AU636101B2 - 1,2,3,4,10,14b-hexahydrodibenzo(c,f)pyrazino-(1,2-a)azepino derivatives and 10-aza, 10-oxa and 10-thia analogues - Google Patents

Description

AU-Al-15904/88

PCII

WORLD INTELLECTUAL PROPERTY ORGANIZATION SInternational Bureau is INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4: CW7D 487/04,498/04,513/04 A61K 31/55 Al (11) International Publication N umber: WO 88/ 07997 (43) International Publication Date: 20 October 1988 (20,10.88) (21) International Application Number: PCT/AU88/00095 (22) International Filing Date: (31) Priority Application Number: (32) Priority Date: (33) Priority Country: 31 March 1988 (3 1.03.88) PI 1363 10 April 1987 (10.04.87)

AU

Flat 3/132 Alexandra Street, East St. Kilda, VIC 3182

(AU).

(74) Agent: sANTER, Vivien; Clement Hack Co, 601 St.

Kilda Road, Melbourne, VIC 3004 (AU).

(81) Designated States: AT (European patent), AU, BE (European patent), CH (European patent), DE (European patent), FR (European patent), GB (European patent), IT (European patent), JP, LU (European patent), NL (European patent), SE (European patent), us.

Published With international search report.

A-.QJ-P- B LI' 988 (71) Applicants (for all devignated States except US): MO- NASH UNIVERSITY (AU/AU]; Wellington Road, Clayton, VIC 3168 AUSTRALASIA*-DRUb'& DEVELPMENT- LIMI4FEJ;) [AUtA-Uj~-46-Buck-' hurat Street, South Melbourne, VIC 3205 (AU).

(72) Inventors; and Inventors/Applicants (for US only) :COPP, Frederick, Charles [GB/GB]; 32 Stanley Avenue, Beckenham, Kent BR3 2PX BOURA, Alan, Louis, Arthur [AU/AU]; 46 Stoney Creek Road, Upper Beaconsfield, VIC 3808 JACKSON, William, Roy [AU/ AU]; 6 Freeman Street, Glen Waverley, VIC 3150 CULLEN, John, David [AU/AU]; of" V NO A\ (54) Title: 1,2,3,4,10,1 4b-HEXAHYDRODIBENZO[c,f]PYRAZINO-[l,2-aAZEPINO DERIVATIVES AND 10-THIA ANjALOGUES AND 1O-AZA, 936101

(I)

z

-(CH

2 -CNR1R 3 n-

N

(nI) (57) Abstract A compound of general formula wherein X 0, S or NR 4 and Yi formula where RI H, lower alkyl or an aryloxyalkyl group, wherein the aryl group is optioally substituted by alkyl, alkoxy, hydrogen, alkyl substituted by hydrogen, and .n is an integer between 0 and 5, and Z S or 14R 2 wherein R 2 H, lower alkyl, hydroxy, amino cyano or acyl, R 3 H, or lowev alkyl, and R4 H, lower alkyl, or lower acyl, and pharmaceutically qcceptable salts thereof.

W u 88 e, 99, WLI 88ji!~99 i 11 AU88/000~95 1,2,3,4,10,14b-hexahydrodjbenzo [cjf] pyrazino-w [1,2-al azepino derivatives and 1O-aza, lO-oxa and 1O-thia- analogues This i~'tion relates to novel structural analogues and derivatives of t'ne compound normiariserin, and to methods of synthesis and therapeutic uses thereof.

Background and Prior Art Mianserin (1,2,3,4,40,14b-hexahydro-2-methyldibenzo Ec,flpyrazirio(1,2-alazepine) is a serotonin inftibitdr and, antihistamine compound whose preparation was disclosed in U.S.

Patent No. 3,534,041 to Organon. Derivatives of this compound are disclosed in British Patents No. 1498632 and 1498633.

WO 88/07997 PCT/AU88/00095 2 Normianserin (Chemical Abstracts no. 71936-92-0), also known as desmethylmianserin, has similar pharmacological activity to that of mianserin but is less potent (Pinder, R.M.

(1985) Acta Psychiatrica Scand. Act. 320 1-9; Doggrell, S, (1985) J. Pharm. Pharmacol. 37 116-20; Przegalinski, E., Rawlow, and Dohnal-Borak, 1. (1986) Polish J. Pharmacol.

Pharm. 38 69-75).

A related class of dibenzo-pyrazino-azepines was disclosed in U.S. Patent No. 3,701,778 (van der Burg). These compounds were stated to have anti-inflammatory, anti-serotonergic, anti-histamine and cardiovascular effects, while certain intermediates in their preparation were also pharmacologically active. The compounds included oxazepines, thiazepines and diazepines, and a variety of synthetic routes for obtaining the desired products was set fErth.

It is kn'wn that many important pharmacological effects are mediated by 5-hydroxytryptamine, which is also known as serritonin. More recently, it ias been established that receptors for 5-hydroxytryptamine are of five distinct sub-types, each having a characteristic pharmacological profile (reviewed by Fozard, J.R. (1987) Trends in Pharmacological Sciences 8 501-506). A variety of physical Ind mental conditions, such as migraine, depression, anxiety, and gastrointestinal disturbances, is susceptible to manipulation using agonists and antagonists of with binding activity at the different types of receptors. Mianserin, ketanserin, ritanserin and altanserin are.all cited by Fozard (op. cit.) as being 2 -receptor antagonists.

Summary of the Invention The present invention provides compounds of the general formula I 3 b%'/AU u u w U .7 MhiYy

(I)

wherein X CH 2 O, S or NR 4

NY

Z

II 1 3 Y (CH 2 C.NR R where R H, lower alkyl or aryloxyalkyl group wherein the aryl griup is optionally substituted by alkyl, alkoxy, halogen, al yl substituted by halogen, and n is an integer between 0 and 5, and Z O, S or NR 2 wherein R H, lower alkyl, hydroxy, amino, cyano, or acyl, R H. or lower alkyl, and 4 R H, lower alkyl, or lower acyl.

Where appropriate, the invention also includes pharmaceutically acceptable salts of these compounds. Both Dand L-isomers are within the scope of the inventicn.

According to another aspect of the invention, methods for preparation of the compounds of formula I are provided, as set out hereinbelow: WO 88/07"7 WO 8807997PCT/AU88/090095 -4

NH

1. MNH R NHCN R RNHCNM MNH LC 411N

SNHR

NH

R NHCNM where MNH normianserin and L is a suijtable leaving group, for example CH 3 O0, CH 3 S, -CH 3 so 2 Ps S 3 H, CH~ 2 CH 3 e-tc.

Compounds according -to formula I wherein Z= S not: only possess useful therapeutic activity per se, but may also be used as intermediates for preparation of compounds of

N

2 formula I wherein Z N MNCN H 2 S 0MNC NH 2 13 S CH I SCH 3 R R NH NH 4. Mr MN=NH ~NNRR3

A

where A 1's a halogen.

An alternative method of synthesis of compounds of formula I is illustrated by the equation: WO 88/07"7 WO 88/07997P CT/A U88/4)095 C O 3 H/H OCH 3 R 1R 31NH NH MNCN MNCr)NH MNC-NR R

A

Compounds according to formula I wherein Z =H2may also be prepared for example from N-cyanonormianserin (i.e.

formula I wherein X =CH 2 and Y CN) and the appropriate rnetallated residue (for example sodam, Ide or metallated amines): NaNR 1R 3 NH 11 1 3 6. MNCN orMNCNR 'R 1 3 BrMgNR R Essentially all of the compounds are derived from riormianserin, which may itself be obtained from mianserin by a variety of routes.

The compounds, where X =CH, may be prepared by the nucleophilic attack of normianserin on the appropY.iate reagents, including S, S-dimetbyl N-cyanodithioimninocarbonate (MeS 2 C :NCN), 2-chloroacetamide, cyano~mide, acrylamide, and 3-bromopropyj-l-cyanide, to yield approprilate compounds i

A

which can undergo,-further reactions, such as he conversion of a tritrile into amidocarbonylf replacement of metthylthio by et-hylaminio, etc. Further reactions also include the c-onversion of N-cyanonormianserin with sodamide to give the parent 2-carboxamidinonormianserin; or by conversion of the N-cyanonormianserin into the corresponding 2- [S-methyliso '"hiocarboxamidolnormianserin, which can then be racted further\ wt the appropriate amines to give dierivative's of .carboxamidinonormianserin, etc.

Othe~ilnethods for preparation of compounds according !!orrnula I wil 1e apparent to those of normal skill in the \art, and are s eci~ically included within the scope of the \present invent'on.

WyO 88/07997 PCT/AU88/00095 6 In particular, it will be apparent that methods suitable for synthesis of compounds of formula I in which X is 0, S or NR 4 are known, for example with reference to the aforementioned U.S. Patent No. 3,701,778.

These reactions are performed on racemic mixtures; however, it will be apparent to those skilled in the art that thestprocedures are equally applicable to D- or L-isomers.

According to a third aspect of the invention there is provided a method of treatment of disturbances of 5-hydroxytryptamine metabolism in a mammal, comprising the step of administering to a mammal suffering from such disturbance a pharmacologically effective amount of a compound according to formula I.

According to a fourth aspect of the invention, there are provided compositionsa' as an effective agent compounds according to formula I, together with pharmaceutically acceptable carriers, diluents, or excipients.

Detailed Description of the Invention Preparation of compounds according to the invention is illustrated by reference to the following non-limiting examples. All temperatures are given in degrees Celsius. It will be appreciated by persons skilled in the art that other synthetic routes may be suitable for preparation of the desired compodnds.

Example 1 (FCC 4) 2-Cyano-l,2,3,4,10,14b-hexahydrodibenzo[c,f] pyrazinol1,2-alazepine. 2-Cyanonormianserin A solution of mianserin (5.2g) in anhydrous benzene ml) was added slowly to a stirred solution of cyanogen bromide (2.3g) in anhydrous benzene (20 ml) in an atmosphere of nitrogen. After 24 hours, the mixture was diluted with diethyl ether (50 ml) and shaken with water (50 ml). The separated aqueous layer was back extracted with a mixture of benzene and ether (equal volumes of each, total 50 ml) and the combined organic layers dried over anhydrous potassium

C

WO 88/07"77 PCT/AU88/00095 7 carbonate and then evaporated under reduced pressure. The residual solid was recrystallised from ethanol to give 2-cyanonormianserin as colourless needles m.p. 164-166 0

C.

This compound is outside general formula I, and was used as an intermediate only.

Example 2 (FCC 2-Carboxamidino-1,2,3,4,10,14b-hexahydrodibenzo [cf]pyrazino[1,2-a]azepine Hydrochloride A solution of sodamide in liquid ammonia was prepared in the usual way from metallic sodium (0.35 g) in dried liquid ammonia (150 ml) in the presence of a trace of ferric nitrate. The reaction mixture was kept at about -70 and moisture was rigorously excluded. 2-Cyanonormianserin (3.4 g) was then added slowly and the mixture stirred whilst dried hexamethylphosphoric triamide (HMPA) was added dropwise until the 2-cyanonormianserin began to dissolve; about 1 ml of HMPA was required. A deep brown sclution was formed. The stirring was continued for 30 minutes and the solution poured cautiously into a solution of ammonium chloride (4 g) in iced water (150 ml). The resulting suspension was kept for some minutes at room temperature and the solid then filtered off and washed with a little water. The residue was reserved.

The combined filtrate and washings were concentrated in vacuo to about 25 ml, when a second crop of solid separated.

The two crops and were combined and recrystallised fZom sopropanol to give 2-carboxam ,dino-l,2,3,4,10,14bhexahydro[c,f]-pyrazino[l,2-a]azepine hydrochloride as a colourless solid; it melted at 290-3000C with decomposition.

The product had variable water content, depending on the drying procedure used.

WO 88107997 WO 8807997PCT/AU88/000% -8- Example 3 (FCC-liT) 2- (2-Imidazolino)-1,23,4,10,14b-hexahydrodibelzo fipyrazino[1,2-alazepine p-toluenesulphonate A, mixture of 2-cyanonormianserin (1.0 g) and 2-aminoethylaimonium p-toluenesulphonate (2.0 g) in propan-l-ol (10 ml) was heated to reflux for 24 hours in an atmosphere of nitrogen. The reactjon solution was then poured into water (50 ml) and the resulting mixture eXtracted with methylene dichloride (3 x 25 ml). The coinbinod extracts were washed with water (3 x 25 ml)f dried over magnesium sulphate and evaporated to gi ve a colourless oil. Fractional crystallization of this oil from propan-2-o, gave the required 2- (2-imidazolino 2, 3, 4,10,14b-hexahydrodibenzo [c,flpyrazino[1,2-a]azepine p-tolueneittphonate. It was a colourless crystalline solid, m.p. 220-221, 0

C.

It will be apparent tht this compound may then be oxidized to produce the corresponding imidazolyl compound.

Example 4 (FCC 9) 2-Thioc-arboxamido- 2 ,3,4 ,l0 .14b-hexahydrodibenzo fc,flpyrazino[ ,2-alazepine Dry hydrogen sulph ide was passed through a solution of 2-cyanonormianserin (500 mg) in a mixture of triethylamine (0.25 ml) and pyridine (25 ml) for 24 hours. The resulting solution was poured into water (150 ml) and the mixture stirred for 30 minutes at room temperature to afford colourless crystals which were filtered off, washed with fresh water and dried in vacuO. Recrystallization from a mixture of diethyl ether and light petroleum gave colourless needles of the des ired, c ompound, m.p. 214-216 0

C.

Examplej5 (FCC 13) 2-Carboxamido-l 2 ,3 ,4 14b-hexahydrodibenzo flpyrazirio( t,2-a~azepine A slurry of 2-cyanonormianserin (0.55 g) %in aqueous hydrogen peroxide (100 Vol, 0.51 ml) and 20% aqueous sodium hydroxide (0.51 ml) was stirred for 30 minutes, during which WQ 88/07997 PCT/A U88/i0095 -9time the reaction mixture became warm, then cooled to room temperature, and some oxygen was evolved. Three portions of methanol (3 x 2 ml) were added to the reaction mixture, at minute intervals with stirring. The mixture was warmed to 600 for 15 minutes, then poured into water (50 ml) to give a white precipitate which was filtered at the pump, washed with water (2 x 10 ml) and dried in vacuo to give 2-carboxamido-l, 2, 3, 4, 10, 14b-hexahydrodibenzo £c,flpyrazino[l,2-alazepile, as a colourless solid, m.p.

186-187.

Example 6 (FCC 2) 1,2,3,4,10,14b-Hexahydrodibenzo[c,flyrazilo [1,2-alazepine. Normianserin A mixture of 2-cyanonormiaq, ,serin (see Example 1) (3.75 conC~. hydrochloric acid (2'O ml) and water (20 ml) was heated to reflux with stirring 1 After 12 hours the mixture was cooled, when a solid separated from solution.

This was filtered of f and dried in v acuc (3.65 g) m.p.

134-135 It was then treated with conc. ammonia (20 mil) in water (100 ml) and, the mixture extracted three times with methylene dichloride (50 ml each time) The combined extracts were dried over potassiuml carbonate, filtered and evaporated to give normianserin which was recrystallised from a mixture of propan-2-ol and water as a crystalline solid, m.p. 83-840.

The comp(ound is outside general formula I, and was used as an interm~ediate only.

Example 7 (FCC 14) 4-Cyano-N'-ethyl-carboxamidino) 1,2,3,4,10,14bhexahydrodibenzotc,flpyrazinot l,2-alazepine A mixtuie of normianserin (500 mg) and S,SI-dimnethyl N-cyanodithioiminocarbonate (292 mg) and ethanol, (50 ml) was st irred at room temperature fc~r 48 hours; methane thiol was evolved and a precipi~tate was formed. The solvent was removed under reduced pressure and the residue triturated with cold water (50 ml) The residual solid was cllected and WO 3/0707 PCT/AU8/910 recrystallised' from a mixture of propan-2-ol and ether. A solution of ethylamine (3 ml) in ethanol (20 ml) was added to a stirred suspension of t 'he solid in ethanol (20 ml); after 12 hours there was a further addition of ethylamine (1 ml) in ethanol (20 ml) and the stirring was then continued for a further 12 hours. The solvent was then evapora ted and the resulting gum chromAtographed (silica; 40% ethyl acetate in light petroleum to 100% ethyl acetate). The resulting oil was dissolved in hot propan-2-ol (5 ml) and, the resulting solution diluted with light petroleum (150 ml). A pale yellow solid was formed, collected and dried in vacuo to give 2(N-cyano-N'-ethylcarboxamidino)-1,2,3,410,14bhexahydrodibenzo(cpflpyrazino(l,2-alazepine, m.p. 205-206O Example 8 (FCC 2-tS-Methyl-isothiocarboxamidol-l,2,3,4,0,4bhexahydrodibenzor c ,f pyrazinot 1,2-al azepine hydriodide Methyl iodide (0.15 ml) was added to a suspension of 2-thiocarboxamido-l,2,3 ,4 ,l0,14b-hexahydrodibenzo(c,f]I pyrazi*no[l,2-alazepine from Example 4 (0.5 g) in methano- ml) and the mixture heated to ref lux for 3 hours. The solvent was removed and the residual gum stirred with ethyl acetate (3 x 10 ml) The resulting solid product was collected and dried in vacuo, m.p. 209-2110 (decomp).

Thisa compound is outside general formula I and was used as an intermediate only.

Examp16 9 (FCC 12) 2-(N-2-Phenoxyethyl carboxamidino)-1,2,3,4,l0,14bhexahydrodibenzo~c,flpyrazino(1, 2-alazepine hydrochloride A mixture of the S-methylisothiocarboxamido hydroiodide (S-rethylisothiouronium iodide) from Example 8 (680 mq) and 2-phenoxyethylamine (2.5 g) in propan-l-ol ml) was heated to refiux for 24 hours. Dilution of the cooled reaction mixture with ether afforded a cream Coloured solid.

W 0 88107"7 WO~I $097L I IUL)735i This was--collected, dissolved in ethanol (10 ml) and the solution passed through Axnberlite IRA 400 (Cl )ion exchanee resin. E Iaporation of the eluate gave the desired hydrochloride as a pale yellow microcrystalline so.Lid, mn.p.

250-253. Aiberlite is a trade mark of Mallinckrodt Australia Pty. Ltd.

Example 10 (FCC 2-(N-Ethylcarboxamido) 2,3,4,10, 14bhexahydrodibenzotc,f 1pyrazinol,2-a] azepir,,e A, solution of normianserin 5 g) in dry benzene ml) was added to a stirred solution. of ethyl isocyanate (0.43 in dry benzene (20 ml) and thq mixture stirred for 48 hours. The solvent was then evaporated and the residue crystallisO-d from propan-2-ol to give the desired 2-(N-ethylcarbox 4ido) -1,2,3,4 l.0, 4bhexahydrodibenzo~c,f I pyrazinotl,2-al azepine as a cream coloured solid m.p.

206-207O Example I11 (FCC 17) 2- (N-Ethylparboxamidino) 2,3, 4,10,14bhexahydrodibenzo~Cr,fI pyrazinorl,2-a~azep '-n hydrochloride A solutiofi of the 2-[S-methiylisothiocarbo ,,amidol, hydriadide derivative from Examp16 8 (0.5 g) and ethyJlamine (0.1 ml) ini propan-l-clI (25 ml) was heated to reflux for 12 2S hours 'in an atmosphere of nitrogen. The solvent was removed and the residue was dissolved in ethanol (5 ml) and the resultinrg solution percolated through Axnberlite IRA-400 (Cl) ion~ exchange resin. The eltvate was evaporated ard the residue purifi( k; by preparaive high performance liquid chromatography on a Delt-ipak C 4 c4JAM t cmn x 19 mm) in a normal gradient olf 20% aque~us methan~ol trifluoracetic acid to 100% methanol riluoradetic acid over a period of mtiutes, at a 'iow rate of 9.5 ml/min to give, af ter ion exchangei on Amberlite IIRA-400 the desired Pyrazinot1'2-ajazepine hydrochloride tn.p, 245-1.50O VVO 88/07"! WO 8807997PCY/AU88/00095 -12 The fractions were checked using an analytical column (3 mm x 9 mm) under the same conditions. Deltapak is a trade mark of Millipore Pty. Ltd.

Example 12 (FCC 18) 2-(N Ethylthiocarboxamido)-1,2,3,4,10,14bhexahydrodibenzo f Ipyrazinot 1,2 -a Iazepine A solution of normianserin (5 g) in dry benzene (125 ml) was added'slowly to a stirred solution of ethyl isothiocvanate (2 g) in dry benzene (125 ml). After 48 hours, the volvent was removed and the residue treated with hot diethyl ether (100 ml). The hot separated extract was cooled and poured into~llight petroleum (500 ml) on cooling, the desired product crystallised. It was collected and dried in vacuo, m.p. 97-105.

Example 13 (FCC 16) 2-(Carboxamidomethyl) -1,2,3,4,10 ,14b-hexahydrodibenzo [c,flpyrazino[1,2-alazepine hydrochloride A solution of 2-chloroacetamide (270 mg) in benzene ml) was added slowly to a solution of normianserin (720 mg) in benzene (20 and the resulting mixture stirred for 7 days at i '5om temperature. The reaction mixture was diluted with,,etlier (40 ml) and extracted, three times with 2N-hydrochloric acid (20 ml each time). Finally the residual solution was extracted twice with water (20 ml each time).

All the aqueous extracts were combined, whereupon a cream coloured solid crystallised out. This was filtered off, washed and dried in vacua to give the desired 2 (c arboxamidomethyl 1,2,3,4,10,l4b-hexahydrodibenzotc,f lpyrazinoI1,2-alazepine hydrochloride which decomposed above 2200.

WO 88/01-097 WO 8$O~)97PCT/A U89/40O95 -13 Example 14 (FCC 19) 2- (2-Carboxamidoethyl 14bhexahydrodibenzo(c, flpyrazino[ 1,2-a] azepine 'A solution ,of normianserin (500 mg) and acrylamide (155 mg) in ethanol (40 ml) was heaed at refl'ux for 12 hours.

On cooling a colourless solid separated which was collected and dried in vacuc to give 2-(2-carboxamidoethyl)- ~2,3,4,10,14b-hexahlydrodibenzo(c,.,Ir pyrazino(1,2-a], azepine, m~~.207-2110 Example_15 (FCC 23) 2 (N-hydroxycaboxam-in!- 3, 4,10, 14bhexahycirodibenzo[c,flpyrazinotl,2-alazepine A mixture of cyanonormianserin (270 mg), hydroxylamine bydrochloride (140 mg) a nd sodium carbi-: p-te (424 mg) in N,N-dimethylformamide (5 ml) was stirred overnight at room temperature. The mixture was poured into water (100 ml) containing a small amrwunt of ammonu chloride (500 mg) to gxve a gel-like precipitate. The gel- was filtered at the pump, dried invacuo, and the resulting amorphous mass crushed to give the desired produqct,, mp. 195-200 0 with decomposition.

Example 16 (FCC 5 alternate synthesis) 2- Carboxamidino-l, 2, 4,10, 14b-hexahydrodibenzo f~pyraztno[ 12-a1Azepine Hydrochloride A mixture 8 f t14he hydrochloride salt of normianserin 200 mg) and cyanamide (32 mg) in propan-l-ol (10 ml) was xrefluxed under an atmospheare of nitrogen for 24 hours. The solvent was removed and the resultant gum dispersed .in aqueous ammnoniumi chloride solutic (10% w/v, 100 ml) then worked up in the usual fashion to give a product identical to that obtained according to the method of Example 2, as shown by melting point and mass spectrum.

WO 88/07"7 WO 88/0797 I'L AU88/0005 -14 Example 17 (FCC 22) 2-%(2-imidazolyl) -1,2,3,4,10,14b- ,1%,xahydrodibenzo( c ,f I pyrazinot 1,2 azepine A solution oL\2 (2-Imidazolino)-1,2,3,4,10,14bhexahydrodibenzo[q,flpyrazino[41,2-alazepile p-toluenesulphonate prepared a~i. in Example 3 (100 mg-) and ~2,3-dichloro-5,6-dicyanobenzoquinone (DDQ: 51 mg) in dry benzene (5 ml) was stirred overnight at room temperature, after which time a solid separated. The mixture was diluted 1 0 with dichioromethane (50 ml) and washed three times with sodium hydroxide solution (50 ml each time) the organic solvent dried, and evaporated to give a green solid which was triturated with hot propan-2-ol (approx, 100 ml), dried and crushed to give 2-(2-izidazolyl)-l1,2,3,4,lQ,14bhexahydrodibenzo~c,flpyrazi(1)E,2alazepine as a pale green solid, rn.p. above 250 0 (decolp) -7 Examples 18 to 27 The followinq') compounds of the formula I are prep~red by methods similar to those described in Examples. 1 to 15 3 0 0 09 ':CEIVED 2 3 FEB 1989 3 1 Example No. X= R R Z= 18 O H H NH 19 0 H H O 0 H 21 0 H 0 H 22 0 H H S 23 CH 2 H PhOCH 2 CH NH

CH

3 24 CH 2 H H NOH

CH

2 H CH 3

CH

2

N.NH

2 26 N.CH 3 H H NH 27 S H H NH Ph phenyl Example 29 Pharmacological activity of compounds of the invention The compound of Example 2 was found in low concentrations to inhibit contractions of the guinea-pig isolated ileum and rat isolated stomach strip caused by histamine and 5-hydroxytryptamine respectively. The antagonism to both amines was persistent and non-competitive in nature, being relatively resistant to washing. After intravenous injection into rats and cats at doses of 0.1 mg/kg body weight or greater, it was found "o cause long-lasting rises in arterial blood pressure and heart rate, accompanied by potentiation of the pressor responses to noradrenaline and 'J i- WO 88/07 WC-r/OAU8R100095 16 sympathetic nerve stimulation with blockade of the pressor responses of the indirectly acting sympathomimetic agent tyramine. Concomitantly, the depressor effects of histamine were blocked, as were the pressor effects of 5-hydroxytryptamine for over 30 minutes. The pressor 4ffects of 5-hydroxytryptamine in anaesthetised and pithed rats wre inhibited by intravenous doses of 0.3-1.0 mg/kg body weight.

S ightly higher doses reduced the bradycardia and ,che dapressor,'La.sponse (the Bezold-Jarisch reflex mediated by 5-HT£. rc&ptors) to 5-hydroxytryptamine in anaesthetised rats.

/The drug inhibited oedema in the rat paw caused by intraplantar 5-hydroxytryptamine. The ratio of the oral to subcutaneous dose causing this effect indicated relatively good oral absorption. In mice it inhibited diarrhoea caused by L-5-hydroxytryptophan. In guinea pigs, intravenous doses of 0.03 mg/kg and above reduced the bronchoconstrictor effects of histamine and In four test situations, using the rat (spinal flexor reflex and riorphine induced catalepsy), the mouse (L-5-hydroxytryptophan-induced head twitch) and behavioural changes in the cat, the compound of Example 2 failed to demonstrate any inhibitory or other actions on the central nervous system, whereas mianserin, in low doses, was effective in the former three tests. No overt behavioural changes or acute toxicity were seen -in conscious cats after relatively large subcutaneoui doses of the compound of Example 2. These data constitute very strong evidence that this compound does not penetrate into the central nervous system to cause central effects.

Intravenous doses of the compound of Example 3 of 0.1 mg/kg or abote depressed the pressor responses to in the rat and also caused rises in arterial blood pressure. In cats, the effects of the ganglion stimulant McNeil -A-343 and histamine were reduced. Following intravenous injection into guinea-pigs, 0.01 mg/kg reduced wc) 88/07"7 PCT/AUS/000915 17 histamine and 5-hydroxytryptamine induced broncho-constriction. cncentrations of 1 pg/mi or greater relaxed the isolated rat uterus in vitro.

The compound of Example 4 when injected into rats at intravenous doses of 0.3 mg/kg or greater reduced the pressor effects of 5-hydroxytryptamine and also the depressor effects of histamine. In cats, the effect of histamine was reduced after these doses also. In guinea pigs, intravenous doses of 0 -01 mg/kg or greater reduced the bronchocons\triction caused 1by histamine or 5-hydroxytryptamine but had smaller effects on arterial blood pressure and heart rate than did the compound of Example 2, indicating some dissociation of sympathomimetic activity. In vitro at concentrations of 0.1 pg/ml or greater, this drug reduced the contractions of the isolated rat uterus csaused by 5-hy.droxytryptamine or high potassium concentrations and also demonstrated an anti-spasmodic action.

The compound of Example 5 was found to possess interesting actions on the central nervous system. Thus doses c-f 1 mg/kg given intraperitoneally attenuated the facilitation c> spinal reflex activity caused by p-chloroamphetamine, and al o the facilitation of spinal reflexes induced by fen lura'mine in spinal and decerebrate rats. In contrast, the arug did not antagonise the facilitation of spinal reflexes cavused by clonidine at these dose levels. The drug in doses S 10 and 20 mg/kg intraperitoneally and in doses of 20 mg/kg lby mouth attenuated morphine-induced catalepsy. We conclude thierefor that this drug is an orally active drug with central actions, particularly affecting serotonergic mechanisms, but as no effect in vitro (Table This drug also showed peripheral actions. Thus it was found after intravenous doses of 0.03 mg/kg to reduce histamine and ltronchoconstriction in the guinea pig.

18 U:J8 /0 00 -U FEB 18 Example 3b Effects on induced contraction of the~ Iisolated guinea-pig ileum.

Compounds according to formula I were t, ested for their ability to block contractions of the isolato'd guinea pig ileum induced by KCl, carbachol, or histamine at a' concentration of 10- 7 M. Ileum preparAtions were prqe'Pared according to standard tnethodol,ogy. The results are summarized in Table 1. The concentrations shown are the minimum' required to show activity.

I

5S Dr WO 88/07"7 WO 8807997PCTJA U88/00095 -19 TABLE 1 Compound Effect on Example,-, FCC no. lkc1 Carbachol "Histamine 0, 2 5 ND

M

49 8 -10 7

M

3 1,1T 8 m 12 10-8-10- 7 m 13 1510817 7 14 10-8 15- 7 7

M

13 16 10 M 11 17 8 _10- 7 m 12 18 10 8 -10- 7 m 14 19 8 -10 7

M

ND not done; no effect; block; complete block On the basis of preliminary results it appears that compounds FCC 16 and F'CC 19 (Examples 13 and 14) are able to penetrate into the CNS, while compound FCC 12 (Example 9) is not.

WO 88/07"77 PCT/AU88/00095 20 Compound FCC 17 (Example 11) caused complete block of the effect on blood pressure, but not the effect on heart rate, in the chloral-anaesthetized rat, of both histamine and Thus the pharmacological properties of the novel compounds according to the invention are substantially different from those of mianserin. The compounds investigated possess the following properties: 1. Sympathomimetic activity increase in heart rate, -increase in cardiac output, -increase\in arterial blood pressure, -augmentati n or depression of adrenergic nerve function potentiation or reduction of responses to sympathetic n rva stimulation in anaesthetised cats and rats potentiation of responses to noradrenaline and sympathetic nerve stimulation in anaesthetised cats and rats (some of the compounds lack this activity).

2. Anti-histamine and anti-5-hycroxytryptamine activity in cats, rats and guinea pigs.

The relative prominence 0o all these effects depends on the dose of the compound and on its structure. Effects were obser ed after intravenous doses of 0.01 mg/kg and above.

Some of these compounds would be expected to gain access to the central nervous system, whilst the more basic compounds will penetrate the blood-brain barrier less readily.

3. Antagonism of histamine and 5-hydroxytrptamine in isolated preparations, such as the guinea pig ileum and rat stomach fundus strip, with some drugs showing dissociation of the two types of activity.

WO 88107"77 PCT/AU88/00095 21 Some (such as Example 2) are less likely than mianserin to cause side effects associated with actions in the central nervous system.

It is clear that the transmitter substance a 5 5-hydroxytryptamine acts both in the central nervous system and periphery by actions at a number of distinct receptor sites. These have been termed 5-HTI, 5-HT 2 and 5-HT 3 These three receptors have been further characterised into a nunber of sub-types (Fozard, TIPS, 1987, Volume 8, p.501). It has been noted that currently available evidence suggests that drugs affecting these receptors will be of use in the treatment of asthma, anxiety, depression, hypertension, migraine attacks, venous stas-i- thrombosis, schizophrenia, diseases of the gastro-intes inal tract, emesis and as appetite stimulants. The inability of some of these comppunds to pass into the central nervous system provides useful peripheral selectivity.

The compounds according to the invention are useful as anti-depressant, anti-hypertensive and anti-asthmatic agents. The ability of the compounds to increase cardiac output shows that they are valuable aglents in the treatment of congestive heart failure. The anti-histamine and activity shows that the compounds are useful for treatment of allergic conditions and of diarrhoea and migraine.

The new compounds may be applied as drugs, for example, in the form of pharmaceutical preparations. For that purpose they are mixed with one or more pharmaceutical vehicles suitable for oral administration, or with liquid or solid auxiliaries, \uch as water, benzylalcohol propylene glycol, polyalkylene glycols, vegetable oils, gelatin, starh, lactose and magnesium stearate. The preparations may be shaped into tablets, coated tablets, grains, pills or capsules, or they may occur in liquid form, such as solutions, emulsions or suspensions. In the latter form they are also suitable for intramuscular or subcutaneous injections.

Furthermore they mAy be used in the form of suppositories.

WO 88/07"77 I, 1/AU 88/4N)95 22 They may also contain the ,equired auxiliaries, such as fillers, lubricants, preservatives and emulsifying agents and are prepared by any' method known per se.

The daily dosage may vary from 0.5 to 800 mg of the active substance, dependent upon the way in which they are to be administered, as well as the nature and the degree of the biological activity.

The compounds may also be applied for external use by introducing them into a spray together with a suitable propellant and, if desired, a solvent, further as a fine powder together with a suitable filler, and as a cream in combination with known auxiliaries.

It will be clearly understood that the invention in its general aspects is not limited to the specific details referred to hereinabove.

Claims (13)

1. 2. A compound- according to Claim 1, ir. which X is CH 2 and Y is seJlect(Ad from the group ccnsisting of 0 -C -NH 2 1 NH S N9,2 0 -NH CH 2 CH 3 24 3U 38/0009~ RLEC1ER11ED 213 FEB 1989 NH S -C-NH. CH 2 CEJ C NH. CH 2 CH 3 1 NCN NH NE. CH CH 3 NH (CH 2 -C 2 C -NH 2 f and -(CH 2 2 NH 21
2. 3. A compound according to claim 31 or Claim 2, ir which 3is CH 2 and Y is NH
3. 4. 2-Carboxaxnidino-l,2,3,411i4b-hex~ahydrodibenzo (cf pyrazinotlf2-alazepine hydrochloride. .2-(2-Imidazolno)-lf23,4fl1O,14b-hexahydrodibeazo (c,f ]pyrazino(1,2-a~azepine p-toJluernesulphonate.
4. 6. 2-Thiocarboxarrddo-1, 2, 3, 4 f10,14b-hexahydrodibenzo Cq, 4 lpyrazino 2-al azepine.
5. 7. 2-Carboxamido-2,,3 f 4 t 1 t4b-hexahydrodibenzo Cc, t pyrazino 2-a) azepine.
6. 8. 2- (N-Cyano-N thylcarboxam~idino 1, 2?3 f4 t 10 f 4b- hexahydrodiberizo(c, f pyrazino 1, 2-al azepine.
7. 9. 2-(N-2-Phenoxyethylcarboxaridino) 102t5,4010, 14b-hexahydrodibenzo(c,f lpyrazino3.,2-alazaptne hydrochloride. 2-(N-Ethylc'z'\,ibox.-mido) 1,2,3.4,J.0,34b- hexahydrodibenzo (cf pyraziio azepinet,
8. 11. 2-(N-Ethylcarboxamtidino)-l,2,,.,41Q,.4b- hexahydrodibenzo Cc,f )pyrazino( 1,2-ajazepine hydrochloride.
9. 12. 2-(N-Ethylthiocarboxanido)-1,2,3,4,.tO,14b- hexahydrodibenzQ 1c, f Ipyrazino C /zepine. 3.3. 2-(Carboxamidomethyl)-.,2,304,3.O,1.4b-hexahydrodibenzo (cfjpyrazino-t1.2-a~azepine hydrochloride.
10. 14. 2-(2-Carboxamidoethy.)-3.,2,3,4,0J4b- hexahydrodibenzo Cc *f pyrazino 2-al azepine. is, 2- (N-hydroxycarboxanddino) 2, 3 04 0 10#14b- hexahydrodibenzoCc, f Ipyrazino azepine r"ECEI\'ED 230 FPO 9
11. 16. A method of synthesis of a compound of formula I, as hereinbefore defined,. comprising a step selected from: reacting normianserin with a compound of formula R 1 'NHCN where 1 A is H, lower alkyl or an aryloxyalkyl groufb Wherein the aryl, group is optionally substituted by alkyl., alkoxy, halogen, or alkyl. substitu~ted by halogen, reacting normianserin with a compound of formula4 L-C 1 where Ris as defined above, and L is a leainggrop, leted from the group consisting of CH{0 CH S, CHiO~ S 21soH, and 3,5-dimethylpyrazol-1-yl, reacting N-cyanonormianserin with KSto form a compound of formula I in which Z is S, thqn reacting said 1 3 cpounuiwt NH to form the desir'~ opud reacting normianserin with ethyl isocyanate or ethyl isothe.cyanate to form the desired compotind, reac:ting cyanononeianserin with a p-toluene ulphoriate to form a desired imidazolinyl compound, and optionally oxidizing the imidazolinyl compound to produce- a desired imidazolyJ. compound, reacting N-cyanonormianserin with H 2 S as in 'ttop (c)o reacting the thus-formed product with methyl iodide in a reacting the product of the second step with R 1 R to form the desir,,,', qompound, reacting N-cyanortormianserin with methanol untda aci d conditions, and re'acting the thus-formred product with R 1R 3 NH to give the desired compoundi and reacting N-cyanonormianser ,n with sodanmide or w;ith a metallated residue to produce the desixred compound.
12. 17. A meth6d of synthesis of a compound of formula I as hereinbefore dcfined wherein X is CH 2 comprising the step of reacting normianserin under nucleophilic conditions with a compownd selected from the group consisting of S,S-dimethy. 1N-cya&jodio thioiminocarbonate, 2-chloroaretamide, cyanamidet acrylamide, and 3-bromopropyl-l--cyanide to produce the said compound of formula 1:. 4" 1
13. 26- 0T/AU 3 8 0 0 9 RECEIVED 23 FEB 1989 18. .A method of treatment of disturbances of metabolism in a mammal, comprising the step of administering to a mammal suffering from such disturbance a pharmacologically effective amount of a compound according to Claim 1. 19. A method according to Claim 18, for treatment of a condition selected from the group consisting of depression, hypertension, congestive heart failure, migraine, anxiety, schizophrenia, gastrointestinal disturbances, diarrhoea and er-esis. A method of treatment of disturbances of histamine metablism in a mammal, comprising the step of administering to a mammal suffering from such disturbances a pharmacologically effectiv amount of a compound according to Cliim 1. 21. A method according to Claim 20 for treatment of asthma or an allergic condition. 22. A composition comp,'ising as effective ingredient a compound according to Claim 1, together with a pharmaceutically acceptable diluent, carrier or excipient. 23. A composition according to Claim 22 for oral, rectal, intra-nasal or intra-vaginal administration. 24. Compounds of formula I substantially as hereinbefore described with reference to the examples. 4. INTERNATIONAL SEARCH REPORT International Application No PCTJAP 88ZQOO095 1. CLASSIFICATION OF SUBJECT MATTER (it several ciasiiclion symbol& acidly, indicate all) According to International Patent Classification (IPC) or to both National Classification and IPC Int. cl. 4 C07D 487/04, 4§8/04, 513/04, A61K 31/55 11. FIELDS 04ARCHED Minimum Documentation Searched Classification System IClassification Symbo13 IPC I C07D 487/04 US Cl. 1 540/578, 540/579, 540/546 CHEMICAL ABSTRACTS ON LINE C07D 487/04, 498/04, 513/04 Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included In the Fields Searched a AU IPC C07D 487/04, 498/04, 513/04 111, DOCUMENTS CONSIDERED TO OR RELEVANT Category Citation of Document,"i with Indication, where appropriate. of the ralevant passages It Relevant to Cia;M No. 13 X AU,fl, 39757/68 (423307) ORGANON) 8 January (1-5,2.1-26) 1970 (08401.70) X AM,, 18387/67 (415312) ORGANON) 5 September (1-5,21-26) 1968 (05.09.68) X EP,A, 126343 (BEECHIAM GROUP PLC) 28 November 1984 (1-5,21-26) (28.11.84) Special categories of cited documents: iT" later document published after the International filing dato document defining the general state of the art which Is not or WPIoty date and not In conflict with the application but considered to be of particular reievance cited to understand the principle or theory underlying the earlier document but published on or ater the international x douetfpatclreeaneth caidivnin filin datecannol be considered novel or cannot be considered to "Ll' document which may throw doubts on priority amt)or involve an Inventive step Which is Cited to establish the publication date of another document of Particular relevance;' the claimed Invention Citation or other Special reason t(As saecified) cannot be considered to Involve an Inventive stop whon the "Oil document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu. other means Monts, such combination being obvious to a person skilied "IP" document publIshed prior to the international filing date but In the art' later then the priority date claimed *."document member of the same patent family MV CERTIFICATION Date of the Actual Completion of the international Search 29 June .1988 (29.06.88) I !firnallonsl Searching Authority I Australian Patent Office Form PCT/iSA12IO (second shoet) (January 19gg5) )at* of Mailing of this International Search Report Signs~utoeder C.A. BRICK ANNEX 'iD THE INTERNATIONAL SEARCH REPORT ON I~ENATIONAL APPLICATION NO. PCT/AU 88/00095 This Annex lists the known publication level patent family nmembers relating to the patent documents cited in the above-mentioned international search report. The Australian Patent Office is in no way liable for these particulars which are merely given for the purpose of irformation. Patent Document Cited in Search Patent Family Members Report EP 126343 GB 8313689 JP 60006614 GB 8313690 AU 18387/67 BE 695304 BR 6787719 CH 501647 DE 1695556 ES 337526 GB 1173783 NL 6603255 US 3534041 AU 39757/68 BE 717677 CH 513911 DE 1770756 ES 355852 GB 1229252 GB 1229253 NL 6709520 US 3701778 END OF ANNEX 23@211/1