CA1153958A - 3-substituted-hexahydro-pyrimido[1,2-a]azepins, process for the preparation thereof and pharmaceutical compositions containing the same - Google Patents

Abstract

Abstract of the Disclosure The present invention relates to antianginal pharmaceutical compositions containing as active ingredient 3-carbamoyl-4-oxo-4,6,7,8,9,10-hexahydropyrimido[l,2-a]azepine, in admixture with a suitable carrier or diluent.

Description

5~3 Patent application Serial No. 351,665 relates to a process for the preparation of 3-substituted-hexahydropyrimido [1,2-a]azepines, acid addition and quaternary salts thereof and pharmaceutical compositions containing the same and to certain 3-substituted-hexahydropyrimido [1 ,2-a]azepines and salts thereof which are new. This application is divided out of application Serial No. 351,665.
Only a few 3-substituted-pyrimido[1,2-a]azepines are disclosed in the prior art. 3-Carbamoyl-4-oxo-4,6,7,8,9,10-hexa-hydro-pyrimido[1,2-a]azepine is prepared in an aqueous solution of pH = 10 in a 2 hours reaction from 3-carbamoyl-4-imino-4,6,7, 8,9,10-hexahydro-pyrimido~1,2-a]azepine with a yield of 81 %, which latter is obtained with a yield of 85 % by reacting 7-ethoxy-3,4,5,6-tetrahydro-2H-azepine and aminomethylene-cyano-acetamide in a butanol solution at the boiling point of the mix-ture after 48 hours reaction time and after chromatographic purifi-cation (Aust. J. Chem. 119, 28 [1975]). There is no suggestion that the 3-carbamoyl-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepine has useful pharmaceutical properties. Ethyl 4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-3-carboxylate is obtained 11~3~58 even by tht3 mo~t adva~ltageous embodi~ent ~ -the proce~s with a yielcl of only 50 % after complicated ~Iroce~sing from 7-methoxy-3,4,5,6--tetrahydro-2H~-azepine and diethyl ethoxy-methylene-malo~ate in the presence o~ ammonium acetate (HU-Patent Spec. ~o. 167,676 and Japanese Pat. Spec. ~o~ 7,334,897). 3-Cyano-4-oxo-4,6,7,8,9,10-hexah~dro-azepino~1,2-a~pyrimidine i8 obtained in the presence o~ ~odium ethylate ~rom 7-amin~
-3,4,5,6-tetr~lydro-2H-azepine and ethyl-e~hoxy-meth~ ne-¢yano-aoetate wi~h a yield of 1~ % ~HU-Pat.
Spec. ~Jo. 167,676 and ~apanese Pat. Spec. ~o.
7,334,~97)-We have no~ found that by reacting 7-amino--3,4,5,6-tetra~dro-2H~azepine o~ the general ~ormula III -d ~III) ~r~
R
wherein R stands for hydrogen or lower alkyl - containing two sirnilar nucleophilic nitrogen~
with an acrylie acid derivative of the general formula IV

i l 5 3~58 C = C (IV) R40 CoOR5 wherein R stands for hydrogen or lower alkyl R stands for lower alkyl, phenyl, cyano~ or lower alkoxycarbonyl, ~R4 stands for hydrogen or lower alkyl R5 represents lower alkyl -a mixture of 4-oxo-pyrimido[1,2-a]azepine of the general formula N ~ R

wherein R and R2 are as defined above and l stands for lower alkyl, phenyl, cyano or lower alkoxycarbonyl and of 2-oxo-pyrimido~1,2-a]azepine of thc general formula II
~ ~ N ~ 0 (II) : ~ N ~ R

R
wherein R

R and R2 are as defined above and Rl stands for lower alkyl, phenyl, cyano and lowcr alkoxycarbonyl -1153f~8 is obtained, which may be if desired separated and if desired the obtained compound of the general formula I or II containing alkoxy-carbonyl as Rl - wherein R and R2 are as defined above - may be a) saponified to a carboxylic acid of the general formula I or II containing carboxyl as R - wherein R and R are as defined above - or may be b) reacted with ammonia to obtain an acid amide of the general formula I or II containing carbamoyl as R - wherein R
and R2 are as defined above or may be c) reacted with hydrazine to obtain a compound of the general formula I or II containing carbohydrazide as Rl and R and R2 are as defined above or if desired a compound of the general formula I or II containing carboxyl as Rl may be esterified to give a compound of the general formula I or II containing alkoxycarbonyl as Rl and R and R2 are as defined above and a compound of the general formula I or II may be converted to an acid addition or quaternary salt there-of.
Application Serial ~o. 351,655 is directed to this novel process, and to novel products of the process.
As starting material of the general formula IV dialkyl ethoxy-methylene malonate, alkyl ethoxy-methylene-cyano-acetate, alkyl 2-formyl-propionate, alkyl 2-formylphenyl-acetate, ethyl 2-ethyl-acetoacetate are preferably used, the end forms of the latter three compounds being within Formula IV. As alkyl esters methyl, ethyl, isopropyl, n-propyl esters are preferred.
The term "lower alkyl" as used herein stands ~1~3~58 for straight or branched alkyl containin~ 1 to 4 carbon atoms, auch a~ methyl, ethyl, isopropyl, n-propyl, isobutyl, tert. butyl.
Compound~ of the general formula III are preferably reacted with compounds of the general ~ormula IV in the presence of an inert solvent.
As solvents preferably alcohols ~uch as ethanol, methanol, esters such a~ ethyl acetate, ketones ~uch as acetone, ethyl methyl ketone etc.,aromatic hydrocarbons such as benzene, toluene, halogenated hydrocarbons such a~ cnlorofo~m, carbontetrachloride, chlorobenzene or a mixture thereof etc. may be employed.
~he reaction is preferably carried out at -15 and 150 C. According to a preferable embodiment-of the proces~ o~ the invention to a solution of the compound of the general ~ormula III a ~olution of the compound o~ the gene~al formula IV i~ added but in some cases the addition may be conducted adversely.
When the solvent i~ distilled off a mixture of the compounds of the general formulae I and II
is obtained. The obtained mixture may be separated according to different solubility, basicity or chromatographic behaviour of the components.
The ester group in a given compound of the formula I or II - wherein R and R2 are given above 1153~58 and Rl stands for ester grDup - may be converted to carboxylic acid, carboxamide or carbohydrazide ~roup by method~ known per ~e.
When converting a compound of the general formula I ~r II containing an e~ter ~roup a~ RL
and R and R are a~ given abo~e, to carboxylic aci.d~
- the eflter group may be hydroiysed with diluted aqueous ~odium hydroxide ~olution, followed by acidifying with hydrochloric acid whereupon the obtained acid is precipitated and the acid i8 treated with aqueou~ or alcoholic ammonia solution or hydrazine h~ldrate and thus carboxamide and carbohydrazide derivative re~p. are obtained.
~y treating a gi~en compound of the general formula I or II - wherein R and R2 are given above and Rl represents carboxamide - with a water removing agent ~uch a~ phosphoryL chloride, a compound of the general ~ormuLa I or II is obtained wherein Rl i8 cyano and R and R are as given above. A compound of the general formula I or II v~herein Rl stands for carboxylic group,may be converted to a compound of the generaL formula I or II, wherein Rl represent9 lower alcoxycarbonyl group, wherein R and R2 are as defined above, by methods known per ~e. The esterifica-tion may be conduclod for example by using diazo-alkanes, such as diazomethane or diazoethane or an alcohol-hydrogen chloride mixture. The compounds of 1153~58 the gelleral formula I or II, wherein R, R a~l.d R are defined above, m~l, if de~ired, be re~cted with acid~ to ~ive 9alt~ and may be reacted with quate~lizing ~ents to give quaternary ~alt~ ~he ba~e may be ~et; free from the ~alts and if desired may be converted to other ~alts. ~hu~ hydrochlor c acid, hydrobromic acid, perchloric acid9 acetic acid, ealicylic acid ~alt~ and quaternary alkyl halide such a~ methyl iodide,dialkyl ~ulphate ~uch as di-methyl-sulphate, p-toLuene-sulphonate, benzene .
eulphonate may be preferably prepared.
Compounds of the general ~ormula IV are commercially available product~ and compounds of the g~eral ~ormula III may be ea~ily prepared from a caprolactame cGntaining optionally a lower alkyl group in the positic)n 7 by reacting it with an alkylating agent ~uch a~ diethyl sul.ph~te and the obtained 0--alkyl-imino-ether is corlverted to a compou~d o~ thc general ~ormula III by reacting it with an agent setting free am~onia, ~uc:h a~ ammonium acetate, ammonium chl~rde etc.
The prepared co~pound~ of the formula I or II, wherein R, Rl and R2 are as de~ined above, are mainLy intermediate product~ ~or the preparation of valuable pharmaceutically active compound~ but ~ome representative3 of the compounds may be employed a~ pharmaceutically actirre ingredient~. Some 1153~S8 representatives are starting materials in the synthesis of compounds acting favourably on the circulating system and some may be used as active ingredients of antianginal pharmaceutical compositions. The present invention is directed to antianginal pharmaceutical composi-tions which contain 3-carbamoyl-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido [1,2-a]azepine, in admixture with a suitable carrier or diluent.
Compounds of the formula I and II as active ingredients may be employed in pharmaceutical compositions containing in addition to the active ingredient inert, non-toxic solid or liquid diluents or carriers. The compositions may be administered in solid form such as tabletsJ capsules, dragees, or in liquid form such as solutions, suspensions or emulsions.
Compounds of the general formula I and II wherein R
stands for hydrogen or lower alkyl, Rl stands for lower alkyl, phenyl, carboxyl, lower alkoxycarbonyl, nitrile, carbamoyl, carbo-hydrazido and R stands for hydrogen or lower alkyl, with the proviso that if in the formula I R2 is hydrogen then Rl cannot stand for nitrile, alkoxycarbonyl or propyl, and pharmaceutically acceptable acid addition salts and quaternary salts thereof, are new and form another aspect of the invention of Appplication Serial No. 351,665.
The further details of the inventions are illustrated by the following Examples which serve merely for illustration and not for limitation.
Example 1 67.2 g of 7-amino-3,4,5,6-tetrahydro-2H-azepine are dissolved in 600 ml. of ethanol and the solution is cooled to -10 C and to the reaction mixture a solution il~3~58 _ g _ .

of 127.8 g. of diethyl ethoxy-methyle~e-malonate in 600 ml. of ethanol i~ added dropwi~e under 3tirri~g within 1 hour. The reaction mixture i8 ~tirred ~or a ~urther hour at a temperature of -10 C to -5 C
whereafter it io boiled for 1 hour. Ethanol i9 di~tilled off at reduced pre~ure. ~he residua~ yellow oil containing an about 10:1 mixture of ethyl 4-oxo--4,6,7,8-hexahydro-pyrimido~1,2-a3azepine-3-oarboxylate ~nd ethyl-2-oxo-2,6,7,8,9,10-hexahydro-pyrimido~192-~ -azepine-3-carboxylate i~ di~solved in 600 ml. o* benzene and shaken out twioe ~ub~equently with 60 ml of water.
The benzene eolution i~ dried over anhydrou9 ~odium ~ulphate and evaporated at reduced pres~ure~ 114 g.
~80.5 %) ethyl 4-oxo-4,6,7,8,9,10-hexahydro-pyrimido-Cl,2-a~azepine-3-carboxylate are obtained melting at 82-84 C after recry~tallization ~ro~ ethyl acetate.
Analy~i~ for the formula C12H16N203 calculated: C 61.00 %; H 6.82 %; ~ 11.85 %
found : C 60.82 %; ~ 6,91 ~0; ~ 11.79 %.
~he combined aqueou~ soLution i~ shaken out twice subsequently with 120 ml. o~ chloroform and the combined chloroform solution dried above calcinated sodium sulphate is evaporated at reduced pres~ure.
Thu~ 2.1 g. (8.9 %) of ethyl 2-oxo-2,6,7,8~9,10-hega-hydro-pyrimido~1,2-aJazepine-3-carboxylate are obtained meltin~ at 156-157 C.

Anal~si~ for the formula C12H16N203 calculated: C 61.00 ~,`0; H 6.82 ~; N llc85 %
~ound : C 60.91 %; H 6.87 ~oj ~ 11.81 %.
Example 2 11.2 g. of 2-amino-3,4,5,6-tetrahydro-2H-azepine are dis~olved in 70 ml~ o~ ethanol and to the ~olution under stirring at 0 C a ~olution of 16.9 g.
of ethyl ethoxy-methylene-cyanoacetate i~ 120 ml. o~
ethanol i~ added dropwi~e within L hour. The reaction at room temperature and 1 hour under boiling mixture i~ then stirred for 1 hou~. Etha~ol i~ di~tillea off at reduced pressure. The residual red oil contain-ing an about 3:1 mixtur~ of 3-cyanD-4-oxo-4,6,7,8,9,10 -hexahydro-pyrimido~1,2-~ azepine and 3-cyano-2-oxo-

-2~6~7~8~9~10-hexahydro-pyrimido~1,2-aJazepine is dissolved in 200 ml of benzene and shaken out twice eub~equently with 5 % by W/V hydrochloric acid sDlution and then w th water.
The benzene solution dried over anhydrou~
~odium sulphate i~ evaporated at reduced pressure and the residue is crystallized ~rom ethanol. Thus 4.6 O~ -(24.2 ~0) 3-cyano-4-oxo-4,6,7,8,9~10-he~ahydro-pyrimido-~1,2-aJazepine are obtained melting at 125 C.
Analysis f~r the formula CloHllN30 calculated: C 63.51 ~0; H 5.86 %; N 22.22 ~0 found : C 63.95 c~iO; H 5.89 c~O; N 22.Q8 c,~.
The combined aqueous layers are neutralized with ~olid ~odium hydrogen carbonate and shak~n out 11~3~58 with ohloroform. ~he combined chloro~orm ~ulution dried abDve ~odium ~ulphate is evaporated at reduced prea~ure and the residue i~ crystallized ~rom ethanol.
1.7 g. (809 %~ 3-cyano-2-oxo-2,6,7,8,9,10~h~xahydro--pyrim~dotl,2-aJazepine i~ obtained melting at 205-206 C
Analy~i~ for the formula CloH~lN30 calculated: C 63.51 %; H 5.86 %; N 22.22 %;
~ound : C 63.92 %~ H 5.90 %; N 21~97 ~0.
Example 3 To a ~olution o~ 11.2 g. o~ 7-amino-3,4,5,6--tetrahydro-2H-azepine in 100 ml. ethanol 13.1 g. of ethyl 2-formyl-propionate are added at room temperature and the reaction mi~ture i~ etirred for 24 hour~ and boiled for 3 hour~. Ethanol i~ then evaporated at reduced pressure and the re~idue i9 treated with a mi~ture of acetone and petrolether. ~he precipitated cry~tal~ are filtered. 6.6 g. (37 %) of 3-methyl-2-oxo-2,6,7,8,9,10--hexahydro-pyrimido~1,2-a3azepine ~re obtained, melting at 202 C after boiling in aoetone.
Analy~i~ for the formula ~loH14N20 calculated: C 67.39 ~; H 7.91 %; N 15.71 %
found : C 67.18 %; H 8,00 %; N L5.72 %.
~ he mother liquor containing acetone and petrol-ether i~ avaporated. The obtained orange-red oil is di~solved in 50 ml. o~ benzene, treated with decolourizing charcoal and ~aturated with dry hydrochloric acid gas.
~he obtained crystals are ~iltered. 5.75 ~. (26.7 ~/~) of 1~3~58

3-methy1-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido~1,2-~ -azepine-hydrDchloride are obtained melting at 207 C.
Analyei~ for ~he formula CloHL5N20Cl oalculated: C 55.94 %; H 7.04 /0; N 13.04 %~ Cl 16.51 '~0 found ~ C 56.05 '~0; H 7.01 %3 N 12.98 %~ Cl 16.70 %.
xample 4 11.8 g. of ethyl 4-oxo-4,6,7,8,9,10-he~a-hydro-pyrimido~1,2-a]azepine-3-carboxylate are di~solved in 40 ml. of 30 % by wei~ht ammonium hydroxide aolution and the reaction mixture i~ alLowed to stand at room temperature for 2 houra. The precipitated crystal~ are filtered and waahed with water. 10.1 g.
(97.5 %) cf 3-carbamoyl-4-oxo-4,6,7,8,9,10-hexahydro--pyrimido~1,2-~ azepine are obtained melti~g at 234-235 C.
Analysis ~or the formula ClOX13~302 calculated: C 57.96 %; H 6.32 %; N 20.27 found : C 57.88 %; H 6.30 %; ~ 20.34 %~
E2ample 5 One may proceed a~ de~cribed in Example 4 but aa ~tarting material ethyl 2-oxo-2,6,7,8,9,10--hexahydro-pyrimido~1,2-a~azepine-3-carboxylate ~ ~and 3-carbamoyl-2-oxo-2,6,7,8,9,10-hexahydr~wpyrimido-~1,2-a~azepine are obtained melting at 219 C. Yield:
69 %.
Analy~ia for the formula CLoH13N302 o~culated: C 57.96 o~O; H 6.32 ,~; N 20.27 ';0 found : a 58.07 '~0; H 6.30 'j~; N 20.30 ',0.

1~53958 11.8 g. of ethyl 4-o~o-4,6,7,8,9,10-he~a-hydro-pyrim:ldo~1,2-a~ az epi~e are di~ olved in 50 mL~ o~ 5 ~' by W~V sodium hydroxide 801uti on a~d the ~olu~ion ia allowed to ~tand at room temperature for 2 hour9~ ~he pH value of the solution i~
adju~ted to three by aclding 36 % bg VJ/V hydro-chloric acid aolution. The precipitated cryatala sre filtered and ~a~hed with water. 9.25 g. t91 %) of 4-Q~o-4~6,7,8,9,10-he~ahydro-pyrimido~1,2_~azepine--3-c~rboxylic acid are obtained melting at 117-119 C
after recry~tallization from methanol (decomposi-tion).
Analy~i~ for the formula CloH12N203 calculated: C 57.69 %; H 5.81 ~0; M 13.45 c~O
found : C 57.27 ~0; H 5.84 ~0; N 13.23 ~0.
ExamPle 7 _ One may proceed aa di~clo~ed in Example 6 but a~ ~tarting material ethyl 2-oxo~2,6,7,8,9jlO~
-hexahydro-pyrimido~ azepine-3-carbo~ylate i~ u~ed and 2~Qxo-2,6,7,8,~,10-hexahydro-pyrimido ~1,2-aJazepil~e-3-carboxylic acid ia obtained with a yield of 67.4 % melting at 198 C under deco~po3i-tion.
Analy2i~ for the f ormula CloHl2N2o3 caL¢ulated: C 57.69 %~ H 5.~1 c~O~ N 13.45 ,~0 found : C 57.31 %~ H 5.88 ,0; N 13.21 ~.

E~ am pl e 8 A solution of 2.36 g. of ethyl 4-o~o-

-4,6,7,8,9,10-hexahydro-pyrimidoCl,2-a] azepine-3--carboxylate in 10 ml. of 98 ~O by W/V hydrazine hydrate i~ allowed t~ ~tand at room temperature for 2 hour~ O ~he precipitated cr~J~tal~ a~e filtered and wa~hed with water and ethanol. 1.8 g. of (81 %~
4-oxo-4,6,7,8,9,10-hexahydro-pyrimido~1,2-aJ,azepine--3-carbohydrazide are obtained meltin~ at 184-186 C .
Analy~i~ for the formula CloH14~T202 calculated: C 54.04 '70; H 6.35 %; N 25.21 %
found : C 53.93 %; ~ 6~41 %; ~T 25.48 %~
Ex am ~l e 9 One ma~ proceed according to Example 8 but a~ ~tartillg mater:lal ethyl 2-oxo-2 9 6,7,8,9,10-hexa-hydro-pyrimido~L,2-al azepine-3-carboxylate i8 used and 2- oxo-2, 6, 7, 8, 9 ,10-hexahydro- pyrimido ~1, 2-a] s zepine--3-carbohydrazide is obtained with a yield 74.3 ~0 mel ting at 201 C.
Analy~ 3 f or the for~Dula CloH14N402 calculated: C 54.04 ,0; H 6.32 ,~; N 25.21 %
found : C 53.84 %; H 6.42 ~0; ~J 25.36 ~.
Ex am pl e 10 1.18 g. of ethyl 4-oxo-4,6,7,8,9,10-hexahydro-25 -~yrimido ~1,2 al azepine-3-carboxylate i~ dis~olved in 12 ml. of acetone and allowed to ~tand ~or 24 hours at room temperature in the pre~ence of 1.25 ml. of .

11539~8 methyL iodide. The reaction mixture i9 diluted wi~h diethyl ether. The precipitated cry~tal~ are filtered~
008 g. (43 %~ o~ 3-ethoxycarbonyl-1-methyl-4-o~o-4~6,7,8,9,10-hexahydro- pyrimid o ~1,2-aJazepinium iodide ia obtained melting at 202-204 C.
Analy~is for the foxmula C13HlgN203I
c~lculatsd: C 41.28 ~ H 5.r~6 %; N 7.40 ~; I 33.55 ~
~ound : C 41.46 ~0; H 5.18 ~; ~ 7.30 ~ I 33.55 %.
Example 11 2.36 g. of ethyl 2-oxo-2,6,7~8,9,10-hexa-hydro-pyrimido~1,2-a3a~epine-3-carboxylate are di~olved in 5 ml. o~ ethanol in the pre~ence of 5 ml.
methyl iodide and the ~olutio~ i9 allowed tD atand for 72 houra at room temperature. ~he alcohol i~
removed by evaporation. The residual oil i9 treated with 20 ml. of ethyl acetate. Ethyl acetate i8 de-canted. ~he obtained hygro~copic oil i9 dried.
Analy~is for the fDrmula C13Hlg~203I
calculated: C 41.28 %; H 5.06 ~0~ N 7.40 ~; I 33.55 %
found s C 41.52 %; H 5~12 %; ~ 7.14 ~0; I 32.9? %.
xam~e 12 4.14 g. of 3-carbamoyl-4-oxo-4,6,7,8,9,10--hexahydro-pyrimido~1,2-a~azepine are boiled in 50 ml.
methanol with 1.3 ml. o~ dimethyl sulphate ~or 1 hour nhereafter the reaction mixture i~ concentrated to half ~olume and allowed to cry~tallize upon cooling belo~ 0 C. The prec~pitated cry9tal9 are filtered.

1153~58

- 5.5 g. of 3-carbamoyL-l-methyl-4-oxo-496,7,8,9910-~hexahydro-pyrimido~1,2-~ azepinium-methyl ~ulphate are obt&i~ed melting at 191-193 C.
A~aly~i~ for the formula C12~19N306S
. oalculated: C 43.23 ~O; H 5.74 %~ ~ 12.60 %; S 9.62 %
found s C 43.05 %~ H 5.61 50~ N 12.58 %; S 9.53 ~0.

lL.2 g. of 7-amino-3,4,5,6-tetrahydro-2H-azepine and 19.2 g. of eth~ 2-form~l-phenylacetate are boiLed in 100 ml~ abs. alcohol for 5 hour~ where-after the reaction mixture i9 evaporated. ~he residue i8 treated with a mixture o~ acetone and petrol ether.
The obtained aolid i8 filtered. 22 g. (~1 %) of a mixture of 3- pheny 1-2-oxo-2,6,7,8,9,10-hexahydro--pyrimido~172-alaæepine and 3~phenyl-4-oxo-4~6,7,8,9,10--hex~hydro-pyrimido~1,2-a~azepine i8 obtained melting in the ran~e of from 126 to 130 C.
Analy~ or the formula C15H16N20 calculated; C 74.97 ~; H 6~71 ~0; N 11.66 qO
found : C 74.21 ~; H 6058 ~; N 11.~4 ~0.
xample 14 1 g. of a mixture of 3-phenyl-2-oxo-2,6,7,8,9,10--hexahydro-pyrimidorl,2-a~azepine and 3-phenyl-4-o~o--~,6,7,8,9,10-hexahydro-pyrimido~1,2-aJazepine obtained according to Example 13 i9 applied to a siLicagel column of a diameter of 1 cm. consistin~ of 10 g.
~ilicagel of particle size 0.063-0.125 mm. and eluted i3~58 with ethyl aoetate. After evaporating the ethyl acetate eluate pure 3-phenyl-4--oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine is obtained melting at 156-Analysis for the formula C15H16N20 calculated: C 74.97 %; H 6.71 %; N 11.66 %;
found : C 74.93 %; H 6.70 %; N 11.58 %.
The elution of the column is continued after removing 3-phenyl-4-oxo--4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine with methanol and after evaporat-ing the methanol eluate 3-phenyl-2-oxo-2,6,7,8,9,10-hexahydro-pyrimido[1,2-a]-azepine is obtained melting at 215-216 C.
Analysis for the formula C15H16N20 calculated: C 74.97 %; H 6.71 %; N 11.66 %;
found : C 74.85 %; H 6.68 %; N 11.42 %.
Example 15 5.6 g. of 7-amino-3,4,5,6-tetrahydro,2H-azepine and 7.5 g. of ethyl 2-ethyl-acetoaoe tate are boiled in 50 ml. ethanol for 3 hours. The ethanol is then evaporated at reduced pressure. The residual oil is dissolved in 20 ml. of 10 % hydrochloric acid and shaken out twi oe with 10 ml. ethyl aoetate. The aqueous layer is neutralized with sodium hydrogen carbonate and shaken out with 3xlO ml. chloroform. The combined chloroform layer is dried a~ove calcinated sodium sulphate and evaporated. me residual colourless oil is fractionated at reduoe d pressure. 6.3 g. (61 %) 3-ethyl-2-methyl-4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[l,2-a]azepine are obtained. Boiling point: 156-160 C/2 mmHg.
Analysis for the formNla C12H18N20 calculated: C 69.87 %; H 8.79 %; N 13.58 %;
found : C 69.98 %; H 8.85 %; N 13.22 %.
X

11 5 3~ S8 Example 16 12.6 g. 2-amino-7-methyl-3,4,5,6-tetrahydro-2H-azepine are dissolved in 100 ml. ethanol and the solution is added dropwise at -5 - O C to a solutionof 22.6 g. diethylethoxy-methylene-malonate in 100 ml. ethanol. When the solu-tion is added the reaction mixture is allowed to warm up to room temperature andallowed to stand for 24 hours. The solvent is then re~oved by evaporation.
m e residual oil is then dissolved in 100 ml. of 10 % by W~V hydr~-chloric acid and shaken out twi oe with 10 ml. diethyl ether.
me aqueous layer is neutralized with sodium hydrogen carbonate and shaken out four-times with 15 ml. of ethyl acetate. me ethyl acetate layers are evaporated after drying above sodium sulphate and after filtration. The residual oil is taken up in aoetone and treated with dry hydrochloric acid gas whereupon white crystals are precipitated. 15.5 g. of ethyl-6-methyl-4-oxo--4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-3-carboxylate-hydrochloride are obtained.
Yield: 56 %.
Melting point: 168-172 &.
Analysis for the form~la C13HlgN2O3Cl calculated: C 54.64 %; H 6.70 %; N 9.80 ~;
found : C 54.31 %; H 6.72 %; N 9.76 %.
Example 17 2.52 g. of 2-amino-7-methyl-3,4,5,6-tetrahydro-2H-azepine are dis-solved in 25 ml~ of ethanol and the solution is added dropwise to a solution of 3.38 g. of ethoxy-methylene-cyanoaoetate in 25 ml. ethanol at -5 C. The reac-tion mixture is stirred for 1 hour at -5 & and allowed to warm up to room temperature and boiled for 1 hour. The solvent is evaporated. m e residual oil is dissolved in 40 ml. of benzene and the solution is shaken out onoe with 10 ml.

1153~S8 of 5 % by W~V sodium carbonate solution and twice with 10 ml. of water. me benzene layer is dried above sodium sulphate and evaporated after filtration.
The residual oil is crystallized from aoe tone. 1.26 g. (31 %) 3-cyano-6-methyl--4-oxo-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine is obtained melting at 154 &.
Analysis for the form~la CllH13N30 calculated: C 65.00 ~; H 6.42 %; N 20.67 %;
found : C 64.32 %; H 6.48 %; N 20.77 %.
Pharmacological test results:
The antianginal activity of the compounds was determined in rats by inhibiting acute coronary insufficiency induoe d by intravenously administered vasopressin (Arch. Int. Pharmaoodyn. 1966, 160, 147). Test-compounds were administered in an aqueous solution intravenously.

Compound i.v. dosage protective activity % (rat) 4-oxo-4,6,7,8,9,10-hexa-hydro-pyrimido~1,2-a]- 10 mg./kg. 50.1 %
azepine-3-carbohydrazide Ethyl-4-oxo-4,6,7,8,9,10--hexahydro-pyrimido[1,2-a]-10 mg./kg. 77.6 %
azepine-3-carb~xylate Ethyl-2-oxo-2,6,7,8,9,10--hexahydro-pyrimido[1,2-a]-10 mg./kg. 85.2 %
azepine-3-carboxylate Papaverine 2 mg./kg. 36.9 %

Claims (2)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. An antianginal pharmaceutical composition which contains 3-carbamoyl-4-oxo-4,6,7,8,9,10-hexahydro[1,2-a]azepine or a pharmaceutically acceptable salt thereof, in admixture with a suitable diluent or carrier.

2. A composition as claimed in claim 1 which contains 3-carbamoyl-4-oxo-4,6,7,8,9,10-hexahydro[1,2-a]azepine.