AU622887B2 - Condensed diazepinones - Google Patents

Description

AUSTRALIA

PATENT ACT 1952 Form

COMPLETESPECIFICATION

(ORIGINAL)

FOR OFFICE USE Short Title: Int. Cl: ~k)JI Application Number: Lodged: Complete Specification Lodged: Accepted: 4. Lapsed: Published: Priority: Related Art: 4 1 It t I IC I I I II

(III

It I I

III

II I

I

0. t~ TOD BE CCR4LETE BY APPLICANT Name of Aplcant: Address of Applicant: Actual Inventors: Adress for Service: DR KARL THOMAE GMIBH D-7950 Biberach an der Riss, Federal Republic of Germany.

WOLECIANG EBERLEIN, WOLFHARD ENGEL, GERHARD NEWi, GONTE TRWMITZ, NORBERT MAYER, HENR DOODS and ADRIAAN DE JONGE CALLINANS, Patent Attorneys, of 48-50 Bridge Road, Richmond 3121, Victoria, Australia.

Capiete Specification for the invention entitled: "CONDENSED DIAZEPINONES" The following statemnt is a full description of .this invention, including the best rrethod of performing it knwn to us: 14 and R7 represents a methyl group or a chlorine atom, and la 0G 53 706 Condensed Diazepinones This invention relates to condensed diazepinones, and more particularly, to certain novel condensed diazepinones, processes for preparing them and pharraceutical compositions containing them.

Condensed diazepinones with anti-ulcerative properties and an inhibitory effect on the secretion of gastric S juices have been described in EP-A-39519 and EP- 0 A-57428 and in US Patents 3660380, 3691159, 4213984, 4213985, 4210648, 4410527, 4424225, 4424222 and 0.

4424226.

0 0 S" It is alsL known from EP-A-156191 that valuable pharmacological properties completely different 15 from those of the compounds of the publications mentioned above can be induced by the introduction of new aminoacyl groups.

We have now found that the certain new condensed diazepinones have superior properties when for use as vagal pacemakers for the treatment of bradycardia and bradyarrhythmia.

Viewed from one aspect the invention thus provides compounds formula I 3 H O R 1 I I X N

(I)

CO A N

R

2 i -2 wherein

R

1 represents C 1 3 alkyl group and

R

2 represents a straight-chained or branched C 1 8 alkyl group optionally substituted from the second carbon atom at the beta, gamma, delta...carbons) by a hydroxy group, a C 3 8 cycloalkyl or (C 3 8 cycloalkyl)-methyl group in which the cycloalkyl moiety optionally is substituted by a methyl or hydroxy group,

G

o eo ,o a phenyl (C 1 3 alkyl) group in which the phenyl moiety oO optionally is substituted by one or two substituents o" which may be the same or different selected from halogen o atoms and methyl, methoxy and trifluoromethyl groups, or 0* R' and R 2 together with the intervening nitrogen atom represent a group of formula

(CH

2 )n -N X 3

(CH

2 m wherein n and m, which may be the same or different, each represents the integer 2,3 or 4, with the proviso that the sum of n and m is 4, 5 or 6.

X

3 is a methylene group, a hydroxy substituted methylene group, an oxygen atom or a group of formula NR' where R' represents a hydrogen atom or a C 1 .3 alkyl, phenyl (C 1 3 alkyl) or phenyl group in which the phenyl nucleus is optionally substituted by on/r or two substituents selected

/^NI

L: .1 i ii 3 from halogen atoms and methyl, methoxy and trifluoromethyl groups;

R

3 rrcresents a C 1 3 alkyl group or a hydrogen or chlorine atom;

R

4 represents a hydrogen atom or methyl group; A represents a straight chain or branched C 5 .g alkylene or alkenylene group, with the provisos that there are at least 5 carbon atoms in the carbon chain linking the semicyclic carbonyl group to the nitrogen R1 atom of the N group, R2 and when A is a CS-alkylene group then -NR'R 2 is other than a 1-pyrrolidinyl or a 4-methyl-l-piperazinyl group; A* 4 CH 8

CH

(B represents a group of formulae RR

R

O

(wherein R 5 and R 6 which may be identical or different, each represents a hydrogen, fluorine, chlorine or bromine atom or a C1.

4 alkyl group,

R

7 represents a methyl group or a chlorine atom or, if R 3 represents a hydrogen atom or a C 1 3 alkyl group, R 7 also iuay represent a hydrogen atom,

R

8 represents a hydrogen atom or a C,.

4 alkyl group, 1 4 1-4or chlorine atom, and 10 2 R n Xc represents hdoe tm a methl group) i represents a group formula R or CI 6C IN to

R

9 6 1 2 X and X may each represent a nitroqen atom or one of X and X 2may represent a methine group and *the other of X 1 and X2may represent a nitrogen atom), 0~ the isomers and acid addition salts thereof, especially for pharmace~utical use the physiologically acceptable salts.

The definition of the 2 N group given above includes, for example, (dimethylaminoi, (diethylaminol, (dipropylamino), f[Ibis(methylethyl) 1amino], [(ethylibutylamino], [(ethyl)methylamino], [(methylethyl)methylaminoj, fl(butyl)methylamino], t'(cyclobexyl)methylami-no], trans-l(4-hydroxycyclohexyl)methylaminol, [(phenylmethvl)methvlaminoj, (1-piperidinyl) (hexahydro-IH-1-azepinyl) Coctahydro- 1-azocinyl) (4-morpholinyl) (4-nethyl-l-piperazinyl) (4-hydroxy-1.-piperidinyl) [4-(phenylmethyl)- 1-piperazinyll, t4(-hnlty)', pprznyJ [4-(3-phenylpropyl)-l-piperazinyll, ((4-(4--chloro- 2-methyiphenyl) methyl) -1-piperazinyl], (methylethyl) 1-piperazinyl], (4-ethyl-l-piperazinyl), methoxy-2--methylphenyl) -1-piperazinyl] or (trifluoromethyl) phenyl] -1-piperazinyl) group; Examples of the CO-A group include: the 1-oxo-hexyl, 1-oxoheptyl, 1-oxooctyl, 1-oxononyl, 2-methyl- 1-oxoheptyl, 2-ethyl-l-oxoheptyl, l-oxo-4-hexenyl, I-oxo-6-octenyl, l-oxo-7-nonenyl, 2-methyl-l-oxo-4-hexenyl or 2-ethyl-l-oxo-4-hexenyl groups, which are substituted in the omega-position, and the 1-oxoheptyl and l-oxo-5-heptenyl group which are substituted in the 6-position by a R1 N group 44R 2 ,1 Thus, for example, in addition to the compounds specified hereinafter in the Examples, the compounds of t4A the invention include th, compounds of formulci 1: ll-dihydro-ll- 16- (dimethylamino) -1-oxohexyl]- 6H-pyrido[2,3-b] [l,4]benzodiazepin-6-one, ll-dihydro-ll- 16-1 (methylethyl) methylamino] -1oxohexyl]-6H-pyrido[2, 3-b)1 [,4]benzodiazepin-6-one, ll-[7-(diethylamino) -i-oxoheptyl]-5, 11-dihydro- 6H-pyrido[2, 3-b) 11,4]benzodiazepin-6-onie, (cyclohexyl)me~thy3.amino]-l-oxohexy'LJ-5,11dihydro-6H-pyrido[2,3-b] [l,4]benzodiazepin-6-one, 422 11-dihydro-11-16-[ (4-hydroxycyclohexyl)methylamino]-l-oxohexyl1P6H-pyrido[2,3b[1,4]benzodiazepin- 6-one, 5,J.1-dihydro-ll-[6-[ (phenylmetyl)methylainl- 1-oxobexyl]-6H-pyrido[2,3-b[1,4]belzodiazepin- 6-one, 11-dihydto- 11-16- (1-piper idinyl) -1-oxohexyll 6H-pyrido[2,3-b][1,4]benzodi.azepin-6-orle, 5,1],-dihydro-ll-[6-(4-hydroxy-1-piperidilyl)-loxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepil6-ofle, 99 5,11-dihydro-ll-[6-(hexaydo-T-1-azepiyl)-l- 15 "~*'oxohexy1]-611-pyrido[2,3-b][l1,4]benzodiazepil- 6 one, 11-dihydro-li- 4- (phenylmethyl) -J-piperazinyl) 9999 201-oxohexyll-6H--pyrido[2,3-bU[1,4]benzodiazepil- 6-one, 5V1dihydro-ll-[6-(4-(2-phenylethy1)-1-piperaziny1)- 1-oxo-hexyll -6H-pyrido[ 2,3-b] benzodiazepin- 6-one7 5,11-dihydro-11-[6-[4-(3-phenylpropyl)-l-piperazinyl)- 1-oxohexyl] -6H-pyrido[ 2,3-b] 11,4] benzodiazepin- 6-one, (4-(4-chloro-2-methylphenyl)methyll-l-piperazinyl)- 1-oxohexy11-6H-pyrido2,3-b1[1,4]benzodiazepil- 6-one, 355, 1J-dihydro-l1-I 6-14- (zethylethyl) -l-piperazinyll l-oxohexyl)-6H-pyrido[2,3-bl[.,4]benzodliazepil 6-one, -7- 5,11-dihydro-11-[6- (4-ethyl-1-piperazinyl)-l-oxohexyl]- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 5,11-dihydro-ll-[6-[4-[3-(trifluoromethyl)phenyl]- 1-piperazinyl)-1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, -5,11-dihydro--i1-[6-(1-pi.peridinyl)-1-oxo-4hexenyl] -6H-pyrido[ 2,3-b] [1,4 ]benzodiazepin-6-one, CE) -5 11-dihydro-li- (1-piper idinyl) -1-oxo-4hexenyvl]-6H-p)yrido[ 2,3-b] [1,4 ]benzodiazepin-6-one, L1-dihydro-i.1-[7-(l-piperidinyl)-1-oxo-5- '9 heptenyl]-6H-pyridoli2,3-b][l,4]benzodiazepin-6- 9. one, -5,1-dihydro-1-[7hy-6-.by--piperidiyl)y-oo-5 heptoeyl-6H-pyrido[2,3-b[1,4]benzodiazepin- .999 one, (5,11-dihro-1-6-[-4ethoxy6--methyl-lphel)- l 30pIprnl--oxohexyl]-6H-pyrido[2,3-b][1,4lbediaep n-o.

diazepi--oe S-51-ihvh-11-l2-ethryl-6-(4-methyl-ppinyl)-nll l-oxohexy1]-6H-pyrido[2,3-b][l,4]benzodiazepin- 6-one, -8- 11-dihydro-11-[ 3-methyl-6- (4-methyl-1-piperaziniyl) 1-oxohexyll-6H-pyridoll2,3-b][1,4]benzodiazepin- 6-one, 5,11-dihydro-ll-[4-mTetyl-6-(4-methyl-1-piperazinyl)- 1-oxohexyl] -6H-pyrido[ 2,3-b] [1,4 ]henzodiazepin- 6-one, 11-dihydro-11-[5-miethyl-6- (4-methyl-l-piperazinyl) 1-oxo--exvl]-6R-pyrido[2,3-b][1,4]benzodiazepin- 6-one, 5,*dhdo-l[-4mebllppeaiy 4-xhpyl 6H-pyrido[2,3-b][1,4]benzodiazep~in-6-one, 5,11-dihydro-1l-[7-(1-piperidi nyl) -l-oxoheptyll :*:6H-pyrido[ 2, A]Ihenzodia~epi n-6-one, 6, 11-dihydro-11-[6- (l-piperidinyl) -1-oxohexyl] 205H-pyrido[2,3-b][1,5]henzodiazepin-5-one, 6, 11-dihydro-li- (hexahydro-1iI-i-azepinyl) -1oxohexyl]-5H-pyrido[2,3-bl[1,5]henzodiazepin-5one, 6,11-dihydro-ll-116-(4-rethyrl-t-piperazinyl)-l-oxohexyl]- 2,3-b] [1,5 -dihydro-8-methyl-11- (1-piperidinyl) -1-oxohexyl] 6H-pyrido[2,3-bhl1,4]benzodiazepin-6-one, 11-Dihydro-3-methyl-ll-[6- (hexahydro-1H1-1-azepinyl) 1-oxo-hexyl] -6H--pyrido[ 2, 3-b] [1,4 1benzodiazepin- 6-one, 11-dihydro-8-methvl-i1- (4-methyl-l-piperazinyl) 1-oxohexyll-6H-pyrido[2,3-bl[1 ,4]benzodiazepin- -9- 6-one, 1J.-dihydro-9-methyl-l1-[6- (1-piper idinyl) -1-oxohexyl] 6H-pyrido[2,3-b] [I,4]berizodiazepin-6-one, ,11-dihydro-9-methyl-l1-[6-(hexahydro-1H-1-azepinyl)- 1-oxo-hexyl] -6H-pyrido[ 2,3-b] [1,4 ]benzodiazepin- 6-one, 5,11-dihydro-9-methyl-l1-[6-(4-tethyl-l-piperazinyl)- 1-oxo-hexyl]-6H---pyrido[2,3-b][1,4]benzodiazepin- 6-one, 9-chloro-5,11-dihydro-11-[6-(1-piperidinyl)-l-oxohexyl]- *.15 6H-pyrido[2,3-b]II1,4]benzodiazepin-6-one, 9. 9-chloro-5,11-dihydro-l-16-(hexahydro-1H-1l-azepinyl)- 1-oxohexyl] -611-pyrido[ 2,3-b] [1,4 ]benzodiazepin- 6-one, 4 4 9-chloro-5,11-dihydro-ll-[6-(4-methyl-1-piperazinyl)- 1-oxohexyl]-6H-py7riio[2,3-b][l,4]benzodiazepin -6-one, 4,9-dihydro-3-nmethyl-4-[6-(l-piperidinyl)-l-oxohexyl]- 1OH-thienol3,4-b] 4, 9-dihydro-4-[6- (hexahydro-1H-1-azepinyl) -1-oxohexyl] 3-methyl-lOHi-thieno[3,4-b][1,5]benzodiazepin-10one, 4, 9-dihydro-3-methyl-4-[ 6- (4-nethyl-1-piperazinyl) 1-oxohexyll -10H-th i,eno[ 3, 4-b] IIJ.,5 ]benzodiazepin- 4, 9-dihydro-1, 3-dimethy1-4-[ 6- (4-methyl-1-piperazinyl) 1-oxo-hexyll] 1H-thieno[ 3,4-b] benzodiazepina C 3 cycloalky'l or (C 8 cycloalkyl)methyl group in which the cycloalkyl moiety optionally is substituted by a methyl or hydroxy group, /12 3-chloro-4, 9-dihydro-4-[ 6- 4 -,methyl-1-piperazinyl) l-oxohexyll--10H-thienofl,4-b][1,5]benzodiazepintetrahydropyrrolo[3,2-bJ[1,Slbenzodiazepino...one, l, 3 -dimethyl-4-[6-(hexahydro-1aze1azeiny).-oxoexyJ...

lv 4 9 ,lO-tetrahvdropyrrolo[3,2-b][1,5]benzodiazepinfi f015 l, 4 9 ,1.-tetrahydropyrrolo(3,2-b][1,5]benzodiazepin- I-oxohexy1I-1,4,9,10-tetrahydropyrroo[3,2b[1,5benzodiazepin-lO-one, lt 4 9 ulO-tetrahydro~yrrolo[3,2-bU1,5]benzodiazepintetrahydropyrazoo[4,3b][1,5benzozdiazepi10.

one, 1,-iebl4[-hxhdolflaeiy)looeyl 1,4,9, O-tetrahydropyrazoi~o[ 4,3-b Ii IbenzodiazepinlI 4 9 ,1O-tetrahydropyrazolo[4,3b[1,]benzodiazepin.

and 11 l-methyl-4-[6-(4-methyl-l-piperazinyl)-l-oxohexyl]- 1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepinand the isomers and acid addition salts, especially physiologically acceptable acid addition salts thereof.

Preferred compounds according to the invention include those of formula I wherein

R

1 represents a methyl or ethyl group,

R

2 represents a C 1 3 alkyl group or a cyclohexyl, trans-(4-hydroxycyclohexyl) or phenylmethyl group or

R

1 and R 2 together with the intervening nitrogen atom represent a 1-piperidinyl, 4-hydroxy-l-piperidinyl or hexahydro-lH-azepinyl group or a 1-piperazinyl group optionally substituted in the 4-position by a C, 3 alkyl, phenyl(C .3alkyl) or phenyl group wherein the phenyl nucleus itself is optionally substituted by one or two substituents, which may be identical or different, selected from methyl, methoxy and Strifluoromethyl groups,

R

3 represents a methyl group or a hydrogen or chlorine atom,

R

4 represents a hydrogen atom or a methyl group, A represents a C 5 -6 alkylene group optionally methylsubstituted in the alpha-position to the semicyclic carbonyl group and/or containing a double bond in the gamma-delta-position, with the proviso that when A is a Cs-alkylene group then -NR 1 R is other than a 4-methyl-lpiperazinyl group.

y r r /i the other of X- and X may represent a nitrogen atom), the isomers and acid addition salts thereof.

ft

-I

1 i i kS i; b ;i irI i 1 ii ;t ci g r 12 @represents a group of formula grou or 6

R

R

8

S.

R

9 4 9 a *4 o 15 a 9 9 i9 94 Ct 4i 4 (wherein R 5 represents a hydrogen atom, R represents a hydrogen, chlorine or bromine atom or a methyl or ethyl group in the 8 or 9-position of the heterocyclic ring system, 8 R represents a hydrogen atom and 9 R represents a hydrogen atom or a methyl group), X represents a methine group, and 2 X represents a methine group or a nitrogen atom, and the isomers and acid addition salts thereof.

However, particularly preferred compounds according to the invention include the compounds of formula Ia #1 (Ia)

R'

N

R

2 wherein R R 2 A and X 2 are as hereinbefore defined and ij j jI

I

1 I 13 represents a group of formula I or

CH

3 and the isomers and acid addition salts thereof.

Viewed from a further aspect the invention also f provides a process for preparing the compounds t4 of the invention, said process comprising at least 4 q one of the following steps: S (to prepare compounds of formula I wherein R 7 R represents a chlorine atom or a methyl group) reacting a compound of formula II 3 H O R I x N 4 SR4 (II) 6444(3

X-

CO A Y S (wherein R3 4 1 2 R R A, X and X are as hereinbefore defined, represents a group of formula CH3 R CH R3 R R N S or R R R 9

R

10 wherein R R and R to R 10 are as hereinbefore defined I L1__ Dest nMtna or: pertorming it XflaOJf to US: 4 J 4 4 4 -4 14 and R 7 represents a methyl group or a chlorine atom, and Y is a halogen atom, preferably a chlorine or bromine atom), with an amine of formula III H N INR2

(III)

V.

V

*4 4 .4 a 9 a.

4 9 4 V.

a.

44 0* 9* a a a £4 t 14

V

t{ V 444 4~ 44 44 444 44 4 4 4 4 12 (wherein Rand R2are as hereinbefore defined); (to prepare compounds of formula I wherein Rrepresents a chlorine atom or a methyl group) reacting a compound of formula UT

B,'

I

(IV)

(wherein R R 4, g and X2are as hereinbefore defined and 0 represents a qroup of f ormula

CH

3R N I Rif R9 or

N

CH

1 3 wherein R, R~ and R to R 1 are as hereinbefore O A N 15 defined and

R

7 represents a methyl group or a chlorine atom) with a compound of formula V

R

Nu CO A N (V) 2 (wherein

R

1

R

2 and A are as hereinbefore defined and t VI It t a R represents a hleH roi or goineu ap 1 to th CO N N B R(oup R 2 (wherein 1 4 R to R andy are as hereinbefore defined and Z represents a straight-chained or branched C alkenylene or alkynylene group, preferably containing the double or triple bond in the 2,3-position relative to the N qroup, with the proviso that the carbon chain linking the semicyclic carbonyl group to the nitrogen atom of the 71- (herei 1 4 '(I UPL.LUally sunstitute by on' or two substituents selected 16

S'

R

I

SN group is at least

R

(to prepare compounds of formula I wherein 3 R represents a hydrogen atom or a C 1 3 alkyl group, R represents a hydrogen atom and A represents a saturated alkylene group) hydrogenolysing a compound of formula VII H O R3 x1 Jl x1 rN 4: N

(VII)

1 5 1 0. 2 CO N o*R 2 wherein )DI, 1 4 1 2 ,c R to R X and X are as hereinbefore defined S' and 2 Z represents a straight-chained or branched C 5-8 alkylene, alkenylene or alkynylene group, with the proviso that the carbon chain linking the semicyclic carbonyl group to the nitrogen atom of the

R

S N group is at least 5-membered and may R2 contain a double or triple bond, preferably in the 1 2,3-position relative to the N group);

R

2 resolving a compound of formula I thus obtained into the diastereoisomers or enantiomers thereof; It j l;

R

8 represents a hydrogen atom or a C 1 4 alkyl group, 17 and converting a compound of formula I thus obtained into an acid addition salt thereof or an acid addition salt of a compound of formula I into the free base.

The amination of step may conveniently be carried out in an inert solvent at temperatures of between 0 C and the boiling temperature of the solvent, preferably with, for each mole of the compound of formula II, either at least 2 moles of the secondary amine of formula III or 1 to 2 moles of a secondary amine of formula III and an auxiliary base. Suitable solvents include, for example, *p 15 chlorinated hydrocarbons such as methylene chloride, 0 *o chloroform or dichloroethane; open-chained or cyclic p ethers such as diethylether, tetrahydrofuran or *dioxan; aromatic hydrocarbons such as benzene, of toluene, xylene, chlorobenzene or pyridine; alcohols such as ethanol or isopropanol; ketones such as acetone; acetonitrile, dimethylformamide or 1,3- Sdimethyl-2-imidazolidinone. Examples of auxiliary bases include tertiary organic bases such as triethylamine, F-methylpiperidine, diethylaniline, pyridine and 4-(dimethylamino)pyridine or inorganic bases such as alkali metal or alkaline earth metal carbonates or hydrogen carbonates, hydroxides or oxides.

If desired, the reaction may be accelerated by the addition of alkali metal iodides. The reaction times range from 15 minutes to 80 hours depending on the nature and quantity of the amine of formula III used.

The reaction of step of the compound of formula IV with the acid derivative of formula v may be carried out using conventional techniaues. The i leaving group Nu is a group which together with i ~1Y 1-piperazinyl], 14-(2-phenylethyl) 1-piperazinyl] 4 -(3-phenylpropyl)-l-piperazinyl], [(4-(4-choro- I i -18 the carbonyl group to which it is bonded forms a reactive carboxylic acid derivative. Examples of reactive carboxylic acid derivatives include acid halides, esters, anhydrides or mixed anhydrides, such as are formed from salts of the corresponding acids where Nu OH) and acid chlorides such as phosphorus oxychloride diphosphoric acid tetrachloride or chloroformic acid esters or the N-alkyl- 2-acyloxypyridinium salts formed when compounds of formula V '(in which Nu OH) are reacted with N-alkyl-2-halopyridinium salts.

Preferably, the reaction of step is carried out with the mixed anhydrides of strong inorganic acids, particularly dichlorophosphoric acid. The reaction is optionally carried out in the presence S. of an acid binding agent (proton acceptor). Examples Sa of suitable proton acceptors include alkali metal .o carbonates or hydrogen carbonates, such as sodium carbonate or potassium hydrogen carbonate; tertiary organic amines such as pyridine, triethylamine, a ethyl diisopropylamine, 4-(dimethylamino)pyridine a or sodium hydride. The reaction is conveniently carried out at temperatures of between -25C and 25 130 0 C, preferably in an inert solvent. Examples of inert solvents include chlorinated aliphatic hydrocarbons such as methylene chloride, 1,2-dichloror :ethane; open-chained or cyclic ethers such as diethylether, tetrahydrofuran or 1,4-dioxan; aromatic hydrocarbons such as benzene, toluene, xylene, o-dichlorobenzene; polar aprotic solvents such as acetonitrile, dimethylformamide or hexamethylphosphoric acid triamide; or mixtures thereof.

The reaction times range between 15 minutes and 3 80 hours depending on the nature and quantity of the acylating agent of formula V used. It is not necessary to prepare the compounds of formula V T 0 19 in pure form; rather, they may be produced in situ in the reaction mixture using conventional techniques.

The catalytic hydrogenation of step is conveniently is carried out in the presence of catalysts based on metals of the VIIIth sub-group of the Periodic Table of Elements, for example palladium on animal charcoal, palladium on barium sulphate, Raney nickel or Raney cobalt, under hydrogen pressures of from 0.1 to 300 bar and at temperatures of from 0 to 130 0 C, preferably at ambient temperature, and in the presence of solvents, for example alcohols such as methanol or ethanol, ethers such as dioxan, 0 diethylether or tetrahydrofuran, carboxylic acids o15 such as acetic acid or tertiary amines such as *o triethylamine.

o Any halogen present in the starting materials f S: formula VI, with the exception of fluorin, is generally split off during the catalytic hydrogenation.

In order to prepare compounds of formula I wherein A represents an alkenylene group starting from a compound of formula VI wherein Zt represents an alkynylene group the procedure used is preferably either to break off the catalytic hydroqenation after the uptake of 1 mole of hydrogen and/or to carry out the catalytic hydrogenation in the presence of a deactivated catalyst, e.q. pa) adium on calcium carbonate deactivated with lead or cadmium (Lindlar catalyst), palladium on barium sulphate with the addition of quinoline or P2 nickel in the presence of ethylenediamine.

Compounds of formula I characterised by Z geometry with regard to the olefinic double bond are predominantly formed.

l-oxohexyl]-6H-pyrido[2,3-b][.,4]benzodiazepin- 6-oner, 20 Obviously, a compound of formula I thus obtained wherein A represents an alkenylene group may subsequently, as described above, be further hydrogenated to obtain a compound of formula I wherein A represents an alkylene group.

The hydrogenolysis of step is conveniently carried out in the presence c" catalysts based on metals of the VIIIth sub.-group of the Periodic Table of Elemo-nts, for example palladium on animal charcoal, palladium on barium sulphate, Raney nickel or Raney cobalt, and under hydrogen pressures of from 1 to 300 bar, and at temperatures of from 0°C to 130 0 C, in the presence of solvents, for example alcohols such as methanol or ethanol; ethers such as dioxan, tetrahydrofuran; carboxylic acids, 6 a acetic acid; or tertiary amines, for example triethylamine. If the operation is carried out in the absence of additional hydrogen chloride acceptors, for example sodium carbonate, potassium hydrogen carbonate, triethylamine or sodium acetate, the hydrochlorides of the desired compounds are formed directly and may be isolated after removal of the catalyst by evaporation of the reaction solution. If in the above hydrogenolysis reaction formic acid is ut. 'in place of hydrogen, the reaction will be successful theory even under preszureless conditions. In this alternative embodiment, the reaction is preferably effected with formic acid in the presence of dimethylformamide as solvent and palladium on charcoal as catalyst at temperatures of between 70 and 110 0 C, and reduction with triethylammonium formate in the presence of excess triethylamine, and palladium on animal charcoal or palladium acetate and triarylphosphines such as triphenylphosphine, tris-(o-tolyl)-phosphine, phosphine, at temperatures of between 40 and 110°C, i Vt1> 1 ft i| s. f 21 have proved particularly successful.

Suitable acids for use in the preparation of addition salts include, for example, hydrochloric, hydrobromic, sulphuric, methylsulphuric, phosphoric, tartaric, fumaric, citric, maleic, succinic, gluconic, malic, p-toluenesulphonic, methanesulphonic and amidosulphonic acid.

The compounds of the invention contain up to two independently chiral elements, and may, in certain circumstances, include an asymmetric carbon atom in the side chain. The second chiral element is 0 the acylated tricyclic group itself, which may 15 occur in two mirror-image forms. It depends on 0 the nature of the tricyclic group whether the energy S" barrier for ring inversion is so high that the .individual isomers are stable at ambient temperature and so are capable of isolation. The substituents in the peri positions adjacent to the aminoacyl side chain are of particular importance to the height of the inversion barrier. It has been found that compounds of formula I wherein X 2 is a methine group and B represents an o-phenylene group always occur in two diastereoisomeric forms which may be separated at ambient temperature. The individual diastereoisomers are totally stable in the crystalline state, but go into solution and, at ambient temperature, revert to the original mixture with a half-life of a few days. In compounds of formula I wherein 2 X represents a nitrogen atom and B represents an o-phenylene group, the activation energy required is reduced so much that at ambient temperature diastereoisomers can no longer be detected (except by complex H-NMR spectra), let alone preparatively separated.

I i: 22 The compounds of formula I according to the invention thus contain, under certain circumstances, two chiral centres, one of which is not always coafigurationally stable at ambient temperature. These compounds may therefore occur in two diastereoisomeric forms or as enantiomeric and forms. Diastereomeric cis/trans forms are also possible if A in the compounds of formula I claimed represents an alkenylene group.

The invention includes the individual isomers as well as the mixtures thereof. The diastereomers may be separated on the basis of their different physico-chemical properties, e.g. by fractional recrystallisation from suitable solvents, by high .15 pressure liquid chromatoaraphy, column chromatography or gas chromatography.

4 The separation of any racemates of the compounds of formula I may be carried out by conventional methods, for example using an optically active acid such as or (-)-tartaric acid or a derivative thereof such as or (-)-diacetyltartaric acid, or (-)-monomethyltartrate or (+)-camphorsulphonic acid.

According to a conventional method of separating isomers, the racemate of a compound of formula I is reacted with one of the optically active acids specified above in equimolar quantities in a solvent and the crystalline diastereoisomeric salts obtained are separated, using their different solubilities.

This reaction may be carried out in any type of solvent provided that the latter exhibits sufficiently different solubilities for the salts. Preferably, methanol, ethanol or mixtures thereof, e.g. in a ratio by volume of 1:1, are used. Each of the 4,9-dihydro-l,3-dimethyl-4-[6-(4-methyl-l-piperazinyl)- 1-oxo-hexyl]-10H-thieno[3,4-b][1,5]benzodiazepin-

L

hL f I ii I

II

I-

-I

S.

23 optically active salts is then dissolved in water and neutralised with a base such as sodium carbonate or potassium carbonate and in this way the corresponding free compound is obtained in the or form.

A single enantiomer or a mixture of two optically active diastereoisomeric compounds covered by formula I may also be obtained by carrying out the syntheses described above with only one enantiomer of formula II or V.

In order to prepare the haloacyl compounds of formula II, the starting compounds of formula IV are reacted with compounds of formulae VIII or IX .R ,15 0 00 *0 0r 00 0 01 0* It Hal-A-CO-Hal (VIII) [Hal-A-CO] 2 0 (IX) I III~

(I

I. tIE wherein Hal represents a chlorine, bromine or iodine atom. This acylation is carried out without a solvent or preferably in an inert solvent at ambient temperature or elevated temperature, up to the boiling temperature of the solvent, optionally in the presence of an auxiliary base and/or an acylation catalyst. The acid halides of formula VIII are preferable to the acid anhydrides of formula

IX.

Examples of suitable solvents include aromatic hydrocarbons such as toluene, xylene and chlorobenzene; open chained or cyclic ethers such as diisopropylether and dioxan; chlorinated hydrocarbons such as dichloroethane; other solvents such as pyridine, acetonitrile and dimethylformamide.

Examples of suitable auxiliary bases include tertiary organic bases such as triethylamine and ethyl diisora i i; -C I' t 4 24 propyiamine and pyridine; and inorganic bases such as anhydrous alkali metal and alkaline earth metal carbonates and hydrogen carbonates and alkaline earth metal oxides. Examples of acylation catalysts include imidazole, pyridine and 4-dimethylaminopyridine.

If in a compound of formula II Hal represents a chlorine atom, it may easily be exchanged for the more reactive iodine by reacting with sodium iodide in acetone or ethanol.

The secondary amines of formula III are commercially obtainable or may easily be prepared by methods analogous to those known from the literature.

4 1 ,The tricyclic groups of formula IV are known from the literature or may be synthesised from common 44 starting materials by adhering closely to published methods.

The starting compounds of formula V may be obtained via the corresponding esters, i.e. compounds of formula V wherein Nu represents an alkoxy group may be obtained by reacting secondary amines of formula III with carboxylic acid esters of formula X Hal-A-C0 2

R

11 wherein Hal and A are as hereinbefore defined and R represents a lower alkyl C 3 61 group, optionally using additional auxilia" bases, e.g.

triethylamine, or catalysts, e.g. Triton B. By saponification of the esters obtained, e.g. with barium hydroxide solution, the carboxylic acids of formula V are obtained which may be used to prepare derivatives with other nucleofugic groups.

I i i 25 The starting compounds of formulae VI and VII may be obtained by reacting a corresponding compound of formula II with a corresponding secondary amine of formula III.

The compounds of formula I and the physiologically tolerable acid addition salts thereof have valuable pharmacological properties; in particular, whilst having excellent stability to hydrolysis, high selectivity and good resorption after oral administration, they have favourable effects on heart rate and, in view of their lack of mydriatic effects or inhibitory effects on the secretion of gastric acid or salivation, they are suitable for use as S' ,15 vaqal pacemakers in the treatment of bradycardia 4rf Ot and bradyarrhythmia in human as well as veterinary medicine; some of the compounds also exhibit spasmolytic properties on peripheral organs, particularly the colon and bladder.

,t A favourable relationship between tachycardiac effects on the one hand and the undesirable effects 0 Ot on pupil size and the secretion of tears, saliva and gastric acid, on the other hand, which occur 25 with therapeutic agents having an anticholinergic component, is of particular importance for the therapeutic use of the substances. The following tests show that the compounds according to the Sinvention exhibit surprisingly favourable properties in this respect.

i u 1 2 2 R R A and X are as hereinbefore defined and A. Studies of binding to muscarinicreceptors: In vitro meat of the IC5 value The organs were donated by male Sirague-Dawley I C 26 A. Studies of binding to muscarinic receptors: In vitro measurement of the ICs 0 value The organs were donated by male Pprague-Dawley rats weighing 180-220 g. After the heart and submandibular gland and cerebral cortex had been removed, all other steps were carried out in ice cold Hepes HCI buffer (pH 7.4; 100 millimolar NaCi, 10 millimolar MgCl 2 The whole heart was cut up with scissors.

All the organs were then homogenised in a Potter apparatus.

S* For the binding test the homogenised organs were diluted in the buffer as follows: S'o o Whole heart 1: 400 Cerebral cortex 1: 3000 Submandibular gland 1: 400 The homogenised organs were incubated in an Eppendorf centrifuge tube at 30°C at a given concentration of the radioligand and at a series of concentrations of the non-radioactive test substances. Incubation lasted 45 minutes. The radioligand used was 0.3 nanomolar 3 3 H-N-methylscopolamine H-NMS). Incubation was "ended by the addition of ice cold buffer followed by vacuum filtration. The filters were rinsed with cold buffer and their radioactivity was determined.

It represents the sum of specific and non-specific binding of 3 H-NMS. The proportion of non-specific binding was defined as the radioactivity which was bound in the presence of 1 micromolar auinuclidinylbenzylate. Each measurement was taken four times.

The IC 50 values of the non-labelled test substances were determined graphically. They represent that

I%

wherein R 6 8 to R10 are as hereinbefore efined wherein R R and R to R are as hereinbefore defined 64

I-,

co U I*M Oslo$ U 44 bes 200 4* 27 concentration of the test substance at which the specific binding of 3H-NMS to the muscarinic receptors in the various organs was inhibited by 50%. The results are set forth in Table I.

B. Investigation of functional selectivity of the antimuscarinic effect Substances with antimuscarinic properties inhibit the effects of agonists supplied exogenically or of acetylcholine, which is released from cholinergic nerve endings. The following is a description of some methods that are suitable for the detection of cardioselective antimuscarinic agents.

"In vivo" methods The obiective of the methods was to confirm the selectivity of the antimuscarinic effect. Those substances which had been selected on the basis of "in vitro" test results were tested for their 1. M 1

/M

2 selectivity in the rat, 2. Salivation-inhibiting effect on the rat and 3. Inhibition of the acetylcholine effect on the bladder, bronchi and heart rate in the guinea pig.

1. M /M 2 selectivity in the rat U a t r The method used was that described by Hammer and Giachetti in Life Sciences 31, 2991-2998 (1982).

minutes after intravenous injection of increasing doses of the test substance, either the right vagus was electrically stimulated (freauency: 25 Hz; pulse width: 2ms; duration of stimulus: 30s; voltage: fj i I i 4if t3 28 supramaximal) or 0.3 mg/kg of McN-A-343 were intravenously injected into male THOM rats. The bradycardia caused by vagus stimulation and the rise in blood pressure caused by McN-A-343 were determined.

The dosage of the substances which reduced either the vagal bradycardia (M 2 or the rise in blood pressure (Mi) by 50% was determined graphically.

The results are set forth in Table II.

2. Salivation-inhibiting effect in the rat b*15 no a a.

20 Using the method of Lavy and Mulder (see Arch.

int. Pharmacodyn. 178, 437-445, (1969)), male THOM rats anaesthetised with 1.2 g/kg of urethane were given increasing doses of the test substance by i.v. route. The secretion of saliva was initiated by subcutaneous administration of 2 mg/kg of pilocarpine.

The saliva was absorbed with blotting paper and the surface area covered was measured every 5 minutes by planimetry. The dosage of the test substance which reduced the volume of saliva by 50% was determined graphically. The results are set forth in Table II.

3. Inhibition of the effect of acetylcholine on the bladder, bronchi and heart rate in guinea pigs 4 t 'I t

I

4,I 5 minutes after the administration of the test substance, 10 microgram/kg of acetylcholine were simultaneously injected intravenously and tiniraarterially into anaesthetised guinea pigs. The heart rate was recorded directly by extracorporeal derivation of the ECG, the expiration resistance according to Konzett-R8Bler and contraction of the exposed bladder. In order to determine the inhibition of the acetylcholine activity on the organs under investigation, dosage/activity curves i .i I ler~; ~~--~srury ~r 42 The following Examples illustrate the preparation of some pharmaceutical administration forms: of the -29 were recorded a~nd from them -log ED 0 values were determined. The results are set forth in Table The following compounds, by way of example, were investiqated according to the procedures set forth above- A =5,l1-dihydro-11I-[6-(1--piperidinyl)-l-oxohexyl]- 6H-pyrido[2,3-bl[1,4lbenzodiazepin-6-one, and as comparison substances B =ll-[[2-[(diethylamino)methyl]l-piperidinyllacetyll- 5,11-dihydro-6H-pyrido[2,3-b'J[1,4]benzodiazepin- 6-one (see US Patent No. 4550107) C 5,11-dih~ydro-11-[ (4-methyl-l-piperazinyl)acetyl]- 6U1-pyrido[2,3-b][l,4]benzodiazepin-6-one (see US Patent No. 3660380) and 1) =atropine.

i' ~I 30 Table I: Receptor Binding Tests in vitro: Results:

S.

4 @4 4 .444 4 4~ Receptor Binding Tests

IC

50 [nmol 1-1] Substance Cortex Heart A 60 B 1200 140 C 100 1500 D 2 4 The information shown in Table I above shows that the compounds of the invention distinguish between muscarinic receptors in different tissues. This is clear from the substantially lower IC 50 values when the test substances are investigated on preparations from the heart compared with those from the cerebral cortex.

4 4 44 44 4 _r icarriea out using conventional techniaues. The leaving group Nu is a group which together with ii 31 Table II:

MI/M

2 selectivity and salivation-inhibiting activity on the rat: Results: t 304 354 -log ED 5 0 [mol kg- 1] Substance Heart Blood pressure Salivation A 7.75 6.42 6.65 B 6.42 5.63 5.00 C 5.60 6.94 6.22 D) 7.94 7.34 7.60 iie aCuyati.jnY agen or rormuia v usea. it is not necessary to prepare the compounds of formula V

W

jj I 1 i r ii; 32 Table III Inhibition of acetylcholine activity on the bladder, bronchi and heart rate in the guinea pig: Results: 41 4 4: 4 4t 4,94: *4 *o II 44 4 4 4 4 4.4% 4 4<.

-log ED 50 [mol kg-1] Substance Heart Bronchi Bladder A 6.88 7.49 6.20 B 5.84 5.58 4.73 C 5.58 6.57 5.36 D 7.70 7.96 7.03 The pharmacoloqical data in Tables II and III above show in total agreement with the receptor binding studies that the heart rate is increased by the above-mentioned compounds even at dosages at which there is no restriction in the secretion of saliva.

Moreover, the pharmacological data in Table III above indicate a surprisingly high power of selectivity between the heart and smooth muscle.

The above-mentioned substances show a substantially improved effectiveness compared with the known compound E. At the same time, their therapeutically useful selectivity is retained. This results in a reduction in the auantity of drug which needs to be administered to the patient without increasing the risk of muscarinic side effects.

it Wii 1 with regard to the olefinic double bond are predominantly formed.

r( *1 .1 wiA e i c-

II

i ii #4 4 t 33 Furthermore, the compounds prepared according to the invention are well tolerated; even in the highest doses administered, no toxic side effects were observed in the pharmacological trials.

For pharmaceutical use the compounds of the invention may be incorporated in known manner in convnetional pharmaceutical preparations, e.g. solutions, suppositories, plain or coated tablets, capsules infusions, etc.

The daily dosage is expected to be between approximately 0.02 and 5 mg/kg, preferably 0.02 and 2.5 mg/kg, in particular 0.05 and 1.0 mg/kq of body weight, optionally administered in the form of several, preferably 1 to 3, individual doses in order to achieve the desired results.

Thus viewed from a further aspect the invention provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable acid addition salt thereof together with one or more pharmaceutical carriers or excipients.

Viewed from a still further aspect the invention provides the use of a compound of formula I or of a physiologically acceptable acid addition salt thereof for the manufacture of a pharmaceutical composition for use as a vagal pacemaker for treating bradycardia and bradyarrhythmia.

Viewed from a yet still further aspect the invention also provides a method of treatment of the human or non-human animal body to combat bradycardia and bradyarrhythmia comprising the administration to said body of a compound of formula I or a physiologically acceptable acid addition salt thereof.

i

I~

3 34 The following Examples are intended to illustrate the invention, without limiting its scope in any way. Percentages and ratios are by weight unless otherwise indicated.

Satisfactory elemental, IR,UV and 1H-NMR analyses are available for all the compounds and mass spectra.

are available for many of them.

Example 1 5,11-Dihydro-1i-[6-(1-piperidinyl)-l-oxoheyyll- 6H-pyrido[2,3-b[ll,4]benzodiazepin-6-one 0.9 g (2.317 mmol) of 5,11-dihydro-ll-[6-(l-piperidinyl)-l-oxo-4-hexynyll-6H-pyrido[2,3-b [l,4]benzodiazepin- 6-one 197*C) were dissolved in 45 ml of "ethanol and after the addition oR 0.3 g of palladium on animal charcoal the mixture was hydrogenated under 3 bar of hydrogen pressure and at o ambient temperature until the uptake of hydrogen had ceased. The mixture was filtered, the filtrate was evaporated down in a water jet vacuum and the oily residue was triturated with a few drops of diethylether. Crystallisation occurred. The precipitate was removed by suction filtering and recrystallised once more from ethyl acetate. 0,84 g (92% of theory) .,of colourless crystals were obtained, m.p. 168-170 0

C.

Example 2 ll-(6- (Cyclohexyl)methylaminol-1-oxohexyll-5,11dihydro-6H-pyrido[2,3-bl1,4 benzodiazepin-6-one Prepared analogously to Example 1 from ll-[6-((cyclohexyl)methylamino1-l-oxo-4-hexynyll-5,11-dihydro- 6H-pyrido[2,3-bl[1,4benzodiazepin-6-one t' _L _r 1

F

35 162-163 0 C) by catalytic hydrogenation in the presence of palladium on animal charcoal in a yield of 56% of theory. Colourless crystals, xn.p. 98-100 0

C

(ethyl acetate).

Example 3 00 0 0 00 @0 00 15 0 0 0 o go 00 0 0'4 00 0 00 00 4000 *0 0* 0 00 00 4 04 0 001444 a Trans-5,1l-dihvdro-l.-46-[ (4-hydroxycyclohexyl)methylamino] -l-oxohexyl] -6H-pyridot 2,3-b] benzodiazepin- 6-one Prepared analogously to Example I from dihydro-ll-[6-[ (4-hydroxycyclohexyl)methylamino]l-oxo-4-hexynyl]-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one 176-l78*C) by catalytic hydrogenation in the presence of palladium on animal charcoal in a yield of 36% of theory. Colourless crystals, 1.79 0 C (ethyl acetate).

Example 4 5,11-Dihydro-ll-[6-( (phenylmethvl)metbvlamino]l-oxobexyl]-6H-pyridor2,3--bfll,4]benzodiazepin- 6-one Prepared analogously to Example 1 from 5,11-dihydro- (phenylrr(ethyl)methylamino]-l-oxo-4-hexynyl]- 6H-pyridoll2,3-b][l,4]benzodiazepin-6-one tm.p.: 204-206*C) by catalytic hydrogenation in the presence of palladium on charcoal in a yield of 47% of theory.

Colourless crystals, m.p. 128 0 C (diethylether).

A t -36 Example ,11-Dihydr-11- (hexahvdro-1H-1-azepinyl) -1oxohexyl]-6H-pyrido[2,3-blfl,4]benzodiazepin-6one Prepared analogously to Example 1 from 5,1.1-dihydrol1-[6- (hexahydro-1H-l-azepinyl)-1-oxo-4-hexvnyl]- 6H-pyrido[2,3-blfil,4]benzodiazepin-6-one 169-170*C) by catalytic hydroqenation in the presence of palladium on charcoal in a yield of 40% of theory.

Colourless crystals, m.p. 140 0 C (ethyl acetate).

Examnle 6 *Ot, 5,11-Dihydro-l1-[6-114-(phenylmethyl)-l.-piperazinyl]- 4 4 1 l-oxohexyl]-6H-pvridor2,3-blfl,4]benzodiazepin- 44 6-one Prepared analogously to Example 3. from 5,11-dihydro- 6414 l1-[6-[4-(Phenylniethyl)-.l-piperazinylj-l-oxo-4hexynyll-6H-pyrido[2,3-bJ[l,4)benzodiazepin-6-one 157-158 0 C) by catalytic hydrogenation in the presence of palladium on animal charcoal in a yield of 50% of theory. Colourless crystals, m-p. 105-107 0 C (ethyl acetate).

4, Example 7 5,1l-Dihvdro-1l.-[2-methyl-6-(4-methyl-l-piperazinyl)- 1-oxohexyll-6H-pyrido(2,3-b][i,4]benzodliazepin- 6-one Prepared analogously to Example 1 from 5,11-dihydro- 3.3-f2-methyl-6- (4-methyl-1-piperazinyl) -l-oxo-4hexynyl] -6H-pyrido[ 2,3-b) [1,4 Ibenzodiazepin-6-one 212-214 0 C) by catalytic hydrogenation in the presence of palladium on charcoal in a yield oE 52% of theory. ('olourless crystals, m.p. 156*C (ethyl acetate/di-'4hyj ether, 1:1 v/v) 37f Example 8 5,11-Dihydro-ll-[7-(l-piperidiflyl)-1-oxoheptyl]-, 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (Z)-5,11-dihydro-11-117-(l-piperidinyl)-l-oxo-5heptenyl]-6H-pyridoll2,3-bI[1,4]benzodiazepil-6-one 800 mg (1.988 mmol) of 5,11-dihydro-11-[7-(1-piperidjnyl)-1-oxo-5-heptynyl]-6H.-pyrido[2,3-b[1,4]benzodiazepil- 6-one 166-167 0 C) were dissolved in 20 ml of methanol and after the addition of 100 mg of palladium/charcoal catalyst the mixture was hydrogenated for 10 hours in a Parr autoclave at t# t ambient temperature under a hydroqen pressure of rr'35 0.7 bar. The catalyst was filtered off, the filtrate 2 was evaporated down in vacuo and the mixture of products obtained was separated by column chromatography on silica gel (30-60 micrometers) using 0 4 t ethyl acetate/methanol/cyclohexane/conc. ammonia by volume) as eluant. By working up the corresponding fractions, 250 mg (31% of theory) of colourless crystals were obtained, m.p. 148-149*C (diisopropylether) which ere characterised by NMR spectroscopy as 5,41-dihydro-l1-[7-(1-piperidinyl)- 1-oxoheptyl]-6H-pyridoll2,3-bJ[1,4]benzodiazepin- 6-one together with 100 izg (12% of theory) of colourless crystals, m.p. 125*C, (diisopropylether), which were assigned the structure of a (Z)-5,11-dihydro- 11.-[7-(1-piperidi-nyl)-J.-oxo-5-heptenyll-6P-pyrido[2,3b][1,4]benzodiazepin-6-one.

Example 9 (Z)-5,11-Dihydro-l1-[6-(1-piperidinyl)-l-oxo-4hexenyl1-6H-pyrido[2,3-b1[1,4]benzodiazepir-6-one Prepared analogously to Example 1 from 5,11-dihydro-

F

38 ll-[6-(l-piperidinyl)-l-oxo-4-hexynyl]-6H-pyrido[2,3-b]- [1,4]benzodiazepin-6-one, but using palladium on calcium carbonate and contaminated with lead (Lindlar catalyst), instead of palladium on animal charcoal as catalyst, in a yield of 58% of theory. Colourless crystals, m.p.

184*C (ethyl acetate).

Example 11-Dihydro-11-r6- d1ii'hylamino)-1-oxohexyl l- 6H-pyridof2,3-b[1,.41benzodiazepin-6-one A mixture of 6.0 g (17.45 mmol) of 11-(6-chloro- 1-oxohexyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepin-6-one 128-130 0 C [decomp.]), 2.3 g (57.7 mmol) of dimethylamine and 160 ml of anhydrous ethanol was heated for 5 hours to 100 0 C in a bomb tube.

The mixture was then evaporated down in vacuo, the oily 4 residue obtained was purified by HPLC using silica gel *as the stationary phase and dichloromethane/cyclohexane/ methanol/conc. ammonia/ethyl acetate (177.5/23/23/3/75.5 by volume) as the mobile phase.

0.2 g of theory) of colourless crystals, m.p.

129-130 0 C (acetonitrile) were isolated from the suitable fractions.

00 7K 0 oi -39 Example 11 ll-Dihydro-1l-r6-(4-hvdroRxv-l-piperidinvl) oxohexvll-6H-pyridor2. 3-bW1F.41benzodiagepin-6-one Prepared analogously to Example 1 from 5,11-dihydroll-[6-(4-hydroxy-l-piperidinyl) -l-oxo-4-hexynyl)- 6H-pyrido[2,3-bJ (1,4]benzodiazepin-6-one l75-176*C) by catalytic hydrogenation in the presence of palladium on animal charcoal in a yield of 54% of theory. The colourless salt with 1 mole of fumaric acid melted at 145 0 C (decomp.) (from ethyl acetate/ethanol= 1:1 v/v).

Example 12 5.ll-Dihvdrj)-1-F-6-r4-(methyltthyl)-l-pipe-7azinvll- 1-oxohexvll1-6H-pvridor2.3-bl rl.41benzodiazepin-6-one Prepared analogously, to Example 1 from 5,11-dihydroll-[6-(4-(methylethyl) -l-piperazinyl]-l-oxo-4-hexynyl]- 6H-pyrido[2,3-b] [l,4]benzodiazepin-6-owe (mp..

124-126*C) by catalytic hydrogenation in the presence of palladium on animal charcoal in a yield of 66% of theory. Colourless crystals, m.p. 141-142*C (ethyl acetate).

Example 13 l%-Dihvdro-1-r6-(4-ethl-l-pierazinyl) -l-oxohexyll- 6H-p3V'ridor2.3-bl rl.41bengodiazepiii-6-one Prepared analogously to Example 1 from ll-(6-(4-ethyl-l-piperazinyl) -3-oxo-4-hexynyl) were determined graphically.Teyrpeet ha They represent that -6H-pyrido[2, 3-b] [l,4]benzodiazepin-6-one by catalytic hydrogenation in the presence of palladium on animal charcoal in a yield of 62% of theory. Colourless crystals, m.p. 161-162*C (ethyl acetate).

Example 14 5,11-Dihvdro-11-r6-r4-r3-(trifluoromethyllphenvll- 1-piperazinvll-l-oxohexvll-6H-pVridor2,3-bl fl.41benzodiazeypin-6 -one-hemi fumarate Prepared analogously to Example 1 from 5,11-dihydroll-[6-[4-[3-(trifluoromethyl)phenylJ-l-piperazinylJ- 1-oxo-4-hexynyl]-6H-pyrido(2,3-b] [l,4]benzodiazepina 6-one by catalytic hydrogenation in the presence of palladium on animal charcoal in a yield of 11% of toa theory. The hemifumarate melted at 199-200*C (acetone).

Example 4. 9-Dihvdro-4 r6- (hexahvdro-lH-1-azepinyl) -1-oxohexyl 1- 3-methvl-10H-thienor3,4-bl Fl.51benzodiazeipin-10-one Prepared analogously to Example 1 from 4,9-dihydro- 192-193-C) in a yield of 15% of theory.

Colourless crystals, m.p. 103-1040C (diisopropylether).

1 41 41 Example 16 5.11-Dihydro-ll-[6-(l-piperidinyl)-l-oxohexyl]- 6H-pyridor2,3-b[ r1.4benzodiazepin-6-one A mixture of 12.60 g (0.0632 mol) of 1-piperidine hexanoic acid and 2.0 g of a 75% sodium hydride dispersion in paraffin oil was heated in 160 ml of anhydrous dimethylformamide at 50 to 80"C until the development of hydrogen had ended. To the resulting sodium salt of the entire acid were added 13.20 g (0.0625 mol) of 5,11-dihydro-6H-pyrido[2,3-b]- [l,4]benzodiazepin-6-one and at -10°C 9.9 g (0.0646 mol) of phosphorus oxychloride were added dropwise within minutes. The mixture was stirred for 4 hours at for 4 hours at 0 C and for 20 hours at ambient temperature. The mixture was stirred into 300 g of ice, adjusted to pH 9 with sodium hydroxide solution and extracted exhaustively with dichloromethane. The combined organic phases were washed once with a little ice water, dried over sodium sulphate and concentrated by evaporation. The oily residue was triturated with a few drops of diethylether, whereupon crystallisation occurred. The precipitate was separated by suction filtering and recrystallised from ethyl acetate using activated charcoal. 5.15 g (21% of theory) of colourless crystals were obtained, m.p. 169-170°C, which were found to be totally identical to a sample obtained according to Example 1 when investigated by thin layer chromatography, mixed melting point, IR, UV and 1

H-NMR

spectra.

j 0 -1 I I r i 42 The following Examples illustrate the preparation of some pharmaceutical administration forms: Example I Tablets containing 5 mg of 5,11-dihydro-ll-[6-(1piperidinyl)-l-oxohexyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 4f I a f ft at a

I

It.

a.

t t 44 1 tablet contains: Active substance Lactose Potato starch Magnesium stearate Total Weight: 5.0 mg 148.0 mg 65.0 mg 2.0 mq 220.0 mg A 10% mucilage is prepared from potato starch by heating. The active substance, lactose and remaining potato starch are mixed together and granulated with the above mucilage through a 1.5 mm mesh screen.

The granules are dried at 45 0 C, rubbed through the same screen again, mixed with magnesium stearate and compressed with a punch of diameter of 9 mm to form tablets weighing 220 mg.

Example II Coated tablets containing 5 mq of 5,11-dihydro- 11-[6-(1-piperidinvl)-1-oxohexvll-6H-ovrido 2,3-bl1,41 benzodiepDin-6-one The tablets prepared according to Example I are coated, by a known method, with a coating consisting essentially of sugar and talc. The finished coated tablets are polished with beeswax and weigh approximately 300 mg each.

cc I 43- Example III Ampoules containing 10 mg of 5,11-dibydro-11-[6- (1-piperidinyl)-l-oxohexyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one 1 ampoule contains: Active substance 10.0 mg Sodium chloride '8.0 mg Distilled water ad 1 ml The active substance and sodium chloride are dissolved .9 in distilled water and then made up to the volume specified. The solution is sterile filtered and transferred into 1 ml ampoules.

.t'Sterilisation: 20 minutes at 120'C.

t, t1 Examp~le IV t Suppositories containing 20 mg of 5,11-dihydro- 4 t I l-[6-(l-piperidinyl)-l-oxohexyl]-6H-.pyrido[2,3-b][l,4)benzodiazepin-6-one 1. suppository contains- Active substance 20.0 mg Suppository mass Witepsol W 45) 1. 680.0 mg 1 700.0 mg The finely powdered active substance is suspended in the molten suppository mass which has been cooled to 40'C. The mass i~s poured at 37*r. into slightly chilled suppository moulds.

Weigjht of suppository: 1.7 g (Witepso. WN45 is a registered trade mark).

i:; t i i Ir 44 Example V Drops containing 5,11-dihydro-ll-[6-(l-piperidinyl)- 1-oxohexyl]-6H-pyrido[2,3-b][1,4]benzodiazerin- 6-one 4,.

*D F 15 0 *0 4 *t 4#

S.,

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 q 0.015 q 0.05 g 0.06 g 10.0 g 0.5 g 1.0 g 15.0 g 100.0 ml The active substance and sodium cyclamate are dissolved in about 70 ml of water and glycerol is added.

The p-hydroxybenzoates, aniseed oil and menthol are dissolved in ethanol and this solution is added with stirring to the aqueous solution. Finally, the solution is made up to 100 ml with water and filtered to remove any suspended particles.

*1 41 1 441 II I 4 44 4 4'

Claims (10)

1. Compounds of formula I 3 H O R I I R X N1 RN 1R CO A N R2 (wherein 449 1 R represents a C 1 alkyl group, K 1 -3 2 S1t a straight-chained or branched CI-8 alkyl group tt optionally substituted from the second carbon atom by a hydroxy group, a C3- 8 cycloalkyl or (C3 8 cycloalkyl)methyl group in which the cvcloalkyl moiety optionally is substituted by a methyl or hydroxy group, to a phenyl(C 1 3 alkyl) group in which the phenyl Sgroup optionally is substituted by one or two substituents selected from halogen atoms and methyl, methoxy and trifluoromethyl groups, or R and R 2 together with the interveninq nitrogen atom represent a a group of formula N X (CH2)m wherein n and m, which may be the same or different, CT 46 each represents the integer 2, 3 or 4, with the proviso that the sum of n and m is 4, 5 or 6, X 3 is a methylene group, a hydroxy substituted methylene group, an oxygen atom or a group of formula NR' where R' represents a hydrogen atom, or a C1. 3 alkyl, phenyl (CI. 3 alkyl) or a phenyl group in which the phenyl nucleus is optionally substituted by one or two substituents selected from halogen atoms and methyl, methoxy and trifluoromethyl groups; R 3 represents a C 1 3 alkyl group or a hydrogen or chlorine atom; R 4 represents a hydrogen atom or a methyl group; A represents a branched or straight chain C 5 8 alkylene or alkenylene group, with the provisos that there are at least 5 carbon atoms in the carbon chain linking the semicyclic carbonyl group and the nitrogen SRI atom of the N group, R 2 and when A is a Cs-alkylene group then -NR 1 R 2 is other than a l-pyrrolidinyl or a 4-methyl-l-piperazinyl group; B)represents a group of formula CH 3 R C3 T Ja I" 1 S T o r T R6 R 9 1 0 ii -47- (wherein R 5 and R 6 which may be identical or different, each represents a hydrogen, fluorine, chlorine or bromine atom or a C1_4 alkyl group, R 7 represents a methyl group or a chlorine atom or, if R represents a hydrogen atom or a C1-3 alkyl group, R 7 may also represent a hydrogen atom, R represents a hydrogen atom or a C 1 4 alkyl group, 9 R represents a C1_ 4 alkyl group or a hydrogen or chlorine atom; and 4*#6 R represents a hydrogen atom or a methyl group); 1 2 f X and X each represent a methine group or, if 9) represents one of the groups figs R 5 R \e N f 6S or R 6 R 9 y and X 2 may each represent a nitrogen atom or 1 2 one of X and X 2 may represent a methine group and the other of X 1 and X may represent a nitrogen atom), the isomers and acid addition salts thereof.

2. Compounds as claimed in claim 1 being compounds of formula I wherein R 1 represents a methyl or ethyl group, R 2 represents a C 1 -3 alkyl group or a cyclohexyl, i d I, 48 trans-(4-hydroxycyclohexyl) or phenylmethyl group or R 1 and R 2 together with the intervening nitrogen atom represent a 1-piperidinyl, 4-hydroxy-l-piperidinyl or hexahydro-1H-azepinyl group, or a 1-piperazinyl group optionally substituted in the 4-position by a C 1 3 alkyl, phenyl (CI.3 alkyl) or phenyl group wherein the phenyl nucleus itself is optionally substituted by one or two substituents selected from methyl, methoxy and trifluoromethyl groups, 3 R represents a methyl group or a hydrogen or chlorine atom, R4 represents a hydrogen atom or a methyl group, A represents a C 5 6 alkylene group optionally methyl- O substituted in the alpha-position to the semicyclic o carbonyl group and/or containing a double bond in the o* gamma-delta-position, with the proviso that when A is a C 5 -alkylene group then -NR 1 R 2 is other than a 4-methyl-l- piperazinyl group. R (wherein R represents a group ofhydrogen atom, or -SR (wherein R 5 represents a hydrogen atom, R 6 represents a hydrogen, chlorine or bromine atom or a methyl or ethyl group in the 8 or 9-position of the heterocyclic ring system, -i-w 49 R represents a hydrogen atom and R 9 represents a hydrogen atom or a methyl group), X 1 represents a methine group, and 2 X represents a methine qroup or a nitrogen atom, and the isomers and acid addition salts thereof.

3. Compounds as claimed in claim 1 being compounds of formula la H 0 S'B J (Ia) CO A N R 2 wherein 1 2 2 R A and X are as defined in either of claims 1 and 2 and represents a group of formula i or S CH 3 and the isomers and acid addition salts thereof.

4. A compound as claimed in claim 1 being 5,11-dihydro-]- 6-l-piperidinyl)-l-oxohexyll- 6P-pyrido[2,3-btl,4]benzodiazepin-6-one, 50 5,11-dihydro-ll[[-[6-4-3-(trifluoromethyl)phenyl]- l-piperazinyl]-l-oxohexyl]-6H-pyrido[2,3-b][1,4]benzo- diazepin-6-one, or an isomer or acid addition salt thereof. A compound as claimed in claim 1 being 5,11- dihydro-ll-[6-(l-piperidinyl)-l-oxohexyl]-6H-pyrido[ 2,3-b][1,4benzodiazepin-6-one, or an isomer or acid addition salt thereof.

6. A compound as claimed in any one of claims r 1 to 5 being a physiologically acceptable salt i" of a compound of formula I. It t 7. A pharmaceutical composition comprising a compound of formula I as clainied in any one of claims 1 to 5 or a physiologically acceptable acid addition salt thereof together with one or more 4* pharmaceutical carriers or excipients. °K 4 1 4* 1It

8. A process for the preparation of the compounds claimed in any one of claims 1 to 6, said process comprising at least one of the following steps: a) (to prepare compounds of formula I wherein R 7 represents a chlorine atom or a methyl group) reacting a compound of formula II 3 H O R X i IN R B(II) x 2 N CO A Y (wherein 3 R4 A 1 and X 2 are as defined in any one R R A, X and X are as defined in any one i i iF C I 51 of claims 1 to represents a group of formula 5 CH 8 R 3 R H3 SS or N rq 6 7' F N R R R 9 R 10 wherein R 5 R and R to R are as defined in any one of claims 1 to 5 and R represents a methyl a. ,group or a chlorine atom, and Y represents an halogen atom) with an amine of formula III i 4 t R 1 4I H N (III) \R2 (wherein 1 2 R' and R are as defined in any one of claims 1 to b) (in order to prepare compounds of formula I wherein R 7 represents a chlorine atom or a methyl group) reacting a compound of formula IV R I X N (wherein II_ (I -52 R R 4 and X 2 are as defined in any one of claims 1 to 5; and Srepresents a group of formula R C R 8CH N 7 1Nor1 R6R R 9 R 1 wherein R 5 R 6 and R 8 to R 0are as defined in any one of cl.aims 1 to 5 and R 1repre~sents a methyl group or a chlorine atom) with a compound of formula 17 I t It t t~ Nu -CO A N/ \R 2 (wherein R 1.1P-2and A are as def~i;ed in any one of claims 1 to Ind Nu represents a nucleofugic group); c) catalytically hydrogenating a compound of formula VI R 3 H 0 R4 B CO \R2 (VI) I IC t II I I f' r 53 (wherein R to R 4 and)j are as defined in any one of claims 1 to 5 and 1 represents a straight-chained or branched C 5 -8 alkenylene or alkynylene group, with the proviso that the carbon chain linking the semicyclic carbonyl group to the nitrogen atom of the 1 RI N group is at least five-membered); R2 3 d) (to prepare compounds of formula I wherein R 3 St, represents a hydrogen atom or a C 1 3 alkyl group, R represents a hydrogen atom and A represents t t* a saturated alkylene group) hydrogenolysinq a compound of formula VII 4 t 4 K \RR CO 2 N' 2 I R (wherein R 1 to R4 IX 1 and X 2 are as defined in any one of claims 1 to 5; and 2R2 Z represents a straight chained or branched C5 8 alkylene, alkenylene or alkynylene group, with the proviso that the carbon chain linking the semi- cyclic carbonyl group to the nitrogen atom of the i i 54 R 1 N group is at least five-membered); R 2 resolving a compound of formula I thus obtained into the diastereoisomers or enantiomers thereof; and converting a compound of formula I thus obtained into an acid addition salt thereof or an acid addition salt of a compound of formula I into the free bases

9. A process as claimed in claim 8 wherein the reaction is carried out in a solvent. A process as claimed in claims 8 and 9 wherein the reaction of step is carried out at temperatures of between -10°C and the boiling temperature of the solvent used.

11. A process as claimed in claims 8 and 9 wherein the 4tt reaction of step is carried out at temperatures of Sbetween -25*C and 130 0 C.

12. A process as claimed in claims 8 and 9, wherein the the catalytic hydrogenation of step is carried out in the presence of a catalyst comprising a metal of the VIIIth subgroup of the Periodic Table of Elements, under hydrogen pressures of from 0.1 to 300 bar and at temperatures of between 0 and 130°C.

43. A process as claimed in claim 12 wherein (to prepare compounds of formula I wherein A contains a double bond) a compound of formula VI wherein Z contains a triple bond is catalytically hydrogenated and the hydrogenation is broken off after the uptake of 1 molar equivalent of hydrogen. 14. A process as claimed in claim 13, wherein (to prepare compounds of formula I wherein A _i I~ R i i 55 contains a double bond) a compound of formula VI wherein Z contains a triple bond is catalytically hydrogenated and hydrogenation is carried out in the presence of a deactivated catalyst. A process as claimed in claims 8 and 9, wherein the hydrogenolysis of step is carried out in the presence of a catalyst comprising a metal of the VIIIth subgroup of the Periodic Table of Elements, under hydrogen pressures of from 0.1 to 300 bar and at temperatures of between 0 and 130*C. 16. A process as claimed in claims 8 and 9, wherein the the hydrogenolysis of step is carried out in the presence of a catalyst comprising a metal of the VIIIth subgroup of the Periodic Table of Elements, in the presence of formic acid or a derivative thereof as the hydrogen source, and at temperatures of between 70 and 110 0 C. 17. A method of treatment of the human or non-human animal body to combat bradycardia and bradyarrhythmia comprising the administration to said body of a compound of formula I as defined in claim 1 or a physiologically acceptable acid addition salt thereof. 18. Compounds of formula I as defined in claim 1 and salts thereof substantially as herein disclosed in any one of the Examples. DATED this 16th day of April 1991. DR KARL THOMAE GMBH By Their Patent Attorneys: CALLINAN LAWRIE L c<