzodiazepin-10-one and 2-methyl-2, 7-diazaspiro- [4,4]nonane in a yield of 44% of theory. Colourless crystals, m.p. 213-214*C (acetonitrile).
C
21
H
24
N
4 0 2 S (396.51) Calc.: C 63.61 H 6.10 N 14.13 S 8.09 Found: 63.30 6.19 14.21 7.94 Example 52 I0 t 0*4,9-Di'hydro-4-[[7-ethyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-3-methyl-10H-thieno[3,4-b] o Prepared analogously to Example 51 from 4- (chlorocarbonyl) -4 ,9-dihydro-3-methyl-10H-thieno II3,4-b] J-one and 2-ethyl-2,7diazaspiro[4,4]nonane in a yield of 65% of theory.
Colourless crystals, m.p. 215-216*C (acetonitrile).
C
22
H
26
N
4 0 2 S (410.54) 000Calc.: C 64.36 H 6.38 N 13.65 S 7.81l Found: 64.28 6.33 13.87 7 ,91 Example 53 1 4 4,9-Dihydro-3-methyl-4-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl~carbonyl]-lOH-thieno[3,4-b] Prepared analogously to Example 1 from 4- (chlorocarbonyl) 9-dihydro-3-methyl-lOH-thieno[3 ,4-blJ- L
I
-67 and 6-methyl--2,6diazaspiro[3,4] octane in a yield of 52% of theory.
Colourless crystals, m.p. 200-203*C (acetonitrile).
C
2 0
H
2 2
N
4 0 2 S (382.49) Cabc.: C 62.80 H 5.80 N 14.65 S 8.38 Found: 62.51 5.68 14.67 8.40 Example 54 4, 9-Dihydro-3-methyl-4- [[2-methyl-2, 6-diazaspiro [3 oct-6-yl]carbonyl]-l0H-thieno[3,4-b] Prepared analogously to Example 1 from 4- (chlorocarbonyl) -4,9 -dihydro-3-methyl-10H-thieno- [l,5]benzodiazepin-l0-one and 2-methyl-2,6- 0 diazaspiro octane in a yield of 28% of theory.
Colourless crystals, m.p. 135-137*C (acetonitrile).
C
20
H
22
N
4 0 2 S (382.49) 0Calc. C 62.80 H 5.80 N 14.65 S 8.38 ~xFound: 62.62 5.81 14.70 8.54 00*0l 4,-iyro4[6ety*,-iaapr[34ot2 PeaeanlgultoExample 55ro 4 o y(clcarbonyl 4diyr-3-methyl-bO-tieo[,4b][l]enzodiazepin-lO-obnoizpn1-n diazaspiro octane in a yield of 30% of theory, Colourless crystals, m.p. 208-210*C (acetonitrile) -68
C
2 1
H
24
N
4 0 2 S (396.51) Caic.: 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 oct-2-yl]carbonyl]-10H-thieno[3,4-b] Prepared analogously to Example 1 from 4- (chiorocarbonyl) -4,9-dihydro-3-methyl-1OH-thipno[3,4-b]j [l,5]benzodiazepin-l0-one and 6-propyl-2,6diazaspiro[3,4]octane in a yield of 44% of theory.
Colourless crystals, l80-181'C (acetonitrile) and R 0.54 (Macherey-Nagel, PolygramO SIL G/UV 254 1 pre-coated 0 plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/mnethanol/cyclohexane/conc. aqueous ammonia 63.5/13/11/11/1.5, v/v/v/v/v).
0~ C 2
H
2 No0 2 S (410.54) 222 C 64.36 H 6.38 N '13.65 S 7.81 Found. 64.26 6.35 13.64 7.71 00*44 0 0 Example 57 440 4,9-Dihydro-4-Ij[2-ethyl-2,6-diazaspiro[3,4]oct-6-yl]- 040004 carbonyl]-3-methyl-1OH-thieno[3 0 ~10-one Prepared analogously to Example 1 from 4- (chlorocarbony -4,9-dihydro-3-methyl-I.OH-thieno[3,4-blbenzodiazepin-l0-one and 2-ethyl-2, 6diazaspiro[3,4]octane in a yield of 61% of theory.
-69 Colourless crystals, m.p. 216-217'C (acetonitrile) and R F 0.47 (conditions as in Example 56).
C 21
H
2 4
N
4 0 2 S (396.51) Caic.: C 63.61 H 6.10 N 14.13 S 8.09 Found: 63.51 6.10 14.27 8.08 Example 58 4, 9-Dihydro-3-methyl-4-[ (2-methyipropyl) -2,6diazaspiro[3,4]oct-2-yl]carbonyll-10H-thieno[3,4-b]- Fl, 51 Prepared analogously to Example 1 from 4- (chlorocarbonyl) 9-dihydro-3-methyl-OHthieno[3,4-b] [l,5]benzodiazepin-0-one and 6-(2methylpropyl) 6-diazaspiro[3,4] octane in a yield of 71% of theory. Colourless crystals, m.p. 186-188'C C 23
H
28 N 4 0 2 S (424.56) Calc. C 65.07 H 6.65 N 13.20 S 7.55 Found: 65.07 6.61 13.30 7.42 Example 59 3-Chloro-l-methyl-4-[[7-methyl-2,7-diazaspiro[4,4]non,-2yl]carbonyl 0-tetrahydropyrrolo C3, 5] benzodiazepin-l0-one Prepared analogously to Example 1 from 3-chloro-4- (chlorocarbonyl) 1-methyl-i, 4, 9, [l,5]benzodiazepin-l0-one and 2-methyl-2,7diazaspiro[4,4]nonane in a yield of 80% of theory.
Colourless crystals, m.p. 205-206'C (acetonitrile) C 2 1
H
24 C1N 5 0 2 (413.92) Calc.: C 60.94 H 5,84 Cl 8.57 N 16.92 Found: 61.13 5.66 8.78 17.20 Example l-Methyl--4-[ [7-methyl--2,7-diazaspiro[4,4]non-2yl]carbonyl]-l,4,9,l0-tetrahydropyrrolo[3,2-b][,5]benzodiazepin-l0-one g (8.46 mmol) of 3-chloro-l-methyl-4-[ [7-methyl- 2, 7-diazaspiro (4,4 ]non-2-yl] carbonyl] tetrahydropyrrolo[3,2-b] 5]benzodiazepin-10-one were dissolved in 350 ml of hot ethanol and after the addition of 3 g of palladium on animal charcoal the mixture was hydrogenated for 2 hours under a hydrogen pressure of 50 bar and at a temperature of The catalyst was filtered of f, the filtrate was evaporated down in 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 0 a~ 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 0 theory) of colourless crystals are obtained, m.p.
223-225'C.
C
21
H
2 No0 (379.47) Calc.: C 66.47 H 6.64 N 18.46 Found: 66.43 6.84 18.44 Example 61 00 3-Chloro-l--methyl-4-( [6-propyl-2,6-diazaspiro[3,4]oct-2yl]carbonyl]-l,4,9,l0-tetrahydropyrrolo[3,2-b] Prepared analogously to Example 1 from 3-chloro-4-A (chlorocarboryl.)-l-methyl-l, 4,9, lO-tetrahydropyrrolo- [l,5]benzodiazepin-l0-one and 6-propyl-2,6diazaspiro[3,4]octane in a yield of 51% of theory.
Colourless crystals, m.p. 164-165*C (acetonitrile).
C
22
H
26 C1N 5 0 2 (427.94) Calc.: C 61.75 H 6.12 Cl 8.28 N 16.37
A}
h. 71 71 Found: 61.48 5.99 8.42 16.37 Example 62 3-Chloro-l-methyl-4- (2-methyipropyl) 6-diazaspiro- [3 oct-2-yl] carbonyl] lO-tetrahydropyrrolo- F3 .2-bi fl,51benzodiazepin-lO-one Prepared analogously to Example 1 from 3-chloro-4- (chiorocarbonyl) -l-methyl-l, 4,9, lO-tetrahydropyrrolo- [l,5]benzodiazepin-10-one and 6-(2-methylpropyl)- 2,6-diazaspiro[3,4]octane in a yield of 23% of theory.
Colourless crystals, m.p. 163-165*C (acetonitrile).
C
23
H
28 C1N 5 0 2 (441.96) Calc.: C 62.51 H 6.39 C1 8.02 N 15.85 Found: 62.47 6.39 8.18 15.89 4 Exam*Ple 63 3 -Chloro-i-methyl-4-[[6-methyl-2,6-diazaspiro[3,4]oct-2yl]carbonyl]1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]- Prepared analogously to Example 1 from 3-chloro-4- 44 (chlorocarbonyl) -l-mnethyl-1,4,9, lO-tetrahydropyrrolo- [l,5]benzodiazepin-lo-one and 6-methyl-2,6diazaspiro[3,4]octane in a yield of 61% of theory.
Colourless crystals, m.p. 215-217*C (acetonitrile) and RF 0.7 (Macherey-Nagel, PolygramO SIL G/UV 254 pre-coated plastic sheets for TLC; eluant: dichloromethane/methanol/ cyclohexane/conc. aqueous ammonia 68/15/15/2, v/v/v/v).
C
20
H
22 ClN 0 2 (399.88) Calc.: C 60.07 H 5.55 Cl 8.87 N 17.51 Found: 60.13 5.39 9.02 17.64 Example 64 72 5,11-Dihydro-ll-[[6-methyl-2,6-diazaspiro[3,4]oct-2vllcarbonyll-6H-pyridoF2,3-bl fl,41benzodiazepin-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 furthir minutes at ambient temperature, then 9.0 g (0.0428 mol) of 5,11l-dihydro-6iH-pyrido[2,3-bj [l,4]benzodiazepin-6-one were added to the reaction mixture and it was then refluxed for 4 hours. The boiling hot .xture 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 ml in vacuo. They were left to cool and kept I occasionally stirred with a glass rod for 2 hours at 0 to 5"C, 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 1 H-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: I. (±)-5,11l-dihydro-ll-[ [7-methyl-2,7-diazaspiro[4,4}non-2yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, m.p. 272-274C (acetonitrile); 5,11-dihydro-8-methyl-ll-[[7-methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-bj[ (1,4]benzodiazepin-6one, m.p. 212-214"C (acetxnitrile); r ~ii ri i i d.
00 0 0 0 0 Poo 0 0 00 0 00Co o 0 o 0 0 0i 000 000 "o )0000 0000 00. 0 0 0 73 5,11-dihydro-8-ethyl-ll-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6one, 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-6one, m.p. 184.0-184.5C (acetonitrile).
Example 5,li-Dihydro-ll-[[6-methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonvll-6H-pridor2,3-blrl,41benzodiazepin-6-one To a suspension of 2.6 g (9.5 mmol) of 11- (chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b] benzodiazepin-6-one in 30 ml of dimethylformamide, a solution of 1.2 g (9.51 mmol) of 6-methyl-2,6diazaspiro-[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 50"C and over diphosphorus pentoxide; then recrystallised from hot acetonitrile and dried in vacuo once more. 2.35 g (68% of theory) of colourless crystals were obtained, m.p. 225.5-227.0*C, 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 t:s t I ii i r, i; L t I A. P -74 l-Methyl-4-[[7-methyl-2,7-diazaspiro[4,4]non-2yl]carbonyl]-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]- 4.02 g (9.71 mmol) of 3-chloro-l-methyl-4-[[7methyl-2,7-diazaspiro[4,4]non-2-yl]carbonyl]-1,4,9,10tetrahydropyrrolo[3,2-b][l,5]benzodiazepin-10-one were dissolved in a mixture of 5 ml of 85% formic acid and 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 G 10% palladium/activated charcoal, the mixture was refluxed for a further 8 hours. It was then filtered while hot, the filtrate was evaporated down in vacuo and the residue was purified by column chromatography (silica gel: dichloromethane/ethyl acetate/methanol/conc. ammonia 3.5:1.5:0.46:0.06, 1.14 g (31% of theory) of colourless crystals were obtained, m.p. 223-225*C (n-propanol), which was found according to thin layer chromatography, IR, UV and 1 H-,NMR spectra, to be identical to a preparation obtained 0oo. according to Example ,o 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-l0-one A mixture of 4.14 g (0.01 mol) of 3-chloro-4-[[7methyl-2,7-diazaspiro[4,4]non-2-ylcarbonyl]-1,4,9,10tetrahydropyrrolo[3,2-b[1,5]benzodiazepin-10-one, 83.3 mg (0.001 mol) of 2:1 tris(o-tolyl)phosphinepalladium acetate catalyst, 2.025 g (0.044 mol) of formic acid and 5.77 g (0.057 mol) of triethylamine in 200 ml of tetrahydrofuran were heated to 100 0 C in an if.
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 Example 66. 1.44 g (38% of theory) of colourless crystals were obtained, m.p.
223-225'C (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-ll- [6-methyl-2, 6-diazaspirot t, [3 ,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]oil~ benzodiazepin-6-one o 4 tt I'll Prepared analogously to Example 1 from 11- (chlorocarbonyl) ll-dihydro-8 ,9-dimethyl-6Hpyrido[2,3-b] [1,4]benzodiazepin-6-one and 6-methyl-2,6diazaspiro[3,4]octane in a yield of 59% of theory.
Colourless crystals, m.p. 247-249'C.
C
22
H
25
N
5 0 2 (391.48).
Calc.: C 67.50 H 6.44N17.89 444Found: 67.25 6.52 18.10 Example 69 ll-Dihydro- 9-dimethyl-ll-[ [2-ethyl-2, 6-diazaspiro- [3,4loct-6-yllcarbonyl-6H-pyrido[2,3-b] [l,4]benzodiaz.in-6-one hydrochloride 3.01 g (0.00998 mol) of l1-(chlorocarbonyl)-5,l1dihydro-8,9-dimethyl-6I-pyrido[2,3--b] [1,4]benzodiazepin- 6-one, 1.4 g (0.00998 mol) of 2-ethyl-2,6diazaspiro[3,4]octane and 100 ml of anhydrous acetonitrile were heated to 60*C for 2 hours with -76stirring. 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.
268-270' 0
C.
C
23
H
27
N
5 2 xHC1 (441.97).
Caic.: C 62.51 H 6.39 Cl 8.02 N 15.85 Found: 62.38 6.34 8.16 15.61 Example ll-Dihydro-8, 9-dimethyl-li-[[2-methyl-2, 6-diazaspiro- [3,4]oct-6-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzo- 0 di a z ein- 6- one 04 0 0 0 Prepared analogously to Example 1 from 11- 04 00 0 0 (chlorocarbonyl) ll-dihydro-8, 9-dimethyl-6H-pyrido- 0*40 a2,-b] [l,4]benzodiazepin-6-one and 2-methyl-2,6- 0 04 diazaspiro[3,4]octane in a yield of 30% of theory.
Colourless crystals, m.p. 292-294 0
C.
C
22
H
2 No0 (391.48).
Calc.: C 67.50 H 6.44 N 17.89 0 0Found: 66.91 6.39 17.71 00 Example 71 0 00 5,11-Dihydro-ll-[[6-methyl-2,6-diazaspiro[3,3]hept--2vll-carbonvl]-6H-Pvridor2,3-bj F1,41benzodiaze in-6-one a) 2,2-Bis (bromomethyl) 3-propanediaminedihydrobromide 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 180*C in a glass autoclave for 12 hours with shaking.
After cooling, the reaction mixture was diltd othe times the volume and then filtered. The filtrate was r 77 evaporated down in a water jet vacuum, the light brown residue remaining was carefully triturated with 2x 100 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. 283-285"C.
Yield: 35.7 g (85% of theory).
C
5
H
1 2 Br 2
N
2 x2HBr (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-ll-rr6-methyl-2,6-diazaspiror3,31hept- 2-vllcarbonyll-6H-pyridor2,3-bl1 l,4benzodiazepin-6o0 0 one s s A suspension of 16.87 g (0.04 mol) of 2,2-bis- S° (bromomethyl)-1,3-propanediamine-dihydrobromide in 500 ml of acetonitrile was combined, with scirring and e 0 ,c 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 11o* (chlorocarbonyl)-5,11l-dihydro-6H- °pyrido[2,3-b][l,4]benzodiazepin-6-one and 4.3 g *O (0.041 mol) of anhydrous sodium carbonate were added to the filtrate and stirred for 30 minutes at a reaction temperature of 50"C. The solvent was then distilled off S_ in 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 in vacuo and the residue remaining was purified by chromatography on silica gel (35-70 mesh) using dichloromethane/ethyl -78 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 (29% of theory) of colourless crystals were obtained, m.p. 226-228"C.
C
1 9 H N 9 5 0 2 (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-ll-[[6-methyl-2,6-diazaspiro- [3,3]hept-2-yl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, m.p. 296-298°C.
C
21
H
2 3
N
5 0 2 (377.45).
ao Calc.: C 66.83 H 6.14 N 18.55 Qo 00 00 Found: 67.05 6.25 18.75 o 0 q oI Example 72 5,11-Dihydro-ll-[[7-methyl-2,7-diazaspiro[3,5]non-2-yl]carbonyll-6H-pyridor2,3-bl1,4]benzodiazepin-6-one a) Ethyl-4-(aminomethl) -l-methyl-4-piperidine 0 carboxylate 52.0 g (0.265 mol) of ethyl 4-cyano-l-methyl-4piperidine carboxylate were dissolved in 400 ml of glacial acetic acid and, after the addition of 10 ml of concentrated 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
AL~
~Qk
I'
4 i I I
'II.
0
I
Ii I rII S
I
79 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 eth(r. 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 of theory) of a colourless oil.
o) 7-Methyl-2,7-diazaspirof3,51nonane 37.5 g (0.187 mol) of ethyl 4-(aminc*,ethyl)-1methyl-4-piperidine carboxylate in 100 ml of anhydrous diethylether were added slowly dropwise, with stirring, to a Grignard solution, cooled to 0 to 5°C, 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 0°C and for 4 hours at ambient temperature. The mixture, cooled to 0 to 5*C 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 in 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 3, 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 rl of water were added dropwise. The precipitate obtained was suction filtered, suspended once more with diethylether and boiled, and then suction filtered again. The combined filtrate,; were dried over sodium sulphate and concentrated by evaporation. The colocurless oil obtained in a yield of 19.0 g (72% of t-heory) was further processed in the next step without any further purification.
c) 5,11-Dihvdro-JlI-[r7-methvl-2,7-diazaspiror3,51Xon-2yllcarbnyll-6H-pvridor2,3-b1 Fl,41benzodiazerzin-6one Prepared analogously to Example 1 from !I- (chlorocarbonyl) -5,11--dihydro-6H-pyrid[2,3-' 2] [1,41benzodiazepin-6-one and 7-methyl-2,7-diazaspiro[3,51- I) nonane in a yield of 61% of theory. Colourless crystils, m.p. 201-203'C (acetonitrile).
C
21
H
23
N
5 0 2 (377.45) Calc.: C 66.83 H 6.14 N 18.55 Found:: 66.95 6.27 18.80 r I t 4 4 1' -81- Example 73 ll-Dihydro-8,9-dimethyl-l.- [7-methyl-2 ,7-diazaspiro- [3,5]non-2-yl]carbinyl]-6H--pyrido[2,3-b] [1,4]benzodiazepin-6-one Prepared analogously to Example 1 from 11- (chiorocarbonyl) ll-dihydro-8, 9-dimethyl-6Hpyrido[2,3-b] [l,4lbenzodiazepin-6-one and 7-methyl-2,7in it yield of 46% of theory.
Colourless crystals, mn.p. 222-224*C (acetonitrile).
C
23
H
27
N
5 0 2 (405.50).
Caic.: C 68.13 H 6.71 N 17.27 Found: 67.95 6.8G 17.-49 Example 74 5,ll-Dihydro-ll-[f2-methyl-2,7-diazaspiro[3,5]non-. vllcarbonyll-6H-pyridor2,3-bl fl,41benzodiazepin-6-one a) 2-Methyl-7- (phenylmethyl) 7-diazaspiroF3,51nonane 4 4 4 11.55 g (0.0534 mol) of 7-(phenylmethyl)-2;7diazaspiro[3,51nonane, 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 94 4 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 by evaporation in vacuo, the residue remaining was purified on silica gel by HPLC using d ichl oromethane/mnth- anol/ cycl1ohexa ne/ con c. aqueous ammonia 631/15/15/2 as eluant, Evaporation of suitable fractions yielded the desired ompound in the form of a viscous colourless oil. Yield: 6.7 g (54% of theory) RF 0.58 (Macherey-Nagel, PolygramO SIL G/UV 2 4 pre-coated F 54 -82 plastic sheets for TLC; eluant: dichloromethane/methanol/cyclohexane/conc. aqueous ammonia 68/15/15/2 v/v/v/v).
2-Methyl-2,.7-diazaspirof3,5inonane 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 10% palladium/animal charcoal catalyst were added and the mixture was then hydrogenated for 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, '9 plastic sheets for TLC; eluant: dichloromethane/methanol/cyclo-hexane/conc. aqueous 4 ammonia 68/20/10/5, v/v/v/v).
Yield: 3.2 g (81% of theory).
c) 5,11-Dihvdro-11-rFf2-methvl-2,7-diazaspiror3,51non-7- Ylcarbonyll-6H-pyrido F2.3-b 111,41 benzodiazepin-6o one D 04 Prepared analogously to Example 1 from 11- (chlorocarbonyl)-5,l1-dihydro-6H-pyrido[2,3-b] benzodiazepin-6-one and 2-methyl-2 1 ,7-diazaspiro[3,5]nonane in a yield of 59% of theory. Colourless crystals, m.p. 186-188*C (diisopropylether).
C
21
H
2 No0 (377.45).
Calc.: C 66.83 H 6.14 N 18.55 Found: 67.05 6.15 18.79
A
4 83 Example ll-Dihydro-8,9-dinethyl-ll-[ [2-iethyl-2,7-diazaspiro- 5]non-7-yl]carbonyl]-6H-pyrido[2,3-b] [l,4]benzod ia zepin -6-one Prepared analogously to Example 1 from 11- (chiorocarbonyl) ll-dihydro-8, 9-dimethyl-6Hpyrido[2,3-b] [l,4]benzodiazepin-6-one and 2-methyl-2,7diazaspiro[3,jjnonane in a yield of 43% of theory.
Colourless crystals, m.p. 245-247'C (acetonitrile).
C
23
H
27
N
5 0 2 (405.50).
Calc. :C 68.13 H 6.71 N 17.27 Found: 68.05 6.86 17.41 o 0 4 0 4 4 400 4404 4 4 4044 4048 4 44 40 4 4440 44 4 444t~t 4 4 444444 4 4
I
J
84 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-ll-[[6-methyl- 2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b]rl.41benzodiaeonin-6-one Composition: 1 tablet contains: Active substance Lactose Potato starch Magnesium stearate 0 9 4 o a ou 9 99 9r D a o o o ao 009 0 0 9 o 090 4 0 00 9 09 0 o o 90 9 e o oQ Q 9 0D 0040 0 99* 0a 0 0 Qu~ 5.0 mg 148.0 mg 65.0 mg 2.0 mc 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 45"C, 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 5f 5,11-dihydro-ll-[[6methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6Hpyridor2,3-blrl,41benzodiazepin-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.
B
i
I
''i t;i k: ii i &1
I',
1 85 Weight of coated tablet: 300 mg Example III Ampoules containing 10 mg of 5,11-dihydro-ll-[[6-methyl- 2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b]- [l.41benzodiazepin-6-one Composition: 1 ampoule contains: Active substance Sodium chloride Distilled water 10.0 mg 8.0 mg 1 ml 44 4 4 4 4 4 *e 4 4 4 44 04 *r 4 0 44 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 120'C.
Example IV Suppositories containing 20 mg of 5,11-dihydro-ll-[[6methyl-2,6-diazaspiro[3,4]oct-2-yl]carbonyl]-6Hpvridor2,3-bl1l,41benzodiazepin-6-one Composition: 1 suppository contains: Active substance 20.0 mg Suppository mass Witepsol W 45®) 1,680.0 mq 1,700.0 mg 4444 4 04B 44a 4 4444 44(i The finely powdered active substance is suspended in the molten suppository mass which has been cooled to At 37"C the mass is poured into slightly chilled suppository moulds.
Weight of suppository 1.7 g
S
t
R
i:j r:-1 iel;1 r r"
V
86 Example V Drops containing 5,11-dihydro-ll-[[6-methyl-2,6diazaspiro[3,4]oct-2-yl]carbonyl]-6H-pyrido[2,3-b]fl,4]benzodiazepin-6-one Composition: 100 ml of drops solution contain: Methyl p-hydroxybenzoate Propyl p-hydroxybenzoate Aniseed oil Menthol Pure ethanol Active substance Sodium cyclamate Glycerol Distilled water ad 0.035 g 0.015 g 0.05 g 0.06 g 10.0 g 0.5 g 1.0 g 15.0 g 100.0 ml 4 4 *l 4 4 1 4 44 4 4 4,l 0 4C I I 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.
i j r ~cI 1 a I

Claims (4)

1. Compounds of formula I 0) (I) /N R o St o 44 44 9 o *r 4 9* (wherein )represents one of the groups R 4 I- (V) 4909 9 9 4044 4444 p 49r 44 9 4999; 4 00 44 9 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; R 4 and R 5 which may be the same or different, each represents a hydrogen, fluorine, chlorine or bromine atom or a C1-4 alkyl group; i r i /I i I i," .Id 88 R 6 represents a hydrogen or chlorine atom or a methyl group; R 7 and R 8 which may be the same or different, each represents a hydrogen atom or C1- 4 alkyl group, and R 8 may also represent a halogen atom, m, n, o and p each independently represents the number 1 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 1 being compounds of o o formula I wherein: 0 a either X represents a nitrogen atom and ]B represents U 0 a group or 0 either X represents a =CH- group and represents the group R represents a methyl group, 0 0 R 4 and R 5 which may be the same or different, each represents a hydrogen, fluorine or chlorine atom or a 0 0* methyl or ethyl group, and m and p each represents the number 1 and n and o each represents the number 1 or 2, and the isomers and salts thereon.
3. A compound as claimedin claim 1 5,11-dihydro-ll-[[7-methyl-2,7-diazaspiro[4,4]non-2- yl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one; l. L f r ~irI 89 ll-dihydro-8-methyl-l-[ (7-methyl-2 ,7--diazaspiro- [4,4]non-2-yl]carbonyl]-6H-pyrido[2,3-b] 4]benzo- diazepin-6-one; b, ll-dihydro-ll-[(6-methyl-2,6-diazaspiro[3,4]oct-2-yl]- carbonyl]-6H-pyrido[2, 3-b] [l,4]benzodiazepin--6-one;
11-dihydro-8-ethyl-1- [6-methyl-2, 6-diazaspiro oct-2-yl]carbonyl]-6H-pyrido[2,3-b] [l,4]benzodiazepin-6- one; or 5,ll-dihydro-8-methyl-ll-[ [2-rethyl-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 4~ 4 0 0 4 4 0# 4 04 4 044 0 44 44 o 4 a 0 o 9 0 0 00 00 0 0000 *904 4 0 0~0* 00 00 0 4440 0 00 4 0 r i;C- 90 191 O a) R/ 00 0 0 00 0 00 00 A 00 0 0* 0 0'+ 0 *0 00 00 0 (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 or as defined in any one of claims 1 to 3 or a group CH 0000 0 0 0000 00 0 8900 4 48 1 T wherein R 4 R 5 R 7 and R 8 are as defined in any one of claims 1 to 3 and R 61 represents a chlorine atom or a methyl group)) reacting a carbonic acid derivative of formula II U i ii 1 i: i_ ::i 6~i i:i r d_" i b, i i r .LLL-~ _1.I_.I1X ~I*CI~~Jr lil.-. .__:li-ti.l-llii ii.illi^ll- 11114_1 ~I- 91 (I I) (wherein and X are as hereinbefore defined and Y represents a halogen atom or a group OR 11 where R 11 represents an optionally halogen-substituted C1- 5 alkyl group, a phenyl group optionally substituted by halogen atoms or nitro groups or a C 7 15 aralkyl group) with a compound of formula III 'o 0 0 0 00 00 O 0 0 Ve 00 0 00 0c 0 o 00 00~ 0 0000 I l) 0000 0 0 0000 04L S /N R (wherein R, m, n, o, and p are as hereinbefore defined) or a metal compound of formula IIIa /M I l a) L -i b Ai -92- (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 H I V IV) 00 H (wherein X and are as hereinbefore defined) with a S0 chlorocarbonic acid derivative of formula V 0 0 's 0 C I nerein R, m, n, and p are as hereinbefore defined); o -N \.vnerein R, m, n, o and p are as hereinbefore defined); c) (to prepare pyrrolo-condensed diazepinone of formula Ib I r! 93 0 CH 3 \C H N N (Ib) N- )o /R °o 0 (wherein X, R, m, n, o and p are as hereinbefore 0 °defined)) hydrogenolysing a compound of formula Ia wherein R 6 v represents a chlorine atom; 0r R 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 saltof a compound of formula I into the free base. 6. A process claimed in claim 5 wherein the reaction 0 of step 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 0a base or an excess of said compound of formula III. 9 6 7. A process as claimed in claim 5 wherein process step is effected in an inert solvent, optionally in the presence of a base, and at a temperature of betwt?.n and +100*C. 8. A process as claimed in claim 5 wherein the hydrogenolysi. of step is carried out in the I. Ik 7 94 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 6 wherein the hydrogenolysis of step 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 0 0 Sc) with palladium acetate and a triarylphosphine at a temperature of between 40 and 110°C. S0 10. A method of treatment of the human or non-human 00 :animal body to combat cholinergically induced spasm and motility disorders in the gastrointestinal tract and in 0 0 the region of the outward leading bile ducts, to combat o o 4 °S cystitis and spasm in urelithiasis, to combat relative °.oo incontinence, tc combat bronchial asthma and bronchitis or to combat ischaemic heart disease, said method "o comprising a.t inistering to said body a compound of formula I as lefined in any one of claims 1 to 3 or a physiologica. ly acceptable salt thereof. 11. Compounds of formula I as defined in claim 1 and salts thereof substantially as herein disclosed in any of the Examples. DATED this 7th day of April 1992. DR KARL THOMAE GmbH By teir Patent Attorneys: p, i.4, CALLIMAN LAWRIE :ii1. t 1 1
AU62352/90A 1989-09-11 1990-09-11 Condensed diazepinones Ceased AU626452B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3930262 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 (2)

Publication Number Publication Date
AU6235290A AU6235290A (en) 1991-03-14
AU626452B2 true AU626452B2 (en) 1992-07-30

Family

ID=6389152

Family Applications (1)

Application Number Title Priority Date Filing Date
AU62352/90A Ceased AU626452B2 (en) 1989-09-11 1990-09-11 Condensed diazepinones

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) FI904469A0 (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)

Families Citing this family (21)

* Cited by examiner, † Cited by third party
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
DE60330456D1 (en) 2002-07-05 2010-01-21 Targacept Inc N-ARYL DIAZASPIROCYCLIC COMPOUNDS, THEIR USE AND THE METHOD FOR THEIR PREPARATION
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
US8809552B2 (en) 2011-11-01 2014-08-19 Hoffmann-La Roche Inc. Azetidine compounds, compositions and methods of use
SG11201407534PA (en) * 2012-06-13 2014-12-30 Hoffmann La Roche New diazaspirocycloalkane and azaspirocycloalkane
IN2015DN00960A (en) 2012-09-25 2015-06-12 Hoffmann La Roche
AR095079A1 (en) 2013-03-12 2015-09-16 Hoffmann La Roche DERIVATIVES OF OCTAHIDRO-PIRROLO [3,4-C] -PIRROL AND PIRIDINA-FENILO
MY187449A (en) 2013-11-26 2021-09-22 Hoffmann La Roche New octahydro-cyclobuta [1,2-c;3,4-c']dipyrrol-2-yl
JP6554481B2 (en) 2014-03-26 2019-07-31 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Fused [1,4] diazepine compounds as inhibitors of autotaxin (ATX) and lysophosphatidic acid (LPA) production
HUE046820T2 (en) 2014-03-26 2020-03-30 Hoffmann La Roche 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
CR20180058A (en) 2015-09-04 2018-02-26 Hoffmann La Roche NEW DERIVATIVES OF PHENOXIMETILO
MX2018001890A (en) 2015-09-24 2018-06-20 Hoffmann La Roche Bicyclic compounds as atx inhibitors.
MX2017015034A (en) 2015-09-24 2018-04-13 Hoffmann La Roche New bicyclic compounds as dual atx/ca inhibitors.
KR20180054830A (en) 2015-09-24 2018-05-24 에프. 호프만-라 로슈 아게 Bifunctional compounds as autotaxine (ATX) inhibitors
CN107922415B (en) 2015-09-24 2022-04-15 豪夫迈·罗氏有限公司 Novel bicyclic 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
CR20190423A (en) 2017-03-16 2019-11-01 Hoffmann La Roche Heterocyclic compounds useful as dual atx/ca inhibitors
US10538530B2 (en) * 2017-09-05 2020-01-21 Blackthorn Therapeutics, Inc. Vasopressin receptor antagonists and products and methods related thereto

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU6235390A (en) * 1989-09-11 1991-03-14 Dr. Karl Thomae Gmbh Condensed diazepinones

Family Cites Families (5)

* Cited by examiner, † Cited by third party
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

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU6235390A (en) * 1989-09-11 1991-03-14 Dr. Karl Thomae Gmbh Condensed diazepinones

Also Published As

Publication number Publication date
IL95622A0 (en) 1991-06-30
PL165197B1 (en) 1994-11-30
IL95622A (en) 1994-04-12
HU905852D0 (en) 1991-03-28
DD299308A5 (en) 1992-04-09
PT95259A (en) 1991-05-22
NO903941D0 (en) 1990-09-10
HU206882B (en) 1993-01-28
RU2017740C1 (en) 1994-08-15
NO903941L (en) 1991-03-12
KR910006286A (en) 1991-04-29
FI904469A0 (en) 1990-09-11
EP0417631A3 (en) 1991-12-11
DE3930262A1 (en) 1991-03-21
YU47372B (en) 1995-01-31
JPH03209382A (en) 1991-09-12
PL286835A1 (en) 1991-08-26
YU171590A (en) 1993-05-28
EP0417631A2 (en) 1991-03-20
NZ235270A (en) 1991-11-26
CA2025005A1 (en) 1991-03-12
HUT55393A (en) 1991-05-28
AU6235290A (en) 1991-03-14
ZA907199B (en) 1992-05-27

Similar Documents

Publication Publication Date Title
AU626452B2 (en) Condensed diazepinones
EP0808318B1 (en) Tricyclic substituted hexahydrobenz[e]isoindole alpha-1 adrenergic antagonists
FI109537B (en) A process for the preparation of imidazo [1,2-a] pyridines and their salts
WO2007140213A1 (en) Pyridoazepine derivatives
JP2011500774A (en) Thienopyrimidiene derivatives as PI3K inhibitors
MXPA04007147A (en) Aza-arylpiperazines.
AU2004251847B2 (en) 5HT2c receptor agonists for the treatment of diabetes and obesity
PL196262B1 (en) Antihistaminic spiro compound, method for its preparation and application as well as pharmaceutical compound and spiran compound as well as the method for its preparation
WO1997049708A1 (en) Tricyclic benzazepine vasopressin antagonists
AU608641B2 (en) Condensed diazepinones
IE872062L (en) PYRIDO (2,3-b) (1,4) BENZODIAZEPIN-6-ONES
IE903279A1 (en) Condensed diazepinones
AU612493B2 (en) Condensed diazepinones
AU724956B2 (en) New 2,3-benzodiazepine derivatives, their production and use as pharmaceutical agents
CZ22697A3 (en) Imidazopyridine-azolidinone derivatives, process of their preparation and pharmaceutical composition containing thereof
IE60265B1 (en) Condensed diazepinones
US5179090A (en) Condensed diazepinones and medicaments containing these compounds
US3631046A (en) Tetracyclic quinazolin-ones
NZ229409A (en) Substituted diazepinones and pharmaceutical compositions
AU612495B2 (en) Condensed diazepinones
MXPA97003288A (en) Oxazolil- and tiazolil imidazo-benzo- and tienodiazepinas and its use as a medicamen
NZ198225A (en) 2-or 3-aminoazacycloalkano(b)pyrazines
NZ229523A (en) Condensed diazepinones and pharmaceutical compositions thereof