AU608641B2 - Condensed diazepinones - Google Patents

Abstract

Condensed diazepinones of the general formula I <IMAGE> in which <IMAGE> represents one of the divalent radicals <IMAGE> and X<1>, X<2>, A, R<1> to R<1><0> and Z have the following meanings: X<1> and X<2> represent a = CH-group or, if <IMAGE> assumes the meanings of the abovementioned divalent radicals (S), (U) or (W), both or only X<1> or only X<2> can also represent a nitrogen atom; A is an alkylene radical having two to seven carbon atoms; which can also be interrupted by an oxygen or sulphur atom or by the methylimino or ethylimino group; Z is a single bond, an oxygen or sulphur atom, the methylene or 1,2-ethylene group; R<1> is a lower alkyl radical or the benzyl group; R<2> is an alkyl radical having 1 to 7 carbon atoms, which can optionally be further substituted by a hydroxyl group on its 2nd to 7th carbon atom, a cycloalkyl or a cycloalkylmethyl radical, where the cycloalkyl ring can optionally be further substituted by a hydroxyl group; R<1> and R<2>, however, together with the nitrogen atom lying in between, can also form a 4- to 7-membered saturated, monocyclic heterocyclic ring which can optionally be interrupted by an oxygen atom or by the N-CH3 group; R<2> can, however, also be linked to A via an alkylene bridge such that, together with the group NR<1>, a saturated, 5 to 7-membered heterocyclic ring system is formed; R<3> is a lower alkyl group, a chlorine atom or a hydrogen atom; R<4> is a hydrogen atom or a methyl group; R<5> and R<6> each denote a hydrogen atom, a fluorine, chlorine or bromine atom or a lower alkyl group; R<7> is a hydrogen or chlorine atom or a methyl group; R<8> is a hydrogen atom or a lower alkyl radical; R<9> is a hydrogen or halogen atom or a lower alkyl group and R<1><0> is a hydrogen atom or a methyl group, where in the case in which <IMAGE> represents the divalent radical (T) and R<7> is hydrogen, R<3> cannot be chlorine and Z cannot be sulphur. Processes for their preparation and medicaments which contain these compounds are also described. In view of the lack of gastric acid secretion-inhibiting, salivation-inhibiting and mydriatic influences, the novel diazepinones are suitable as vagal pacemakers for the treatment of bradycardias and bradyarrhythmias in human and veterinary medicine.

Description

Form

AUSTRALIA

PATENTS ACT 1952 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: Complete Specification Lodged: Accepted: Lapsed: Published: S Priority: 0 0 o o,+ 4 I 4 0 6 f{

I

1 4 t 41 I I Tnis documint conmtin the atmendments made iutTr Section 49 and is correct for priting.| Related Art: TO BE COMPLETED BY APPLICANT Name of Applicant: Address of Applicant: Actual Inventors: Address for Service: DR. KARL THOMAE GmbH D-7950 Biberach an der Riss, Federal Republic of Germany.

WOLFHARD ENGEL, GUNTER TRUMMLITZ, WOLFGANG EBERLEIN, GERHARD MIHM, NORBERT MAYER, ADRIAAN DE JONGE, KLAUS RUDOLF.

CALLINANS, Patent Attorneys, of 48-50 Bridge Road, Richmond 3121, Victoria, Australia.

Coplete 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 i 1A- Condensed diazepinones The invention relates to new condensed diazepinones, processes for preparing them and pharmaceutical compositions containing these compounds.

Condensed diazepinones with anti-ulcerative properties and an inhibitory effect on gastric juice secretion are known from EP-A-39519 and EP-A-57428 and from US Patents Nos. 3660380, 3691159, 4213984, 4213985, 4210648, 4410527, 4424225, 4424222 and 4424226.

EP-A-156191 describes how valuable but completely different pharmacological properties than those described for the compounds disclosed in the abovementioned publications can be induced by introducing certain aminoaiyl groups into the molecular structure.

S5, We have now found that certain novel condensed e diazepinones in comparison with these known compounds exhibit substantially more powerful effects and S* marked resistance to hydrolysis, whilst having comparable or better selectivity and resorption 20 after oral administration.

I Is 4 'More particularly, the new compounds exhibit valuable ,pharmacological properties, especially a favourable Seffect on heart rate and lacking mydriatic effects and inhibitory effects on gastric acid secretion ,25 and salivation they are suited for use as vagal 1 pacemakers.

Thus viewed from one aspect the present invention provides compounds of formula I 2 H 0

R

3 X1 X ri" 4 X2 (wherein I represents a group selected from the groups and (W) R N

R

R

(wherein represents a group selected from the groups U) and (W)

RRN

,O o

(W)

9 0

X

1 and X 2 each represents a =CH- group, or if S\ represents a group or each or either 1 2 one of X and X may instead represent a nitrogen atom; 4 4 4 1 A represents a straight-chained or branched C2-7 saturated alkylene group optionally interrupted by an oxygen or sulphur atom or by a ,ethylimino or ethylimino group; i Z represents a single bond, an oxygen or sulphur atom or a methylene or 1,2-ethylene group; R represents a branched or unbranched _1-4 alkyl group or a benzyl group, and

I

3

R

2 represents a branched or unbranched C 1 7 alkyl group optionally substituted at its 2nd to 7th carbon atom by a hydroxy group, a C3_ 7 cycloalkyl or (C3- 7 cycloalkyl)methyl group optionally substituted in the cycloalkyl ring by a hydroxy group, or

R

1 and R 2 together with the intervening nitrogen atom represent a 4- to 7-membered saturated, monocyclic, heterocyclic ring optionally interrupted by an oxygen atom or by an N-CH 3 group, and

R

2 may also be linked to A via ar alkylene bridge whereby to form in conjunction with the group NR a saturated 6- or 7-membered heterocyclic ring;

R

3 represents a C 1 4 alkyl group a chlorine or hydrogen atom; 0* 0 4 15 R represents a hydrogen atom or a methyl group; o** 0 0 S 5 6 R and R which may be the same or different, each represents a hydrogen, fluorine, chlorine S'or bromine atom or a Cl-4 alkyl group;

R

7 represents a hydrogen or chlorine atom or a methyl group; S10 R represents a hydrogen atom or a meth alkyl group; R represents a hydrogen or halogen atom or a C_ 4 .alkyl group; and R represents a hydrogen atom or a methyl group; with the proviso that where is a group (T) wherein R is hydrogen, R is other than chlorine and Z is other than sulphur) and acid addition salts thereof.

4 Preferred compounds according to the invention include compounds of formula I wherein A is C2- 4 alkylene chain in the 3 or 4 position of the saturated heterocyclic ring -N Z Z is a methylene group, R and R 2 each represent C 1 -4 alkyl groups or R and R 2 together with the intervening nitrogen atom represent a 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl or hexahydro-lH-l-azepinyl group, and either 1 X is a =CH- group,

X

2 is a nitrogen atom, is a group R *o o5 and R are hydrogen atoms and R is a hydrogen, chlorine or bromine atom or a methyl or ethyl group 015 in the 8 or 9 position, I 0 or o 9,

X

1 and X 2 are =CH- groups and B is a group (wherein R 8 is a hydrogen atom and R 9 is a o ot* 3 4 methyl group) or at least one of R and R is a '00 20 hydrogen atom and is a group 0 Q 00 and acid addition salts thereof.

The compounds of formula I may form salts, e.g.

0 0" with inorganic or organic acids, the particularly preferred salts clearly being those which are physiologically acceptable. Suitable acids for use in salt preparation include, for example, hydrochloric, hydrobromic, sulphuric, methylsulphuric, phosphoric, tartaric, fumaric, citric, maleic, succinic, gluconic, LlC i _1 i -L W -I i- -l malic, p-toluenesulphonic, methanesuiphonic and amidosuiphonic acid.

The following compounds may be mentioned as illustrative of the compounds according to the invention: 6,11-dihydro-ll-[[3-[3-(l-piperidinyl)propyl]-lpiperidinyl]-carbonylll-5H-pyrido[2,3-b][1,5]benzol1-[ (cyclopentylmnethylamino)ethyl]l--piperidinyl]carbonyl]-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin- 6,11-diliydro-ll-[[3-[3-(l-pyrrolidinyl)propyl]l-piperidinyllcarbonyll--5H-pyrido[2,3-b]II1,5]benzodiazepin- 6,11-dihydro-ll-[[3-[2-(hexahydro-lH-1-azepinyl)ethyl]- 1-piperidinyl]carbonyl]-5H-pyrido[2,3-b][l,5]benzodiazepin- 1-piperidinyl]carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin.- (+)-6,11-dihydro-11-[[3-[2-(1-piperidinyl)ethyl]l-piperidinyl]carbonyll-5H-pyridoj72,3-b][1,5llbenzodiazepin- (--)-6,1-dihydro-ll-[[3-[2-(l-piperidinyl)ethyl]- 1-piperidinyl]carbonyll-5H-pyrido[2,3-b][1,5]benzodiazepin- 1l-[[3-[2-(diethylamino)ethyll-l-piperidinyllcarbonylj- 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin- -6 6,11-dihydro-5H-pyrido[2,3-b1[1,5]belzodiazepinpiperidiny1Jcarbony1)-5H-pyrido[2,3Th1[1,5]belzodiazepi1- 6,11-dihydro-ll-[[3-[3-(4-morpholifl)propyll piperidinyllcarbonyl]-5H-pyrido[2,3-b][1,5]benzodiLazepin- (diethylamino) propyllmethylaminolmethyl]- 1-piperidinyllcarbonyl] 11-dihydro-5H-pyrido[ 2,3-b) [1,51 benzodiazepin-5-one-dihydrochlor ide; 00 01-piperidiny1]carbony11-6,11-dihydro-5H-pyrido[2,3-b1S> 6,11-dihydro-l1-[[3-[3-(1-piperidinyl)propyl] 1 l pyrrolidinyllcarb~ony1]-5H-pyrido[2,3-b][1,5]benzodiazepin- 4 0 1H-1-azepinyllcarbonyl]-5H-pyrido[2,3-b][1,5]belzodiazepin- It (cyclopentyl)ethylaminollethyl]-1-pyrrolidinYllcarbonyl]-6,11-dihydro-5H-pyrido[2,3-bl[1,Sllbenzodiazepin- -444 14 1 (cyclobutylmethyl)methylaminollethYll- 1-pyrrolidinyllcarbonyll-6,11-dihydro-5H-pyrido[2,3-blf[1,5]b 4 -7- 6,11-dihydro-l1-f[3-[4-(l-pyrrolidinyl)butyl]-1 pyrrolidinyllcarbonyl]-5H-pyrido[2,3-b(1,5]belzodiazepil 6,11-dihydro-11-[ (1-pyrrolidinyl)ethyl]-hexahydro- 1H-1-azepinyllcarbonyll-5H-pyrido[2,3-bI[1,5]benzodiazepin- 6,11-dihydro-l1-[[3-[2-(hexahydro-lH-1-azepinyl)ethyl]- 1-pyrrolidinyllcarbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin- 6 ,11-dihydro-11-[ (hexahydro-lH-1-azepinyl) ethyl.hexahydro-1H-l-azepinyllcarbonyl]-5H-pyrido[2,3-b]- [1,51benzodiazepin-5-one; ll-[[3-[2-(diethylamino)ethyll-1-pyrrolidinyilcarbonyl]- 6,11-dihydro-5H-pyrido[ 2,3-b] 1l-[[3-[2-(diethylamino)ethylllhexahydro-lH-1-azepinyl]- 4 carbonyl]-6,ll-dihydro-5H-pyrido[2,3-b]II1,5]benzodiazepin- 6,ll-dihydro-1l-[[3-[4-(dimethylamino)butyl]-lpiperidinyllcarbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepinl1-[[3-[2-(butylethylamino)ethyl]-l-piperidinyl]carbonyl]i-6,11-dihydro-5H-pyrido[2,3-bl,5]benzo- 6,ll-dihydro-ll-[[3-[3-(dipropylamino)propyl]-1piperidinyllcarbonyl]-5H-pyrido[2,3-b] -8 [3-[2-(dibutylamiio) ethyl] -1-piperidiriylcarbonyl]- 6,1l-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepil- 6,11-dihydro-11-[ (1-methyl-4-piperidinyl)methylaminolmethyl]-1-piperidinyl]carbonyl]-5H-pyrido[2,3-b]- 6,1l-dihydro-1l-[[2-[[ (1-methyl-4-piperidinyl)methylamino]methyl]-4-morpholinyllcarbonyll-5H-pyrido[2,3-b][1,51- 6,l1-dihydro-l1-f114-[3-(l-piperidinyl)propyl]-lpiperidinyl]carbonyl]-5H-pyridoll2,3-b][1,5]benzodiazepinll-[[4-[3-(diethylamino)propyl]-l-piperidinyl]carbonyl]- 6,l1-dihydro-5H-pyridol2,3-b][1,5]berizodiazepino015 0 00 900 ll-[[4-[4-(diethylamino)butyl]-l-piperidinyllcarbonyl]- 6,11-dihydro-5H-pyrido[2,3-bl,5]benzodiazepin- 5,1l-dihydro-ll-[[4-[3-(l-piperidinyl)propyl]-1- O '~<20piperidinyllcarbonyl]-6H-pyrido[2,3-bl,4]benzodiazepin- 6-one; 5,11-dihydro-ll-[[3-[3-(l-piperidinyl)propyl]-lpiperidinyllcarboriyl]-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one; piperidinyllcarbonyl]-6H-pyridoll2,3-b][1,4]benzodiazepin- 6-one; -9- (cyclopentyl)methylaminolethyll-1-piperidinyllcarbonyl]-5,11-dihydro-6H-pyridoII2,3-bl [1,4llbenzodiazepin- 6-one; 5,11-dihydro-11-[ [3-113- (l-pyrrolidinyl)propyll- 1-piperidinyl]carbonyll-6H-pyrido[2,3-bI11,4]benzodiazepin- 6-one; 11-dihydro-li- 4- (1-pyrrolidinyl) butyl] -1piperidinvllcarbonyl]-6H-pyrido[ 2,3-b] [1,4]benzodiazepin- 6-one; 5,i1-dihydro-11-[[3-[4-(1-pyrrolidinyl)butyl]-ipiperidinyllcarbonyl]-6H-pyrido[2,3-b][i,4ibenzodiazepin- 6-one; 5,1i-dihydro-11-[[3-[3-(1-pyrrolidinyl)propyl]hexahydro-lH-1-azepinyllcarbonyl]-6H-pyrido[2,3-b][1,4]- 915 benzodiazepin-6-one; (+)-5,i1-dihydro-ll-[[3-[2-(1-piperidinyl)ethyl]- 1-piperidinyl]carbonyl]-6H-pyrido[2,3-b][i,4llbenzodiazepin- 8 6-one; (-)-5,1i-dihydro-1i-[[3-[2-(i-piperidinyl)ethyl]- 1-piperidiny1]carbony1]-6H-,pyrido[2,3-b][1,4]benzodiazepin- 6-one; 5,1i-dihydro-11-[[3-112-(bexahydro-lH-1-azepinyl)ethyl]- 1-piperidinyllcarbonyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin- 6-one-methanesuiphonate; 11-[[3-[2-(diethylamino)ethylll-piperidinyllcarbonyl]- 5,11-dihydro-6H-pyrido[2,3-bl,4]benzodiazepin- 6-one; 10 11-[ (diethylaxnino)propyll-l-pipridiylIcarboflyl]- 5,11-dihydro-6H-pyrido[2,3-bII1,4]benzodiazepil- 6-one; l1-[[2-[3-(dietylamino)propylI-4-morpholiiylIcarboflyll- 5,11-dibydro-6H-pyrido[2,3-bI[1,4]berlzodiazepin- 6-one; 11-[[4-[3-(diethylamino)propyl]-l-piperidinyllcarbonyll- 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one; 8-chloro-5,11-dihydro-ll-[[3-[2-(1-piperidinyl)ethyl]- 1-piperidirylcarbonyl-6H-pyrido[2,3-bl1,4]benzodiazepin- 6-one; 9-chloro-5,11-dihydro-ll-[[3-[2-(1-piperidinyl)ethyl]- 1-piperidinyl]carbonyll-6H-pyrido[2,3-b][1,4llbenzodiazepin- 6-one; ~~**5,11-dihydro-8-methy'L-11-I[3-[2-(l-piperidiiyl)ethyl]i1-piperidiny1]carbony1]-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one; 5,11-dihydro-8-ethyl-ll-[[3-[2-(l-piperidinyl)ethyl]- 1-piperidiny1]carbony1II-6H-pyrido[2,3-b1[1,4]benzodiazepin- 6-one; 5,11-dihydro-9-methyl-l1-[[3-[2-(l-piperidinyl)ethyl]- 1-piperidinyllcarbonyllj-6H-pyrido[2,3-bl [1,4lbenzodiazepin- 6-one; 5,11-dihydro-'11-[[3-[3-(4-morpholinyl)propyl]-lpiperidinyljcarbonyl]-6H-pyridoll2,3-b][1,4]benzodiazepin- 6-one; 11 11-[ [[3-(diethylamino)propylmethyamiflmethyl>- 1-piperidinylcarbony11-5,11-dihydro-6Hpyrido[2,3b][1, 4 benzodiazepin-6-one-dihydrochloride; piperidinyllcarbonyl]-6H-pyrido[2,3b[1,4]belzodiazepil 6-one-hydrochloride; 5,11-dihydro-ll-[ (2-methylpropyl)methylaminollethYll- 1-piperidiny1]carbonyl]-6H-pyrido[2,3-b[1,4]belzodiazepin- 6-one-hydrochloride; 5,11-dihydro-1l-II[3-[2-[ (methylethyl)methylamiflethyi> 1-piperidiny1Icarbony1]-6H-pyrido[2,3-b[1,4]belzodiazepil 6-one; 0 carbonyl]-l1H-dibenzo[b,e][,4]diazepin1l-ne; 6-chloro-5,lO-dihydro-5-[[3[2-(1piperidilyl)ethyl>- 0 0 1-piperidiny1]carbonyl-11H-dibelzo[b,e][1,4dia.,epin- :.1:10 11-one; 0410014,9-dihydro-3-methyl-4-I[3-[2-(l-piperidinyl)ethyl>- 1-piperidiny1]carbonyl-l0H-thielo[3,4-b[1,5]belzodiazepincarbonyl]-1,4,9,10-tetrahydropyrro1o[3,2-b][1,5]benzodiazepin-lO-one; 3-chloro-1-methyl-4-[[3-[4-(l-piperidinyl)butyl]- 1-piperidinyllcarbonyl]-1,4,9,1O-tetrahydropyrrolo 3 2 -bP carbonyl]-l,4,9,l0-tetrahydropyrrolo[3,2-b][1,5]benzodi- -12 4-[[3-[3-(diethylamino)propy]--piperidilcarbor1y]- 1,3-dimethyl1l,4,9,1O-tetrahydropyrazo1o[4,3.b[,5]belzodiazepin-lO-one; Ii3-[3- (diethylamino) propyl] -1-piper idinyllcarbonyl] l1-methyl-1,4,9,1O-tetrahydropyrazo1O[4,3b][1,5belzodiazepin-lO-one; and 4-[[3-[3-(diethylamino)propyl--pipe'idiflyl]carbonyl]- 1-methyl-i 1O-tetrahydropyrazolo[ 4 ,3-elpyrido[ 3, 2-b] [1,4 ]diazepin-lO-one.

viewed from a further aspect, the present invention provides a process for the preparation of the compounds of the invention, said process comprising at least one of the following steps: (to produce compounds of formula Ia 3 H 0 R xi I R4 N (Ia) 0 A-Ne wherein R 1, R 2, R3 R 4 X 1 X 2 A'and Z are as hereinbefore defined and 30 represents a group or as hereinbefore defined or a group (TI) 13

CH

3 N3 R7' wherein R 7 is a chlorine atom or a methyl group) reacting a carbonic acid derivative of formula II R3 X H 0 R 1 X N-- Si4

R

Y 0 (wherein

R

3

R

4 3( X l and X 2 are as hereinbefore defined and Y represents a halogen atom, preferably bromine or chlorine, or a group OR wherein R represents an optionally halogen-substituted C 1 5 alkyl group, a phenyl group optionally substituted by halogen 10 atoms or nitro groups or a C7- 15 aralkyl group) with a compound of formula III

H

R

N

(III)

I -4-A-N -14 (wherein

R

1

R

2 A and Z are as hereinbefore defined) or a salt thereof; (to produce compounds of formula Ia as hereinbefore defined) reacting a tricyclic compound of formula

IV

i j N -I

(IV)

(wherein

R

3 y R 4 F x 1

X

2 and are as hereinbefore 4110 it.. defined) with a chlorocarbonic acid derivative of formula 00 V 0 \C 1 T t4 21 1 4 X1 3 71(b (weri

R

1 2 I 2 ,~lln---~~CI.-----lII-IIIl--Llllr~^L~ 15 (wherein R R R, X X and A are as hereinbefore defined, Z' represents a single bond, an oxygen atom or a methylene or 1,2-ethylene group, 7"

R

7 represents a hydrogen atom and 3' represents a C 4 alkyl group or a hydrogen atom) R represents a C1-4 alkyl group or a hydrogen atom) ot S 0 0 0 4414 0 4 4 0 0 4 0 4 0 0 4 4 0 4 01 t

I

hydrogenolysing a compound of formula Ib' 3' H CH 3 R 2 0 4x N i R

R

N O

R

1 (Ib') A N

R

2 1 2 3' 4 1 2 wherein R R R R 4 X X A and Z' are as hereinbefore defined and R represents a chlorine atom; converting a compound of formula I into an acid acid addition salt thereof or an acid addition salt of a compound of formula I into the free base; and separating a compound of formula I or salt thereof into the optical isomers thereof.

The reaction of step may be carried out without or preferably in the presence of solvents such as water, toluene or alcohols such as-methanol, ethanol or isopropanol, but preferably it is effected in the presence of aprotic polar solvents, e.g. tetrahydrofuran, 1,4-dioxan, AIT LL -i i 16 acetonitrile, N,N-dimethylformamide, dimethylsulphoxide, hexamethylphosphoric acid triamide, or mixtures thereof.

The reaction is conveniently effected at temperatures between -10°C and the boiling point of the reaction mixture, preferably between 40 and 100 0 C. It has proved satisfactory to use additional inorganic or organic bases, e.g. alkaline or alkaline-earth metal hydroxides, alkoxides or carbonates, e.g. sodium hydroxide, sodium methoxide, potassium tert. butoxide, sodium carbonate and potassium carbonate; tertiary amines, such as triethylamine, ethyl diisopropylamine, N,N-dimethylaniline, pyridine or 4-(dimethylamino)pyridine; it is also advantageous to carry out the reaction in the presence of an excess of a compound of formula III.

('15 If the amines of formula III and the carbonic acid 44 4 derivatives of formula II are used in equimolar f6 o amounts, provided that Y represents a halogen atom, the hydrohalic acid salts of the desired compounds of formula la are obtained directly.

4 4 0

O

out with a metal compound of formula IIla 4 44

M

N\

R

1 "A N R (IIIa) z R 2 wherein M represents an alkali metal atom or one equivalent of an alkaline earth metal atom. Metal compounds of formula IIIa may readily be prepared in situ from compounds of formula III by reacting with alkali or alkaline earth metals, e.g. sodium, potassium or barium, or with alkali or alkaline earth metal hydrides, e.g. sodium, potassium or calcium hydride, or by reacting with alkali or alkaline earth organo- 17 metallic compounds, e.g. with n-butyllithium or phenyllithium.

The reaction of step is preferably carried out in inert organic solvents, for example in aromatic hydrocarbons such as toluene or xylene, in ethers such as diisopropylether, tetrahydrofuran or dioxan, in ketones such as 3-pentanone, in chlorinated aliphatic hydrocarbons such as 1,2-dichloroethane or in other solvents such as acetonitrile or dimethylformamide or in mixtures thereof, optionally in the presence of tertiary organic bases such as pyridine and conveniently at temperatures up to the boiling point of the reaction mixture, preferably at temperatures of between +30 and +100 0

C.

l5 The hydrogenolysis of step is conveniently s carried out in the presence of catalysts of metals a0 of the VIIIth sub-group of the periodic table of elements, for example palladium on animal charcoal, ,oo palladium on barium sulphate, Raney nickel or Raney cobalt, and under hydrogen pressures of from 1 to 300 bar, preferably at temperatures of 0 C to 130 0 C, and conveniently in the presence of solvents, e.g. alcohols (such as methanol or ethanol), ethers (such as dioxan or tetrahydrofuran), carboxylic acids (for example acetic acid) or tertiary amines (for example triethylamine). If the prciess 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 obtained directly and may be isolated after removal of the catalyst by evaporation of the reaction solution. If in the above-mentioned hydrogenolysis reaction the hydrogen is replaced by formic acid, the reaction will in principle 18 18 take place even under unpressurised conditions.

In this variant, it has proved particularly useful to carry out the hydrogenolysis reaction of step 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 to carry out the 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 0

C.

Bases of formula I thus obtained may subsequently be converted into the acid addition salts thereof 15 or, if acid addition salts are obtained, they may be converted into the free bases or other pharmacologically acceptable acid addition salts.

In some instances the aminoacylated condensed diazepinones o, of formula I according to the invention contain an asymmetric carbon atom in the side chain. These compounds may therefore occur as enantiomeric and forms. The invention includes within its scope all such individual isomers and their racemates.

The separation of any racerates of the compounds of formula I may be carried out by known methods, for example using an optically active acid such as or tartaric acid or a derivative thereof such as or diacetyltartaric acid, or monomethyltartrate or camphorsulphonic acid.

According to a conventional method of isomer separation, the racemate of a compound of formula I is reacted in equimolar amounts with one of the above-mentioned I 19 optically active acids in a solvent and the crystalline diastereomeric salts obtained are separated by making use of their different solubilities. This reaction may be carried out in any type of solvent provided that it shows sufficient differences in solubility of the salts. Preferably, methanol, ethanol or mixtures thereof are used, e.g. in a ratio by volume of 50:50. Each of the diastereomeric salts is then dissolved in water, neutralised with a base such as sodium hydroxide or potassium hydroxide and in this way the corresponding free compound is obtained in the or form.

Only one enantiomer is obtained if the methods of synthesis described above are carried out with 15 only one enantiomer of formula III or V.

t4a& The carbonic acid derivatives of formula II used "o as intermediates are obtained, by methods analogous to those described in DE-A-32 04 169, DE-A-32 04 158 and DE-A-32 04 401, by reacting a tricyclic compound of formula IV

R

3 1 0 X N-

H

N I

(IV)

'R4 I (wherein R 3

R

4

X

1

X

2 and are as hereinbefore defined} with a halocarbonic acid derivative of formula VI Hal C Y (VI)

I

0 (wherein (wherein i. i- I W I- I--ccc-- 20 Hal represents a bromine or chlorine atom, preferably the chlorine atom, and Y is as hereinbefore defined).

The reaction is carried out in an inert organic solvent (for example aromatic hydrocarbons, such as toluene, chlorobenzene or xylene; open-chained or cyclic ethers such as diisopropylether, tetrahydrofuran or dioxan; open-chained or cyclic aliphatic ketones, for example 3-pentanone; chlorinated aliphatic hydrocarbons such as 1,2-dichloroethane; or other solvents such as acetonitrile or dimethylformamide) or in mixtures thereof and preferably in the presence of tertiary organic bases, especially preferably pyridine, and at temperatures up to, at most, the boiling point of the solvent or mixture of solvents used, preferably between +30 and +80 0

C.

o Intermediate compounds of formula III which have an alkylene group A interrupted in the 8-position relative to the saturated heterocycle by a heteroatom a o0 0"00 may be synthesised by methods analogous to the 2p0 methods discussed in detail in DE-A-36 26 095.

Intermediate compounds of formula III wherein Z represents a methylene group are conveniently prepared t from correspondingly substituted pyridines, for example by catalytic hydrogenation in ethanolic/hydrochloric acid solution and using platinum(IV) oxide as catalyst (see F.F. Blicke et al., J. Org. Chemistry 26, 3258 (1961)) or in glacial acetic acid and in the presence of platinum(IV)oxide (see W.F.

a Minor et al., J. Med. Pharm. Chem. 5, 96, 105 et seq. (1962) and A.H. Sommers et al., J. Amer.

Chem. Soc. 75, 57, 58 et seq. (1953)). The substituted pyridines may in turn easily be synthesised by methods familiar to those skilled in the art, e.g.

by the addition of corresponding secondary amines,

PC

I 5 i o P oP 6GQ Q o a D oe a PC iit a a t 5 I 25 21 dialkylaminoalkanols or dialkylaminoalkanethiols to vinyl pyridines, by reduction of s itable pyridine alkanoic acid amides with lithium aluminium hydride, by alkylation of picolines with dialkylaminoalkylhalides in the presence of lithium diisopropylamide or sodium amide (see A.E. Tschitschibabin, Bull.

Soc. Chim. France 1938, 436) or by reacting (omegahaloalkyl)-pyridines with dialkylaminoalkanols, dialkylaminoalkanethiols or secondary amines (see L. Rondahl, Acta Pharm. Suec. 13, 229-34 (1976)) or the metallised derivatives thereof.

A generally applicable method of synthesising amines of formula III consists of reducing suitable heterocyclically substituted alkane carboxylic acid dialkylamides which are optionally interrupted by heteroatoms in the alkylene group, for example using lithium aluminium hydride. Any protecting groups still present from the preliminary stages and occurring on the nitrogen function of the saturated heterocycle may subsequently be split off in the usual way; thus a benzyl group may, for example, be split off by hydrogenolysis in the presence of palladium/animal charcoal. For example, 5-oxo-2-pyrrolidine acetic acid Evans et al., J. Amer. Chem. Soc., 72, 2727 (1950)) may be reacted successively with thionyl chloride and a dialkylamine of interest and the resulting N,N-dialkyl-5-oxo-2-pyrrolidinoacetamide may subsequently be reduced with lithium aluminium hydride to yield the desired 2-[2-(dialkylamino)ethyl]pyrrolidine; or the 4-benzyl-3-(chloromethyl)morpholine hydrochloride obtainable from 4-benzyl- 3-(hydroxymethyl)-morpholine Brown et al., J. Chem. Soc. Perkin Trans. I 1985, 2577) by the action of thionyl chloride may be converted into (4-benzyl-3-morpholinyl)alkanoic acids by chain lengthening in the usual way and thus be used for the synthesis of 3-(dialkylaminoalkyl)morpholines.

a I t 1 t I t ta 30 t I Iaaa*3 C a P9 22 The tricyclic compounds of formula IV are known from the patent literature or may be synthesised from available starting materials by adhering closely to published methods.

Halocarbonic acid derivatives of formula VI are known.

The invention further relates to pharmaceutical compositions which contain one or more base substituted diazepinones of formula I or the physiologically acceptable salts thereof.

Thus 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.

4000 a o For this purpose, the compounds of formula I or salts thereof may be incorporated, for example in a known manner, in conventional pharmaceutical preparations, e.g. solutions, suppositories, tablets, coated tablets, capsules or infusions.

f 4 4 t 4 The compounds of formula I and the salts thereof have valuable properties; in particular, they have favourable effects on heart rate and, owing to their lack of mydriatic effects and inhibitory effects on gastric acid secretion and salivation, they are suitable for use as vagal pacemakers for treating bradycardia and bradyarrhythmia in human and veterinary medicine; some of the compounds also have spasmolytic properties on peripheral organs, particularly the colon and bladder.

-23- The daily dosage is generally between 0.01 and mg/kg, preferably 0.02 and 2.5 mg/kg, more particularly 0.05 and 1.0 mg/kg of body weight, preferably administered in the form of several, preferably 1 to 3, individual doses, to achieve the desired results.

Thus in a yet still further aspect the invention provides a method of treatment of the human or non-human animal body to combat bradycardia or bradyarrhythmia, which method comprises administering to said body a compound of formula I or a physiologically acceptable salt thereof.

In another aspect the invention also provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of 15 a therapeutic agent for use in a method of treatment of the human or non-human animal body to combat bradycardia or bradyarrhythmia.

S 60* 0 A favourable relation between tachycardiac effects on the one hand and on the other hand the undesirable effects on pupil size and the secretion of tears, 4 saliva and gastric acid which occur in therapeutic Sagents with an anticholinergic component is of particular importance in the therapeutic use of the compounds of the invention. The following tests show that the compounds according to the invention show surprisingly good relations of this SI kind.

S'A. 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 24 nerve endings. The following is a description of some methods used to detect cardioselective antimuscarinic agents.

"In vitro" organ preparations Dissociation constants (K B values) were determined "in vitro" on the ileum and spontaneously beating atrium of the guinea pig. The ileum was taken out and incubated in Krebs-Henseleit solution in an organ bath. Contractions were induced by increasing concentrations of methacholine so that total concentration/activity curves could be recorded.

Metacholine was then washed out, the test substance was added and kept in contact for 30 minutes and another concentration/activity curve was recorded 15 with metacholine.

0 a The dosage ratio i.e. the extent of displacement S° of the concentration/activity curve, was used to calculate the dissociation constant according to S'the method of Arunlakshana and Schild (Brit. J.

Pharmacol. 14, 48, 1959).

Metacholine had a concentration-dependent heart o rate reducing effect on the isolated, spontaneously beating, right atrium. This effect was cancelled out by the addition of an antimuscarinic. Dissociation constants for the muscarinic receptors of the atrium were obtained in the manner described above. Comparison of the dissociation constants obtained in two tissues made it possible to identify cardioselective substances. The results are presented in Table III below.

I-c- 25 "In vivo" methods The objective of these methods was to confirm the selectivity of the antimuscarinic effect. Those substances whi'h had been selected on the basis of "in vitro" tests 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 /M2 selectivity in the rat The method used was that described by Hammer and Giachetti (Life Sciences 31, 2991-2998 (1982)).

5 minutes after intravenous injection into male c THOM rats of increasing doses of the test substance, 4' "15 either the right vagus was electrically stimulated (frequency: 25 Hz; pulse width: 2ms; duration of stimulus: 30s; voltage: supramaximal) or 0.3 mg/kg of McN-A-343 were intravenously injected. The St bradycardia caused by vagus stimulation and the 1 20 rise in blood pressure caused by McN-A-343 were determined. The dosage of the test substances which reduced either the vagal bradycardia (M 2 or the rise in blood pressure (M 1 by 50% was determined graphically. The results are presented Table II below.

2. Salivation-inhibiting effect in the rat Using the method of Lavy and Mulder (Arch. int.

Pharmacodyn. 178, 437-445, (1969)) male THOM rats anaesthetised with 1.2 g/kg of urethane were given LC U 26 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 presented in Table II below.

3. Inhibition of the effect of acetylcholine on the bladder, bronchi and heart rate in guinea pigs minutes after the administration of the test substance, 10 microgram/kg of acetylcholine were simultaneously injected intravenously and intra- .15 arterially into anaesthetised guinea pigs. The heart rate was recorded directly by extracorporeal o derivation of the ECG, the expiration resistance o according to Konzett-R8l8er and contraction of 4. 0 the exposed bladder. In order to determine the :20 inhibition of the acetylcholine activity on the 4 4 4 organs under investigation, dosage/activity curves were recorded and from them -log ED 50 values were determined. The results are presented in Table V 4 ,below.

B. Studies of binding to muscarinic receptors: 1) In vitro: Measurement of the IC 50 value The organs were donated by male Sprague-Dawley rats weighing 180-220 g. After the heart and submandibular gland had been removed, all other steps were carried out in ice cold Hepes HCI buffer (pH 7.4; 100 mmolar NaCl, 10 mmolar MgC12). The whole -i i ii u i 27 heart was cut up with scissors. All the organs were then homogenised in a Potter apparatus.

For the binding test the homogenised organs were diluted as follows: Whole heart 1: 400 Submandibular gland 1: 400 The homogenised organs were incubated at a certain concentration of the radioligand and at a series of concentrations of the non-radioactive test substances in an Eppendorf centrifuge tube at 30 0 C. Incubation lasted 45 minutes. The radioligand used was 0.3 nmolar 3H-N-methylscopolamine (3H-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 H-NMS. The proportion of non-specific b binding was defined as the radioactivity which was bound in the presence of 1 micromolar quinuclidinylbenzylate. Each measurement was taken four times.

The IC 50 values of the non-labelled test substances n were determined graphically. They represent that 4' i concentration of test substance at which the specific binding of 3 H-NMS to the muscarinic receptors in the various organs was inhibited by 50%. The results are presented in Table 1 below.

S2) In vivo: Determination of ID 50 values For these experiments, female rats with a body weight of about 200 g were used. Before the start of the experiment the animals were anaesthetised with a dose of 1.25 g/kg of urethane. The animals were given the dosage of test substance by i.v.

i 28 injection. After 15 minutes, 113 ng/kg of 3-N methyiscopolamine 3 H-NMS) were given by the same route. After another 15 minutes the animals were killed and their heart, bronchi and lachrymal glands were taken out. These organs were dissolved in Soluene R and the radioactivity was measured.

These measurements were taken as representing total binding. The proportion of non-specific binding was defined as the radioactivity which could not be suppressed by the administration of 2 mg/kg of atropine. The ID 50 values for the individual organs were determined from these experiments.

The ID 50 values are the dosages of test substances which inhibited 50% of specific binding of 3

H-NMS

to the muscarinic receptors of the particular organs.

The results are presented in Table IV below.

The following exemplary compounds were investigated 0 as described above: 0 0 o A =5,11-dihydro-ll-[[3-[3-(1-piperidinyl)propyl]- ~.420 1-piperidinyllcarbonyl]-6H-pyrido[2,3-b][1,41benzodiazepin-6-one B =5,11-dihydro-l1-[[3-[3-(l-pyrrolidinyl)propyl]l-piperidinyl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one-hydrochloride C =5,l1-dihydro-ll-II[3-[2-(l-piperidinyl)ethyl]- 1 -piperidinyllcarbonyl]-6H-pyrido[2,3-b][1,4]benzodi azepi n-6 -one-methanesulphonate D =5,11-dihydro-ll-[[3-[2-(l-pyrrolidinyl)ethyl)- 1-piperidinyllcarbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one-hydrochloride 29 E (cycloperityl)methylamiiolethylj- 1-piperidinyllcarboriyl]-5,1l-dihydro-6H-pyridoli2,3-b]- 4]benzodiazepin-6-one-hydrochloride F 5,11-dihydro-1l-[113-[2-(hexahydro-1H-1-azepinyl)ethyl]-1-piperidinylllcarbonylj-6H-pyrido[2,3-b][l,4]benzodiazepin-6-one-hydrochlor ide G 6,1l-dihydro-11-[173-[2-(l-piperidinyl)ethyll- 1-piperidinyllcarbonyl]i-5H.-pyrido[2,3-bl1,5]benzoand as comparison substances X (diethylamino)methyllj-l-piperidinyllacetyl]- 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one (see US Patent No. 4 550 107) 00 Q15 Y =5,11-dihydro-ll-[(4-methyl-l-piperazinyl)acetylloff.

ot** 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (pirenze- :pine, see US Patent No. 3 660 380) and Z atropine.

The following Tables show the results found: 30 Table I Receptor binding tests in vitro: 4 4 I t 154 444t4A Substance

A

B

C

D

E

F

x y Receptor binding tests log IC 50 [nMla~eart Submandibular gland 8.70 7.70 8.00 7.40 8.52 7.52 8.22 7.30 8.52 7.52 8.52 7.52 8.40 7.40 6.82 5.30 5.82 6.70 8.40 8.40 Selectivity factor: ratio

IC

50 submandibular gland to IC 50 heart 4 8.3 33 0.13 1 Mr- i I 31 Table II M l/M 2 selectivity and salivation-inihibiting activity on the rat: Substance M 2 activity (rat)

ED

50 [mcg/kg] 1 .v.

M 1 activity Salivation Ratio of (rat) inhibition salivation

ED

50 [mcg/kgj (rat) inhibition i.v. ED 50 [mcg/kgj to 2 i.v. activity 44 4 4 44 4 40 4 444444 o 4 *4.40 4 40 44 4 4444 4 4 too.

44 4 I 4 4 I 44 44 4 44 4' 4 4 A 6.9 49 35 C 7.6 39 58 7.6 G 8.13 7.16 6.83 20.00 X 160 988 4215 26.3 Y 883 40 84 0.1 Z 4 16 9 2.2 32 Table III Dissociation constants values) on the ileum and spontaneously beating atrium in the guinea pig: K B [mol/1] Substance Heart ileum A 3.47 x l10 3.23 x x 1.05 x 1076.17 x 10-7 Y 2.4 x 10- 1.55 x 1- Z 1.41 x 10- 8.13 x 1-1 4 154 2044 Table IV Receptor binding tests, in vivo: Substance Atr iurn Heart Ventricle ID 50 [mg/kg] Bronchi Lachrymal glands Ratio of ID 50 in the lachrymal glands to ID 50 in the at r ium A 0.01 0.005 0.06 0.2 x 1.0 0.6 15.0 30.0 Y 5.0 1.0 10.0 10.0 2 Z 0.08 0.03 0.1 0.2 33 Table V Inhibition of acetylcholine activity on the bladder, bronchi and heart rate in the guinea pig: Results: 4 a0 10 9 0 *0 a0 Substance

A

B

C

D

E

F

G

-log ED 50 [Mol.kg 1 1 Heart Bronchi 7.06 6.93 7.18 7.06 7.37 7.38 7.32 7.49 7.09 7.01 7.79 7.40 7.83 7.58 Bladder 5.87 6.16 6.45 6.15 6.05 6.42 6.52 5.84 5.85 7.70 5.58 6.57 7.96 4.73 5.36 7.03 i 34 The information shown in Table I above shows that the new compounds of formula I distinguish between muscarinic receptors in different tissues. This is clear from the substantially lower IC 50 values when the test substances are investigated on preparations from the heart compared with those from the submandibular gland.

The pharmacological data in Table II above show in total agreement with the receptor binding studies that the heart rate is increased by the abovementioned compounds even at dosages at which there is no restriction in the secretion of saliva.

The ratio of the ED 50 in salivation inhibition to the ED 50 of the M 2 activity shows a sufficient safety gap from the side effect of dryness of the mouth for compounds A to G. This demonstrates tot that substances A to G, whilst having increased °effectiveness (cf. Table IV), show adequate, therapeutically useful selectivity comparable with that 4 420 of substance X.

t 4 4 Moreover, the pharmacological data in Table III above indicate a surprisingly high power of distinction between the heart and smooth muscle. A is significantly more effective than X and Y, and a clear selectivity in favour of the heart is apparent and compound A has significant advantages of efficacy over X and Y. Atropine (compound Z) is a known non-selective anti-muscarinic and under these model conditions it shows an inverse selectivity ratio.

The compounds mentioned are resorbed extremely well since they have a low dosage ratio p.o. to i.v. The smaller the ratio of ED 50 p.o. to ED 50 the better the resorption of the active substance.

35 Table IV shows the preferential binding to receptors of the heart (atrium/ventricle). Substance A shows a significant improvement in potency compared with substances X and Y on the heart. This is an important therapeutic advantage in the provision of a vagal pacemaker. This increase in effectiveness is achieved while retaining the useful selectivity gap from the effects on the exocrine glands, as is clear from the ratio of the ID 50 values on the lachrymal glands to the ID 50 values on the atrium. Atropine (compound Z) on the other hand is not selective.

Moreover, the compounds of the invention are well tolerated; even in the highest doses administered, no toxic side effects were observed in the pharmacological trials.

f it All the substances of formula I are characterised .0 by exceptional resistance to hydrolysis. Consequently, it is possible to produce solutions for parenteral administration which will withstand long storage.

20 The non-limiting Examples which follow are provided to illustrate further the present invention: indicates "melting point", indicates "decomposition". Satisfactory elemental analyses by IR, UV, 1 H-NMR and in many cases mass spectrometry have been obtained for all the compounds. Unless otherwise expressly stated, the percentages, ratios and parts are by weight.

ile I 36 Example 1 5,11-Dihydro-ll-[[3-[3-(l-piperidinyl)propyllpiperidinyl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one A solution of 2.00 g (9.51 mmol) of 3-[3-(1-piperidinyl)propyl]piperidine in 10 ml of dimethylformamide is added dropwise at ambient temperature and with stirring to a suspension of 2.6 g (9.50 mmol) of 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one in 30 ml of dimethylformamide.

The initially clear solution becomes cloudy within «o O a few minutes. After half an hours' stirring at 0 0 C ambient temperature the colourless solid was removed 900000 S0 by suction filtering and was washed thoroughly 0090 0 a 1 5 three times with 3 ml of ice cold ethanol. The cooa S0ooo° colourless monohydrochloride of the desired compound 0 o 1 obtained, m.p. greater than 260°C, was dissolved in 10 ml of water, a saturated aqueous potassium carbonate solution was added until an obvious alkaline 0 .o.20 reaction occurred and the mixture was then filtered.

The solid material obtained was thoroughly washed with water and then dried in a vacuum dryer at o* 50 0 C and over di-phosphorous pentoxide. 3.0 g (71% of theory) of the desired 5,11-dihydro-ll- [[3-[3-(l-piperidinyl)propyl]-l-piperidinyl]carbonyl]- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one were obtained, "00' m.p. 123-125 0 C, Rf 0.41 (Merck DC ready made plates, silica gel 60 F 254 eluant: dichloromethane/methanol/ aqueous conc. ammonia 90/10/1, v/v/v) To convert it into the hydrochloride, 500 mg of the base were dissolved in a mixture of 70 ml of ethyl acetate and 3 ml of ethanol and 1.12 ml of an ethereal 1-molar hydrogen chloride solution was added. The precipitate obtained was dissolved 37 in a mixture of 50 ml of methanol and 2 ml of water, then evaporated down in vacuo to a total' volume of 10 ml, and 30 ml of acetone were added. After trituration, colourless crystals were obtained which were dried and melted at above 260 0 C. The solubility in water was about 0.2%.

C

26

H

34 C1N 5 0 2 (484.04) Calc: C 64.52 H 7.08 Cl 7.32 N 14.47 Found: 63.99 7.13 7.21 14.35 300 mg of 5,1l-dihydro-1l-[[3-[3-(1-piperidinyl)propyl]1-l-piperidinyllcarbonyl-6f-pyrido[2,3-bI[1,41benzodiazepin-6-one were analogously dissolved in 100 ml of warm ethyl acetate and converted into the corresponding salt by treating with 60 mg of methanesuiphonic acid. Col-ourless crystals, m.p.

0 183-187*C, readily soluble in water.

4,C 26

H

33

N

5 0 2

CH

3 SO 3 H (543.68) 0Calc: C 59.65 H 6. 86 N 12.88 S 5.90 Found: 59.42 6.75 12.33 5.91 The salt with N-cyclohexylsulphamidic acid melted at 204-208*C and was soluble in water, to about 1%.

C

32

H

46

N

6 0 5 S (611.80) Calc: C 61.32 H 7.40 N 13.41 S 5.11 Found: 60.83 7.44 13.08 5.16 Example 2 ll-[[2-[2-(Diethvlamino)ethvl]-l-piperidinyllcarbonyll- 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one Prepared analogously to Example 1 from l1-(chlorocarbonyl) l1-dihydro-6H-pyrido[ 2,3-b] [1,4 Jbenzodiazepin- 38 6-one and 2-[2-(diethylamino)ethyllpiperidine in a yield of 37% of theory. Colourless crystals, m.p. 100 0 C (from acetonitrile), R f 0.*25 (Macherey- Nagel, Polygram SIL G/UV 254 pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/ cyclohexane/methanol/conc. ammonia 57/25/8/8/1, v/V/v/v/v) C 24

H

31 N 5 0 2 (421.54) Calc: C 68.38 H 7.41 N 16.61 Found: 68.18 7.47 16.80 Example 3 11-Dihydro-ll- 2- (dimethylamino) ethyl] -1piperidinyllcarbonyl]-6H-pyrido[2,3-bH1,4]bezodiazepinl- 6-one Prepared analogously to Example 1 from 11-(chlorocar- 4 bonyl)-5,1l-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one and 2-[2-(dimethylamino)ethylilpiperidine in a yield of 37% of theory. Colourless crystals, 188-190*C (from acetonitrile), R f 0.6 (Macherey- Nagel, Polygram SIL G/UV 254 pre-coated plastic sheets for TLC; eluant: dichloromethane/cyclohexane/ methanol/conc. ammonia 68/15/15/2, v/v/v/v) C 22

H

27 N 5 0 2 (393.49) Calc: C 67.15 H 6.92 N 17.80 Found: 66.97 6.63 17.83 Example 4 l1-[[2-[4-(Diethylamino)butylji-l-piperidinyllcarbonyllll-dihydro-6H-pyrido[ 2,3-b] [1,4 ]benzodiazepin- 6-one A mixture of 4.5 g (0.0164 mol) of 1l-(chlorocarbonyl)- 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepingCpLI 39 6-one, 2.2 g (0.02 mol) of anhydrous sodium carbonate, 4.3 g (0.0202 mol) of 2-[4-(diethylamino)butyl]piperidine and 100 ml of acetonitrile was refluxed for 1 hour with stirring. Then the solvent was distilled off in vacuo, the highly viscous residue remaining was taken up in 30 ml of water, made alkaline with sodium hydroxide and extracted exhaustively with dichloromethane. The combined dichloromethane phases were dried over sodium sulphate and evaporated down, the residue was purified chromatographically on silica gel (35-70 mesh) using dichloromethane/ethyl acetate/cyclohexane/methanol/conc. ammonia 58/25/8/8/1, v/v/v/v/v, as eluant. 4.0 g (56% of theory) of a colourless resin were obtained, which could not be crystallised.

C

26

H

35

N

5 0 2 (449.59) Calc: C 69.46 H 7.85 N 15.58 Found: 69.42 7.96 15.51 The water soluble dihydrochloride melted at 174-175 0 C

C

26

H

37 C1 2

N

5 0 2 (522.51) S* Calc: C 59.77 H 7.14 Cl 13.57 N 13.40 Found: 60.13 7.07 13.50 13.45 44' Example 5,11-Dihydro-ll-[[2-[4-(dimethylamino)butyllpiperidinyl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one and 2-[4-(dimethylamino)butyl]piperidine in a yield of 55% of theory. Colourless crystals, m.p. 145-147 0 C (from ethyl acetate), Rf 0.1 (Macherey- Nagel, Polygram

R

SIL G/UV 254 pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/ Li I cyclohexane/methanol'coflc. ammonia 58/25/8/8/1, V/v/v/v/v) C 24

H

31

N

5 0 2 (421.54) Caic: C 68.38 H 7.4 N 16.61 Found: 68.40 7.53 16.45 Example_6 5,11-dihydro-6H-pyridol2,3-b][1,4]belzodiazepil- 6-one Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-bI[1,4]benzodiazepin- 6-one and 2-[3-(dIiethylamino)propylllpiperidine in a yield of 70% of theory. Colourless crystals, m.p. 125-128*C (ethyl acetate), Rf 0.15 (Macherey- Nagel, Polygram(R SIL G/UV 254 pre-coated plastic sheets for TLC; eluant: dichloromethane/ethyl acetate/ cyclohexane/methanol/conc. ammonia 58/25/8/8/1,

C

2 H 33

N

5 0 2 (435.57) Calc: C 68.94 H 7.64 N 16.08 P'ound: 69.00 7.66 15.90 5,11-Dihydro-ll-1112-[3-(dimethylamino)propyl]-lpiperidinylllcarbonyl]-6H-pyrido[2,3-bl[1,4]benzodiazepin- 6-one Prepared analogously to Example 4 from 11- (chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b111,4]benzodiazepin- 6-one~ and 2-[3-(dimethylamino)propyllpiperidine in a yield of 51% of theory. Colourless crystals, m.p. 142-144*C (from acetone and ethyl acetate), R f0.7 (Macherey-Nagel,.Polygram ()SIL /V24 41 pre-coated plastic sheets for TLC; eluant: dichioromethane/cyclohexane/methanol/coic. ammonia 68/15/15/2, v/v/v/V) C 23 H 29 N 5 0 2 (407.51) Calculated: C 67.79 H 7.17 N 17.19 Found: 67.80 7.27 16.99 Example 8 5,11-Dihydro-ll-[[4-[2-(l-piperidinyl)ethyll-lpiperidinyllcarbonyll-6H-pyrido[2,3-b][1,4]benzodiazepin- .6-one Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-bl[1,4]benzodiazepin- 6-one and 4-[2-(1-piperidinyl)ethyllpiperidine in a yield of 47% of theory. Colourless crystals, 0:0:15 m.p. 178-180 0

C.

0000::Example 9 ,11-Dihydro-11-[ (l-methyl-4-piperidinyl) -1piperidinyllcarbonyl]-6H-pyrido[2,3-bI[1,4]benzodiazepin- 4 Et 6-one-hydrochloride Prepared analogously to Example 4 from ll-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-- 6-one and 4-(l-methyl-4-piperidinyl)piperidine in a yield of 21% of theory. Colourless crystals, m.p. 254-255 0

C.

Example 5,11-Dihydro-ll-[[2-[2-[[l-(phenylmethyl)-4-piperidinyl]methylaminolethyl] -l-pyrrolidinylicarbonyl] -6Hpyrido[2,3-blil,4]benzodiazepin-6-one 42 Prepared analogously to Example 1 from 11- (chiorocarbonyly)-5,1l-dihydro6H-pyrido[2,3-b[1,4]benzodiazepin- 6-one and [1-(phenylmethyl) -4-piperidinyllmethylaminolethyllpyrrolidile in a yield of 13% of theory.

Amorphous resinous colourless substance, Rf 0.06 (Merck DC ready made TLC plates, silica gel

F

254 eluant: dichloromethane/methanol/conc. ammonia 90/10/1, V/v/v)

C

32

H

38

N

6 0 2 (538.69) Caic: C 71.35 H 7.11 N 15.60 Found: 70.80 7.34 15.31 Example 11 5,11-Dihydro-ll-[[4-13-(l-piperidinyl)propylI-l- Piperidinyllcarbonyllj-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one Prepared analogously to Example 4 from 11- (chlorocarbonyl) -5 ,11-dihydro-6H-pyrido[ 2, 3-b][11,4 ]benzodiazepin- 9 6-one and 4-[3-(1-piperidinyl)propylllpiperidine 99 in a yield of 81% of theory. Colourless crystals, m.p. 200 0

C.

Example 12 99 ll-[[3-[3-(Diethylamino)propyl]-l-piperidinylcarbonllP 5,11-dihydro-6H-pyridoll2,3-bI[1,4]benzodiazepin- 6-one-hydrochloride

I

125 Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,l1-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one and 3-13-(diethylamino)propyllpiperidine in a yield of 84% of theory. Colourless crystals, m.p. 257-258 0 C (ethanol/diisopropylether)

C

25

H

34 C1N 5 0 2 (472.03) Calc: C 63.61 H 7.26 Cl 7.51 N 14.84.

Found: 64.00 7.35 7.44 14.88 -43 Example 13 5,11-Dihydro-ll-[[3-[3-(dimethylamino)propyl]-lpiperidinyllcarbonyl]-6H-pyrido[2,3-b[1,4]benzodiazepil- 6-one-hydrochloride Prepared analogously to Example 1 from 11-(chlorocarbonyl) 11-dihydro-6H-pyrido[ 2,3-b] [1,4 ]benzodiazepin- 6-one and 3-[3-(dimethylamino)propyllpiperidine in a yield of 71% of theory. Colourless crystals, of the base m.p. 115-117*C (ethanol/ether 1:30, Rf 0.35 (Merck DC ready made TLC plates, silica gel

F

2 4 eluant: dichloromethane/methanol/conc. ammonia 90/10/1, v/v/v) The monohydrochioride melted at 222-224 0

C.

C 23

H

30 ClN 5 0 2 (443.98) Calc: C 62.22 H 6.81 Cl 7.99 N 15.77 *Found: 62.00 7.07 7.79 15.58 o Example 14 *00 piperidinyllcarbonyl]-6H-pyrido[2,3-bl,4]benzodiazepin- 6-one-hydrochloride 0 a 4 Prepared analogously to Example 1 from 11- (chiorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-bII[1,4]benzodiazepino00 6-one and 3-[3-(4-morpholinyl)propyllpiperidine in a yield of 61% of theory. Colourless crystals, m.p. greater than 260 0 C (from ethanol/water/acetone).

C

25 H 32 C1N 5 0 3 (486.01) Calc: C 61.78 H 6.64 Cl 7.29 N 14.41 Found: 61.41 6.68 7.26 14.18 -44 Example .1-Dihdro-ll-[[3-113- (hexahydro-1H-1-azepinyl) propyl] 1-piperidintyllcarbonyl]-6H-pyridol2,3-b][1,4]benzodiazepin-6-one hydrochloride Prepared analogously to Example 1 from 11- (chiorocarbonyl)-5,ll-dihydro-6H-pyrido[2,3-bI11,4]benzodiazepin- 6-one and (hexahydro-1H-1-azepinyl) propyllpiperidine in a yield of 60% of theory. Colourless crystals, m.p. greater than 260 0 C, Rf 0.4 (Merck, DC ready made TLC plates, silica gel 60 F 254 eluant: dichloromethane/methanol/conc. ammonia 90/10/1, v/v/v) C 27

H

36 C1N 5 0 2 (498'.07) Calc: C 65.11 H 7.28 Cl 7.12 N 14.06 Found: 65.51 7.21 7.18 13.92 09 0:0:15 Example 16 9000 5,11-Dihydro-ll-[[3-[3-(l-pyrrolidinyl)propyl]- 040 1-piperidinyllcarbonyl]-6H-pyrido[2,3-bIJ[1,4]benzodiazepin- 6-one-hydrochloride Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one and 3-[3-(1-pyrrolidinyl)propyllpiperidine .4 in a yield of 56% of theory. Colourless crystals, m.p. greater than 260*C (from water/acetone), water solubility: about 0.3%.

C 25

H

32 C1N 5 0 2 (470.01) Calc: C 63.89 H 6.86 Cl 7.54 N 14.90 Found: 63.90 6.92 7.25 14.86 Example 17 5,11-Dihydro-ll-[[2-[4-(l1-piperidinyl)butyl]-lpiperidinyllcarbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one Prepared analogously to Example 4 from 11- (chiorocarbonyl)-5,1l-dihydro-6H-pyrido[2,3-blil,4]benzodiazepin- 6-one and 2-[4-(1-piperidinyl)butyllpiperidine in a yield of 41% of theory. Colourless crystals, m.p. 199-201*C (after being recrystallised twice from ethanol using animal charcoal).

C

27

H

35

N

5 0 2 (461.61) Calc: C 70.25 H 7.64 N 15.17 Found- 70.07 7.58 15.02 Example 18 5,11-Dihydro-].l-[[3-[2-(dipropylamino)ethyll-lpiperidinyllcarbonyll-6H-pyridoll2,3-b][1,4]benzodiazepin- 6-one-hydrochloride Prepared analogously to Example 1 from (chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b3111 1 4lbenzodiazepin- *0'20 6-one and 3-[2-(dipropylamino)ethyllpiperidine in a yield of 67% of theory. Colourless crystals, o~ m.p. 202-205 0 C (ethanol).

C

26

H

36 C1N 5 0 2 (486.06) Calc: C 64.25 H 7.46 Cl 7.29 N 14.41 00 O 25 Found: 64.00 7.39 7.41 14.25 Example 19 5,11-Dihydro-ll-[[3-[4-(dimethylamino)butyl]-lpiperidinyljcarbonyll-6H-pyrido[2,3-bl[1,4]benzodiazepin- 6-one-hydrochloride 46 Prepared analogously to Example 1 from 11- (chiorocarbonyl) -5 ,ll-dihydro-6H-pyrido[ 2,3-b] [1,4 ]benzodiazepin- 6-one and 4- (dimethylamino) butyllpiperidine in a yield of 69% of theory. Colourless crystals, m.p. 234-235 0 C (isopropanol).

C 24

H

32 C1N 5 0 2 (458.0) Calc: C 62.94 H 7.04 Cl 7.74 N 15.29 round: 63.03 6.90 7.90 14.89 Example 5,11-Dihydro-ll-[[3-[14-(l-pyrrolidinyl)butyll-lpiperidinyllcarbonyll-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin- *saw 01 6-one and 3-[4-(l-pyrrolidinyl)butyllpiperidine in a yield of 50% of theory. Colourless crystals, m.p. 153-156 0 C (ethyl acetate/diethylether 1/1, Rf 0.25 (Merck DC ready made TLC plates, silica gel 60 F 254 eluant: dichloromethane/methanol/conc.

ammonia 90/10/1, v/v/v).

C' H 33 N 0 (447.58) 26 3354 4. Calc: C 69.77 H 7.43 N 15.65 Found: 69.72' 7.27 15.25 Example 21 6l-Dihydro-ll-[[3-113-(l-piperidinyl)propyl]-lpiperidinyllcarbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin- Prepared analogously to Example 4 from ll-(chlorocarbonyl)-6,ll-dihydro-5H-pyrido[2,3-b][l,5]benzodiazepin- 5-one and 3-[3-(l-piperidinyl)propyllpiperidine in a yield of 58% of theory. Colourless crystals, m.p. 165.5-167.0 0 C (acetonitrile).

I

-47 C 26

H

33

N

5 0 2 (447.58) Caic: C 69.77 H 7.43 N 15.65 Found: 69.65 7.44 15.50 Example 22 (Cyclopentyl)methylaminlethyl]-l-piperidilvl]carbonyl1-6,11-dihydro-5H-pyrido[2,3-b]1,5]belzodiazepil- Prepared analogously to Example 4 from 11- (chiorocarbonyl)-6,ll-dihydro-5H-pyrido[2,3-b[,5]belzodiazepil- 5-one and (cyclopentyl)metbylaminolethyllpiperidine in a yield of 61% of theory. Colourless crystals, m.p. 148-150 0 C (acetonitrile).

C 26 H 33 N 5 0 2 (447.58) *Calc: C 69.77 H 7.43 N 15.65 %&000: 15 Found: 69.75 7.55 15.76 Example 23 5,11-Dihydro-ll-t113-[2-(l-piperidinyl)ethyl]-lpiperidinyllcarbonyllj-6H-pyrido[2,3-b ][1,41benzodiazepin- 044 6-one-methanesulphonate Prepared analogously to Example 1 from 11- (chlorocarbonyl)-5,ll-dihydro-6H-pyrido(2,3-bH[1,4]benzodiazepin- 6-one and 3-r2-(1-piperidinyl)ethyllpiperidine in a yield of 66% of theory. Colourless crystals, m.p. 231-234 0 C (ethanol).

C

2 6

H

35

N

5 0 5 S (529.65) Calc: C 58.96 H 6.66 N 13.22 S 6.05 Found: 58.84 6.69 13.07 6.26 48 Example 24 ll-[[3-[4-(Diethylamino)butyll-l-piperidinyllcarbonyl]- 5,1l-dihydro-6H-pyrido[2,3-b[l,4lbenzodiazepin- 6-one-hydrochloride Prepared analogously to Example 1 from 11- (chlorocarbonyl) 11-dihydro-6H-pyrido[ 2,3-b] benzodiazepin- 6-one and 3-[4-(diethylamino)butyllpiperidine in a yield of 90% of theory. Colourless crystals, m.p. 182-184 0 C (ethanol).

C

26

H

36 C1N 5 0 2 (486.06) Calc: C 64.25 H 7.46 Cl 7.29 N 14.41 Found: 63.80 7.62 7.35 13.49 Example l-piperidinyllcarbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin- "0 J906-one Q ,0 0 .0 Prepared analogously to Example 1 from 9-chloro- 11- (chlorocarbonyl) 11-dihydro-6H-pyr ido[ 2,3-b] 0 00-benzodiazepin-6-one and 3-[2-(1-pyrrolidinyl)ethyl]- 020 piperidine in a yield of 42% of theory. Colourless crystals, m.p. 136-139 0 C, R f 0.25 (Merck DC ready made TLC plates, silica gel 60 F 254 eluant: dichloromethane/methanol/conc. ammonia 90/10/1, v/v/v).

C

24 H 28 C1N 5 0 2 (453.97) 0 n Calc: C 63.50 H 6.22 Cl 7.81 N 15.43 Found: 63.41 6.43 7.70 15.52 Example 26 5,11-Dihydro-ll-[ [3-[2,-(methylethylmethylamino) ethyl]- 1-piperidinyllcarbonyl] -6H-pyrido[ 2,3-b] [1,4 ]benzodiazepin- .6-one-hydrochloride 49 Prepared analogously to Example 1 from 11- (chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-bl[1,4]belzodiazepil 6-one and 2- (methylethylmethylamino) ethylipiperidine in a yield of 38% of theory. Colourless crystals, m.p. 196-198*C Rf 0.21 (Merck DC ready made TLC plates, silica gel 60 F 254 eluant: dichloromethane/ methanol/conc. ammonia 90/10/1, v/v/v).

C 25

H

34 C1N 5 0 2 (472.03) Caic: C 63.61 H 7.26 Cl 7.51 N 14.84 Found: 63.55 7.37 7.61 14.61 Example 27 5,1l-dihydro-6H-pyrido[2,3-b][1,4]benzodiazep2in- 6-one Prepared analogously to Example 4 from 11- (chlorocarboniyl)-5,1l-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin- 4040 6-one and 4-[2-(diethylamino)ethyllpiperidine in a yield of 34% of theory. Colourless crystals, m.p. 1.54*C (ethyl acetate).

4,",20 Example 28 5,11-Dihydro-ll-[[3-[2-(l-pyrrolidinyl)ethyl]-lpiperidinyl]carbonyll-6H-pyrido[2,3-blI[l,4]benzodiazepin- 6-one-hydrochloride Prepared analogously to Example 1 from 11- (chlorocarbonyl)-5,11-dihydro-6H-pyrido(2,3-bII[1,4]benzodiazepin- 6-one and 3-[2-(1-pyrrolidinyl)ethyl]piperidine in a yield of 58% of theory. Colourless crystals, R f0.25 (Merck DC ready made TLC plates, silica gel 60 F 254 eluant: dichloromethane/methanol/conc.

ammonia 90/10/1, v/v/v).

C 24

H

30 C1N 5 0 2 (455.99) 50 Caic: C 63.22 H 6.63 Cl 7.78 N 15.36 Found: 63.10 6.76 7.63 15.21 Example 29 ll-r[3-r2-[ (Cyclopentyl)methylaininolethyl]-l-piperidinyljcarbonyll-5,11-dihydro-6H--pyrido[2,3-b3171,4]benzodiazepin- 6-one-hydrochloride Prepared analogously to Example 1 from 11- (chiorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-bI[l,4]benzodiazepin- 6-one and 3-[2-r (cyclopentyl)methylaminolethyl]piperidine in a yield of 54% of theory. Colourless crystals, m.p. 244-246*C (ethanol), R f 0.31 (Merck DC ready made TLC plates, silica gel 60 F254 eluant: dichloromethane/methanol/conc. ammonia 90/10/1, v/v/v).

C C 26

H

34 C1N 5 0 2 (484.04) Calc: C 64.52 H 7.08 Cl 7.32 N 14.47 Found: 64.33 7.11 7.53 14.39 0 0 Example A,--Dihydro-ll-[[3-[2-(hexahydro-lH-1-azepinyl)ethyl]- 1-piperidinyllcarbonylI-6H-pyrido[2,3-b][1,4]benzodiazepin- 0 20 6-one-hydrochloride Prepared analogously to Example 1 from 11- (chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3bl[,4]benzodiazepin- 6-one and (hexahydro-11H-l-azepinyl) ethylipiperidine in a yield of 78% of theory. Colourless crystals, m.p. 255-257*C (ethanol/water/acetone 45/5/50, R f 0.27 (Merck DC ready made TLC plates, silica gel 60 F 54 eluant: dichloromethane/methanol/conc.

ammonia 90/10/1, v/v/v).

C 26 H 34 CINO (484.04) Calc: C 64.52 H 7.08 Cl 7.32 N 14.47 Found: 64.39 7.17 7.50 14.29 ,I 11 -51 Example 31 l1-Dihydro-ll-[ (methylethylethylamrino) ethyl]l-piperidinyllcarbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one hydrochloride Prepared analogously to Example 1 from 11- (chiorocarbonyl) 1l-dihydro-6H-pyrido[ 2,3-b] benzodiazepin- 6-one and 3-112- (methylethylethylamino) ethylipiperidine in a yield of 43% of theory. Colourless crystals, m.p. 228-230 0 C, R f 0.39 (Merck DC ready made TLC plates, silica gel 60 F 2 5 4 eluant: dichloromethane/ methanol/conc. ammonia 90/10/1, v/v/v).

C 25

H

34 C1N 5 0 2 (472.03) Calc: C 63.61 H 7.26 Cl 7.51 N 14.84 Found: 63.27 7.40 7.81 14.80 Example 32 04 1-piperidinyllcarbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin- I Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepinand 3-[3-(l-pyrrolidinyl)propyllpiperidine in a yield of 56% of theory. Colourless crystals, M.P. 174-176*C (acetonitrile), R f 0.65 (Macherey-Nagel, Polygram ()SIL G/UV 254 1 pre-coated plastic sheets for TLC; eluant: dichloromethane/cyclohexane/methanol/ conc. ammonia 68/15/15/2, v/v/v,/v) C 25

H

31 N 5 0 2 (433.55) Calc: C 69.26 H 7.21 N 16.15 Found: 69.20 7.19 16.45 52 Example_33 6,11-Dihydro-11-[[3-[2-(hexahydro-lH-1-azepinyl)ethyl]- 1- iperidinvl]carbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin- S3-one Prepared analogously to Example 4 from 11- (chiorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][l,5]benzodiazepinand (hexahydro-1H-l-azepinyl)ethyl]piperidine in a yield of 58% of theory. Colourless crystals, m.p. 152-154 0 C (acetonitrile), R f 0.64 (Macherey- Nagel, Polygram ()SIL G/UV 254 pre-coated plastic sheets for TLC; eluant: dichioromethane/cyclohexane/ methanol/conc. ammonia 68/15/15/2, v/v/v/v) C 26

H

33

N

5 0 2 (447.58) Calc: C 69.77 H 7.43 N 15.65 Found: 69.74 7.51 15.64 0 0 0 Example 34 4. 6,11-Dihydro-ll-Ii[4-[4-(1-Pyrrolidinyl)butvl]-lpiperidinyljcarbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin- 4 Prepared analogously to Example 4 f rom 11- (chiorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepinand 4-14-(-pyrrolidinyl)butyllpiperidine in a yield of 72% of theory. Colourless crystals, m.p. 193-195*C (ethanol).

C

26

H

33 N 5 0 2 (447.58) Calc: C 69.77 H 7.43 N 15.65 Found: 69.97 7.45 15.78 53 Example 4-[[3-[3-(DiethylaminlO)propyl]-l-Pi~eridinllcarbonll- Prepared analogously to Example 4 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]belzoand 3-[3-(diethylamino)propyllpiper.idine in a yield of 34% of theory. Colourless crystals, m.p. 136.0-137.5 0 C (diisopropylether).

JO0 Exam le 36 4,9-Dihydro-4-[[3-II3-(dimethylamino)propyl]--1-piperidinyl]t carbonyl]-3-methyl-10B-thienoll3,4-bl[1,5]benzodiazepintoo. Prepared analogously to Exampl.e 4 from 4-(chlorocarboiy)-4,9-dihydro3-methyl-10H-thieno[3,4-b][1,5]bflzodiazepin-lO-one and 3-[3-(dimethylamino)propyllpiperidile in a yield of 35% of theory. Colourless crystals, m.p. 137-139 0 C (acetonitrile).

C

23

H

30 N0 S (426.58) Calc: C 64.76 H 7.09 N 13.13 S 7.52 Found: 64.77 7.25 13.07 7.75 Example 37 6,11-Dihydro-ll-[[3-[3-(l-p2iperidinyl)propyV1]-lpiperidinyllcarbonyl]-5H-pyrido[2,3-b111,5]benzodiazepin- 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, 8.94 g (0.0425 mol) of 3-[3-(l-piperidinyl)propyl]i 54 piperidine were added dropwise with external cooling with ice. The mixture was stirred for a further minutes at ambient temperature, then 9.0 g (0.0428 mol) of 6,11-dihydro-5H-pyrido[2,3-b][1,ijbenzodiazepin- 5-one were added to the reaction mixture and this was then refluxed for 4 hours. The boiling hot mixture was filtered, the precipitate was thoroughly washed with three times 10 ml of hot acetonitrile and the combined filtrates were evaporated down in vacuo to a total volume of 50 ml. This was left to cool and kept at 0 to 5 0 C for 2 hours with occasional stirring using a glass rod, the crystal slurry obtained was suction filtered, recrystallised from acetonitrile and colourless crystals were obtained, m.p. 166-167 0 C, which were identical according to their mixed melting point, IR and 1H-NMR spectrum, to a preparation prepared according to Example 21.

Yield: 6.2 g (33% of theory).

20 The following were obtained correspondingly: 4 a.

5,11-dihydro-11-3-[13-(l1-piperidinyl)propyl]-lpiperidinyl]carbonyl]-6H-pyrido[2,3-b[,4]benzodiazepin- 6-one, m.p. 123.5-125.5 0 C (acetonitrile); ll-[3-[3-(diethylamino)propyll-l-piperidinyl]carbonyl]- 5,11-dihydro-6H-pyrido[2,3-b[1,4]benzodiazepin- 6-one, which, after being converted into the monohydrochloride, melted at 257.5-259.0 0 C (ethanol); ll-[[3-[2-(cyclopentyl)methylamino]ethyl]-l-piperidinyllcarbonyl]-6,11-dihydro-5H-pyrido2,3-bJ[1,5]benzodiazepin- 5-one, m.p. 149-150 0 C (acetonitrile); 55 5,ll-dihydro-1l-[[3-[2-(l-piperidinyl)ethyl]-lpiperidinyllcarbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one, which when converted into the methanesuiphonate melted at 233-234 0 C (ethanol).

Example 38 5,1l-Dihydro-ll-[[3-[2-(l-piperidinyl)ethyl]-lpyrrolidiny1Icarbonyl]-6H-pyrido[2,3-bJ[1,4]benzodiazepin- 6-one Prepared analogously to Example 4 from 11- (chiorocar- 6 I30 bonyl)-5,1l-dihydro-6H-pyrido[2,3-bIfl,4]benzodiazepin- 6-one and 3-[2-(1-piperidinyl)ethyljpyrrolidine in a yield of 75% of theory. Colouz~ess crystals, m.p. 234-236 0 C (methanol).

0 6 2H2 (419.53) 00 15 Calc: C 68.71 H 6.97 N 16.69 Found: 68.38 7.05 16.70 Example 39 6 ,11-Dihydro-ll-[ r3-[3- (4-morpholinyl) propyl] -1piperidiny.tlcarbonyl-5H-pyrido[2,3-b][1,5]benzodiazepin- Prepared analogously to Example 4 from l1-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepinand 3-[3-(4-morpholinyl)propyllpiperidine in a yield of 43% of theory. Colourless crystals, m.p. 161-163*C (acetonitrile).

C 25

H

31 N 5 0 3 (449.55) Cale: C 66.79 H 6.95 N 15.58 Found: 66.21 6.99 15.63 The mbnohydrochloride melted at 221-223 0

C.

56 Example 6,11-Dihydro-ll-[[3-[2-(l-piperidiflyl)ethyl]-l- 2iperidinyljcarbonyll-5H.-pyridoll2,3-b][1,5]benzodiazepin- Prepared analogously to Example 4 from ll-(chlorocar-, bonyl)-6,ll-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepinand 3-[2-(l-piperidinyl)ethyllpiperidine in a yield of 50% of theory. Colourless crystals, m.p. 168-169*C (acetonitrile).

C

25

H

31

N

5 0 2 (433.55) Calct C 69.26 H 7.21 N 16.15 Fouind: 69.22 7.20 16.04 Example 41 ~oo 0 1l-[13-[2-(Diethylamino)ethyll-l-piperidinyllcarbonyl]- 0 o15 6,11-dihydro-5H-pyrido[2,3-bJl1,5]benzodiazepin- Prepared analogously to Example 4 from 11- (chlorocar- 0 ~o bonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin- 0 0005-one and 3-[2-(diethylamino)ethyllpiperidine in a yield of 54% of theory. Colourless crystals, a 000m.p. 1l0-1l3*C (acetonitrile)

C

24

H

31 N 5 0 2 (421.54) Calc: C 68.38 H 7.41 N 16.61 0 aFound: 69.00 7.73 16.56 Example 42 ll-[[3-[3-(Diethylamino)propyl]-l-piperidinyllcarbonyl]- 6,11-dihydro-5H-pyrido[2,3-bI[1,5]benzodiazepin- Prepaired analogously to Example 4 from 11-%(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,Sljbenzodiazepin- 57 and (diethylamino) propyllpiperidine in a yield of 38% of theory. Colourless crystals, m.p. 123-125*C (acetonitrile).

C 25 H 33 N 5 0 2 (435.57) Calc: C 68.94 H 7.64 N 16.08 Found: 68.80 7.64 15.79 Example 43 11- 4 4 -(Diethylamino)butyl]-l-piperidinyllcarbonyl]- 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one 00 0 00 a 0 00 0 0 0 2 Prepared analogously to Example 4 from 11- (chiorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b[1,4]benzodiazepin- 6-one and 4-14-(diethylamino)butylllpiperidine in a yield of 62% of theory. Colourless crystals, m.p. 126-127-C.

C26 H 35 N 5 0 2 (449.5L9) Calc: C 6 9.46 H 7.85 N 15.58 Found: 69.18 7.86 15.70 Example 44 9 -Chloro-ll-[[4-[4-(diethylamino)butyll-l--piperidinyllcarbonvl]-5,ll-dihydro-6-pyrido[2,3-b[1,4benzodiazepin- 6-one 0 0 0 0 00 000 00 0 0 Prepared analogously to Example 4 from 9-chloroll-(chlorocarbonyl)-5,1-dihydro6Hpyrido,3...b[,4]benzodiazepin-6-one and 4-[4-(diethylamino)butyl]piperidine in a yield of 38% of theory. Colourless crystals, m.p. 126-127*C.

C 26

H

34 C1N 5 0 2 (484.04) Calc. C 6.4.52 H 7.08. N 14.47 Cl 7.32 Found: 64.12 7.23 14.53 7.37 58 Example 3-Methyl-4-[[4-[4-(l-piperidinyl)butyl-l-piperidinllcarbony'l]-4,9-dihydro-1OH-thieno[3,4-bI[1,5]benzodiazepin- Prepared analogously to Example 4 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-blfl,5ibenzodiazepin-lO-one and 4-14-(l-piperidinyl)butyllpiperidine in a yield of 31% of theory. Colourless crystals, m.p. 209-210*c (ethyl acetate).

Example 46 ll-[[2-[2-[[3-(Diethylamino)propyllmethylaminolethyl]- 0 0 9 01-piperidinyllcarbonyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Prepared analogously to Example 4 from 11- (chlorocar- 15 bonyl)-5,12-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepinand 2-[2-[[3-(diethylamino)propyllmethylaminol- Pethyllpiperidine 01 mmHg 130-134 0 C) in a of 80% of theory. Colourless crystals, m.p.

123-125'C (acetonitrile).

o: 2 C 28

H

4 N 0 2 (492.66) Calc: C 68.26 H 8.18 N 17.06 Found: 68.08 8.30 17.34 Example 47 11- (Diethylamino) ethoxy] ethyl] -l-piperidinyl] carbonyl]-5,11-dibydro-6H-pyrido[2,3-b][1,4]benzo.diazepin- 6-one Prepared analogously to Example 4 from 11-(chlorocarbonyl) ll-dihydro-6H-pyrido[ 2,3-b] [1,4 ]benzodiazepin- 6-one and 2-[2-[2-(diethylamino)ethoxylethyllpiperidine -59 (b-p.

0 4 mmng 95-99*C) in a yield of 79% of theory.

Colourless crystals, m.p. 134-136*C (acetonitrile).

C2 6

H

35 N 5 0 3 (465.59) Calc: C 67.07 H 7.58 N 15.04 Found: 67.14 7.64 15.16 Example 48 4-Hi2-[2-[[2-(Diethylamino)ethyllmethylamino]ethyl]- 1-piperidinyllcarbonyll-4 ,9-dihydro-3-methyl-10Hthieno[3,_4-bl [1,5]benzodiazepin-10-one Prepared analogously to Example 4, but using dichioromethane instead of acetonitrile as solvent, from 4- (chiorocarbonyl) -4 ,9-dihydro-3-methyl-1OH-thieno[ 3,4-b] [1,5]benzodiazepin-10-one and 2-[2-[112-(diethylamino)ethyllmethylaminolethyllpiperidine (b.p.

0 3 mmHg 15 92-95 in a yield of 22% of theory. Colourless $too crystals, m.p. 131-133"C (acetonitrile).

H* C 7 3 N 0 S (497.70) Calc. C 65.16 H 7.90 N 14.07 S 6.44 Found: 65.00 7.70 14.00 6.63 Example 49 4-[[2-[2-[2-(Diethylamino)ethoxylethyl]-l-pi]peridinyl]carbonyl] -4 ,9-dihydro-3-methyl-10H-thieno[ 3 4-b] Prepared analogously to Example 4 from 4-(chlorocarbonyl)-3-methyl-10H-thieno[3,4-bfl[,5]bt~nzodiazepinand 2-[2-[2-(diethylamino)ethoxylethyllpiperidine in a yield of 53% of theory. Colourless crystals, m.p. 105-107 0 C (diisopropylether).

C 26

H

36 N 4 0 3 S (484.66) Calc: C 64.43 H 7.49 N 11.56 S 6.62 Found: 64.00 7.44 11.70 6.60 60 Example ll-[[2-[2-[[3-(Diethylamino)propyllmethylaminolethyl]- 1-p2iperidinyllcarbonyl] 1l-dihydro-5H-pyrido[ 2,3-b] [1,5]benzodiazepin-5-one dihydrochioride hydrate Prepared analogously to Example 4 from 11- (chiorocarbonyl) 11-dihydro-5H-pyrido[ 2,3-b] [1,5 ]benzodiazepinand 2-[2-[[3-(diethylamino)propyllmethylaiino]ethyllpiperidine in a yield of 48% of theory.

The colourless dihydrochlor ide-hydrate melted at 145-150 0 C C 2 8

H

4 0 N 6 O0 2 x2HClxH 2 O0 (583.60) Calc: C 57.63 H 7.60 Cl 12.15 N 14.40 4.Found: 57.64 7.80 12.05 14.49 Example 51 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one Prepared analogously to Example 4 from 11-(chlorocar- 444,4bonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one and 3-12-(diethylamino)ethyllpyrrolidine in a yield of 13% of theory. Colourless crystals, m.p. 137-138 0 C (from ethyl acetate/methaniol 98/2 v/v).

C 2 3

H

2 9 N 5 0 2 (407.51) Calc: C 67.79 H 7.17 N 17.19 Found: 67.19 7.05 17.15 Example 52 5,11-Dihydro-ll-[114-[3-(4-methyl-l-piperazinyl)propl- 1-piperidinyllcarbonyl]-6H-pyrido[2,3-bl[1,4]benzodiazepin- 6-one 61 Prepared analogously to Example 4 from 11- (chiorocarbonyl)-5,11-dihydro-6H-pyridoI2,3-bl[,4]belzodiazepil- 6-one and 4-r3- (4-methyl-l-piperazinyl) propylilpiperidine in a yield of 17% of theory. Colourless crystals, m.p. 213-214 0 C; Rf 0.25 (Merck DC ready-made TLC plates, silica gel 60 F 254 eluant: ethyl acetate/methanol/ cyclohexane/conc. ammonia 80/10/10/1 v/v/v/v).

Example 53 4-[14-[2-[2-(Diethylamino)ethoxylethyl]-l-piperidinyl]carbonyl]-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-l0-one Prepared analogously to Example 4 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-bI[l,5]benzodiazepin-lO-one and 4-[2-[2-(diethylamino)ethoxylethyl] 15 piperidine (b.p.

0 009 mmFg 101-102 0 C) in a yield *of 71% of theory. Colourless crystals, m.p. 125-126*C (diisopropylether).

C 26

H

36 N 4 0 3 S (484.66) Calc: C 64.43 H 7.49 N 11.56 S 6.62 Found: 64.50 7.27 11.80 6.52 Example 54 11- (Diethylamino) ethoxyl ethyl] -1-piper idinyl] carbonylll-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one Prepared analogously to Example 4 from 11-(chlorocarbonyl) 11-dihydro-6H-pyr ido[ 2,3-b] [1,41benzodiazepin- 6-one and 4-[2-[2-(diethylamino)ethoxylethyljpiperidine in a yield of 71% of theory. Colourless crystals, m.p. 119-120*C (cyclohexane), R f 0.43 (Macherey- Nagel, Polygram SIL G/UV 254 pre-coated plastic sheets for TLC; eluant: ethyl acetate/methanol/conc.

ammonia 100/30/3, v/v/v) -62 Example 1-piperidinyllcarbonyll-5,ll-dihydro-6H-pyrido[2,3-b][1,41benzodiazepin-6-one Prepared analogously to Example 4 from 9-chioroll-(chlorocarbonyl)-5,ll-dihydro-6H-pyridol2,3-b][1,4'benzodiazepin-6-one and 4-[2-[2-(diethylamino)ethoxy]ethyllpiperidine in a yield of 43% of theory.

Colourless crystals, m.p. 145-146*C (acetonitrile), RfO0.

39 (conditions as in Example 54).

C 26

H

34 C1N 5 0 3 (500.04) Calc: C 62.45 H 6.85 Cl 7.09 N 14.01 Found: 62.16 6.97 7.30 14.12 Example 56 "000 acarbonvll-6,11-dihydro-5H-pyrido[ 2,3-b] o 0 Prepared analogously to Example 4 from 11- (chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin- 5-one and 4-[2-[2-(diethylamino)et~hoxylethyllpiperidine in a yield of 83% of theory. The colourless hydrochloride melted at 148-150*C (ethyl acetate).

C

26

H

36 C1N 5 0 3 (502.05) Calc: C 62.20 H 7.23 Cl 7.06 N 13.95 Found: 61.96 7.37 7.20 13.77 Example 57 5,1l-Dibydro-ll-[[2-[2-(l-piperidinyl)ethyl]-4morpholinyllcarbonvl]-6H-pyrido[2,3-b][1,4]benzodiazepin- 6-one -63 Prepared analogously to Example 4 from 11- (chiorocarbonyl)-5,1l-dibydro-6H-pyrido[2,3b[1,4]benzodiazepil- 6-one and 2-[2-(l-piperidinyl)ethyllmorpholine (R f 0.4 [Macherey-Nagel, Polygram SIL G/UV 254 pre-coated plastic sheets for TLC; eluant: dichioromethane/methanol/cyclohexane/coflc. ammonia 68/15/15/2, in a yield of 79% of theory. The colourless hydrochloride melted at 274-275*C.

C

24

H

30 C1N 5 0 3 (471.99) Calc: C 61.07 H 6.41 Cl 7.51 N 14.81 Found: 60.86 6.37 7.69 15.08 Example 58 6,11-Dihydro-ll-[[2-[2-(l-piperidinyl)ethyl]-4morpholinyllcarbonyl]-5H-pyrido[2,3-b][1,5]benzodiazepin- 000 ,oooo Prepared analogously to Example 4 from 11- (chiorocar- 0 e bonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin- 0 5-one and 2-[2-(l-piperidinyl)ethyllmorpholine in a yield of 78% of theory. Colourless crystals, I :.20 m.p. 136-138 0 C (diisopropylether), R f 0.46 (Macherey- Nagel, Polygram(R SIL G/UV 254 pre-coated plastic sheets for TLC; eluant: ethyl acetate/methanol/conc.

ammonia 100/30/3, v/v/v).

C

24

H

29

N

5 0 3 (435.52) Caic: C 66.19 H 6.71 N 16.08 Found: 66.01 6.64 16.10 Example 59 5,11-Dihydro-8-methyl-ll-[[2-[2-(l-piperidinyl)ethyl]- 4-morpholinyllcarbonylll-6H-pyrido[2,3-bI[1,4]benzodiazepin- 6-one Prepared analogously to Example 4 from 11- (chlorocarbonyl) -5,11-dihydro-8-methyl-6H-pyrido[2,3-b]I[1,4]benzo- 64 diazepin-6-one and 2-f 2-(1-piperidinyl)ethyllmorpholine in a yield of 79% of theory. R f 0.43 (conditions as in Example 58). The colourless hydrochloride melted at 272-273 0 C with decomposition.

C

25 H 32 C1N 5 0 3 (486.01) Calc? C 61.78 H 6.64 Cl 7.29 N 14.41 Found: 61.49 6.65 7.43 14.50 Example ll-[[2-[2-[2-(Diethylamino)ethoxylethyl]-l-piperidinyl]carbonyl]-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin- Prepared analogously to Example 4 from l1-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-bI[1,5]benzodiazepinand 2-[2-[2-(diethylamino)ethoxylethyllpiperitill 15 dine in a yield of 86% of theory. The colourless hydrochloride melted at 186-187 0

C.

C

26

H

6 C1N 0 3 (502.05) Calc: C 62.20 H 7.23 Cl 7.06 N 13.95 Found: 61.91 7.13 7.09 13.90 Example 61 4,9-Dihydro-3-methyl-4-[[2-[2-(l-piperidinyl)ethyl]- 4-morpholinyllcarbonyl]-lOH-thieno[3,4-b][1,5]benzodiazepin- Prepared analogously to Example 4 from 4-(chlorocarbonyl)-4,9-dihvdr-o-3-methyl-1OH-thieno[3,4-b][1,5]benzodiazepin-lO-one and 2-12-(-piperidinyl)ethyllmorpholine in a yield of 74% of theory. R f 0.48 (conditions as in Example 58). The colourless hydrochloride melted at 254-256 0 C

C

24 H 31 C1N 4 0 3 S (.491.05) Caic: C 58.70 H 6.36 Cl 7.22 N 11.41 S 6.53 Found: 58.51 6.38 7.31 11.56 6.71 r~u The following Examples illustrate the preparation of some pharmaceutical administration forms: Example I Tablets containing 5 mg of 5,11-dihydro-ll-[[3- [3-(l-piperidinyl)propyl]-l-piperidinyl]carbonyl]- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Composition: 1 tablet contains: Active substance 5.0 mg Lactose 148.0 mg Potato starch 65.0 mg Magnesium stearate 2.0 mg 220.0 mg 4 0 Method of preparation a0 0 15 A 10% mucilage is prepared from potato starch by Q 0 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.

t, The granules are dried at.45°C, pressed through the same screen again, mixed with magnesium stearate and compressed using a 9 mm punch to form tablets of 220 mg weight.

Example II Coated tablets containing 5 mg of 5,11-dihydroll-[[3-[3-(l-piperidinyl)propyl]-l-piperidinyl]carbonyll- 6H-pyrido[2,3-b][1,4]benzodiazepin-6-one Tablets prepared according to Example I are coated, by a known method, with a coating consisting essentially of sugar and talc. The finished coated tablets are polished with bee ii of weight 300 mg 66 swax yielding coated tablets Example III Ampoules containing 10 mg of 5,11-dihydro-ll-[(3- [3-(l-piperidinvl)propyll-l-piperidinlllcarbonyl]- 6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one-methanesulpbonate Composition: 1 ampoule contains: Active substance Sodium chloride Distilled water Method of Preparation 1 0. 0 mg 8. 0 mg 1 ml 4 4 4 4 .4.4 444444 4 4 44,4 04 4 0440 4 4 4404 004 4 4 44 4 Ii I 44.

*0 4 4 4 The active substance and sodium chloride are dissolved in distilled water and then made up to the volume specified. The solution is sterile filtered arnd transferred into 1 ml ampoules.

Sterilisation: 20 minutes at 120 0

C.

Example IV Supjpositories containing 20 mg of 5,11-dihydroll-j[3-[3-(l-piperidinyl)propyll-l-piperidinyllcarbonyl]- 6H-pyrido[2,3-b][1,4]benzodiazep in-6-one Composition: 1 suppository contains: Active substance 20.0 mg Suppository mass Witepsol W 45) 1 680.0 mg 1 700.0 mg 67 Method of preparation Finely powdered active substance is suspended in the molten suppository mass which has been cooled to 40 0 C. The mass is poured at 37 0 C into slightly chilled suppository moulds to produce suppositories of 1.7 g weight.

Example V Drops containing 5,11-dihydro-l-[[3-[3-(l-piperidinyl)propyl]-l-piperidinyl]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one-methanesulphonate 4 44 15 4 4 o 444 4n a 4 4n 4; .4 4 40 Composition: 100 ml of drops solution contain: Methyl p-hydroxybenzoate Propyl p-hydroxybenzoate Anisole 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 Method of preparation I $(I4 8 The active substance and sodium cyclamate are dissolved in about 70 ml of water and glycerol is added.

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

Claims (6)

1. Compounds of formula I H O 2 X N R (L) St 0 S 1R 1 SA N 42 R S(wherein represents a group selected from groups and (W) CH 8 3 R R 6 R 7 R 9 R 9 (V) 1 2 SX 1 and X 2 each represents a =CH- group, or if .(1 ~represents a group or each or either 41 2 one of X and X may instead represent a nitrogen atom; A represents a straight-chained or branched C 2 -7 saturated alkylene group optionally interrupted by an oxygen or sulphur atom or by a methylimino or ethylimino group; Z represents a single bond, an oxygen or sulphur atom or a methylene or 1,2-ethylene group; rar*-- i-- 69 R 1 represents a branched or unbranched C 1 4 alkyl group or a benzyl group; R 2 represents a branched or unbranched C1_ 7 alkyl group optionally substituted at its 2nd to 7th carbon atom by a hydroxy group, a C3_ 7 cycloalkyl or (C3- 7 cycloalkyl)methyl group optionally substituted on the cycloalkyl ring by a hydroxy group or R 1 and R 2 together with the intervening nitrogen atom represent a 4- to 7-membered saturated, monocyclic, heterocyclic ring optionally interrupted by an oxygen atom or by an N-CH 3 group, and t 2 R 2 may also be linked to A via an alkylene bridge 1 t C, whereby to form in conjunction with the group NR S'a saturated 6- or 7-membered heterocyclic ring; R 3 represents a C 1 4 alkyl group or a chlorine or hydrogen atom; o4 S. R represents a hydrogen atom or a methyl group; 5 6 R and R 6 which may be the same or different, II each represents a hydrogen, fluorine, chlorine or bromine atom or a C 1 4 alkyl group; 1-4 R 7 represents a hydrogen or chlorine atom or a methyl group; 8 R represents a hydrogen atom or C 1 4 alkyl group; R represents a hydrogen or halogen atom or a C1-4 alkyl group; and R 10 represents a hydrogen atom or a methyl group; i- w "li U4 70 with the proviso that where B)3 is a group (T) wherein R is a hydrogen atom, R is other than a chlorine atom and Z is other than a sulphur atom) and acid addition salts thereof.

2. Compounds of formula I as claimed in claim 1, wherein A is a two- to four- membered alkylene chain in the 3 or 4 position of the saturated heterocyclic ring -N z Z is a methylene group, 1 2 1 R and R each represent Cl 4 alkyl groups or R 2* 1-4 2 and R together with the intervening nitrogen atom represent a 1-pyrrolidinyl, 1-piperidinyl,

4-morpholinyl or hexahydro-1H-1-azepinyl group, and S O" either 1 S X is a =CH- group, X is a nitrogen atom, is a group R 4 5 6 I R 4 and R are hydrogen atoms and R 6 is a hydrogen, chlorine or bromine atom or a methyl or ethyl group in the 8 or 9 position, or X 1 and X 2 are =CH- groups and is a group (wherein R 8 is a hydrogen atom and R 9 is a methyl group) or at least one of the groups R and R 4 is a hydrogen atom and is a group and the optical isomers and acid addition salts thereof. 1_ i 1 71 3. A compound as claimed in claim 1 being 6,11- dihydro-1l-[[3-[2-(1l-piperidinyl)ethyll-1-piperidinyl] carbonyl]-5H-pyrido[2,3-b][1,5]benzo-diazepin-5- one, or 5,11-dihydro-ll-[[3-[3-(l-piperidinyl)propyl]-l- piperidinyl]carbonyl]-6H-pyrido[2,3-b][l,4]benzodiazepin-

6-one, or an acid addition salt thereof. 4. A compound as claimed in any one of claims 1 to 3 being a physiologically acceptable acid addition salt of a compound of formula I. A pharmaceutical composition comprising a o compound of formula I as claimed in claim 1 or 00 q 0. a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient. 6. A process for the preparation of compounds 0 0 as claimed in any one of claims 1 to 4 said process o °o comprising at least one of the following steps: 0 o °0 (to prepare compounds of formula Ia 3 H 0 R 1 i R4 N (Ia) A N 7 wherein 1 2 3 4 1 2 R R R, R, X X, A and Z are as defined in claim 1 and represents a group 72 or as defined in claim 1 or a qroup CH i 3 N 7' R wherein R 7 is a chlorine atom or a methyl group) reacting a carbonic acid derivative of formula II o 09 SR 1 R3 X 1 0t X N- I I o 4 S R I Y 0 0 oo 0 0 (wherein R 3 R 4 X 1 and X 2 are as hereinbefore sdefined and Y represents a halogen atom or a group OR wherein 11 R represents an optionally halogen-substituted alkyl group, a phenyl group optionally substituted by halogen atoms or nitro groups or a C7_15 aralkyl group) with a compound of formula III H N (III) R^ NZ^ ir- 73 or a metal salt thereof of formula IIla LA N z -NZ (IIla) (wherein M represents an alkali metal atom or one equivalent of an alkaline earth metal atom, and R 1 R 2 A and Z are as hereinbefore defined); (to prepare compounds of formula Ia as hereinbefore defined) 00 0 0 00 0 AU 0006 Al 0 A tAUt o A A At A 'At, 0 A @000 00 0 o 00 0 00 O 0 0 0 00 0 0 0 0 00 0 tO At A 0 At reacting a tricyclic compound of formula IV R 3 1 x N x N® (IV) (wherein R R X x 2 and 30 are as hereinbefore defined) with a chlorocarbonic acid derivative of formula V 0 \\C1 N A< CzR2 (wherein R 1, R 2, A and Z are as hereinbefore defined); k 74 (to prepare compounds of formula Ib S3' H CH3 R 2 X N--l N R I I N O 7* 1 'AN (Ib) A N- S R 2 O oe o 0 wherein 0 R 1 R 2 R 4 X 1 X 2 and A are as defined in claim 1, Z' represents a single bond, an oxygen atom or a methylene or 1,2-ethylene group, R 7 represents a hydrogen atom and 0 0 R 3 represents a C14 alkyl group or a hydrogen atom) 0 0 S00 0 0 hydrogenolysing a compound of formula Ib' S3 H CH 3 SR 2 0 o o N-- N 0 (Ib') hereinbefore defined and R represents a chlorine 0 -A (wherein R 1 ,'R 2 R 3 R 4 X 1 X 2 A and Z' are as hereinbefore defined and R 7 represents a chlorine atom); 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; and 1 75 separating a compound of formula I or salt thereof into the optimal isomers thereof.

7. A method of treatment of the human or non-human animal body to combat bradycardia or bradyarrhythmia, which method comprises administering to said body a compound of formula I as claimed in claim 1 or a physiologically acceptable salt thereof.

8. Compounds of formula I as defined in claim 1 and salts thereof substantially as herein disclosed in any S° of the Examples. 4 0 0 0a oeo DATED this 10th day of January, 1991. O 0 00 o S° DR. KARL THOMAE G.m.b.H. By Their Patent Attorneys: CALLINAN LAWRIE O 0 0000.1 6 e> SaT ao o