AU596258B2 - Novel aminoalkanoyl-dibenzo(d,g)(1,3,6)dioxazocines and a process for the preparation thereof - Google Patents

Description

11 4- Form COMMONWEALTH OF AUSTRALIA PAYENTS ACT 1952069 COMPLETE SPECIFICATION

IORIGINALI

Class Application Number: Lodged: I t. Class 596258r Complete Specification Lodged: a

S

-Priority: S S

S.

I Relatd Art: S fI S t Accepted: Published: This dOc1l-ent conL tinsth lmfldmn-ts TmadeUfdr Ctjin 49 itrid is cojrfe, L for pr* ting a Namnfof Applicant: Addres.~of Applicant: Actual I~vmntor: Address for Servce: 1103 Budapest, Kereszturi ut 30-38, Hungary LASZLO ROZSA, LUJZA VETOCZ, tkIART0N FEKETE, ENIKO SZIRIT, MARIA H-EEDUS and ISTVAN QACSA74YI EDWI). WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

EGIS GYOGYSZERGYAR Complete Specification tor the Invention entitled: NOVEL AMINOALKAN0YL-~DIBENZ0(D,G] [1,3,6]IrOXAZOCINEs AND A PROCESS FOR THE' PREPARATION THEREOF The f ollowing stitement It a full description of this Invention, Including the best method of perf otm Ing It known to, f.

NOVEL AMINOALKANOYL-OIBENZO/-d,g7/-1,3,67OIOX\AZOCINES AND A PROCESS FOR THE PREPARATION THEREOF The invention relates to novel aminoalkanoyl- -dibenzo/-d,a7/-1,3,67dioxazocines, a process for the preparation thereof and pharmaceutical compositions comprising such active subs-tances.

0* The novel conwpounds possess valuable pharmaceutical properties such as local anaesthetic, tranquillo-sedative and/or antidepressant, antiparkinsonic, furthermore antiarrhytmic and antianginous activities.

12-Aminoalkyl-12H-dibenzo/-d,a7L1, 3 ,67dioxazocines having local anaesthettc and antiparkinsonic activities are described in the US-Pat. No. 4,208,410.

It was found that the pharmaceutical activity of the known compounds can be favowjrably modified by substituting the ring nitrogen by an aminoalkanoyl group instead of an ***aminoalkyl group.

k ~*Thus, thk invention provides for the novel compounds of the formula, 0%NO

COD

RI

A 4124-62/MR -2wherein X represents hydrogen or halo, A stands for a valence bond or a Gtraight or branched chained alkylene having 1 to 10 carbon atoms, ,and R 2in dependently represent hydrogen, an alkyl having 1 to 4 carbon atoms or a cycloalkyt, having 3 to 6 carbon atoms, or Rand R 2 together with the nitrogen atom they are attached to and optionally with one or more further nitrogen, oxygen and/or sulfur atoms(s) formi a 5- to 6-membered heterocyclic group selected from piperazine, piperidine, pyrrolidine and morpholine, optionally substituted with an alkyl group having 1 to 4 carbon atoms, preferably a methyl group and p'41%.maceutically acceptable 15acid addition salts thereof.

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

The straight or branched chained alkylene having 1 to 10 carbon atoms is for example methylene, ethylene, 20 isopropylene, n-propylene, n-butylene# isobutylene, pentylene, hexylene, heptylenet octylene, nonylene or decylene group.

The alkyl having 1 to 4 carbon atoms can be methyl, ethyl, n-propyl, isopropy1, n-butyl, isobutyll sec.-butyl or 25 tert. -butyl.

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

9 9 9.49 9*99 9 *9~9 .9 99*99* 4, I~ 9 t f- 9 9 9* 9' 9* *999 9 *9.9 99 49 94 9 9~ *9 9 99 t# 9 9 1

K--

i i ii nz~~r I1 3 If A stands for a valence bond, the group of the formula 0 R

/C

1

-C-N

4s #6* 9 4 *r 6 99 94 *i S #9 #9 #L 4 is attached directly to the ring nitrogen.

The compounds of the formu. I) may form pharmaceutically acceptable acid addition salts. ror the salt formation, suitable inorganic or oiganic acids are for example hydrogen chloride, hydrngen bromide, sulphuric acid, acetic acid, fumaric acid, lactic acid, maleic acid, methanesulfonic acid, ethanssulfonic acid, citric acid etc.

The compounds of the formula may comprise one or more chiral carbon atom(s), depending on the meaning of A.

15 In such cases, optically active isomers may exist. The invention relates to the optically active antipodes and any mixtures thereof.

Preferred compounds of the invention are compounds of the formula wherein X represents hydroger or halo, A stands for a valence bond or an alkylene having 1 to 3 carbon atoms,

R

1 and R 2 independently represent hydrogen, an alkyl having 1 to 3 carbon atoms or a cycloalkyl having 3 to 6 carbon atoms, or

R

1 and R 2 together with the nitrogen they are attached to and optionally with an oxygen atdm form a 4-methylpiperazinyl, 2-methylpiperidinyl, pyrrolidinyl or

I'

i i; 4 morpholinyl group, and pharmaceutically acceptable acid addition salts thereof.

Especially preferred compounds of the formula (I) are as folloWs: 12H-12-/(4-methylpiper a zinyl)- a cetyL7-dibenzo/d 3 ,6 7 dioxazocine, 12H-2-chloro-12-/'4-methylpiparazinyl)-acetyl7-dibenzuso% L'd,R7/ -1,3,67dioxazocine, 10 /d,27q/-l3,67dioxazocine, 9, *9 1 2H-12-diethylarbamoyl-2-hloro-dibezo~/-d,'g,7/31,3,67 dioxazocine, 12H-2-chloro-l2-/-3-(diethylamino)propionyll-dibenzo/-d 7 s-1 Cl,3,.67dioxazocine, and pharmaceutically acceptable acid addition salts thereof.

The compounds of the formula are prepared as follows: .9.9 a) a dibenzo/d,.g7_/1,3,67dioxazocine of the formula 9 0 4 200 O (II) wherein X is as defined above, is acylated with a compound of the formula i Hal-C-A-Hal' 0 0

(III)

wherein A is as defined above, Hal and Hal' independently represent a halo, and the obtained alkanoyl-dibenzo/ d,q7- 7 dioxazocine of the formula 4444 t 4 44 r I 4 44 rt 44c

I

I I( I C I It (I 44 9 44 r* 4 4 0 0 0N<0 S CHO

I

A -Hal

(IV)

wherein X, A and Hal' are as defined above, is reacted with an amine of the formula HN> (vIII) wherein R and R are as defined above; or b) a dibenzoLd,g7/- ,3,67dioxazocine of the formula (II) is acylated with a compound of the formula 77F K

V

4 ~1 I 6

/R

Hal-C-A-N 0 R 2 wherein A, R 1 and R 2 are as defined above, Hal stands for a halo; or c) a dibenzo/-d,g7/-1,3,67dioxazocine of (II) is acylated with a compound of the formula I '4 ~i t I I It III I t I I CI

II

a ai i*it e formula

(VI)

Hal-C-A'-CH=CH 2 0 wherein Hal stands for halo, A' represents a valence bond or a straight or branched chained alkylene having 1 to 8 carbon atoms, and the obtained compound of the formula 0 0 C =0 A CH=CHz

(VII)

wherein X and A' are as defined above, is reacted with an amine of the formula (VIII); and, if desired, a compound of the formula is converted into an acid addition slt with a pharmaceutically acceptable inorganic or organic acid, or from an acid addition salt the compound of the formula is deliberated with a base.

I

E

Ct 1'~

L

7- In the compounds of the formulae (III), (V) and (VI) halo is preferably chioro or bromo.

The dibenzo dioxazocines of the formula (II) which are used as starting compounds fo'r the preparation of the compounds of the invention 3re prepar ed as dey~cribed in US-Pat. NIo. 4,208,410.

The compounds of the formixlae (III), (VI) and (VIII) are known reagents being commercially available or tsaey can be prepared by known methods.

10 !in process a) of the invention, the compound of the formula is acylated in apolar or diploar aprotic solvents, preferably benzene, toluene, xylene or dimethylformamide, in the presence or absence cf an acjid *binding agen~t. The acylating agent of the formula (III) Ills employed in an equivalent amount or in excess relative to the amount of the dibenzo dioxazocine of the formula (II).

It is preferred to acylate the compound of, the formula (nI) in toluene, generally at a temperature of 60 to 110 0 C with the compound of the formula (III) which is used in an excess of 200 to 300 per cent.

:The omega-halo-alkanoyl-dibenzo [d~gjH1,3,6j dioxazocine of the formuila (IV) whichj is Varmed in the acylation reaction is reacted i~it a poi-jr,, apolar or dipolar solvent with the amine of the fcormuJlA (VIWI) Preferably benzenpt toluene, xylenet isopropanol lor 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 bi. the 3( hydrogent halide formed in the Wil -8reaction. However, other usual acid binding agents can be used for this purpose, too.

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 iL base such as a tertiary amine e.g. triethylamine, N,N-diisopropyl-N-ethylamine, pyridine etc.

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

(VIII).

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

In process b) of the invention, the compound of the formula (II) is aoylated with the compound of the formula (V) K in a similar way, generally at 0 to 140 °C.

It is preferred to prepare the alkali metal salt of A' the compound of the formula (II) at first, then to roact it with ani excess of the compound of the formula at a temperatVe of 0 to 50 In process o) of tho invention, the reaction of the compounds of the formulae (II) and (VI) is performed in an apolar organic solvent such as benzene, toluene or xylene, A 9 in general, at 50 to 140 OC. 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).

In case of compounds of the formula comprising one or more chiral carbon atom(s), the enantiomers can be ft<, separated by resolving the racemic compound. To effect this, the racemic compound comprising a basic nitrogen is reacted r~t@ 10 with an optically active carboxylic acid to give pairs of diastereomeric salts which are separated and the enantiomers 4t %are deliberated. As an optically active organic acid practically any carboxylic acid used for resolutions can be employed I t r such as optically active tartaric acid, dibenzoyltartaric 15 acid, lactic acid, atrolactic acid, mandelic acid etc., furthermore optically active sulfonic acids such as sulfonic acid etc.

The enantiomers of the novel aminoalkanoyl-dibenzo- -d,l7/-l,3,67dioxazocines comprising a chiral carbon atoms can be also prepared by acylating the compound of the formula (II) with an optically active agent; of the formula S(III), or (VI).

The compounds of the formuila have valuable pharmacological activities as indicated by the following screening tests.

K

I

10 Acute toxicity on white mice' Acute toxicity of the compounds was tested on white mice of both sexes from the strain CFLP in groups consisting of 10 animals weighing 18 to 22 g. The compounds to be tested were administered perorally in a volume of 20 ml/kg.

After the administration, the mice were observed for 7 days while keeping them in plastic mouse boxes over a litter made of scrapings at room temperature. The animals could consume tap water and standard mouse feed ad libitum. The LD 5 0 -values 0 were determined according to Litchfield and Wilcoxon Pharmacol. Exp. Thee., 96, 99 (1949)7, The results obtained are shown in Table. I.

I

9t41

'II.

I~I~q* 1 I, ~j Table I

I

t

I

I 1

I

I

I

Compound (Example No,) L0 50 p.o. in mgc/kg 2000 700 280 2000 2000 250 1000 450 900 900 2000 I I7 11 continuation o~f Table I Compound (Example No.) LD 50 p.o. in mg/kg 12 260 13 300 14 160 250 16 250 17 6 5 oi 18 250 19 370 20 220 21 300 ca* p.

4 4 i- Local anaesthetic atUivity The tepts were performed according to Truant dfAmato (Aqti Chir, Scand., 116, 351, (1958)), 0.2 ml of a 0,25 or 0.SLN per cent solution of the test compound were injected around the netvus ischiadicsI, into the centre of 20 the femur. The absence of the motor control ofthe leg muscles was looked upon a the ceiterium of anaesthjesia, *i The test animal.s were mice, The duration of the effect was recorded, and from the dpoe versus action plot, the concentration at which the ac,'ivIty aMounted to 50 po-r cent (EC6 0 was determined, In the tea, liciocaine (.2-diethylamino-2',6--acetoxy-xylidideI qd for comprison. The results obtained fire given

I

I

I

I

12 Table II.

Table II Compound (Example No,) EC 50 in percentage Ouration of the effect at a concentration of 0.25 9o 0.50 21.0 4 4 4 t 0.21.

0.25 0.15 0.14 0.16 0.25 0.10 0.22 Q0111 0.08 0. 17 55.8 51,1 54.1 122.1 83,2 52.4 85.7 43.7 91.1 97 .7 98.8 107 .3 21.7. 3 160.0 113,86 114.6 146.4 73 .8 67. 8 93,.1 40,1 14 4 4 4 4 .1 4 4 *~4 *4 *4 4 4 lidocaine From Tab1F. T1 it eanl be seen that most compounde tested are effective io a loawer concentration than lidooalne. The duratIon of etfect of all the compounds ot the invention is Much. longer th9n that of lidooaine in both ooncen Lration.

Sleep induced with hexobarbital on mice Groups consisting qf 6 mIce each were -treated with the comipound to be exarminedo parora2.ly, After~ one hour, -13 was injected, intravenously, at a dosage of 40 mg/kg. The contcaol group was treated only with hexobarbital to provoke sleep. The dura~tion of sleep was re3corded. If. the duratioin 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 ED -value was calculated. From the values of LD 5 and 5 050 ED 0 the therapeutical index was, determined for each compound tested. In the test, meprobamate 12-metbhyl-2--propylpropandiol-1,3-.dicarbamatej and chlordiazepoxide [7-chloro-2-methylamino-5-phenyl-3n-1, S4-benzodiazepine-4-oxidel were useO. for comparison. The results obtained are summarised in Table III.

TABLE III Compound ED 50 Therapeutical index (Example No.) in mg/kg LD 5

./ED

5 0 20 1 21.0 95.2 I3 25.0 31.2 8.5 235.0 6 15.0 16.7 12 30.0 8.7 15 9.8 25.5 ma19 15.0 24.7

C.U

-14 continuation of Taible III Compound E D 50 Therapeutical index (Example No.) ill mg/kg

LD

50

'ED

5 0 meprobamate 260.0 4.2 (L0 50 1100 mg/kg) chlordiazepoxide 10.0 62.0 (LD 50 =620 mg/kg) From the data given in Table III it can be seen that the therapeutical index, of the most effective novel compound the compound prepared in Example 4) is higher by one order of magnitude than that of chlordiazepoxide. At the same time, the compounds of thq invention are more effective than the meprobamate used as the reference.

CC t A.Qtaqonism of tetrabenazine ptosis on mice The tests were performed according to the me-%;hod of Hoffmeister et al, which was adapted 'to mice /_Aiznuim. cc -Forschung, 19, 846-858 (196)i)7f Groups consisting of mice each were treated, perorally, with dJif erent doses of the compounds to be tested. The control group was -treated only with the corresponding carrier. After 30 minutes tetra- 2 5 benazine /-3-isobutyl-9,10-dimethoxy-1,2,3,4,,6,7-hexahydrobenzo/"aiquinolzine-2-one7 was admini~itered intraperitoneally at a dosage of 50 mg/kg, The numbet of animals having closed palpebral fissure was determined in each group after 15 30,60f 90 and 120 minutes. Then, the mean value of ptosis was calculated in each group, and the deviation~ from t hat of the control gromp the inhibition) was expressed in percentage. From the data obtained, the ED0-value and the therapeutical index were determined for each novel compound tec-ted as well as for amitryptiline (5-(3-dimethyl-amino- Lpropylidine)-10,11-dihydro-5H-debenzo[a,dI cycloheptene hydrochloride) employed for comparison. The results obtained are shown in Table IV.

TABLE IV Compound (:'Rxample No.,) ED 5 0 in mg/kg Therapeutical Index

LD

5 0 ,/ED 5 0 4 *94,15 9 9444 9 999994 9 9* 99 9 9 9 9* 9 20 99 9 6 99 99 9. 9 09 99 ~4 .9 2 13.0 53.9 11 23.0 86.9 20 13.5 13.6 amitryptiline 12.0 18.7 The the riApeuti nal index of the coinpounds of the invention is, iii general, higher than that of the amitryptiline used for comparison.

Inhibition of nicotine lethality on mice The tests were performed on while mice using the method of Stone [Arch. Int. Pharmacodyn., 177, 419 (1958)J.

The 4 1 4 0*47 16 animals were treated with the compounds to be tested, perorally, then, after 1 hour, nicotine was injected, intravenously, at a dosage of 1.4 mg/kg. The spasms as well as the lethality observed within one hour were recorded, the

ED

5 0 -value and the therapeutical index were calculated for each novel compound tested and for trihexyphenidyl /-alpha- -cyclohexyl-alpha-phenyl-piperidinepropanol hydrochloride7 used for comparison. The results obtained are given in Table V.

I

iII 0o*: 0 .1*

I

e I I *0 II *I 0

I

II

*Il I iI Table V E0 50 in mg/kg Compound (Example No.) Therapeutical index

LD

5 0 /E0 5 0

I*

o @n r

I

1 3 4 5 6 7 8 9 trihexyphenidyl 27.8 111.0 57 154.0 30.0 52.9 42.9 18.25 71 i n (Th 17~ 17 Inhibition of tremor induced by tremorine on mice 'he tests were carried out according to Everett (Science, 124, 79 (1956)]. Tremor was induced by tremorine [lfl-(2-butynylene)-dipyrollidineJ administered intraperitoneally at a dosage of 20 mg/kg. The compounds.,to be examined were given perorally to the animals one hour prior to the administration of tremorine, and the tremor developed was evaluated 45 minutes after the administration of tremorine. The results are set forth in Table VI.

TABLE VI Compound (Example No.)

ED

5 o in mg/kg Therapeutical index

LD

5 0 /EDs 15 rc t 4 t F' 20 it f .25

S*

1 16.0 125.0 3 15.0 52.0 4 42.0 47.6 7 37.5 26.7 13 4.0 75.0 14 8.1 19.5 triphexyphenidyl 15.0 24.3 Since the inhibition of nicotine lethality and of tremor is characteristic of the antiparkinsonic activity of a substancce, from Tables V and VI it can be concluded that the ant$iarkinsonic activity of the compounds of the invention surpasses that of the known compound used for 4 4~ 1: 18 comparison, considering either the absolute dosage or the therapeutical index.

Antiarrhythmic activity on rats The antiarrhythmic activity of the novel compounds was examined by influencing the arrhythmia provoked by aconitine on rats weighing 160 to 200 g according to a modified method of Marmo et al. /-Arzneim.-Forsch., 20, 12 (1970)7. The animals were anaesthetized the administration 10 of 1.2 g/kg of ethyl urethane, intraperitoneally. Aconitine was given at a dosage of 75 /ug/kg, intravenously. The compounds to be tested were administered perorally, 30 minutes prior to the treatment with aconitine. The inhibition observed is shown in Table VII in percentage. In the test, lidocaine and quinidine was employed for comparison.

Table VII it Compound Dose Inhibition (Example No.) in mg/kg in percentage /21 7/ t< 25 .4 3 4 45.5 4 54.2 21 4 62.9 lidocaine 4 23.4 quinidine 4 27.3 p~l i I i ra~lll~-- l Il)p+l*~rrm-*ktsc~sP 19 From Table VII it appears that the antiarrhythmic activity of the compounds of the invention surpasses that of the known compounds used for comparison.

Antiangi'ious activity on rats The antianginous activity of the compounds was determined on anaesthetized (for this purpose chloralose urethane was used)male rats weighing 180 to 220 g according to Nischultz /-Arzneim.-Forsch., 5, 680 (1955)7. An experimental coronary insufficienc was developed by the administration of glanduitrine an extract of the posterior lobe of pituitary at an intravenous dosage of 4 Id/kg. The height of wave T in ECO was measured before and after the administration of glanduitrine in both the control and treated groups, 15 and the inhibition provided by the compounds tested was calculated. In the test, prenylamine /-3,3-diphenylpropyl-l- -methylphenetylamine lactate7 was used for comparison.

t Sr L Se 4 9* a 4 4 5C4

I

*i 4 Table VII Dose in mg/kg Compound (Example No.) Inhibition in percentage 2 55.4 21 3 83.6 prenylamine 2 61.3 ;il l s 20 From the above pharmacological test results it can t be concluded that the novel compounds of the formula (I) 4 or the pharmaceutically acceptable acid addition salts 4 thereof can be used as the active substance in pharmaceutical compositions. The pharmaceutical composition of the invention comprises a therapeutically active amount of a compound of the formula or a pharmaceutically acceptable acid addition salt thereof and one or more usual additive(s).

The pharmaceutical composition of the nvention, 10 which has especially local anaesthetic, tranquillo-sedative or antiparkinsonic activity, is prepared by admixing a compound of the formula or a pharmaceutically acceptable acid addition salt thereof to one or more pharmaceutically S acceptable additive(s) e.g. carrier( and converting the mixture obtained to a pharmaceutical ncmpciitii in a manner known per se. As to the additives and meahods see t e.g. Remington's Pharmaceutical Sciences, 16th Edition, Mack Publishing Company, Easton, USA, 1980.

In general, the pharmaceutical compositions of the 20 inventioni are suitable for peroral or parenteral administralion or for local treatment, and can be solid or liquid.

The solid pharmaceutical compositions may be powders, capsules, tablets, dragdes etc., and can comprise binding agents such as gelatine, sorbitol, polyvinylpyrrolidone etc.; filling agetrts such a) lactose, glucose, starch, calcium phosphate etc.; auxiliary substances for tabletting such as magnesium stearate, talc, polyethyleneglycol, silica etc.

wetting agents such as sodium laurylsultate etc. as the ;i 21 additive.

The additives of the liquid pharmaceutical compositions used for oral treatment are preferably suspending agents such as sorbital, sugar solution, ,gelatine, carboxy-methylcellulose etc.; emulsifiers such.as sorbitane mono-oleate etc.; solvents such as oils, oil esters glycerol, propyleneglycol, ethanol etc.; preservatives such as methyl p-hydroxybenzoate etc.

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

The pharmaceutical composition of the invention contains, in general, 0.1 to 95.0 per cent of the active substance. A typical dose for adult patents amounts to 0.1 4"t, to 20 mg of the compound of the formula or a pharmaceutically acceptable acid addition salt thereof, daily. The actual dosage is determined depending on many t~ factors such as the state and person to be treated, the j^ method of treatment etc.

The invention is further elucidated by means of the 0 9 1 following Examples.

Example 1 12H-12-((4-Methylpiperazinyl)-acetyl)-dibenzo[d,g] -[1,3,6j dioxazocine dimaleate A mixture of 30.0 g (0.141 mole) of 12H-12-dibenzo-(d,gJ(1,3,6]. dioxazocine 189 to 191 OC), 150 cm 3 of anhydrous toluene and 19.5 g (0.173 moles) Sof chloro-acetyl chloride is heated to boiling point and refluxed for 2 hours. Then, further 19-5 g (0.173 moles) of chloroacetyl S I i -22chlori~e are added to the reaction mixture that is refluxed for fu, ther 4 hours, The mixture is cooled to 25 0 C and poured into crushed ice under stirring. After one hour stirring, the solids are filtered, washed with water and recrystallized from isopropanol.

Thus, 35.6 g (87.3 of 12H-12-(2-chloroacetyl)-di.benzo/Th,,Q7/1,3,67dioXazocine are obtained. M. 151 to 153 'C.

Analysis for C 15

H

12 ,CIN0 3 (289.7): calculated: C 62119 H 4.18 %,Cl 12.24 N 4,83 V found; C 62.57 %1 H 4.12 ~,Cl 12,23 4.77 B) A mixtur~e of 12.0 g (0.041 moles) all l2H-12-(2--chloroacetyl)-dibenzo/Th7Fl,3,67dixazocin, 130cm of anhydrous, precipitated is filtered, The organic filtrito is washed 4 with water, driedi over anhydrous magnesium sulfate, thea srlvent Is distilled off and the residue is cr~ystallized1 rrom Isopropanol. The product is recrystallized from i8opc~panol.

Thus, 9,7 g (66.4 of 12H-12-(-methylpiperaziny,)- -acetYl7-dibenzof d,,q7fl,3,67oioxaZocine are obtained.

M. 160 to 162 oC.

Analysis for C 20

H

23

N'

3 0 3 (353.425)#, calculated: C 67.97 6.56 N 11.80% found: C 68.14 7.02 11.78 23 C To a stirred solution of 8.4 g (0.024 moles) of 12J*-12-'(4-methylpiperazinyl)-acetyl j-dibenzo(d,gi-[l, 3,61 dioxazocine in 100 cm 3 isopropanol, a solution of 5.6 g (0.048 moles) of maleic acid in 30 CM3 of isopropanbi1 is added at 20 0 C. The reaction mixture is stirred for 2 hours, then cooled to 0 0 C, stirred for a further hour, the product is filtered, washed with isopropanol and recrystallised from methanol.

10.5 g of the title compound are obtained.

179 to 183 0

C.

Analysis for C 28 1131 N 3 oi (585.572); calculated: C 57.43%, H 5,34%t N 7.18%; found; C 57.38%0 H 5.31%f N 7,06%.

04ttotExample 2 1211-12-f (N-Cyclohexyl.-N-methylamino)-acetylJ-dibenzo(d,gI [1,3,6j dioxazocine maleate rt t A) A mixture of 13,,0 g (0.045 Moles) of 1211-12-chloro- .:~acotyl-dibenzoldfg](1,3,61 dioxazocine, 15o cm.

3 of anhydrous benzene and 32.2 g (0.28 moles) of N-uyclohexyl--N-metljylamine is heated under" reflux for 8 hourai The product is isolated as described in Example 1, section B) and recrystallined from isopropanol tq give 13.9 g of 1211-12-f (N-cyclohexyl-N-methylamino)-acetylI dibenzo fdjg] 25 [1,3,61 dioxazocine. 103 to 1056Ct.

Analysis for' C 2 2 H 2 6 N 2 0 3643; calculated: C 72.11l%, H 7.15%, 0 7.64%; found; C 72,17%o H 7.18%, N 7.60t.

-24 12.8 g (0.035 moles) of 12H-12-/C(N-cyclohexk, 1-N- -methylamino)-atetyll-dibenzod ,7dioxa zocine are reacted wit2h 4.2 g (0,036 moles) of maleic acid as described in Example 1, section After recrystallization from isopropanol, 14.9 g (88.2 of the title compound are obtained. M. 148 to 150 0

C,

An~lysis for C 2 6

H

3 0

N

2 0 7 (482,536): calculated: C 64,72 Hf 6,27 N 5.81 found: C 64.58 H 6.34 N 5,67 49,.

Example 3 12H-12-/P2-(Isopropyl amino)- acetyl7-2-chlro -diben zod ,g"7Ll,3,;7dixszocine hydchloride A) A mixture of 24,8 g (0,10 moele) of 12H-2-chloro- -dibenZo/_dR7 t3,.67disoxazoine 182 to 184 0

C),

300 cmV o anhydrous toluene and 23.0 g (0.20 moleS) of 2-chloroacetyl chloride is heated under reflux for 4 hours, The mixture Is cooled to 25 0 C, the solvent joI removed undqz reduced presuran, and the residue If rubbed with bazitene to indupe crystallization, The produet is reovy tot1liza'd, from, isopropanol to give 23.1 0 (71.3 6) of 12Hl2-chloroauetyIdhr -ddbonzo/-d .aBfl 3, A.7dxazaclne M. p 149' t- 151 0 0.

Analyats for C 1 5

H

1 C1 2 N0 3 (324,2): ca1culated: C 55.57 H, .42 C.1 21,117 N l 4.2, k4 found: C 5$,48 H 3.63 CZ'5 %j N 4.28 B) A mixture of 1$.0 g moles) of chioroacetyl derivative prepared in, Cx ql section 180 cm 3 anhydrous benzene and 17,7, g 4g)esy of isopropylamine is heated under reflux for 4 homrs. The organic solvenit is removed under reduced pressuro tile esidue is mixed with 100 cm 3 of diethyl ether and 80 aoi4 Qf water for 30 minutes, The organic phase is separbtod, dried over anhydrous magnesium sulfate, cooled to 0 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 repeatkid twice, and the product is recrystallised from ethanol to give 13.0 g of the title compound as white crystals.

235 tp 240 0

C.

Analysis for C,,H 20 C1 N2 0 3 (383.282): calculated: C 56.41%f H 5,26%, Cl 18.50%t N 7,31%, C11 9.25% found: C 56.15%f H 5,60%, Cl 17.96%, N 7.16%0 C1- 0 v20 9.08% Example 4 12H-12-(4-methy(lpiperazinyl)-acetylJ-2-chloro-dibenzo(dilgJ- (l,3,p6l dioxazocine dimaleate A) A mixture of 49.0 g (0.129 moles) of 12H-12-chloroace tyl-2-chloro-dibenzo (d fg) 1, 3, 6 1dioxazocine j8o.0og(0.0( moles) of 4-methylpiperazine and 410 cm 3 of anhydrous *benvqne Is heated under reflux for 4 hours, Then, the organic solvent and the excess of 4-inethylpiperazine are removed, under reduced pressuve. To the residue, 150 cm 3 of benzerto and 10 cm 3of water are added, the 'mixture is stirred for 0 4 -26 Rrvinutety, the orgjanic phase is separated and washed with water three times using 80 cm 3 of water each time. 45.0 g (0.39 moles) of tartaric acid in 150 cm 3 of -water arp.

added to the organic solution, the mixture is stlired for an hour are the phases are separated. To the aqueous phase, 150 cm 3 of benzene are added, the mixture is stirred and treated with 25 per cent aqueous ammonia until a pH value of, 9 to 10 is obtained. Stirring is continued for an hour, then the organic phase is separated, dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure. The residue is stirred with benzene to induce crystallizatilon, the crystals are filtered, suspended is benz~ne and filtered again. The product is recrystallized fvom Isopropanol, to obtain 30.0 9 (76.0 of 12H-12-/-(4dioxazo,7ine. M. 124 to 127' oC.

Analysis for C 0

H

22 ClN 0 (387 .070): calculated; C 61.93 4) H 5,72 %,Cl 9.14 10.83 f ond C 62.18 5.93 kt Cl 9.18 N 10.61 8) 34.1 g (0.088 moles) of 12H-12-/C(4-methylpiperazinyl)- -acetyl j-2-chloro-dibenzo~d~g] [113 i dioxazocine are reacted with 20,4 g (0-.l76 moles) of maleic acid as described in Example 1, section 0) to give the aoid addition salt. After recrystallization from methaniilj 44.2 g (81 of the title compound are obtained. M. 188 to 150~ 0

C.

A ni Iys,'s TA-cr C 28

H

30 CXN 50 11 (6204014): 277 calculated: C 54.24 H 4.88 %j Cl 5.72 N 6.78 found: C 54.18 5.12 %,Cl 5.70 N 6.62 .12 H -12 -7N Cy clah e xy- N- m et h ya m in oa ce tY17 -2 -chloro--diben;ro/-d,.a7L1, 3 ,6dioxaz ocine maleate A) A mixture of 35.0 g (0.108 moles) of 12H-12-chloro- -,'tyl-2-chloro-dibenzo/-d,gj 7 /C1,3,67dioxazocine, 350 cm 3 of ydrous benzene mnd 2 x 76.9 g (2 x 0.678 moles) of N-cycloil-methylamine is heated under reflux for a total of 12 hours. The product is isolated as described in Example 4, secticn The crude product is crystallized, then recrystallized from. petroleum ether -to obtain 32,1 g (79.8 of 12H-12-/7(N-cyc'Lohexyl-N-methylamine) -acety.L7-2-chloro- -dibenzo-d ,q7/-l 3 67diaxazooine. M p 93 to 95 QC Analysis for C 2 2

H

5 C1N 0 3 (400.909): calculated, C 65.91 H 6.29 Cl 8,84 N 6.,9 9 lound: C 65,60 7.00 %,Cl RI.89 N 6.61 B) 30.10 g (0,075 moles) of 12H-12-/-(N-cyclohexyl-N-methylamino) -acety.L7-2-chlor-dibenzo"d,R7-/N 3 67dioxazocine are reate wih -7 (.05 moles) of maleic acid as described in Example 1, section The product is recrysta 14-2ud f ro m methanol to obtain 34.8 g (89.7 Q) of the title compound.

191 to 193 OC.

N Analysis for C 6

H

9 CJN 0 7 (516.980): calculated:, C 60 .41 H 5.65 %,Cl 6.66% N 5.-4 2 found: C 61,23 5.92 Cl 6.79 N 5 .30 94.

closed palpebr al fissure was determn'ired in each group after ~.ii1~

MP_

28 *999 9 9*94 99.9 9 9 9 9 9. 99 9 9 S 9 99 a a 99 99 9 999 9 *9 9 9 99 9* 9 4.

94 4 9.944 9 99*9 99 99 99 9 9 9 Example 6 12H-12- (Diethylamino-acetyl) -2-chloro-dibenzo/ d ,ag7- ,67dioxazocine hydrochloride A) A mixture of, 32.4 g (0.10 moles) of 12Hi-l2-chloroacetyl-2-cliloro-dibenzo/-d ,fl/-1,3 ,67dioxazocine, 2 x 36.5 g (2 x 0.50, moles) of diethylamine and 250 cm 3 of anhydrous benzene is heated under reflux for 6 hour, altogether. The product is isolated as de,9cribed in Example 4, section A).

The yellowish-brown, viscous liquid obtained as the crude .0 t,_-,oduct is crystallized, i;hen recrystallized from n-hexane.

Thus, 28.5 g (78.9 of l2H-12-(diethylamino-acetyl)-2- -chloro-dibenzo/-d,~,l ,67dioxazocine are obtained.

75 to 80 0C.

Analysis for C 19 H 2 ,0N 2 0 3 (360.844); 5 calculated: C 63.24 5,87 Cl 9.83 7.76 found; C 63.96 5.32 %,Cl 9.85 7.50 1 B) 19.0 g (0.053 moles) of dioxszocine prepared in Example 6, section A) is treated with isopropanol containing 20 20 per cent hydrogen chloride to give the corresponding acid addition salt. After crystallization from isopropanol, 1.7.5 g (B2.9 of the title compound are obtained. M. p.: 198 to 201 00 Analysis for C 1 9

H

22 C1 2 N 2 0 3 (397.302): calculated: C 57.44 5.58 Cl 17.85 7.05 Cl. 8.92 found., C 57.56 5.84 %~Cl 17.50 7.06 %,O C17 8.B8% 0 i.i777T 29 Example 7 (t)-12H-12-/-(2-Methylpiperidinyl)-acetyl7-2-chloro- -dibenzo/-d,2g7L1,3,67dioxazocine hydrochloride A) A mixture of 32.4 g (0.10 moles) of 12H-12-chloroacetyl-2-chiloro-dibenzo/ d,7/ 1,3,67dioxazocine, 39.7 g (0.40 moles) of 2-methylpiperidine and 250 cm 3 of anhydrous benzene is heated under reflux for 4 hours. The reaction product is isolated as described in Example 4, section A).

The crude product is crystallized, then recrystallized from isopropanol to obtain 30.8 g (79.6 of -methylpiperidiny 1)-acety17 -2-chloro-dibenzo/ d,g7/l 1,3,7dioxazocine. M. 90 to 92 C.

Analysis for C21H 23 C1N 2 0 3 (386.882): calculated C 65.20 H 5.99 Cl 9.16 N 7.24 found: C 65.01 H 6.33 Cl 9,15 N 7.08

I

8) 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 (98.1 of the title compound. 146 to 154 0 C (deromposition).

Analysis for C 21 H 2 4 C1 2

N

2 0 (423 .342): calculated: 0 59.58 5.71 C, 01 16.75 N 6.62 Cl- 8.38 found: C 58.45 H 6.11 C 16.92 N 6.65 Cl- 8.47 I I:.n r 30 Example 8 12H-12-Pyrrolidinylacetyl-2-chloro-dib n z od,/7- L/1,3,67dioxazocine maleate A) A mixture of 22.0 g (0.068 moles) of 12H-12-chloroacetyl-2-chloro-dibenzo/ d,g7/ 1,3,67dioxazocine, 24.2 g of pyrrolidine and 250 cm of benzene is heated under reflux for 3 hours. The reaction product is isolated as described in Example 4, section The crude product is crystallized, *Sol then recrystallized from petroleum ether to obtain 19.8 g 10 (81.1 of 12H-12-pyrrolidinylacetyl-2-chloro-dibenzo/d ,n 7 A0 Vel /<1,3,67dioxazocine. M. 80 to 83 C.

Analysis for C 1 9

H

19 C1N 2 0 3 (358.827) calculated: C 63.60 H 5.34 01Cl 9.88 N 7.81 found: C 63.11 H 4.82 Cl01 9.80 N 7.71 r tL 4 4 U 8) 14.0 g (0.039 moles) of 12H-12-pyrrolidinylacetyl-2- .'ci1.oro-dibenzo/ d,7/1, 3,67dioxazocine is reacted with 4.6 g (0.04 males) of maleic acid as described in Example 1, section The acid addition salt formed is recrystallized from ethanol to obtain 15.8 g (85.5 of the title compound.

187 to 192 o Analysis for C 23

H

23 C1N 2 0 7 (474.899): calculated: C 58.17 H 4.88 Cl 7.47 N 5.90 found: C 58.48 H 4.50 Cl 7.47 N 5.93 -31 Example9 12H-12-Morpholinylacetyl-2-chloro-dibenzo/-d ,q7- L,3,6~7dioxazocine maleate A) A mixture of 25.0 g (0.077 moles) of 12H-12-chloroacetyl-2-chloro-dibenzo/-d,fl7/P,3,6k7dioxazocine, 30.4 g (0.35 mol es) of morpholine and 250 cm 3 anhydrous benzene is heated under reflux for 3 hours. The reaction product is isolated as described in Example 4, section The crude 0*4 product is crystallized from hexane and recrystallized from isopropanol. 24.9 g (86.2 of 12H-12-morpholinylacetyl-2- -chloro-dibenzo/Th,,7Ll1,3,67dioxazocine are obtained. M-p.: 123 to 125 OC.

Analysis for C 19

H

19 C1N 2 0 4 (374.827): calzuulated, C 60.88 5.11 Cl 9.46 7.47 fudC597 ,H 5.70 Cl 9.52 N 7.21 fon: C 97 B) 20.0 g (0.053 moles) of 12H-12-morphlinylacetyl- -2-chloro-dibenzo/ ,af7l,3,67dioxazocine are treated with 6.2 g (0.053 moles) of maleic acid as described in Example 1, section C) to give the corresponding maleate -that is recrystallized from ethanol, Thus, 20.2 g (77.7 of the title compound are obtained. M. p.:i 197 to 199 oc' Analysis VAfr C 23

H

23 1N 2 0 8 (490.898); V> calculated: C 56.28 4.72 %,CI 7.22 5.71 found: C 56.71 4.88 %,Cl 7.23 5.72 I -32 Example 12H-12--2-(Cyclopropa aeylamino)-acety-2-chloro- -dibenzo/-d,7/-1,3,67dioxazocine maleate A) A mixture of 25.0 g (0.077 moles) of 12H-12-chloroacetyl-2-chloro-dibenzo/-d,l7/~1,3,67dioxazocine, 2 x 8.6 g (2 x 0.15 moles) of cyclopropylamine and 200 cm 3 of anhydrous benzene is heated under reflux for 11 hours. The reaction product is isolated as described in Example 4, section A).

The crude product is crystallized, then recrystallized 10 from petroleum ether to obtain 18.3 g (69.1 of 12H-12- S/-2-(cyclopropylamino)-acetyl7-2-chloro-dibenzo/-d,7/- 1,3, 7dioxazocine. 80 to 85 C.

Analysis for C 1 8

H

1 7 lN 2 0 3 (344.800): calculated: C 62.70 H 4.97 C1 10.28 N 8.12 15 found: C 63.02 H 4.60 C1 10.35 N 8.01 S" B) 11.4 g (0.033 moles) of base prepared in section A) above are treated with 3.9 g (0.034 moles) of maleic acid as described in Example 1, section C) to give the correspond- S 20 ing maleate that is recrystallized from ethanol to obtain 11.9 g (78.3 of the title compound. 176 to 181 oC.

Analysis for C 2 2

H

2 1 N 2 0 7 (460.872): calculated: C 57.34 H 4.59 Cl 7.69 N 6.08 found: C 57.70 H 5.00 C1 7.91 N 6.15 SL Ir. i_ 1 33 Example 11 12H-12-Diethylcarbamoyl-2-chloro-dibenzo/ d,a7- 1,3, 67dioxazocine An 50 per cent dispersion of 4.8 g (0.10 moles) of sodium hydride in mineral oil is added to 100 cm 3 of dimethylformamide at 25 °C under stirring. Then, 24.8 g (0.10 moles) of 12H-2-chloro-dibenzo/ d,g7/Ll,3,67dioxazocine are added to the mixture at a constant temperature of 25 0 C. The reaction mixture is heated to 40 C and stirred for an hour 10 at this temperature, then cooled to 20 oC. 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 cm 3 of water are added to the mixture cooled to 0 0

C,

o The viscous oil formed is separated, dissolved in 150 cm m 3 S 15 of benzene, washed with water 3 times using 80 cm of water x each time. The organic solution is dried over anhydrous magnesium sulfate, the solvent is removed under reduced pressure, the residue is treated with petroleum ether to induce crystallization. The crude product is recrystallized from isopropanol. Thus, 22.9 g (66.0 of th- title compound are obtained. 93 to 95 OC.

Analysis for C 18 H 19

CN

2 3 (346.823): calculated: C 62.34 H 5.52 Cl 10.22 N 8.08 found: C 62.83 H 5.45 Cl 10.48 N 8.00 l:fc"-~I ii -Iwetting agents such as sodium laurylsulfate etc. as the

A

34 Example 12 12H-12-/C3-(4-Methylpiperazinyl)-propionyl-2-chloro- -dibenzo/-d,q7/-1,3,67dioxazocine dimaleate A) A mixture of 24.8 g (0.10 moles) of 12H-2-chloro- -dibenzo/-d,a7/N,3,67dioxazocine, 150 cm 3 of anhydrous benzene and 25.4 g (0.20 moles) of 3-chloropropionyl chloride i.s heated under reflux for 5 hours. The solvent is removed under reduced pressure, the residue is dissolved in 150 cm 3 tiffsbenzene, and the solution obtained is poured into crushed ice. The mixture is stirred for an hour, the organic phase 3 is separated, washed with 4 x 100 cm of 5 percent aqueous 3 sodium bicarbonate solution, -then with 100 cm of water.

The organic solution is dried over anhydrous magnesium sulfate, the solvent is removed under reduced pressure,, and -the residue is crystallized with isopropanol. The crude product is rocrystallized from isopropanol to give 26.7 p (79.0 of l2H-l2-(3-chloropropionyl)-2-chloro-dibenzo4-d,,7/j>, k67dioxazocine. M. 76 to 81 OC.

Analysis for C 16

H

1 CA NO 3 (338.193); calculated: C 56.82 IH 3.87 C! 20,97 sN 4,14 found: C 56,41 3.30 Cl 21.35 4.04 k.

B) A mixture of 33.8 g (0.10 moles) of 12H-12-(3-chloropropionyl)-2-chloro-dibenzo/ -d,,7/,3,67dioxaooIrne, 60.0 g (0.60 moles) of 4-methylpiperazlne and 250 cm 3of anhydrous benzen-e is heated under refilux for 5 hours, The ration pr'oduct is isolated as described. in Example 4, section A).

30.0 g of crudei 12H-12 (4-nthy'lpipe razino )-prop iony7 35 -2-chloro-dibenzo~d,gJ ill3,61 dioxazocine are obtained as a brown, vis~'ous liquid.

C) 30.0 g of the crude baa~ prepared in section B) above is reacted with 18.6 g (0.16 moles) of maleic ac'id as described in Example 1, section C) to give the corresponde-ing salt that is recrystalliised from methanol.

Thus, 24.6 g of the title compound are obtained.

185 to 187 0

C.

Analysis for C ~32 ClN 3 Oi (634.041): calculated: C 54.94%, H1 5.09%, C1 5.59%, N 6.63%; found.- C 54.74%, H1 5-46%, Cl 5.56%f N 6,52%.

Example 13 12H-12-(3-(Diethylmino)-propionyl-2-chloro-dibelzo-d,gJ trC 9r (1,3,61 dioxazocine hydrochloride A) A mixture of 33.8 g (0.10 moles) of 121-12-(3chloto-propionyl)-2-chloro-dibenzo(d,9l,3,61 dioxazoc4,ne, 2 x 29.2 g (2 xc 0.40 moles) of diethylamine and 250 cm 3 of anhydrous benzene is heated under reflux for 6 hours, altogether, The reaction is performed and the reaction product is isolated as described in Example 4, section A), The crude product is crystallised, then recrystallised from n-hexane to obtain 30.9g 182.5%) of 12H-12-1 3- (die thylamino) -propiony1).-2-chloro-dibenzo(dog)(l,3,6J dioxazocine, fi,p.: 68 to 72 0

C.

Analysis for C-c, H23ClN,0 3 (374.870): calculated; C 64.08%, H1 6.18%, C1 9,46%, N 7.47%; found-, C 63.52%f 6.61%, Cl 9.59%, N 7,25%.

cc'

PIP

-36- B) 1).7 g (0.05 moles) of l1H-12-/ 3-(diethylamino)- -p op onyyL7-2-chloro-dben zo/-d~a7/-1,3,67dioxa o i e are dissolved in 70 cm3 of iFopropanol. To tne stirred solution cooled to 0 OC, isopropanol cqmprising 20 per cent gaseous hydrogen chloride iii dissolved form is added until a pH value of 3. The mixture is stirred for an hour, the cryst'Als are filtered and recrystallized from isopropanol. Thus, 17.9 g (81.0 of the title comp ind are obtained. M. p.: 176 to 182 0 C.

10 Analysis for C 20

H

2 HC1 2

N

2 0 3 (441.329); o*1 calculated: C 58.40 H 5.88 Cl 17,24 N 6.81 Cl 8,62 9; found: C 58.12 H 6.07 %4 Cl 17,12 N 6.(8 Cl- 8.66 k.

Example 14 12 H -12-P3-( I SQ pro pylamino) -pv L op 1 on yl/ -c2 hl 1 o- -dibenzo/-d,7/ l,3,.7di Oxazo ine hydrochloride.

eiL A mixture of 30,0 g (0,089 moles) of 12H-12-(3-ohloropropionyl)-2-chloro-dibenzo/ d 1, 67dioxezocine, 2 x 21,0 g (2 x 0.356 moles) of isopropylamine and 250 cm 3 of anhydrous benzene is heated under reflux for 6 hours, altogether. The reaction Is performed and the reaction product is isolated as described in Exampje 4, section A) to obtain 28.5 g 12H-12-.73-(isopropylamino)-proplony.L7-2-ohlaro- -dlbenzo/-dfl7C1r,3$, l dioxazOclne as a viscous iliquid.

The d1ipxazocirie base is convertel -t the hydrochloride as described in Examp~l 3, section After recrystalliz- A; 4L4 M :ji i~ k* N -37tion from ethanol, 25.8 g (73.0 of the title compound are obtained. M. 240 to 243 0

C.

Analysis for C 19

H

22 C1A 0 3 (397.301): calculated: C 57.44 5.58 %,Cl 17.86 7.05 Cl- 8.93 f ound: C 57,66 5.45 %,Cl 17.86 6.98 Cl_ 8.92 12H-l2-(3-Py1rrolidiny1-propioflyl)-2-chlo-dibenzo- /d,g,7/,3,.7dioxazocine maleate A) A mixture of 25.0 g moles) of 12H-12-(3-chloroprpoy)2Qlr-ibno/dR/136d~aoie 21.3 g (0,30 moales) of pyrrolidine and 250 cm 3 of anhydrous benzene is heated under reflujX for 3 hours. The reaction product is C isolated as described in Example 4, section the crude product is crystallized from petroleum ether and recrystallized from the same s9,, vent to obtain 21.8 g (79,0 of 12Hdioxazocine. M. 1,15 to 118 Cc.

Analysis for 0 20 H 21 G1N 2 0 3 (372.,54)t calcuiated,; C 64.43 %t H 5.68 Cl 9.51 N 7.$1 found., C 64.00 %0 H 5.12 1, C 9.61. N 7.40 8) 20.0 g (0.054 moles) of the base prepared in section A) above Is reacted with 6.4 U (0.055 moles) of maleic acid a S d escribed in Example 1, section C) to give -the correspond- Ing Salt that is recrystallized from ethoinol. Thust 22.7 g 38 (85.9 of the title compound are obtained. M. 16. to 164 0

C.

Analysis for C 24

H

25 ClN 2 0 7 (488.926): calculated: C 58.96 H 5.15 %i C1 7.25 N 5.73 found: C 59.52 H 5.28 Cl 7.35 N 5.79 Example 16 12H-12-F3-(Cy C:Lpropylamno) -propior Y17-2-chloro- 9,99 c' -dibenzo/Th,.g //l,3,67dioxz7,oCine hydrochloride A mixture of 25.0 g (0.074 moles') of 12H-L2-0(-chloropropionyl)-2-hl ro-dlbenzo/-d, 7 h/ 1:3,g6.7dioXazocine 2 x 8,7 9 (2 x .1,6 moles) of cyclopropylamine and 250 cm 3 of anhydrous benzene is heated under reflux for 15 hours, aOtogeotho, The veaction is performed and the reaction product is isolated as described in Example se(tbiaon A) to obtain 21,7 of 12H-124L2 -Uoycloprpysmi no) -pvopiony 17- -2-chloro- dibenzod ,f7LI.,3,A7dioxazocine as a viscous liquid.

The dioxazocine base obtained above is converted to the hydrohloride as desribed in Example 3, eetion 0).

After recrystallization from athanoI, 16.7 g (64.0 94) of the title compound ar obtained. M. p 1 396 to 204 0C.

Analysis for 0 19

H

20

CL

2

N

2 0 3 (H95,28) caloulatedt C $7.73 H 5.10 Cl 1794 N 7.09 -1, .4 2$ W 8.97 found 1 C 508,4 H 5.38 %t C12,18 N 7,l1 0., ~V 8.89c~ b-4 39 Example 17 12H1-12 3-mor pholiinyl propi onyl))-2 -chlo ro-diibenzso- I di I (1,3,6j dioxazocine hydrochloride A) A mixture of 25.0 g (0.074 moles) of 12H-12-' (3-chloro-proprionyl)-2-chloro-dibenzo d,gl(1,3,61 dioxazocine, 30.4 g (0.35 moles) of morpholine and 250 cm 3 of anhydrous benzene is heated under reflux for 5 hours, The reaction product is isolated as described in Example 4, section A) and crystallised in n-hexane, The crude product is recrystallised from isopropanol to obtain 23.9 g (83.0%) of 121-12-(3-morpholinyl-propionyl)-2-chloro-dibenzo(d.g (1,3,63 dioxazocine. Mp, 122 to 125 0

C.

Analysis for C 20

H

1 ClN 4 04 (388,854); $fill calculated; C 61.78%t 4 5,44%, Cl 9.12%, N 7.20%; found; C 60.98% i 5.93%, CI 9,21%, N 7.03%.

gB) 15.0 g (0,0386 moles) of 12H-12- '2 (3-morpholinylpropionyl)-2-ohloro-dibenzofd gJ(1,3,61 dioxazocine is converted to the hydrochloride as described in :Example 3, sectioj After recrystallisation from ethanolf 13.5 g of the title compound are obtained.

225 to 2291C, Analysis for C 2 0 Hl2C12 N 2 0 4 (425.315); calculated: C 56.481, If 5,21%, C1 16.67%, N 6.59%, Clr 8.34% '2 found: C 56,92%, H 5.35%, CI 1607%, N 6.55%, CU- 8.36%, 1(30 CK/Melb, Disk 1 r 1 i i' li;; i h- )L 1 i 40 *911

I

ctrA A a £4 t Al A At A *i A A I At.

A

A.A t4l A A A AIA A. A

IA,'

Ar At At A A A Example-.18 (t)-12H-12-C2- (4 -methylpiperazinyl) -propiony17-2- -chloro-dibenzo/cd,il7r'l,3,67dioxazoine maleate A) A mixture of 1,23.9 g (0.50 moles) of 12H-2-chloro- -dibenzo/.7d,Rf,'-l,3,67dioxazoine, 750 cm 3 of anhydrous toluene and 127.0 g (1.00 mole) of 2-chloropropionyl oh: ride i6 heated under reflux for 3 hours. The reaction product is isolated as describe. in Example 3) section After recrystallization from isopropanol, 131.1 g (77.5 of 10 (t)22H-12- (2-choropropionyl) -2-chLoro-dibenzo[ d, g1.3, 6 dioxazocine are obtained, M. 152 to 15"5 OC.

Analysis for C 16

H

13 C1 2 N0 3 (336,201)', calculated! C 56.82 H 3.87 Cl 20.97 H 4.14 found; C 56.32 H 3.99 Cl 21.20 H 4,10 %0 B) A mixture of 20.0 9 (.0Q$9 moles,) of chloropropionyl- -dioxazocine prepared in section A) above, 2 x 25ii g (2 x 0.25 moles) of 4-methylpiperazine and 200 cm 3 of anhydrous benzene is heated under roflx for 11 hours, altogether. The reaction is performed and the reaction product is isolated as described In Example 4 sectLn The crude product Is treated with petroleum ether to Induce orystallzation, and the crystls are recrystallized from Isopropanol.

1s, 10g8 g (70,2 oif 12H-12-/(4-ethylpipra. in)) -p--roplony17--chloro-dib e7zodn7-,3,67dioxazocine are oLtainadi M. 133 to 136 OC, Analysis for C 2 iH 4 C1N 3 a 3 (401.896)t calculated: C 62,76 P, H 6.02 Cl 8.82 N 10.46

U-

A 4 7; I- (I 41 C 61.98 H 6.60 Cl 8.93 N 10.20 found: ae 44 4 4 4 4 $4 4i *r 44 49 4i 44 S 4 4 C) 13.0 g (0.032 moles) of the dioxazocine base prepared in section 8) above is reacted with 7.6 g (0.066 moles) of maleic acid as described in Example 1, section C) to give the acid addition salt. After recrystallization from ethanol, 17.1 g (84.2 of the title compound are obtained. M. p.: 177 to 182 OC.

Analysis for C 29

H

32

CIN

3 0 11 (634.041): calculated: C 54.94 H 5.09 Cl 5.59 N 6.63 foundt C 55.27 H 4.89 Cl 5.63 4, N 6.61 Example 19 ()-12H-1'!-(2-Pyrrolidinylpropionyl)-2-chloro-dibenzo- /-d,7/-1,3,6/dioxazocine hydrochloride A) mixture of 28.0 g (0.083 moles) of (t)-12H-12-(2- -chloropropionyl)-2-chloro-dibenzo/-d,7/~1l,3,67dioxazocine, 21.3 g (0.30 moles) of pyrrolidine and 250 cm 3 of anhydrous benzene is heated under reflux for 10 hours. The reaction product is isolated as described in Example 4, section 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 (80.3 of t )-12H-12-(2pyrrolidinll/pro,ionyl)-2-chloro-dibenzoP/ d,7/-1,3,67dioxazocine are obtained. 98 to 102 'C.

Analysis for C 20 H2C1N 2 0 3 (372.854): calculated: C 64.43 H 5.68 Cl 9.5 N 7.51 found: 0 63,89 H 6.03 Ci 9.60 N 7.43 1 .1 -42 8) 16.0 g (0.043 moles) of the dioxazocine base prepared in section A) above is converted to the hydrochloride as described in Example 3, section After rkcrystallization from isopropanol, 14.2 g (80.7 of the ti.tle compound are obtained. M.p. 223 to 225 0

C.

Analysis for C 20

H

22 C1 2 N 2 0 3 (409,315): calculated: C 56.69 5.42 Cl 17.32 N 6.84 Cl 8.66 f ound: C 59.03 5.88 C1 16.93 6.91 10 Cl- 8.47 t t 9 Ia ,I e 2-Isopropylaminopropionyl )-2-'chloro- -dibenzo/-d,a7Ll ,3,7dixazd.Zine hydi'ochloride A) A mixtu~re of 23,7 g (0.070 moles) of (t)-12H-12-(2- -chloropropionyl)-2-chlro-dibezo/d,Q7/l1,3,67dioxazoclne, 17.7 g (0.21 moles) of isopeopylamine and 250 cm 3 of anhydrous 22 benzene is heated unlder reflux for 6 hours. Thj reactioni V product is isolated as described in Example 4, section A).

The crude produc-#t is treated with petrol to induce crystalilization, and -the crystals are recrystallized from -the same solvent. Thus, 18.2 g (72.1 of (t)-.l2H-12-(2sp r o pyl ami noprop ion y chlovo di ben z a/ d ,l 7 ,3 67 dioxazocine are obtained., M p,.a 102 to 105 OC 4 Analysis for C 9

H

1 C1N 2 0a (360.843):, calculated:, C 63.24 Id 5.87 %,Cl 9.83 7.76 f ound: C 62.85 k, H 6 .13 %,Cl 9.98 7.61%

,.A

ii i 43 B) 10.0 g (0.0277 moles) of dioxazocine base prepared in section A) above is converted to the hydrochloride as described in Example 3, section After recrystallization from isopropanol, 9.6 g (87.3 of the title compound are obtained. M. 224 to 227 0

C.

Analysis for C 19

H

22 C1 2

N

2 0 3 (397.304): calculated: C 57.44 H 5.58 Cl 17.85 N 7.05 Cl- 8.92 found: C 57.44 H 5.70 Cl 17.63 N 6.94 10 Cl 8.90 ea 14 c Sr I ti e It i. I t I Example 21 )-12H-12-/-2-Methyl-3-(4-methylpiperazinyl)- -propionyl7-2-chloro-dibenzo/d,l/l,3 67dioxazocine dimaleate A) A mixture of 26.1 g (0.11 moles) of 12H-2-chloro-dibenzoL/da7/1l,3,67dioxazocine, 300 cm 3 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 OC, 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 100 cm 3 of 5 per cent aqueous sodium bicarbonate and 100 cm 3 of water, and dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure, the residue is treated with isopropanol to induce crystallization, and the crystals are recrystallized from the same solvent. Thus, 33,2 g (76.1 of -bromo-2-methylpropionyl) -2-chloro-dibenzo-d 3,67i 1_L 44 dioxazocine are obtained. 115 to 119 0

C.

Analysis for C 1 7

H

1 5 BrC1N0 3 (396.688): calculated: C 51.47 H 3.81 Br 20.15 Cl 8.94 N 3.53 found: C 51.35%, H 3.98%, Br 20.20 C1 8.90 N 3.52 t ri 8) A mixture of 28.6 g (0.072 moles) of the bromomethylpropionyl-dioxazocine prepared in section A) above, 2 x 30.0 g (2 x 0,295 moles) of 4-methylpiperazine and 250 cm 3 of anhydrous benzene is heated under reflux for 7 hours, altogether. The reaction is performed and the reaction product is isolated as described in Examnple 4, section The crude product is treated with petroleum ether to induce crystallization, and the crystals are recrystallized from n-hexane to obtain 25.3 g (84,6 of (-)-L2H-12-/2-methyl-3-(4- -methylpiperazinyl) propionyl7-2-chlorodibeanzo/d ,73, 37dioxazocine. M. 128 to 131 1(" Analysis for C 22

H

26 C1N 3 0 3 (415. 921): calculated: C 63.53 H 6.30 C1 8.52 N 10.10 found: 0 62.80 H 6,75 Cl 8.63 N 9,87 C) 9.0 g (0.022 moles) of the dioxazocine base prepared in section 8) above is reacted with 5.2 g (0.045 moles) of maleic acid as described in Example 1, section C) to give the acid addition salt, After vecrystallization from acetonitrile, 11.8 g (82.5 of the title compound are obtained. 152 to 157 0

C.

11~- I 45 Analysis for C 30

H

34 1N 3 0 11 (648.068): calculated: C 55.60 H 5.29 %,Cl 5.47 N 6.48 found: C 55.78 5.52 %,Cl 5.42 N 6.42 t C

Claims (7)

1. Novel aminoalkanoyl-dibenzo(d,g][1,3, 6]dioxazoc 4 nes R. of the formula 00 X O (I) A R I'i" wherein X represents hydrogen or halo, a A stands for a valence bond or straight or branched chained alkylene having 1 to 10 carbon atoms, a R and R 2 independently represent hydrogen, an 15 -C Salkyl having 1 to 4 carbon atoms or a cycloalkyl having 3 to a 6 carbon atoms, or R, and R 2 together with the nitrogen they are attached to andd optionally with one or more further -d nitrogen, oxygene and/or Isulfur atoms(s) form a 5- to 0 6-imembered heterocyclic group selected from piperazine, piperidine, pyrrolidine and morpholine Optionally substituted with an alkyl group having 1 to 4 catbon atoms, and pharmaceutically acceptable acid addition salts thereof. ad S2. Compounds of the formula as claimed in Claim 1, wherein ac -d 47 X represents hydrogen or haloo A stands for a valence bond or an alkylene having 1 to 3 carbon atoms, Rand R2 independently represent hydrogen, an alkyl having 1 to 3 carbon atoms or a cycloalkyl having 3 to 6 carbon atoms, or Rand R 2 together with the nitrogen they are attached to and optionally with an oxygen form a 4-methyl- etc# tpiperazinyl,

2-rethyl-piperidinyl, pyrrolidinyl or *Wirt#W morpholinyl group.

3. 12H-12-/C(4-methylpiperazinyl)-acetYl17-dibenzo- L-d,a7ZL13,7dioxazocine and pharmaceutically acceptable acid addition salts thereof.

4. l2H-2-Chioro-l-C(4-methypiperaziny!)cti- -dibenzo/-d,a7/ft,3,67dioxazocine and pharmaceutically f$ acceptable acid addition salts thereof. 141# -dibenzo/ d,271 1,3,67dioxazocine and pharmaceutically ~acceptable acid addition salts thereof.

6. 12H-12-0lethylarbamoyl-2-chlor.--dibenzo/cJ,fl7- <l1,3,67dioxazocine and .'armaceutically acceptable acid addition salts thereof.

7. 12H-2-Chloro-12-/-3-(diethylamino)propionYI7- -dibenzo/T,q7Ll,3,67dioxazocine and pharmaceutically acceptable acid addition salts thereof. B. A process for the preparation of novel aminoalkanoyl- -dibenzo/"d,g7/'l,3,67dioxazoclnes of the formula I i 1 I -48- 0 0 C=OD2 wherein X represents hydrogen or halo, A stands for a valence bond or a straight or branched chained alkylene having 1 to 10 carbon atoms, R, and R independently represent hydrogen, an alkyl having 1 to 4 carbon atoms or a cycloalkyl having 3 to 6 carbon atoms, or R and R 2 together with the nitrogen they are attached to and optionally with one or more further nitrogen, oxygen and/or sulfur atoms(s) form a 5 to 6 membered heterocyclic group selected from piperazine, piperidine, pyrrolidine and morpholine optionally substituted with an alkyl group having 1 to 4 carbon atoms, and pharmaceuti.ally acceptable acid addition salts thereof, in which a) a dibenzo[d,gj(1,3,6]dioxazocine of the formula S(II) 0 9 t0 0 4 A tt NO O V iI w~herein X is as defined above, is acylated with a compound of the formula Hal- Vi-A-Hall 0 (I I I) wherein A is as defined abuve, Hal and Hal' independently represent a halo, and -the obtained alkanoyl-dibenzofd,.27- Cl_,3,67dioxazocinp of the formula IV) t =0 A -Had wherein X, A sod Halt ore as defined above, is reacted with an amine of the formula H N RI (Vill) wherein Rand R, ar as definted abovp; or b) a Oibenzo_/d,,97l',36doxazocine of the formula (11) is acylated with a compound of -the tormula -j /1 Hal- j-A-Nz (V) bR wherein A, R 1 and R2are as defined above, Hal stands for halo; or *041P o) a dibenzo/,d,.a7/l1,3,67dioxazocine of the formula 0449 (11) is acylated with a compound of the formula 4,4 10 Halj,-A-CH=CH 2 (VI) 4 t wherein Hal stands for halo, A' represents a valence bond or a straight or branched chained alkylene having 1 to 8 carbon atoms, and the obtained compound of the formula o o CO, C:O -l' wherein X and A' aire as defined abovc, is reacted with an amine, of the formula (VI11); and, it des~ired, a compound, of the formula is conver-ted into an acid addition salt with a Pharmateuticaliy acceptable inoroanic or organic acid, or tram an acid addition salt, the compound of the formula Is deliberated with a base. 2I 51

9. A pharmaceutical comporiition having local anaesthetic, tr~nquil~lo-sedative or antiparkinsonic activity, comprising a therapeutically effective amount of a compound as claimed in Claim I in admixture with one or more pharmaceutically acceptable carrier(s). a ,~I q o~ e ,t f~ DATED this 29th day of December 1987. EGIS GYOGYSZERCYAR 0 t 4 4 #1 0 t 15 %t .1 4 I q 4~ S EDWD. WATERS E ONS PATENT ATTORNEYS 50 QUJEEN STREE~T MELBOURNE. viZO. 3000. I 1"N