GB2199827A

GB2199827A - 12-aminoalkanoyl-dibenzo-[d,g] [1,3,6] dioxazocines and a process for the preparation thereof

Info

Publication number: GB2199827A
Application number: GB08730298A
Authority: GB
Inventors: Laszlo Rozsa; Lujza Petocz; Marton Fekete; Eniko Szirt; Maria Hegedus; Istvan Gacsalyi
Original assignee: Egyt Gyogyszervegyeszeti Gyar; Egis Pharmaceuticals PLC
Current assignee: Egyt Gyogyszervegyeszeti Gyar; Egis Pharmaceuticals PLC
Priority date: 1986-12-30
Filing date: 1987-12-30
Publication date: 1988-07-20
Anticipated expiration: 2007-12-30
Also published as: FI875767A0; SE8705187D0; DK691087A; CH675877A5; PL151402B1; NO875465L; AT389304B; YU235287A; DD267038A5; GR872083B; NO875465D0; NL8703150A; ZA879733B; SU1575938A3; BE1001240A3; CN87108190A; CS1009187A2; SE8705187L; IT1233443B; DK691087D0

Description

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-i- l0 NOVEL AMINOALKANOYL-DIBENZOZ'd,ú7-I,3,7OIOXAZOCINES PROCESS FOR THEPREPARATION THEREOF AND A The invention relates to novel -dibenzoL-d,ú7-l,3,TdioÎazocines, a tion thereof and pharmaceutical compositions such active substances.

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The novel compounds possess valuable 2199827 aminoalkanoyl- process for the prepara- comprising pharmaceutical properties such as local anaesthetic, tranquillo-sedative and/or antidepressant, antiparkinsonic, furthermore antiarrhytmic and antianginous activities.

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12-Aminoalkyl-12H-dibenzoL-d,ú7-l,3,7dioÎazocines having local anaesthetic and described in the US-Pat. No.

It was found that the known compounds can be the ring nitrogen by an aminoalkyl group.

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Thus, the of the formula anti'parkinsonic 4,208,410. pharmaceutical activities are activity of the favourably modified by substituting aminoalkanoyl group instead of an invention provides for the novel I C:O compounds (i) ! I0 wherein X represents hydrogen or halo, r A stands for a valence bond or a straight or branched chained alkylene having 1 to lO carbon atoms, Rl and R2 independently represent hydrogen, an alkyl having 1 to 4 carbon atoms or a cycloalkyl having 3 to 6 carbon atoms, or R1 and R2 together with the nitrogen atom they are attached to and optionally with one or more further nitrogen, oxygen and/o sulfur atom(s) form a 5to 6-membered heterocyclic group optionally substituted with an alkyl having I to 4 carbon atoms, and pharmaceutically acceptable acid addition salts thereol.

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Claims

In the specification and Claims, halo means fluoro, chloro, bromo or iodo.

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The straight or branched chained alkylene having 1 to lO carbon atoms is for example methylene, ethylene, isopropylene, - propylene, -butylene, isobutylene, pentylene, hexylene, heptylene, octylene, nonylene or decylene group.

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The alkyl having 1 to 4 carbon atoms can be methyl,..

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ethyl, -propyl, isopropyl, -butyl, isobutyl, se__2c.-butyl or tert.-butyl.

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The cycloalkyl having 3 to 6 carbon atoms can be cycZopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

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The 5- to 6-membered heterocyclic group is preferably piperazine, piperidine, pyrrolidine or morpholine. The hereto- cyclic group can be substituted with an alkyl group having I to 4 carbon atoms, preferably a methyl group.

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lO formula If A stands for a valence bond, the group of the 0 R R2 is attached directly to the ring nitrogen.

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The compounds of the formula (I) may form pharmaceutically acceptable acid addition salts, for the salt formation, suitable inorganic or organic acids are for example hydrogen chloride, hydrogen bromide, sulphuric acid, acetic acid, fumaric acid, lactic acid, maleic acid, methanesulonic acid, ethanesulfonic acid, citric acid etc.

The compounds of the ormula (I) may comprise one or more chiral carbon atom(s), depending on the meaning o5 A. In such cases, optically active isomers may exist. The invention relates to the optically active antipodes and any mixtures thereof.

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Preferred compounds of the invention are compounds of the formula (I) wherein X represents hydrogen or halo, A stands for a valence bond or an alkylene having i to 3 carbon atoms, RI and R2 independently represent hydrogen, an alkyl having I to 3 carbon atoms or a cycloalkyl having 3 to G carbon atoms, or RI and R2 together with the nitrogen they are attached to. and optionally with an oxygen atom form a 4-methylpiperazinyl, 2-methylpiperidinyl, pyrrotidinyl or I [3.

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] O C r-H E O t- O E 0 O3 0 r- U3 tlj C 0 r-i "13 "[3 (Ll "13 O --4 I] c0 C O3 O O r O -4 ] O E 3Z C I] C H E O O3 H O "O O (3.

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E O L1 no 4-4 0.l O- -,- 3:

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L) O O3 (3- r UI O Ul (0 qJ o3 I r r-I ! ol "O I O N E O3 J] "O I r---.

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U ii1 ! C -..t N m (11 n r"t n r-" E I I ! I ("4 113 C .-4 O O N X O ,.-{ "13 I O N C n no i (1) O o3 I r---t C -r"l N r0 n rt n -4 r- E I v "--I I ("-4 I 12) O r-'t r" L.] ! I T C',I W E r.4 O O N x O "0 r-..

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I "-I crl I I O N C 0.l I -,-4 "o 1 ol --4 I >, "-1 -,-I N -13 C" n O O ±'.IZ LI I L3 >-, "-J 0 0 m m r-I X.ID I O I-4 O "-4 r0 O P'-- m't c" C" ! O3 ("4 r-4.,'-I I! "[3 7- "1 I +1 I 0) C .-t O O N ('0 X O -I nO I c "O I O N E O3 [D 4-1 "13 I c- O 4 n O C1 O E -4 E r---t 2 f2 o3 I t I I c-,l r'- I O O r--'t 1"- 1.3 I C'4 I C'4 r-t I1) C -'-t (-3 O N (' X O -,-.I ! O O3 o3 t- O -I r-I O -,-4 O 0J r-I E) (o + n (11 O L (O -H r- (1) O -I O3 O (0 E 00 J2 [3- "lED C 0l (0 "O 00 [3.

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O3 (3.

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O3 4 CO H (O r-H E O 4-4 F" 4 O o "13 E 2) O E1 E O L) O3 I-- oo 03 .DTD:

O O (0 E O 0J r" O O3 C 4-i O O N 00 x O "O r--t i "-I crl "0 I "-I O N C Ill n .-I "[3 no C 0 13.

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E 0 O (13 C r-I nO 11) (0 (.l O J3 o0 "D (i) C 4-4 0J nO (0 Ul X C r- (1) r--I E O r- 4 O C3 O (,y Hal-C-A-Hal' n (III) wherein A is as defined above, Hal and Hal' independently represent a halo, and the obtained alkanoyl-dibenzoL-d,7/--l,3,TdioÎazocine of the formula I A ' (IV) wherein X, A and Hal' are as defined above, is reacted with an amine of the formula HN RI R2 (VIII) wherein R1 and R2 are as defined above; or b) a dibenzo-d,7L-1,3,Tdioxazocine of the formula (II) is acylated with a compound of the formula I xO ! n- C \/ ZI I L-"- O I --'4 (I) r--t O E "13 r- 0.) U) ---I 0,--I I O) E r- --.I 0 (I) 0 9-4 0 O N O) (10 X - O "O --H 4- 02 "13 O C r- - ol "o "O O CL -I O O "(2 C n O.

N "O C I-- "(3 (.D O t-H "O (I) (1@., f- (..) O --I O.r-I C s I-" S f- F" CO H I-- O H -- E C O) O -I (0 32 (.

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- CZ O C (1) W,1 TO Q2.L.'3 - O CI (0 O- I- %3 0 (ii 0 (..2.- "13 II (1.l 2E C2 O O O " \ I --I tU I /5. 0 (_)____---.O I L) I O E2 0J 7- 0].El 7O C C cO O CO C LO - O) E (7o.,-4 O C -, C, ( O I co n ob I- O LI li o! tl r.-i C m m -I --I (1 C- -.O I O O H U1 r- ('0 EE qH O -t "0 O 0 H.r - D 7O (o L) (0 C cO (I) "O 0 C O C E. C - -.,, O (1) O (.I. O H CO (9 0 ( v "E) 70 0 (3- E I (1@ I- (2 (.I O E C m (1) 0 0 "0.,-I.I C C C -, X C 13,- m C 0 + m 0 (.,- C 0 13 +a I- F 0 0 "13.-4 m 0 m m lO In the compounds of the formulae (III), (IV), (V) and (VI) halo is preferably chloro or bromo.

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The dibenzo-d,7-I,3,Tdioxazocines of the formula (II) which are used as starting compounds for the preparation of the compounds of the invention are prepared as described in US-Pat. No, 4,208,410.

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The compounds of the formulae (III), (V), (VI) and (VIII) are known reagents being commercially availabie or they can be prepared by known methods.

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In process a) of the invention, the compound of the formula (II) is acylated in apolar or dipolar aprotic solven s, preferably benzene, toluene, xylene or dimethylformamide, in the presence or absence of an acid binding agent. The acylating agent of the formula (III) is employed in an equivalent amount or in excess relative to the amount of the dibenzo/,-d,F-l,3,Fdioxazocine of the formula (II).

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It is preferred to acylate the compound of the formula (II) in toluene, generally at a temperature of 60 to llO C with the compound of the formula (III) which is used in an excess of 200 to)00 per cent.

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The omega-halo-alkanoyl-dibenzo'd,TL-l,,7dioxazocine of the formula (IV) which is formed in the acylation reaction is reacted in a polar, apolar or dipolar solvent with the amine of the formula (VIII). Preferably benzene, toluene, xylene, isopropanol or dimethylformamide is employed as the solvent. The amine of the formula (VIII) can be employed in an equimolar amount or in excess. The excess of the amine of the formula (VIII) can bind the hydrogen halide formed in the !O reaction. However, other usual acid binding agents can be used for this purpose, too.

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The acid binding agent used both in the acylation and amination can be a suitable inorganic base e.g. sodium carbonate, potassium carbonate etc., or a suitable organic Wase such as a tertiary amine e.g. triethylamine, N,N-diisqpropyl-N-ethylamine, pyridine etc.

It is preferred to react the compound of the formula (IV) in benzene with an excess of the amine.of the formula (VIII).

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Process a) of the invention can be performed starting from a metal salt of the compound of the formula (!i). In this case, the compound of the formula (II) is reacted with e.g. sodium hydride or sodium amide in a Oipolar aprotic solvent, suitably dimethylformamide, to give the corresponding sodium salt thereof which is acylated, in general, at 0 to 40 C. Of course, in the acylation, no further acid binding agent is necessary.

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In process b) of the invention, the cemsound of the formula (II) is acylated with the compound of the formula (V) in a similar way, generally at 0 to I0 C.

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It is preferred to prepare the alkali metal salt of the compound of the formula (If) at first, then to react it with an excess of the compound of the formula (V) at a temperature of 0 to 50 C.

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In process c) of the invention, the reaction of the compounds of the formulae (II) and (Vl) is performed in an apolar organic solvent such as benzene, toluene or Îylene, lO in general, at 50 to 140 C. The obtained compound of the formula (VII) is reacted with the amine of the formula (VIII) at atmospheric pressure or under higher pressure. For the reaction, the solvent is an apolar organic solvent or an excess of the amine of the formula (VIII).

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In case of compounds of the formula (I) comprising one or more chiral carbon atom(s), the enantiomers can be separated by resolving the racemic compound. To effect this, the racemic compownd comprising a basic nitrogen is reacted with an optically active carboÎylic acid to give pairs of diastereomeric salts which are separated and the enantiomers are deliberated. As an optically active organic acid practically any carboxyliC acid used for resolutions can be employed such as optically active tartaric acid, dibenzoyltartaric acid, lactic acid, atrolactic acid, mandelic acid etc., furthermore optically active sulfonic acids such as lO-camphorsulfonic acid etc.

The enantiomers of the novel aminoalkanoyl-dibenzo-d,7-l,3,Tdioxazocines comprising a chiral carbon atoms can be also prepared by acylatino the compound of the formula (II) with an optically active agent of the formula (III), (V) or (VI).

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The compounds of the formula (I) have valuable pharmacological activities as indicated by the following screening tests.

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V1 0 n 0 V 0 0 (Z3 V 0 V 0 0 CO 0 (-) 0 0 C3 C3 0 0 0 C) 0 0 0 P C) D d Z)" (11 Eu Z" - (I) -b -'- ) W '7 "0 I--,. tn 0 H q) (.n F- fD - I--J (D oJ 0. t-j EL 0 "13 3 0 C E] ( (13. I G) l,--I- Z3 17-I ' 3 UI (3. I- T X C C3 U1 --4 -13 q) I - O. (/1 - w CL Ol I- re 3 0 CT r" " I-" " 0 X X I--' ---I ( (11 'd (I) UI l I-', (I) I--" fD o) 0 -e I--'. C UI 0 (1) 0 13. 0 (. 2" -'- H - -j "7 t 3 "< O. El. r+ I-'. I-J 0 "13 0:el 0 I,.: 3 3 -':3 o. i 0 0 O) c0 I-'. " t-I 0 (3) kO - 0 (1) 0 tq r-, I.-'- -I:3:::I I 'd 0 i-,-+ (X) ('D 0 -" O) ",.0 0 O. r" 0 I- -'- "13 - 01 ('D ' 0 .0 Im -- c q) (I) O" ('O]" -7 CL O_ IC..F'" a) X (1) I)J '-0 ---t O" 7 (1) 0 E E I -. -U1 0 0 t-" O. O 0 tO P- -0 CD U1 (O - 33 'd ('0 U1 I-'.,. ('D Z] 0 to C F --4 0 CD O. C,--I- F-' 0 _-T 0 ( O. 0 01 "0 r+ 0 (I) C e- bO O.

0 F 3. F-'. 0 0 0 0 I I 3 P -'" 2-]" . < UI CL 01 b.-,- O_ r- (I) O. (,rl ('D 0 Ul F) C (I) X 0 F J, < E :3"- ('I) ('I I I - Ii - continuation of Table I Compound {Example No.) LOs0 p.o. in mglkg lO 260 300 250 250 650 250 570 220 300 Local anaesthetic activity The tests were performed according to Truant d'Amato /_'Acta Chir. Scand., ll6, 351 (19587. 0.2 ml of a 0.25 or 0.50 per cent solution of the test compound were injected around the nervus ischiadicus, into the centre of the femur. The absence of the motor control of the leg muscles was looked upon as the criterium of anaesthesia. The test animals were mice. The duration of the effect was recorded, and from the dose versus action plot, the concentration at which the activity amounted to 50 per cent (ECs0)was determined.

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In the test, lidocaine '2-diethylamino-2',6'-acetoxy-xyliid7 was used for comparison. The results obtained are given in I r-I I I--I H (1) r-I (10 t--" 0 o\ (i) 0 9 C U' (1) 0,-4 0 O).I- C (0 9- C 0 (I) 0 r- C 0 0,-I f_) o\ (T) rO C) mC m c c) 0) u o ILl (i) CI C "0 (i) C,' 13.

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0 E 0_(0 E X OW rn oo u7 u7 O2) CO --I (]3 - C',I r---4 r--I r--d (N r- C3 r-H O O O O O O O C3 (23 O C3 C) (1) E 4 L) O -r-I r'--t "(3 0) C O) O r".-i D C C C 0.,- (1) (1) E 0 C C O O - O O "O O -I (1) O C O C O - C (0 U3.,-t r- C "13 + 0 C O r-.i 0.,- OJ (10 Q. (0 Ul 0 0 C.C C O " "4 3: t- O H r- O C r-4 C n., -4 (I) (- E.,-4 H C 0 -.I--I 0 0 0 r- -I (.) E (70.-i 3 0 O (D C O r- (1.,.-4 (3 O O r- (3) - C 3., "13 (1).,.

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O "13 O C O --I O. O (- - O (1) O I-4 - r' r'-I (13 O O.

"13 (1) C -,'-I E X J3.

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O 7O C O O- O (..) C t= lO hexobarbital L-5-(1-cyclohexenyl)-l,5-dimethylbarbituric acid7 was injected intravenously, at a dosage of 0 mg/kg.

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The control group was treated only with hexobarbital to provoke sleep. The duration of sleep was recorded. If the duration of sleep of an animal exceeded that of the mean value of the control group by a factor of 2.5, it was considered as a positive reaction. From the data referring to the animals indicating a positive reaction, the ED50-value was calculated. From the values of LDSO and E050, the therapeutical index was determined for each compound tested. In the test, meprobamate -2-methyl-2propylpropandiol-l,3-dicarbamat7 and chlordiazepoxide L-7-chloro-2methylamino-5-phenyl-3H-I,&-benzodiazepine--oxid7 were used for comparison. The results obtained are summarized in Table III.

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Compound (Example No.) .DTD:

1 3 4 6 12 15 19 Table III .DTD:

EDso in mg/kg 21.0 25.0 8.5 15.0 30.0 9.8 15.0 Therapeutical index LD50/EDso 95.2 31.2 235.0 16.7 8.7 25.5 2.7 (7 r, 1- 1,-.'.:-7- FT fl) _7" 4 r0 -o (0 -q [) C O (1) 0.) F--' [7- (]) I-'. rl- -7 [D- q),',.ú3 X I-'.

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< O H 7 I-.

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CO --4 O ET U1 0 0 0 C) O O rt- r- I--'.

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O O I F- I lO 30, 60, 90 and 120 minutes. Then, the mean value of ptosis was calculated in each group, and the deviation from that of the control group (i.e. the inhibition) was expressed in percentage. From the data obtained, the EOso- value and the therapeutical index were determined for each novel compound tested as well as for amitryptiline -5-(5-dimethylaminopropylidine)-lO,11- dihydro-SH-dibenzo-a,Fcycloheptene hydrochlorid7 employed for comparison. The results obtained are shown in Table IV.

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Table IV .DTD:

Compound (Example No.) .DTD:

E050 Therapeutical index in mg/kg LDso/EDso amitryptiline 13.0 53.9 23.0 86.9 13.5 13.6 12.0 18.7 The therapeutical index of the compounds of the invention is, in general, higher than that of the amitryptiline used for comparison.

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Inhibition of nicotine lethality on mice lhe tests were performed on white mice using the method of Stone 'Arch. Int. Pharmacodyn., 177, 419 (19587. The I r- I X -E3 O -.-M --.-4 C3 f--...

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r,,'% C3 ---I --.-i C3 C) 0 O O C3 (4 ( u t O I (30 O u C) 3 r C ) JZ (3X 0 Z U C3 r u O ur Inhibition of tremor induced by tremorine on mice The tests were carried out according to Everett -Science, 124., 79 (19567. Tremor was induced by tremorine -l,l'-(2-butynylene)-dipyrollidin7 administered intraperitoneally at a dosage of 20 mg/kg. The compounds to be examined were given perorslly to the animals one hour prior to the administration of tremorine, and the tremor developed was evaluated 45 minutes after the administration of remorine. The results are set forth in Table VI.

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Table VI .DTD:

Compound EDso (Example No.) in mg/kg 1 16.0 3 15.0 4 42.0 7 37.5 13 4.0 14 8.1 trihexyphenidyl 15.0 Therapeutical index LD50/ED50 125.0 52.0 47.6 26.7 75.0 19.8 24.3 Since the inhibition of nicotine lethality and of tremor is characteristic of the antiparkinsonic activity of a substance, from Tables V and VI it can be concluded that the antiparkinsonic activity of the compounds of the invention surpasses that of the known compound used for --, C-) r'o x OJX3 3 0 "U C -'Z3 (1) (3.

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Z F.J.

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-3 L--I (I3 0 - (,q 7TCO (C) T1 T3:J I--' I-' H- -.

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r+O (O CO [ F. "C) F) 2) U) -1 0 (u (3_. U (n 0 "13 I -3" -1 0 LF3 C {--) C " -.,-4-.'3 < -3 0 C1 (I} O. I-,. r--t- I..3 2]" r O) -3 (1) 0,-t- q) --4 OJ c- t-J" (1) CT t- Ct) W (1) CL to O 13) - 0 c-I- fl) tO q):-I Cn 0.) _I H (I),-4- (.E) %1 F--i 5.) [ O ('D 0 -" 0 (t) b-' tO L7_ -r.l r-+ "..-J 0) L.T q) O C) (1) (i rl q) 0 O_ (- 2) 0 --:J U3 0 [_3 I-" " 0 o F,. T.] '- "C) (D - (J - - O) ('I) I" I-'. I--I 71 2[] (.'3 (1) c-" () -H C.,L -J _" T (I) T] <" (O CO CD -'- 2} r 2]) 0 C) [l e. OJ U) 0 0 (D 0 0 I-. U I-" CD (1) FI C t'I) 0 (3. (n 0 ', ( E (3_ 0 U) (23 F- t-'- (l) bO I--J t-'. 1- x "-J CO I-o I (13 O. ---4 (D -.-'- (0 (1) 0 CO (1):) n O) 0 2)2) fO e. H- Oo 4-:-3 0 U F.-,. -} O) F-. C,.--t- (D -I 0 I--'- 0.

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T fD LO Z3 W 03 t- (3 O) J- c+ -.

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CI) I I--'J Co F-,. 0 Z3" 0 nO N N 0 " H (1) (1) 13 -+ -1 El- ('D (13 _-T 4- CT OJ - (1) 0 C1 OJ 2] I 0 1 ('0,-+ "-rl 0 0 o 0 - -I < O_:3" (13 - C} (D 0 0 0 "l 0 -,bO 0 2) Ol 0 O0 C I-'. m Ol ('0 I-'- i.0 I--I II- < -I:3" i-.

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< i.J.

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c+ 0 U1 211" 0 (1) 3 1 X3 Ill 13) I' -F 0 F-'.

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0 0.) 0 U CO (3_ X fD (ú3 (D IòT (D ZI" ('D O) (3" U) 0 (D O. 0 U) OJ {ú3 O3 -+ Z)(D I (3O I !0 From Table VII it appears that the antiarrhythmic activity of the 'compounds of the invention surpasses that of the known compounds used for comparison.

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Antianginous activity on rats The antianginous activity of the compounds was determined on anaesthetized (for this purpose chloralose urethane was used) male rats weighing lB0 to 220 g according to Nischultz -Arzneim.-Forsch.,, 680 (19557. An experimental coronary insufficience was developed by the administration of glanduitrine - an extract of the posterior lobe of pituitary - at an intravenous dosage of 4 IU/kg. The height of wave T in ECG was measured before and after the administration of glanduitrine in both the control and treated groups, and the inhibition provided by the compounds tested was calculated. In the test, prenylamine -3,3- diphenylpropyl-1-methylphenetylamine lactate7 was used for comparison.

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Table VIII .DTD:

Compound Dose Inhibition (Example No.) in mg/kg in percentage 12 55.4 21 31 83.6 prenylamine 2 41.3 IòX re O ET O) I--,- 11) O- r+ (I) "13 _--T o) 0 CO C I-,- 0 oJ C) r+ I.-'- I--'.

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[I) (.('] O I L--) l0 additive.

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The additives of the liquid pharmaceutical compositions used for oral treatment are preferably suspending agents such as sorbitol, sugar solution, gelatine, carboxymethylcellulose etc.; emulsifiers such as sorbitane monooleate etc.; solvents such as oils, oil esters glycerol, propyleneglycol, ethanol etc.; preservatives such as methyl phydroxybenzoa e etc.

Pharmaceutical compositions suitable for parenteral administration consist of sterile solutions, in general.

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The pharmaceutical composition of the invention contains, in eneral, 0.1 tO 5.0 per cent of the active substance. A typical dose for adult patients amounts to 0.1 to 20 mg of the compound of the formula (I) or a pharmaceutically acceptable acid addition salt thereof, daily. The actual dosage is determined depending on many factors such as the state and person to be treated, the method of treatment etc.

The invention is further elucidated by means of the following Examples.

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A) /-d - _,i/ 1,3,6_Tdioxazocine (m. p: 189 to 191 C), 150 cm) of anhydrous toluene and lg.5 g (0.17) moles) of chloroacetyl chloride is heated to boiling point and refluxed for 2 hours. Then, further lg.5 g (0. 1?) moles) of chloroacetyl Example i 12H-12--(4-Me hylPiperazinyl)-acety7-dibenzo-d,7-l,3, 7dioxazocine dimaleate A mixture of 30.0 g (0.141 mole) of 12H-12-dibenzo- O kfl i-= O - I5).. ' I I-" II-J r+ U1 I- "'4 "--I O e-J N e-' O CL o\o o\o I "I" -r". o\o t Ux o\o \o I"0 0 I'-0 Z Z O C-I! F.- CO ! cD a OO (3J I o\ o"P (D (0 rF" O "-2'- ET ".,.-" T_.I N l..J, ::::I -,. m T9 e. (0 --- C:

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O E bE) x "21 I-'. ('I) 0) 0 U I"-) r- - i- I) 0 El. P-I F-- C-i 0 O. < {0 (D CD C'I) 0 CO U) CD to. 0 . F-h 1 N CIJ!,. I-'.

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CO C: 0 El. I-'- "_'] -+ C- Ul [:) OJ -" I,-'. rI- CII -I- (J1 O CO 0 J -. ':. (0 -1 b-,- r-± U1 0 N Z]- LT m "13 (D CO CO I- 0 - 0 =-] El- Co C CO f% "-J :.3 C N - CO CO ",-/ :3. _7 rj,.

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CO x e-o _-7 W 0 e- Ox I ('D I n 0 t.o I x - 0 0 -h N --] 0 0 I -" (D 2) On -Z 0 "- I-- t "h "U L_ - IJ' r'..) T2]:.l.

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) t--D N 0 I F-'- l'-h /- CO O l ::3" 3;" (2 0 0 0 I-- I U1 H) oo 0% r-,o k3 ::2 l.-J b.O (7 I--' r-o r%D Fl (7 C r+ D C-) 0% r,o kO o\ -r CO o\o C-) Ix.) ox, C o f Ul I-h 0 H I bo Z E3 CO H-" 0 ('3 - D N 'I 0 ' tn n ---I m :r r- n n F... -o 0 tn N 1 t-I 0 0 0 o\O " F- v ( C CD I' 0 n I 0 oo (- I n I.. I L F-,0 ('I) n (I) CD -h I--,.

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i--J CD n E :3" C n :E i-.

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:3" :E_ C + -I n "I0 0 C ed ('0 O.

l..J.

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re (-l C 01 :3- ('0 Cl.

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I-'.

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r- -I C1 (0 Or) I-,.

.DTD:

O] :3, 0 C Id 0-h F-h C 0"-I O I-- 0-9 CO "-4 C I..

.DTD:

X (2 I..

.DTD:

CS Cl O O (I) r4- O Ln O O.9 O.

13.

.DTD:

('i) ('1) o.

(]_ 13.

.DTD:

('1) X C O) T -+ i.

r- (3_ ! I I0 C) To a stirred solution of 8.4 g (0.024 moles) of 12H-12--(4-methylpiperazinyl)-acet>7-dibenzoL-d,ú7L-1,3,67dioxazocine iq 100 cm3 isopropanol, a solution of 5.6 (0.048 moles> of maleic acid in 30 cm3 of isopropanol is added at 20 C. The reaction mixture is stirred for 2 hours, then cooled to 0 C, stirred for a further hour, the product is filtered, washed with isopropanol and recrystallized from methanol.

.DTD:

10.5 g (74.7 %) of the title compound are obtained.

.DTD:

M. p.: 179 to 185 C. Analysis for C28H31N3011 calculated: C 57.45 %, found: C 57.58 %, (585.572): H 5.34 %, H 5.31%, N7.18%; N7.06%.

.DTD:

Example 2 .DTD:

12H-12-L-(N-Cyclohexyl-N-methylamino)-acety!7-dibenzo-d,ú7-l,3,2dioxazocine maleate A) A mixture of 13.0 g (0.045 moles) of 12H-12-chloro- acetyl-dibenzo/_-d,7-l,3,Tdioxazocine, 150 cm3 of anhydrous benzene and 52.2 g (0.28 moles) of N-cyclohexyl-N-methyl- -- amine is heated under reflux for 8 hours. The product is isolated as described in Example I, section B) and recrystallized from isopropanol to give 13.9 g (84.2 %) of 12H-12-L-(N-cyclohexyl-Nmethylamino)-acety!Tdibenzo8,ú7-l,3,TdioÎazocine. M. p.: 103 to 105 C.

.DTD:

Analysis for C22H26N203 calculated: C 72.11%, found C 72.17 %, (366.,63):

.DTD:

H 7.15 %, N 7.6a. %; H 7.18, N 7.60 %.

.DTD:

V1 O V O V1 O O O i0 B) A mixture of 15.0 g (0.046 moles) of chloroacetyl derivative prepared in Example 3, section A), 180 cm3 anhydrous benzene and 1.7 g (0.30 moles) of isopropylamine is heated under reflux for 4 hours. The organic solvent is removed under reduced pressure, the residue is mixed with I00 cm3 of diethyl ether and BO cm3 of water for 30 minutes, The organic phase is separated, dried over anhydrous magnesium sulfate, cooled to 0 C and treated with diethyl ether saturated with hydrogen chloride under stirring until a pH value of 4 is reached. The crystals are filtered, suspended in diethyl ether and filtered again. The process is repeated twice, and the product is recrystallized from ethanol to give 13.0 g (7.0) of the title compound as white crystals. M.p.: 235 to 240 C.

.DTD:

Analysis for CI8H20CI2N203 (383.282):

.DTD:

calculated: C 56.A1, H 5.26, C1 IB.50, N 7.31, C1- 9.25; found: C 5.6.15, H 5.6D, C1 17.96:, N 7.16, CI- 9.DB.

.DTD:

Example .DTD:

12H- 12-- ( A-Met hy I p i p e r a z i n y i) aoetyl_7-2oro-cbezo_/B,/'l,3,Tdioxazocine dimaleate A) A mixture of 49.0 g (0.129 moles) of 12H-12-chloro- acetyl-2-chloro-dibenzoL-d,7-l,),Tdioxazocine, 80.0 g (O.BO moles) of 4- methylpiperazine and 410 cm) of anhydrous benzene is heated under reflux for 4 hours. Then, the organic solvent and the excess of 4methylpiperazine are removed under reduced pressure. To the residue, 150 cm) of benzen'e and i0 cm) of water are added, the mixture is stirred for I ! calculated: C 54.24, ound: C 54.18, 27 - H 4.88, H 5.12, C1 5.72, C1 5.70, N6.78; N6.62.

.DTD:

lO Example 5, .DTD:

12H-12--(N-Cyclohexy1-N-methylamino)-acety7-2-chloro-dibenzo-d,7-l,3,Tdioxazocine maleate A) A mixture of 35.0 g (0.108 moles) of 12H-12-chloro- acetyl-2-chloro-dibenzo-d,TL-l,3,Tdioxazocine, 350 cm3 of anhydrous benzene and 2 x 76.9 g (2 x 0.678 moles) of N-cyclohexyl-N-methylamine is heated under reflux for a total of 12 hours, The product is isolated as described in Example 4, section A), The crude product is crystallized, then recrystallized from petroleum ether to obtain 32.1 g (79.8 %) o% 12H-12-L-(N-cyclohexyl-N-methylamine)acety7-2-chloro-dibenzo-d,úF-l,3,Tdioxazocine. M. p.: 93 to 95 C.

.DTD:

Analysis or C22H25CIN203 (400.909):

.DTD:

calculated: C 65.91%, H 6.29, C1 8.84 Q, N 6.99 4; found: C 65.60, H 7.00, C1 8.89, N 6.61.

.DTD:

B) 30.0 g (0.075 moles) ol 12H-12--(N-cyclohexyl-N-methElamino)-acety7-2-chloro-dibenzoL-d,ú7-l,3,7dioxazocine are reacted with 8. 7 g (0,075 moles) of maleic acid as described in Example l, section C). The product is recrystallized from methanol to obtain 34,8 g (89.7) of the title compound. M.p.: 191 to 193 C.

.DTD:

Analysis for C26H29CIN207 (516.980):

.DTD:

calculated: C 60.4!, H 5.65, C1 6.86, N 5.42; found: C 61.23, H 5.92, C1 6.79, N 5.30.

.DTD:

V1 C3 k 0 0 C O.

Z Z V'l C3 Ox o\o o\ ++ I CO I lO Example 7 (2)-12H-12--(2-Methylpiperidinyl)-acety!7-2-chloro-dibenzo-d,7-l,3,Tdioxazocine hydrochloride A) A mixture of 32.4 g (0.i0 moles) of 12H-12-chloro- acetyl-2-chloro-dibenzoL-d,7L-l,3,7dioxazocine, 39.7 g (0.40 moles) of 2- methylpiperidine and 250 cm3 of anhydrous benzene is heated under reflux for 4 hoursòThe reaction product is isolated as described in Example 4, section A). The crude product is crystallized, then recrystallized from isopropanol to obtain 30.B g (79.6 9) of (1)-12H-12--(2methylpiperidinyl)-acety!7-2-chloro-dibenzo-d,72-1,3,Zdioxazocine. M p: 90 to 92 o Analysis for C21H23CiN203 (386.882):

.DTD:

calculated: C 65.20, H 5.99, C1 9.16, N 7.24; found: C 65.01 9, H 6.33, C1 9.15 &, N 7.08.

.DTD:

B) 9.6 g (0.0248 moles) of the base prepared in section A) is treated with diethyl ether saturated with hydrogen chloride as described in Example 3, section B) to give 10.3 g (98.i) of the ti ie compound. M.p.: 146 to 154 C (decomposition).

.DTD:

Analysis for C21H24CI2N203 (423.342):

.DTD:

calculated: C 59.58 9, H 5.71, CI 16.75, N 6.62, CI- 8.38 9; found: C 58.45 %, H 6.11%, CI 16.92 %, N 6.65 %, CI- 8.47 9.

.DTD:

C3 Co o\o o\O -.I "--J J O[3 I- I--' o\o o\ lO Example .DTD:

12H-12-Morpholinylacetyl-2-chloro-dibenzoL-d,7- L-1,3,Tdioxazocine maleate A) A mixture of 25.0 g (0.077 moles) of 12H-12-chloroacetyl-2-chloro-dibenzo-d,7-l,3,Zdioxazocine, 30.4 g (0.35 moles) of morpholine and 250 cm3 anhydrous benzene is heated under reflux for 3 hours. The reaction product is isolated as described in Example 4, section A). The crude product is crystallized from hexane and recrystallized from isopropanol. 24.9 g (86.2) of 12H-12- morpholinylacetyl-2" -chloro-dibenzo-d,7-l,3,Tdioxazocine are obtained. M. p.: 123 to 125 C.

.DTD:

Analysis for C19H19CIN204 (37&.827):

.DTD:

calculated: C 60.8B, H 5.11%, C1 9.46 9, N 7.47 %; found: C 59.70, H 5.70 %, C1 9.52, N 7.21%.

.DTD:

B) 20.0 g (0.053 moles) of 12H-12-morpholinylacetyl-2-chloro-dibenzo'd,7-l,3,Zdioxazocine are treated with 6,2 g (0.053 moles) of maleic acid as described in Example I, section C) to give the corresponding maleate that is re- = crystallized rom ethanol. Thus, 20.2 g (77.7 9) of the title compound are obtained. M. p.: 197 to 199 C.

.DTD:

(90.B98).

.DTD:

Analysis for C23H23CIN208 calculated: C 56.28, H a.72, C1 7.22 %, N 5.71%; found: C 56.71, H 4.88, C1 7.23, N 5.72.

.DTD:

0 r- "1 n o --.,I I C3 C:) a t") Z 0 C (i Ox k 0 I-o o\ I (Tx k.n o\ O0 (3) 2) I--" I--' O O F-' X C "< O) H (.rl N 13) I-'. 0 rb (# (1 C0 I--'.

.DTD:

- 0 (D (-3 C-) " 0"x F- bo Q3 %) I .j b..

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C) "--J (-] CO \ I- C3 Z bO l- ZE O O %4 4- (30 --J O - C-) o\O..

.DTD:

CO C3 O O C) 1",,3 CO o\o Z i-a 1"O o\ C3 I - ---4 CT I -1 " "1 0) I',O O (1) O 3 I - I]. N O C I'I) -< CO C r- CO (7 4- O.

I- -1 C0 I' '" O 0 Ol O0 -I F- 3" 0 C. 0 Ol (1) "13 C1 O I- CO O 03 {1) ( r-I-,-4- 1- (3.

.DTD:

ZT r0 t-4. (1) I-'. n t- O rl r4- O (.8 (I) I O I-1 O O r) (1) -I CO El" car (J 17) c4-,-4- O H - 13.) I- I- I I'- I-. F- I-" C "-4 =' C7 X I N (I) b0 b- q) CI.

.DTD:

0 (3O (I O O " O {13 --I" f - 0 O I 0", 33 O O " - I " (1) "-4 7" D 0 0 ! " b-,0), 0 i0.

.DTD:

! Z O O U1 v O t") O O O I'D C& tO C3 O O O C]" 13.

.DTD:

O (I) rl- ! 1",3,! I (3.

.DTD:

O E] I--'" ]:7". ET I- X CD O rl- 1 '- N O 1 O J (1) -- (3.

.DTD:

" O (3.

.DTD:

21 ""-4 O! ! D " O 12) F-- U1 X m 12) N m 12) - I,-" r,d fD! O Î 2J" O ! I I r'O I I- I r,O I t--) O O 13 -1 O I-,.

.DTD:

O I O CO rt- ! bO ! t") O O ! m o i t ! lO Example 11 12H-12-Diethylcarbamoyl-2-chloro-dibenzo-d,7'l,37dioxazocine An 50 percent dispersion of 4.8 g (0.10 moles) of sodium hydride in mineral oil is added to I00 cm3 of dimethylformamide at 25 C under stirring. Then, 24.8 g (0.i0 moles) of 12H-2-chloro-dibenzo-d,7-l,3, Tdioxazocine are added to the mixture at a constant temperature of 25 C. The reaction mixture is heated to 40 C and stirred for an hour at this temperature, then cooled to 20 C. 20.3 g (0.15 moles) of N,N- diethylcarbamoyl chloride are added to the mixture, then the reaction mixture is stirred for 16 hours at 40 C, 120 cm3 of water are added to the mixture cooled to 0 C. The viscous oil formed is separated, dissolved in 150 cm3 of benzene, washed with water 3 times using 80 cm3 ol water each time. The organic solution is dried'over anhydrous magnesium sulfate, the solvent is removed under reduced pressure, the residue is reared with petroleum ether to induce crystallization. The crude product is recrystallized from isopropanol. Thus, 22.9 g (66.0 %) of the title compound are obtained. M.p.: 93 to 95 C. Analysis for CI8HIgCIN203 (346.823): calculated: C 62.34 %, H 5.52 %, gl I0.22 %, N 8. 0B %; found: C 62.83 %, H 5.45 %, CI 10.48 %, N 8.00 %.

.DTD:

* --'7 I I t - 35 as a brown, viscous liquid.

.DTD:

lO C) 30.0 g of the crude base prepared in section B) above is reacted with 18.6 g (0.16 moles) of maleic acid as described in Example l, sec%ion C) to give the corresponding salt that is recrystallized from methanol. Thus, 24.6 g (67.0 %) of the title compound are obtained. M.p.: 185 to 187 C.

.DTD:

Analysis for C29H32CIN3011 (634.041):

.DTD:

calculated: C 54.94 %, H 5.09 %, C1 5.59 %, N 6.63 %; found: C 54.74 %, H 5.46 %, Cl 5.56 %, N 6.52 %.

.DTD:

EÎamole 13 12H-12--3-(Oiethylamino)-propiony!7-2-chloro-dibenzoL-d,7L'l,3,6_Fdioxazocine hydrochloride A) A mixture of 53.8 g (O.lO moles) of 12H-12-(3-chloropropionyl)-2-chloro-dibenzoL'd,F-l,3,ZdioÎazocine, 2 Î 29.2 g (2 x 0.40 moles) of diethylamine and 250 cm3 of anhydrous benzene is heated under reflux for 6 hours, altogether. Th% reaction is performed and the reaction product is isolated as described in Example 4, section A). The crude product is crystallized, then recrystallized from n-heÎane %o obtain 30.9 g (82.5 %) of 12H-12--3-(diethylamino)-propiony7-2-chloro-dibenzo/-d, 7-l,3,Ydioxazocine. M. p.: 6B to 72 C. Analysis for C20H23CIN203 (374. 870): calculated: C 64.08 9, H 6.1B %, C1 9.46 9, N 7.47 %; found: C 63.52 %, H 6.61 9, C1 9.59 9, N 7.25 9.

.DTD:

O C1 ('3 t-J.

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O CI) l--'- X O #-,.

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O ..J cl) O "d (i1 c4- #...

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N 0J I i-..o C7 Lm --" CO O) 03 0 N F- --4 0 O) I t.O,-4- 0 I 7- (I) 0! Z O "4 1 m x I"- r--- O) I I n N l-a I O I (,rl o,,.,4 (I lJ" "o I-" m CD "'4 0 0" I-" O3 x XD (1) m "< N FJ. 0 I1) U'I (") 3 0 m 0 (I) t.n I"D "1 i.. 0 () f-),.,.- 0 I--' --4- c- M 17) bo -.- fl kT_. c -j I-'. 0 F.. n CO -+. x 0 O) (0 "7 1 T -t-.

.DTD:

L' 0 (1) i-1 1 0 Q3 C O) r',, --I I,,b zr CT X I"t N 0 " I o I.D.

.DTD:

CO 0 tn 3 Cl -7 0 I-,7 "0 0 X 0 rl 0 I I-1 a "J 0 7.3 e-,.

.DTD:

rO 0 0 11) "0 + + x 0 -h 0 CO 0 -" 0 I.% 0 r" n 0 I CO " 0 k.4 t- O 0 0 -1 O. I',o I I--,. ['J" I I I- "-1 I'0 [3 f- N I ZT fO ' I 0 I %4 I'I 0 O_ I 0 I- f' O. 4 "'.4 U I--,. C3 I'. 0 ET I -0 CO C3 :3 0 N (C) %4 "0 o o., "< I CD ".4 n 3 IZZ?. " "..4 ",43 x 0 I N I I- 0 0 13 -- Lo -'J "t.3 I ('D I., o., ""-J 0 i.-.,,....,.

.DTD:

0 O. -' W bO 0 I N C') t',,J 0 I " I t'-) i.- F (7 -'") 0 7J" I fO 0 0 I Z3" 0 I I H 3 0- oo kl OJ O3 0% bO 0% o\ o\o., I 0% CD "4 o\ (7 F- I-..

.DTD:

l-J O% C O0 c,\o (7 I CO o\o (I) U) I-" U) H) -) I'-0 C3 I f'O (7 I",0 Z C3 O C b 0.) EL o (7 k (3O C3 O3 Co I-", \o I- b,.) ",4O t.-- Z O CO o\o t - F-' O% + O (O CO c 1"-,3 F- O (-3 q) - (1) - O n o\ 0) (3.

.DTD:

0 H, el (1) < r4- 1t--'" I1),-4" CO I- N O (3.

.DTD:

O 1 r- 0 Cl.

.DTD:

I-1 O r0 "TJ I--t O O 13" "O I- 0J 0J _-'3 1, O t- (3_ --4 C (/% < Z3" O 1)< O b-'17 O C I"I (0 0 CO tO (3.

.DTD:

O (8 I-h:3 " O 4 O :3" O -4 O O CO I- - 17 (1) " iò(.

.DTD:

X I-'. O 4- "7 "13 ('- Id (3. 0 fl) 0 "O I--,- tO "1 (/% O O --'- (3. O d H "13 O t-1 (3- I-1 I-'.

.DTD:

I-b t.

0 ' t- ( (13 OL 0 (3.

.DTD:

C - r (- (0 CO (13 0 m 7" (0 ( 0 I 130 0") I"1 0") 0 O I-.

.DTD:

< O O. "< (3O I'-" I..-'. ""-4 ro Q3 ..4 I {23 O 2I" O O O O %4 1.-.1 O O I 3 17 O Io O Z3 _ a I-1 O O O I H " I O3 (3.

.DTD:

0 -r ---I I 21r uI --o --.

.DTD:

t- o CD x r+ -"" -t 0 CO r4- -I I I I tion from ethanol, 25.8 g (73.0 %) of the title compound are obtained. M. p.: 240 to 243 C. Analysis for C19H22CI2N203 (397.301): calculated: C 57. 44 %, H 5,58 %, C1 17.86 %, N 7.05 %, CI- B.93 %; found: C 57.66 %, H 5.45 %, C1 17.86 %, N 6.98 %, CI8.92 %.

.DTD:

lO Example 15 .DTD:

12H'12-(3-Pyrrolidinyl-propionyl)-2-chloro-dibenzoZ-d,RTZ-l,3,Tdioxazocine maleate A) A mixture of 25.0 g (0.074 moles) of 12H-12-(3-chloro- propionyl)-2-chloro-dibenzoZ-d,TZ-1,3,Tdioxazocine, 21.3 g (0.30 moles) of pyrrolidine and 250 cm3 of anhydrous benzene is heated under reflux for 3 hours. The reaction product is isolated as described in Example 4, section A), the crude product is crystallized from petroleum ether and recrystallized from the same solvent to obtain 21.8 g (79.0 %) of 12H-12(3-pyrrolidinyl-propionyl)-2-chloro-dibenzo-d,7Li,3,7dioxazocine. M. p.: 115 to I18 C.

.DTD:

Analysis for C20H21CINz03 (372.B54):

.DTD:

calculated: C 64.43 %, H 5.68 %, CI 9.51%, N 7.51%; found: C 64.00 %, H 5.12 %, CI 9.61%, N 7.40 % B) 20.0 g (0.054 moles) of the base prepared in section A) above is reacted with 6.4 g (0.055 moles) of maleic acid as described in Example i, section C) to give the corresponding salt that is recrystallized from ethanol. Thus, 22.7 g I oO I O o\o u\ I Z o\ (]3 r"l CC) r"l r'"l o\ OC) "1"" o\o o\ o\ r--- o% l0 Example 17 .DTD:

12H-12-(3-Mozpholinylpropionyl)-2-chloro-dibenzo- -d,TL-l,3,Tdioxazocine hydrochloride A) A mixture of 25.0 g (0.0?4 moles) of 12H-12-(3-chloropropionyl)-2-chloro-dibenzo-d,TL-1,3,Tdioxazocine, 30.4 g (0.35 moles) of morpholine and 250 cm3 of anhydrous benzene is heated under reflux for 5 hours. The reaction product is isolated as described in Example 4, section A) and crystallized in n-hexane. The crude product is recrystallized from isopropanol to obtain 23.9 g (83.0) ol 12H-12-(3morpholinylpropionyl)-2-chloro-dibenzo-d,7-l,3,TdioÎazocine. M. p.:

.DTD:

122 to 125 C.

.DTD:

Analysis for C20H21CIN204 (388.85&):

.DTD:

caculated: C 61.78, H 5.44, C1 9.12, N ?.20; found: C 60.98, H 5.93, C1 9.21, N ?.03.

.DTD:

B) Cl-8.34; found: C 56.92, H 5.35, CI 16.77, N 6.55, CI- 8.36.

.DTD:

15.O g (0.0386 moles) of 12H-12-(3-morpholinylpropionyl)- W]3 O1 "[3 3- " -J U1 IJ] bO O_ -' W,-4-,I C O O -+ - t-" 0 - 0 n. 0 x 0 ft" (J1 O. CO -'] I)J T r- 1",3 O - O _ -'--4 C1 CT 3.

.DTD:

I-1 I (O (1) O CD X C--) IO (0 t-J I1) ---I 3 t- O -J I CO UJ N @ " F- (Tx bO (") O (3; I'D CO (J1 t-j r-t t) b- O U) (1 Ol CD O O C-) k O,\o 00 1 O CO (I) o\ F- I F- -. b. rF 0- 4 0 " 0 I'D 0 " I C) C- t-h O El. O ('D 23 C2) Or', N I+ -1 (. O. ' CI) r.o - O I I (D O I-1"1 "13 73 - O I I- O X 23 i-4.!--'- 0 (-'3 o\ I--' QO v o.

I-,0 oo Z r--- 0", o\o (3_ r i-1 ( tl O_ 113 O O --.j F- t- i- O3 IN I',3 0.1 (1) (1) N =:t I I 1- CD I-,. O I I..-,. CD I--' (D CT ('D I ('D I. ' X I < "0", O. ('I) O.:3 CO -d O ('3 O. O O CD O O O O X:::t O. O X 23" N "< I-,. O 3:> O O O O O trl (1) - O "1:3 O O O, 0 I--,. I-'. 13 O l- r 13 I'D I1) O ' " O H 0 0J D3 D3 t0 -J N 3 CO O O I'D m.-,. 0 I- e- -< -'o CI. O. I- t- N (1) C, I c2 b- 3) r- ( F- I-'.

.DTD:

C) I-- b 1 " T (- 01 O_ C ' I-'..bO ' U% CO CD CO I UI 0 (] O I--'. el) ix0,- I.--',- (I) N o_ I m m o i -- I (3) I- (3. I I C') I + X O_ H,, FJ (1) I ( - O,-. 13. C (3. O- -,. I-.-' I i,, O ox Ox -. O (3. I 0 (3.

.DTD:

32 23 (1) t- O I..-,. I'-,J k (3o I- t- (.n CI) O 13" I bo ho k,4 k.n o -h (C - -h I-,-- (-3 t bO F- " I r-I- ". ET X I%) O I Z O m'O O) (3_ kl I 212 C3 '. (3. -h C3 " I 4> -.. O) O O O (3. I "43.-..4 k.,4 O O r'rl I-.-, O I..

.DTD:

C-) "13 X 5 (1) O O I '< o\ o\ 03 130 0 j..a F_ r-o - o 13 O ('0 O 4 I-,.

.DTD:

C-) (7 C3 uu. b-' L H - - "O t bO.. "-- - --t I V F. C1 13) t- O kl 3" (1 O (0 -" N I- CI) (J) O --'" I-0 ',43 I- v X -.J O (1D t- W 0 N I- o\O o\O (.[2] Ill 0 0 I-'. b-" O " 0 O I O O I- i-- I-,- "13 O "13 m -r (1) O r-> 4> a 2) " I "13 O k.n v O:3" t.

I--, b- O "I3 "< I I 0 C3 - I-. o\o I-1 "< O. O 3 o,O o,O o o. o m I 0 r0 C 0 - 0) H O T U - (I) I ('D ". O I I I I-'.

.DTD:

(3- ! O I lO C 61.98,, H 6.60 4, C1 8.93 4, N 10.20 4.

.DTD:

C) 13.0 g (0.0]2 moles)of the dioxazocine base prepared in section B) above is reacted with 7.6 g (0.066 moles) of maleic acid as described in Example I, section C) to give the acid addition salt. After recrystsllization from ethanol, 17.i g (84.2 4)of the title compound are obtained. M. p.: 177 to 182 C.

.DTD:

Analysis for C29H32CIN3011 (634.041):

.DTD:

calculated: C 54.94, H 5.09 4, C1 5.59 4, N 6.63; found: C 55.27, H 4.89 4, C1 5.63, N 6.61.

.DTD:

Example 19 (3)-12H-12-(2-Pyrrolidinylpropionyl)-2-chloro-dibenzoL-d,7-l,3, Tdioxazocine hydrochloride A) A mixture of 28.0 g (0.083 moles) of (t)12H-12-(2-chloropropionyl)-2-chloro-dibenzo-d,TL-l,3,Tdioxazocine, 21.3 g (0.30 moles) of pyrrolidine and 250 cm3 of 8nhydrous benzene is heated under reflux for 10 hours. The reaction product is isolated as described in Example 4, sec ion A). The crude product is treated with petroleum ether to induce crystallization, and the crystals are recrystallized from the same solvent. Thus, 24.9 g (BO.3) of (t)-12H-12(2pyrrolidinylpropionyl)-2-chloro-dibenzo-d,7-l,3,Tdioxazocine are obtained. M.p.: 98 to 102 C. Analysis for C20H21CIN203 (372.854): calculated: C 64.43 4, H 5.68 4, C1 9 51 4, N 7.51 4; found: C 63.89 4, H 6.03 4, C1 9.60, N 7.43 4.

.DTD:

O C oo [] I"..3 o\ I o\o I---' .j o\o Z -..J ...] o\o n O x 00 N O O (I) O3 O O n I oo O O O 0 {7 :IT CO OJ 3 ('0 U} O F-J < CO I UI O 7O O 12) 0) O O --4 O C ! (3O I',.) I O 2J" (O l--J O -j...j O I O. b- N O O - i.

I f'" ! r,J 212 "-4 t! O t'}..-4 CO U1 - (-I 0J 1 C I-, Cb N 4- 1 I-. O O EL D C (7 Co I- O- (.n (1) 0) Oo O r+ wl (1) U1 4-:E 13) I-'.

.DTD:

:3" (3) CO (1) U1 -I- l-. N O (3.

.DTD:

Wl O B O CO -O C3" O "7 O- N -4 E CO O "1 LO r4- (1) I-'. 1-"" C) U) U) 1",3 " 23- t U1 (1) O 0 9 r4- O. CO fD U1 [q_. C "J 0 O. O U1 (1) H (-'1 I-- CO - tO 01 (1) O -" C O ET X I3 O. H b-' O W "1 "13 2 -" CO Ox --3 177 CO O 0 O 0) C.

R:) -1 O.

-'- --I C) qJ O (1) '1 k.,4 O q) [U O O O r" --- I-. (] 3 2J n C ! (Q :2T i-J O rl O "13 0 "13 F-a Y w 21 (3_ 0 C O_ I+ F...

.DTD:

-. LT I x q) F r+ l l.) C N:I:

.DTD:

w- O I (3) I-.

.DTD:

I bo (2) (21_ I I t',O C] t "'-,4 I I Lrl O Lr3 %,J - O.,, T3 U" n N C23 X -' O 0J _-3 I' N o I O O l_] C3. O,-1 0 ('0 P-" (D Co U I'-. 1_7 O:

.DTD:

i4 C) l O bO "--4 I:I" I EL i- O " b0 O 73" C] I X I I-" 0 O --' O.

N (1) O O I I (7 z--- I" I >- O b--h O C 23 O.

(-3 (-3 - I k.M --d o\o T o\o C"I k.,4 oN':' U', M) o\o ! o\o o) PI b- 0p (I) O t-J - "-< 0 I-O3 O" I F.,. r+ fl) I" (3- H 2] - O (9 - O- (7 (7 O3 O 7- "13 OX bO 3 1".3," O o\o I bO I"O Z 4 32 O O rt- V1 4 O 4P" I bO r bO ",40 O O ('3 k4 I--' I- I-- v J,, k4 Ix0 o\o Z 0", CO p- o\ (3- 1 CO O tn w-I to O- O (1) 13 n O I--'.

.DTD:

(1; :3 m o x t- (3) i- i--, -I> Co (13 o3 1..., (I) (3o f) C3 - 4 O v 13o O H -+ CO I' P1 r+ (1) (1) 1 O In O "13 O I- r- F-.

.DTD:

"7 N i.J.

.DTD:

O "1 U (1) O i. F.J O Ox (23 :P> C3 O < O El) 4 k4 i....

.DTD:

to 5] O O F O 0) 7 n CO O O. r+:2T O CL I--,.

.DTD:

:T O (1) X I); :3" N "- O O. (3 O O (l) :T O 0) I-,. ('D n (l) "13 01 13 (1) I:L I p.

bO I B) i0.0 g (0.0277 moles) of dioxazocine base prepared in section A) above is converted to the hydrochloride as described in Example 3, section B). After recrystallization from isopropanol, 9.6 g (87.3 %) of the title compound are obtained. M. p.: 224 to 227 C. Analysis for CI9H22C12N203 (397.304): calculated: C 57.44 %, H 5.58 %, C1 17.85 %, N 7.05 %, CI- 8.92 %; found: 0 57.44 %, H 5.70 %, Cl 17.6} %, N 6.94 %, Cl- 8.90.

.DTD:

Example 21 (t)-12H-12--2-Methyl-3-(4-methylpiperazinyl)-propiony7-2-chloro-dibenzo-d,7-l,3,Tdioxazocine dimaleate A) A mixture of 26.1 g (0.Ii moles) o 12H-2-chloro-di- benzo-d,7L-l,3,Tdioxazocine, 300 cm3 of anhydrous toluene and 39.0 g (0. 21 moles) of 3-bromo-2-methylpropionyl chloride is heated under reflux for 8 hours then cooled to 25 C and poured into 300 g of crushed ice under stirring. The mixture is stirred for 2 hours; the organic phase is separated, washed with 3 x I00 cm) of 5 per cent aqueous sodium bicarbonate and IO0 cm3 of water, and dried over anhydrous magnesium suIfate. The soIvent is removed under reduced pressure, the residue is treated with isopropanol to induce crystallization, and the crystals are recrysiallized from the same solvent. Thus, 33.2 g (76.1%) of ()-12H-12()-bromo-2-methylpropionyl)-2-chloro-dibenzo-d,7-l,3,7- O O" 0) O- 0 O O O O I",,9 O (1) 01 O O.

:3" ('I) 13. iòO X N O O O U1 i.

0) O O (1) O O 'I 0 "-I tn ('-) O (1) I-I - (1) O l-J. (1) < O.

(1) O r- -1 13.

.DTD:

C'-) 03 C3 o\ "1- --4 F-- (30 0", k4 Z O0 o\ O r- (0 o0 o ('3 E0 I k, bo (-3 o\o I- Z o\ O0 IO o\ Z I--' C) o\o 13_! 0) O (O I- X -< 0 ZT Ill N q( O 13 -1 "13 (1) n0.0 bO CO O b--' k..4 )--, k.rt O t- .O o.

O 0 O,,-4O.) F-," )-'J O3 N 02] "O O \o O O 1 I+ I I 1- t,O 0 I 0 I! CZ I- I.-. I O" t-d t D -3 N t'I) 0 e4- I"::r n I M I O O E- El 0 r4- ElL I"" Ln r-t- :3" CO (7 Ln -+ i-J q [l) (1) (1) f3 Q.I . .DTD:

N (I) O_ O ! X u U1 O r-l03 (3.

.DTD:

(1) 13) r ED O- r-l- L3- "E) fO ( (D -+ T CO r [I t- O ( r+ F N I r+ [1) 23- ]3" O- (Jl [IJ --4 U' =" CI" (1) (1) ro,-1 N Ln r q) E1 D [3" t--t.-.

.DTD:

(1) O UI El I, I-,- CD Ul 0 X (I) O_ "13 O b- - (21_ q) r0 (1) - --- {2).

.DTD:

0 (1) (1) El.

.DTD:

() r- r-l- r+ X O (1) H O ('0 O ---4 --" O 2T O r- Ul - O O. (3.

.DTD:

O I'O nO 0o x 0 -- t-,.

.DTD:

O O [:3:> 3 t -]3 O. t..-,.

.DTD:

t-,- X E= N [3 1",,.3 I"- ",,D --3 kin (rid h] O3 ---3 "O r.J 0" (9 "O tO r0 O O O..

.DTD:

H (23 -P" 1".,3 I tn 9 (1) (1) O r O t--' 2]- '+ ('0 O -O D "I3 " -- 00 0) ET N ET (1) - O < 13- (1) (1) I"t " O O ('0 l:3" '- O I kA Z %4 k.n I'O o\ O O.

o\ "1- %,4 O0 o\ [30 1",3 C3 I'O CO o\ (-3 O0 .0 O Z %4 k.n k.,4 o\ o O E1 C m 0) (3.

.DTD:

o, ('3 V1 --.4 o\o CO e\ C O o\o t--+ OD -0 o\ t 0- I.

0 X Co N 0 E1 (1) 0) (-) 1 t--' q) E;" k.n 1- ("3 Z O.

[23 k4 k.4 ).-.) Ore,)--' (3o k.n OO v,-4- o O O C'D ! ! Analysis for C30H34CIN3011 (648.068):

.DTD:

calculated: C 55.60 4, H 5 29 4, CI 5.47 4, N 6.4B 9; ound: C 55.78, H 5.52 4, C1 5.42, N 6.42 4.

.DTD:

i0 i0 I. Novel aminoalkanoyl-dibenzo-d,7-l,3,7di- oxazocines of the formula wherein Î A represents hydrogen or ha!o, stands for a valence bond or straight or branched chained alkylene having i to i0 carbon atoms, RI and R2 independently represent hydrogen, an alkyl having i to & carbon atoms or a cycloalkyl having 3 to 6 carbon atoms, or R1 and R2 together with the nitrogen they are attached to and optionally with one or more further nitrogen, oxygen and/or sulfur atom(s) form a 5- to 6-membered heterocyclic group optionally substituted with an alkyl having 1 to 4 carbon atoms, and pharmaceutically acceptable acid addition salts thereol.

.DTD:

.CLME:

2. Compounds of the formula (I) as claimed in Claim I, .CLME:

Wherein lO X, A R1 and R1 and represents hydrogen or halo, stands for a valence bond or to 3 carbon atoms, an alkylene hawing I R2 independently represent hydrogen, an alkyl having 1 to 3 carbon atoms or a cycloalkyl having 3 to 6 carbon atoms, or R2 together with the nitrogen they are attached to and optionally with an oxygen form a 4-methylpiperazinyl, 2-methyl-piperidinyl, pyrrolidinyl or morpholinyl group.

.CLME:

3. 12H-12-L-(4-methylpiperazinyl)-acety7-dibenzo-d,TL'l,3,Tdioxazocine and pharmaceutically acceptable acid addition salts thereof.

.CLME:

4 12H-2-Chloro-12--(4-methylpiperaziny1)-acety7-dibenzo-d,TL-1,3, Tdioxazocine and pharmaceutically acceptable acid addition salts thereof.

.CLME:

5. ()-12H-2-Chloro-12-L-(2-methylpiperidinyl)-acety7-dibenzo-d,TL-1,3, Tdioxazocine and pharmaceutically acceptable acid addition salts thereof.

.CLME:

6. 12H-12-Diethylcarbamoy1-2-chloro--dibenzo-d,7-l,3,Tdioxazocine and pharmaceutically acceptable acid addition salts thereof 7. 12H-2'Chloro-12-L-3-(diethylamino)propiony7-dibenzo'd,7-l,3, Tdioxazooine and pharmaceutically acceptable acid addition salts thereof.

.CLME:

8. A process for the preparation of novel aminoalkanoyl-dibenzo-d,7-l,3, Tdioxazocines o the formula (I) lO wherein X A represents hydrogen or halo, stands for a valence bond or a straight or branched chained alkylene having I to i0 carbon atoms, R1 and R2 independently represent hydrogen, an alkyl having i to 4 carbon atoms or a cycloalkyl having 3 to 6 carbon atoms, or R1 and R2 together with the nitrogen they are attached to and optionally with one or more further nitrogen, oxygen and/or sulfur atom(s) form a 5 to 6 membered heterocyclic group optionally substituted with an aikyl having 1 to 4 carbon atoms, o and pharmaceutically acceptable acid addition salts thereof, in which a) a dibenzo-d,7-l,3,Tdioxazocine of the formula (II) wherein X is as defined above, is acylated with a compound of the ormula HaI--A-HaI' (III) t0 wherein A is as defined above, Hal and Hal' independently represent a halo, and the obtained alkanoyl-dibenzo-d,R7'l,3,Tdioxazocine of the formula wherein X, A and Hal' are as defined above, is reacted with an amine of the formula HN< R1 R2.

.CLME:

(VIII) wherein RI and R2 are as defined above; or b) a dibenzo-d,ú7-l,3,Tdioxazocine of the formula (II) is acylated with a compound of the formula -. O. 0 0 q- (3. Q r "0 CO 0 11) p- n (1) 0a I-1- --I,-I- I.

0 0 - CO OJ:3 (D (1 I-'- I1} I--" 0 0 0 -J 3 " (!) 3 7 0 - n r4- :3" E l-re. X n O C 0 O -13 0 n 0 (-- Q) 0 (3_ O. - 13_ 0 (1} H:3 I-'.

.CLME:

I-'- 0 -t- 0 ('D (/I 0 O_ W I-,- 13) LO Cl) 0 bJ b-.

.CLME:

I-, O.

O" CD O) I'D O.

n 0 " " 3 7O O CI C 13" O E "7" 2]" " O :3" 33 3 0 CI tO | 0 0 212 l! H H 0 0 E B] I Ul (- n 11} 0 0 :3.

.CLME:

fD 0 - -J fD 7 (D (.n 7Z fD < < H 3 I- 0 03 (1) r" CO ( 0 (3" 0 CO EL H H (/} (1 O) v I!1 - (3.

.CLME:

(1) I- 17 (I) 7-:E "7 I1) " N + 0 I m r"l I 0 M 7- I 1 0 t- 0 (-" 7-, "---J n m N 0 I--,- E fl? m 0 r-t- O e-I C DI zr o o :3" (1} O n n O" 0 < Ul 17 If) I I Ira. I Z /\ ! I 51, 9. Compounds as claimed in claim 1 which are substantially as hereinbefore described in any one of Examples 1 to 21.

.CLME:

i0. A pharmaceutical composition having local anaesthetic, tranquillosedative or antiparkinsonic activity, comprising a therapeutically effective amount of a compound or salt as claimed in any one of claims 1 to 7 or 9 in admixture with one or more pharmaceutically acceptable carrier(s).

.CLME:

II. Compounds as claimed in any one of claims 1 to 7 or 9 for use in treating the human or animal body by way of therapy.

.CLME:

i0 12. Use of the compounds as claimed in any one of claims 1 to 7 or 9 in the prepa'ation of a medicament having local anaesthetic, tranquillosedative or antiparkinsonic activity.

.CLME:

13. A process as claimed in claim 8 substantially as hereinbefore described in any one of Examples i to 21.

.CLME:

Publahe 1985 at The Paent Ofice. SuLte Ho'se. 6671 lagh Ho!born. London WCIR 4TP. Fu.w-her cople$ may be obmned rom The Patent ce.

.CLME:

r:les Branch. S" Ma.'-y Cray, 0r'4ton. Kent BI5 3RD, Printed Mt%/plex %ecb.nques ltd. 87, Ms.,-y Cr&y, Kent Con. 1/87.

.CLME: