CA1163629A - Pyrimido(6,1-a)isoquinolin-4-one derivatives - Google Patents

Abstract

PYRIMIDO(6,1-a)ISOQUINOLIN-4-ONE DERIVATIVES
Abstract of the disclosure:
A novel class of pyrimido(6,1-a)isoquinolin-4-one deri-vatives, new intermediates used in their preparation and pro-cesses for the preparation of the intermediates and the compounds of the invention are described. The pyrimido(6,1-a)isoquinolin-4-one derivatives of the invention posses valuable pharmacolo-gical properties, for example blood pressure lowering proper-ties, bronchodilatory properties and anti-allergic properties.

Description

OE 77~F 091 1 1636~9 This in~Tenti~n relates to a novel class of pyrimido(~ a~-isoquinolin-4-one derivativesr to new intermediates used in their prepara~ion and to processes for the preparation of the inter-mediates and the compounds of the invention. The pyrimido(6,1-a)-isoquinolin-4-one derivatives of the invention possess valuable pharm~cological properties1 for example blood pressure lowerin~
properties as demonstrated in cats and dogs, bronchodilatory properties as demonstrated by antagonism to histamine-induced bronchoconstriction in guinea pigs and anti-aller~ic properties as demonstrated by the inhibition of passive cutaneous anaphy-laxis (pca) in rats.
The invention, therefore, provides pyrimido(6,1-a) iso~uino-lin-4-one derivatives bearing a novel heterocyclic ring system of the formula I

. I

~ '6 in which R1, R4 and R5, which may be the same or different, stand for hydrogen, hydroxy, lower alkoxy, dialkylphosphinylalkoxy, acyloxy or halogen, two of the radicals R1, R4 or R5, when in adjacent positions and taken together, may form a methylenedioxy or an ethylene-dioxy gxoup, R2 and R3,which may be the same or different, stand for hydrogen,

- 2 -E~OE , 7/F 091 1 163~2~

h~dro~y, lower al~oxy, a~ino, alkylamino, dialkylamino, aryl-amino, amino or alkyl substituted by a 5- or 6-membered carbon ring containing up to 3 hetero atoms selected from the group of N, O, and S~ alkyl, cycloalkyl, hydroxyalkyl, alkoYyal~yl, dialkoxyalkyl, haloal~yl, dialkylaminoalkyl/ aralkyl, acyl and optionally substituted aryl,aryl denoting an aromatic hyd-o-carbon radical having up to 10 carbon atoms;
R2 represents a pair of electrons if R6 stands for one of the radicals defined below and R2 and R3 when taken together with the nitrogen atom to which they are bound may form an optionally substituted nitrogen heterocycle possibly containing a further nitrogen or oxygen atom, and R6 stands for hydrogen, alkyl, cycloalkyl, hydroxyalkyl, alkoxy-alkyl, dialkoxyalkyl, haloalkyl, dialkylaminoalkyl, aralkyl, heterocyclically substituted alkyl, dialkylphosphinylalkyl, acyl and optionally substituted aryl or R6 represents a pair of electrons if R2 represents one of the radi.cals defined above;
and the acid addition salts and quaternary ammonium salts thereof.
In the case of at least one of the two radicals R2 and R3 being hydrogen, the above definition of the pyrimido(6,1-a) i50-quinolin-4~one derivatives also encompasses the isomers of the following formula Ib, obtained by complete isomerization of com-pounds ~ of formuia Ia or being in equilibrium with the compounds of formula Ia~

~T ' .. ~ - ' -~ ~ HOE 77/ 091 1 1~3~29 .
`~

R4 ~ ~ ~0 ~ a . I ~
.. . . .. .. . . . ... . ..
The definition o~ the pyrimido(6,1-a)isoquinolin-4-one ~eri-vatives also encompasses the isomer of formula IC

.. . . .. . .. .... .... _ . .. _ . ., R4 j~R
N ~3 Ic . .

in which R1, ~3, R4 R5 and R6 have the above meanings.
If R~, R2, R3, R and R5 stand for lower alkoxy groups ~hose having up to 3 carbon atoms are suitable.
Suitable acyloxy radicals for R1, R4 or R are those in which the acyl group is linear or branched C~-C6 alkanoyl, ,or example acetyl, or aroyl, especially benzoyl in which the phenyl nucleus may be substituted one to three times by halogen, nitro, hydroxy, C~-C3 alkoxy and C~-C3 alkyl.
R1, R4, or R5 stand ~or halogen, chlorine is preferred.
Suitable dialkylphosphinylalkoxy radicals for ~1, R4 or R5 are ~hose in which the alkyl and alkoxy groups caxry at most

3 carbon ~toms, for example dimethylphosphinylmethoxy.

.
' `

. .

1163~29 Especially suitable alkylamino or dialkylamino radicals for R or R3 are those in whi~h the alkyl groups ha~e at most 3 car-bon atoms, for example methylamino or dimethylamiIlo.
Suitable arylamino radicals for R or R3 are phenylamino radicals in which the phenyl residue may be substituted one or several times by halogen, for example chlorine, C1-C3alkyl, for example methyl, or nitro. A suitable nitrogen-containing hetero-cyclic amino radical for R2 or R3 is, for example, the N-morpho-linoamino radical.
As alkyl radical for X2, R3 or R6 there can be used thcse having at most 6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec.butyl, or tert.butyl.
Suitable cycloalkyl radicals for R2, ~3 and R6 are those having at most 6 carbon atoms, for example cyclohexyl.
In tne case or R~, R3 or R6 being a substituted alkyl radi-cal there may be used those having up to 6 carbon atoms and sub-stituted by one or two hydroxy or C1-C alkoxy groups, halogen atoms, for example chlorine, amino or di(C1-C4alkyl)amino, di-alkylphosphinylalkyl, for example dimethylphosphinylmethyl~
Examples of aralkyl radicals for ~ , R3 and R6 are those ha~ing at most 8 carbon atoms, in which the aryl radical may be mono- or polysubstituted, especially substituted one, two, or ~hree times by the substituents defined above for R1~
Suitable heterocyclic alkyl radicals for R2, R3 and ~6 are, for example,furfuryl and tetrahydrofurfuryl.
Suitable examples o aryl radicals for R , R3 and ~6 are phenyl radicals optionally substituted one or several times, preferably one, two or three times by halo~en, for example 29 fluorine, chlorine and bromine, C1-C3 alkyl and C~-C3 alkoxy, .,j~ . , '' ~: ' .:, . .

~ HOE 77~F Q91 1 1~3629 for example methyl, ethyl, methoxy and ethoxy, haloalkyl, for example trifluoromethyl, amino or hydroxy, in the latter the hydrogen atoms possibly being replaced by an al~ali metal, for example sodium.
Suitable nitrogen-containing heterocyclic radicals are, for example, pyrrolidino, piperidino, morpholino, and piperazino, optionally substituted by alkyl, alkoxycarbonyl, aryl or a ni-trogen heterocycle, the terms alkyl, alkoxy, aryl and nitrogen heterocycle havin~ the above meaning.
Examples of suitable acyl radicals for R2, R3 a~d R6 are linear or branched C1-C6 alkanoyl, such as acetyl, or aroyl, such as benzoyl, wherein the phenyl residue may be substituted one or several times by the substitue~ts defined above for R , R3 and R6 when they represent an aryl rad~cal.
As salts Qf the pyrimido(6,1-a)isoquinolin-4-one derivatives of the invention there are mentioned by way of example those of inorganic or or~anic acids, for example the hydrochlorides, hydrobromides, sulfates, phosphates, acetates, oxalates, tartra-tes, citrates, maleates, or fumarates.
Suitable quaternary ammonium salts of the pyrimido(6,1-a) isoquinolin-4-one derivatives of the in~ention àre.~`~for exàmp~e, the salts derived from alkyl halides, such as methiod;des.
Preferred substitutents are:
alkoxy f~r R and R , hydro~en for R , C1-C~ alkyl or phenyl optionally substituted one to three times as defined above for R2, hydrogen, C~-C6 alkyl, cycloalkyl, subs~i:tuted alkyl. aralkyl, heterocyclic alkyl, substituted aryl and c1-e6 alkanoyl for 29 R and R .

1 163~29 Particularly preferred compounds of the inv~ntion are:
9,10-dimethoxy-2-tert-butylamino-6 t 7-dihydro-4E~-1?y~imidot6~1-a1 isoquinolin-4-one hydxochloride, 9,10-dimethoxy-2-sec-butylamino-G,7-dihydro-4~I-pyrimido(6,1-a) isoquinolin-4-one hydrochloride, 9,10-dimethoxy-2-(2,6-dimethylanilino)-6,7-dih~dro-4H-pyrimido t6,1-a)isoquinolin-4-one, 9,1Q dimethoxy-2-(2,4-dimethylan.ilino)-6,7-dihydro~4H-pyrimido (6,1-a)isoquinolin-4-one, 9,10-dimethoxy-~-(2-chloroanilino)-6,7-dihydro- ~~pyrimido(5,1-a~
isoquinolin-4-one hydrochloride monohydrate, 9,10-dimethoxy-2-(2,4,6-trimethylanilino)-6,7~dihydro 4H-pyri-mido(6l1-a)isoquinolin-4-one hydrochloride dlhydrate , 9,10-dimethoxy-3-methyl-2-mesitylimino- 2,3,6,7-tetrahydro-4H-pyrimido(6,1 a~iso~uinolin-4-one hydrochloride, 9,10-dimethoxy-3-acetyl-2-mesitylimino~2,3,6,7-tetrahydro-4~-pyrimido(6,1-a)isoquinolin-4-one, 9,10-dimethoxy-2-(N-mekhyl-2,4,6-trimethylanilino)-6,7-dillydro-4H-pyrimido(6,1,-a)isoquinolin- ~one hydrochloride, 9,10-dimethoxy-2-(N-isopropyl -2,4,6-trimethylanilino~-6,7-di-hydro-4H-pyrimido~6,1-a)isoquinolin-4--one, 9,10-dimethoxy-3-isopropyl-2-mesitylimino~2,3,6,7-tetrahydro-4H-pyrimido(6,1-a)isoquinolin-4-one, 9,10-dimethoxy-2-(N--ethyl 2,4,6-trimethylanilino)-6,7-dihydro-4H-pyrimido(6,1-a)isoquinolin-4-one, : 9,10-dimethoxy-3-ethyl-2-mesitylimino-2,~,6,7-tetrahydro-4H-pyrimido(6,1-a)-isoquinolin-4-one, 9,~0~dimethoxy-2~(N-acetyl-2,4,6-trimethylanilino)-6,7-dihydro-29 ~H-pyrimido(6,1-a~isoquinolin-4-one.
_ 7 _ ~' HOE 7 7 /F ? 1 In the following Table I there are listed some of the new pyrimido~6, 1-a)isoquinolin-4 one deri~ati~es~
-\ .,_ ~' ~

1163629 ~-~
'' ` . ~

~ N N N -- N ~ ~ ' ~g~
. `o `, ~ ~

~ , ~, .- ~
, ,,. . o. ,~

_ _~ ~ ~ ~ ~ ~ N ~ ~

o o~oo o O o ') O
- In .

, 9 _ " ,, ~

i163629 ~. 77/F 091 . ` . `.
_ ` ~_ ` ~' ,~
N ~ O Cl~ ~ N O 11 ~i -- ~ ~ ~ N N N -- N N
, - ~) ~ O CO ~) O ~ U'`l N U ~ t` tS:I O
N ~ N N _ N

~ X
~`
. ' . ~i . ` B~
~0 . '~ ` .
~ , . .
t~ ~ N C~ Ch .D el~
~ ~ N ~ N ~-- ~ N

~ N N

(,~ N N ~! ~ ~æ~ 3; _ ~
v ~ ~ U ~ ~ V E; C-) ~.1 v ~1 N
:~ N
U
,';~
- `
~ ~ ~1 ~ rY ~ N ~1 N tY N

. U ~ ~ o o o ' o ~ O O 'O O O O
.~. O O C:~ O O O - O o O O O O O 1 ~ N
.. ' O - O

.
... ` " - 10 - ' , ,. J .

`I i 6 3 6 2 9 ~E 77/F 09 7 ~_ ~

,~ ~R N ` ~ N Q N
O O~
_ ~ N N N

~.~ I I I t) O--u~ a) o o ~r i I I I I I I I I I I J
.~, ' '. `~

- ~OO~o~N~N J Q~
~mN wN w m~ ON

:: ~ o o o o o o ~ o o o v o~
<~ o o o o c~ o o o o o o ` N
~ ~ m $

~ ' - 11 -~L ` , . . .
",,,, ~ . . , ~, , 1163629 HOE 77~ 091 o . `
,~oc~' ~ . ' -- ~

.

. ~, .~, ,,~
N C~ ~ ~ N

'~ ~ c~ a~ O a~

~ 8 ~ v ~ u ~ ~J~
.. .

.

N ~ N ~ t~ J t~ t~l ~ t~l ~

p . O O O O O O ~ O
O C:~ O C~ O C~ O O ~ O O
. t`~
. ~ .
.~
. . ` . O.

. :, ' ~ .

- . . .~ ~

` ` HOE 77/F 091 ` 1163629 .
~, .

8 ¦ a~ N

. ~ I` ~
.
~o~ .
'~

~ l N

~C ~ U ~-, ~ P W` ` ~

~, U U U D U W ~ h S~ U

~..i. - , .~ ... . ...

~ , `.

HO~ 77~F 091 1 16362~ ` -'~Ot'`

~ c 3~
. . ~

. ~ . ` .
~ o . -a i I ~ t '~

¦ ~u ~ ~ D~ ~

~ m . . I
. ' ', ...

~: c~ o c> o ~ û
~ o o O O O o o ~ ~ ~ ~ ~ o o ~. ~ .
In~

. `, .... . ` ` ~ :

. ~

1163629 HOE 77/F C)91 '~o~
~ ~n ~ I 1 1 - .
o l l l ~o o o ; l~
~ ~:
~ ~; . I` ~D
., . , I
~ :~
_~ C,) ~; t~ P: O

~1 ~ N
_ _ ~

K o U o o ~ o ~ ~_ r P~ ~ O'~

P~ s: m .. . . . .

, -,, . .` . . ` . - ` `
`.

ô o ~ ~
o~
O ~
a) ,~
~,~ - `''`''.
.~ o. ~
,, o ~J ~ O ' ` .

N
'' 3 ~ o ~

: ~ ~ x ' ' - 16 -` 116362~ Ho E 77/F 091 ~, .
, ~,o ` O O
~0 -.

O ~

4 . ,_ ~_ a~
~, . ~
~7~ ~

't ~ N N N N
r- O O O C~
c~

~ ~ ' ,, .

~ .. . ~ . ~ ................. .

~X ~7/l~ 091 It is another object of the present inven~ion to prov~ide novel intermediates and their salis suita~le fox the prepara-tion Or the pyrimido~6,1~a)isoquinolin-4-one derivatives of the invention. ~he novel inte~mediates correspon~ to the formuL2ê
III and IV

~S ~ ~ ~ ~ ~ N~ 0 - IV
, in which R1, R , R and R6 have the ~.bove n1eanirlcJ, X is oxygen or sulur and Y is halogen, for example chlorin~; alkoxy or alkylthio, ~ .coY.
and alkyl having the meaning as define~ earlier in this text~
with the exception of tne compound ~f ormul~ III in which ~ 6, R and R are hydro~en and X is oxysen (cf. L. Capuano and K. Mueller, Che~.Ber. 10~, 1541 (1~75~).
The intermediates of formulae III ~nd I`~ ~re list~ in Table II which also includes the meltin~ pOilltS of these compounds.

. ' ` . -.

~''' '' '' ' '' .

T A B L E II

R ~ R4 R p~6 X Y melting point ( C) _ _ . . .. _ _ .
2H H H O - 2~0 C

2H ~ - ~ Cl 179 ~ 180 9,10(OCH3)2 H H O - 323 - 325 9~10(OCH3)2 H H S _ 236 - 237 9,10(OCH3)2 H _ ~ SCH3 203 - 205 9r10(OcH3) H _ _ Cl 235 - 236 9~10(OCH3)2 H - _ OBu 158 ~ 159Q
9~10(OH) H H O ~ ~260 9~10(OCH3)2 11-OCH3 H O - 215 ~ 218 9,10(OCH3)2 11-OCH3 - - Cl 176 - 178 H~ 10-Cl H H O ~ ~ 250 H~ 10-Cl H _ _ Cl >250 9,10(OCH3)2 ~ 3 260 - 262 9,10(OCH3)2 ~ ~ 3 S _ 230 - 231 9~10(OCH3)2 ~ _ C ( 3)2 190 - 192 . It is another object of the prese~t invention to provide a process for the preparation of the intermediate~of formula III
in which X is oxygen~ s which comprises reacting a com-pound of formula V ---~

V
P~ ;IH-P~
, ~ , lr -, .....
- 19 ~-'~ 1 - -HOE 7?/F 091 l lS3~29 in ~hich R , R , R and R ha~Je the aforesaid meaning but are not each hydrogen with a com-pound of the formula RX-C-Ry , in which X is oxygen~

Rx = Ry is NH2, Cl, or alkoxy, or Rx is alkoxy and Ry is Cl using known methods ~cf. Shaw & Wooley, J.Biol.Chem. 181, 89 (1949); A. Dornow ~ D. Wille, Chem.Ber. 98; 1505 (1965)). As alkyl haloformate ethyl chloroformate and as dialkyl carbonate diethyl carbonate may be used. Suitable bases are alkali metal alkoxides, for example sodium methyla'e, sodium ethylate, po-tassium methylate, potassium ethylate, an alkali metal hydride, for example sodium hydride, or an organic base, for example an alkyl amine such as triethylamine. The reaction may be carried out in a non polar or polar sol~ent, for example an aromatic hydrocarbon such as benzene, toluene, or xylene, an alkancl having from 1 to 6 carbon atoms, for example methanol or etha-nol, an ether, for example dioxane or tetrahydrofurane, or sol-vents such as dimethylsulfoxide, dimethylfon~de or hexamethyl-phosphortriamide. The reaction can be accelerated or completed by the application of heat, for example by heating to the boil-ing point of the solvent.
It is a further object of the presPnt invention to provide a process for the preparation of the intermediates of formula III in which X is oxygen and R6 has the above meaning, which comprises alkylating or acylating in known manner a compound of formula III in which X is oxygen and R6 stands for hydrogen.
It is a further object of the present invention to provide a process or the preparation of the intermedIates of formula III in wnich X is sulfur and R stands for acyl, which com-.

prises acylating in known manner a compound of formula III in which X is sulfur and R~ stands for hydrogen The starting compounds of formula V necessary for the afore-said processes are prepared by known methods (cf. C.A. 64, 6627 t

5 (1966); Hoffmann La Roche & Co. AG., Netherlands Patent

6,~01,827, 27th August 1965).
.
The starting co~ s of formula V in which R is hydrogen can also be prep~ by the following process, which is also an object of the mv~n-tion, and which comprises treating a cY~rN~d o~ ~oD~a VI
. _ . . .. _ . . . . . . ... . .. . . . .

R4 ~ V1 ... ..

in which R , R4 and ~5 have the above meaning with a suitable acid, for example formic acid, trifluoro~cetic acid or poly-phosphoric acid. The reaction can be accelerated or completed by heating to, 'or example~80 to 15a C.
The compounds of formula VI can be prepared by know~
methods (cf. C.A. 64, 6627 (1966), Hoffmann La Roche & Co. ~G, Netherlands Patent 6,401,827, 27th ~ugust 1965; K. Harsanyi, K. Takaes, E. Bendeh & A. Neszmelyi, Liebigs Ann. ~hem~ 1606 (1973~.
It is a urther object`of the present Invention to pxo-vide a process for prepar~ng the intermediates of formula III
in which X is~fur and R1, R , R5 and R6 have the aforesaid meaning but are not eac~ hydrogen, which ccmærises treating a c~x~nd of foLmula III in ~h~ch X is oxygen wi~h.an inorganic sulfide according to kno~ metho~s.
It is also a feature of the present invention to provide a process for preparing the intermediat~ of formula IV in . .

''` ' ' ' HOE 77fF 091 1 1~3629 which Y is a halogen~which comprises treating a compound of formula III in which X is oxygen with an inorganic halide by a known method.
The present invention further pro~ides a process for pre-paring the intermediates of formula IV in which Y is an alkoxygroup having at most G carbon atoms, which comprises trea~ing a compound of formula IV in which Y stands for a halogen, pre-ferably chlorine, with an alkali metal alcoh~late according to a known method.
The intermediates of formula I~ in which Y is an alkoxy group having at most 6 carbon atoms may also be prepared by a different process according to which a compound of formula III
in which X is oxygen is reacted with a trialkyloxonium fluoro-borate, for example triethyloxonium fluoroborate. The reaction may be carried out in the presence of a solvent, for example a halogenated aliphatic hydrocarbon, for example dichloromethane.
It is another object of the invention to provide a process for preparing an intermedi~te or formula ~V in which ~ is alkylthio, which comprises treating a compound of formula III in which X is sulfur with an alkyl hal~de, for example me-thyl iodide according to a known method.
In the first place the present invention provides a process for preparing pyrimido(6,1-a)isoqu~nolin-4-one derivatives of formula I and their salts, which comprises reacting a compound of formula III or IV in which R1, R4, R5 and R6 have the mean~
ing as indicated in claim ~ and X stands for sulfur and Y
stands for halogen, alkoxy or alkyl~hio, with a compound of the formula HN''~3 in which R2 and R3 ha~e thle aforesaid mean-29 ing, with the exception, however, that they do not represent .. .... . ..
~ 22 -` HOE 77/F 091 ~ 163~9 acyl, in the presence o~ a base, and treating the free base ob-tained wi~h an acid to obtain the salt. As a base the compound of the formula HN R3 itself can be used which is added in ex-cess of that required for the reaction, or an alkali metal hydri-de, for example sodium hydride, or a tertiary aminer for example t triethyl amine, or an acid acceptort for example diazobicyclono-nene. The reaction may be carried out in the presence of polar solvents such as dimethylformamide, dimetllylsuloxide, halogenat-ed aliphatic hydrocarhons, for example chlorofor~, or alkanols, for example butanol r or in the presence of aprotic solvents such as high boiling ethers such as diethylene glycol dimethyl ether.
The reaction may be accelerated or completed by the application of heat, for example by heating to the boiling point of the sol-vent.
Compounds of the formula I in which either R2 or R6 and R
represent alkyl, cycloalkyl, substituted alkyl, aralkyl, hetero-cyclically substituted alkyl and aryl as defined above can be pre-1 16362g pared from compounds of formula I in which either R or R6 are hydrogen by a treatment, in the presence of a base or of a salt, with a halide of the formula RX in which R has the same meaning as indicated above for R and R . In the case of R being phenyl;
the phenyl nucleus carries appropriate substituents in order that the halide has a sufficient reactivity. X in formula ~Y is halo-gen, for example chlorine, bromine or iodine. Suitable ~ases are alkali metal carbonates, for example potassium carbonate, alkali metal hydrides, for example sodium hydride, a tertiary amine, such as triethylamine, or an acid scavenger such as dia~o-bicyclononene. Suitable salts are metal fluorides, for example potassium fluoride. The reaction may be carried out in the pre-sence of polar sol~ents, for example dimethylformamide or dimethyl sulfoxide, halogenated aliphatic hydrocarbons such as chloroform, or ~etones such as acetone, or in the presence of aprotic solvents, for example high boiling ethers such as diethylene glycol di~
methyl ether. The reaction can be accelerated or completed by the application of heat, for example by heating to the boiling point of the solvent. This process is especially suitable for transforming compounds of formula I, in which either R2 or R6 denotes hydxogen and R3 is an aryl radical, into compounds of for-mula I in which either R2 or R6 denotes alkyl or substituted alkyl and R3 stands for aryl.
The process described in the preceding paragraph may lead to quaternary al~monium salts of the isomers of formula I. Alter-na*ively the free bases of formula I can be transformed separate-ly into quaternary ammonium salts or acid addition salts by knowr.
methods.
29 Cvmpounds of formula I in which R , R or R stands ~or an i . - ?4 ~

., , .

acyl radical c~n be prepared from compounds of ~ormula I in which at least one of the radicals R , R or R represents hydrogen by a treatment with an acyl halide or acyl anhydride in which the acyl radical is an alkanoyl group having at most 6 carbon atoms;
for example acetyl, or an aroyl group, for example benzoyl, in which the phenyl nucleus can be substituted as defined ab~ve, and the halogen may be chlorine. The reaction may be carried out in the presence of a base, for example an alkali metal carbo-nate, such as potassium carbonate, or a tertiary amine, such as triethylamine. The react.ion can be accelerated by heating to the boiling point ~f the acylating agent.
~ he pyrimido(~ a)-i-s-oquinolin-4-one derivatives of the inven-tion possess valuable pharmacological propert~es, for example hypotensive, broncho-dilatory and antiallergic acitivity.
Owing to the hypotensive acitivity the novel compounds are suitable for the treatment and prevention of heart and circula-tory diseases, for example essential and malignant hypertonia, heart insufficiency, Angina pectoris and disturbances of the peripheral circulation. The novel compounds canals~ ~eused in co~
bination with other pharmacologically ac ti~re substances, for example with diuretics, antiarrhythmic agents, B-~lockers, tran-quilizers, heart vasodilating agents and hypolipidemics.
Because of their ~ronchodilatory and antiallergic effect, the novel compounds can be used for the treatment and prevention of disseases of the respiratory system, for example bronchial asthma, chronic bronchitis, emphysema and allergies such as al-lergic asthma, hay fever, allergic rhinitis and conjunctivitis urticaria~.The novel compounds can a~o;e u3ed in combination wi~h 2~ other pharmacologically active substances such as corticoste~ids, ....
,~ ~ 1 , .

.

` HOE 77/F 091 1 ~36~9 s~mpathomimetics, xanthine de.rivatives, antihistamines, tran~
quili~exs, cardiac stimulants etc.
The active substances according to the invention can be administered perorally, parenterally (intra~uscularly,. intra- .
venously, subcutaneously) rectally, or topically, optionally i.n the form of an aerosol.
The following doses are used in mammals5particularly man:
to reduce the blood pressure: a daily dose o~ 0.1 to 200 m~, dosage unit ~ l to 25 m~
; 10 as bronchospasmolytic and antiallergic agent: a daily dose of 1 to 500 m~, dosage unit 1 to 100 mg.
The novel compounds can be adminis~-ed either per se or in admixture with pharmacologically tolerable carrier materia].s.
For oral administration the active compounds are mixed with the usual substances and transformed into the usual form of admini-stration, for exa~ple tablets, push-~it capsules,aqueous alco-holic or oily suspensions or solutions. Suitable inert carrier materials are, for example,magnesium carbonate, milk sugar or 2n maize star~h,which can be used w;th the addition of other su~-stcinces such as magnesium steara~e, The composit~ons can be prepared in the form of dry or moist granules. AS oily carriers or solvents vegetable and animal oils can be used, for example sunflower oil and cod.liver oil.
In emergency-s~uations, the active compounds can be admi--nistered intraven_ously~ To this end, the active compounds o~
the physiolo~ically tolerable salts thereof, as far as they ha~e a sufficient solubility, are dissolved in the usual auxi-liaries, which may also act as dissol~ing intermediary or buffer.
Physiologically tolerable salts are formed, for example, .. -.

HOE 77!F 091 with the ~ollowing acids: hydrochloric acid, hydrobromic acid and hydroiodic acid, phosphoric acid, sulfuric acid, methylsul-furic acid, amidosulfonic acid, nitric acid, tartaric a~id, lac-tic acid,malonic acid, fumaric acid, oxalic acid, citric acid, malic acid, mucic acid, benzoic acid, salicylic acid, aceturic acid, embonic acid, naphthalene-1,5 disulfonic acid, ascorbic acid, phenylacetic acid, p~aminosalicylic` acid, hydroxyethane-sulfonic acid, benzene-sulfonic acid, or synthetic resins con-taining acid groups, for example those having an ion exchange effect.
Suita~le solvents for intraven~s~administration are, for example, water, physiological sodium chloride solution or di]ute alcohols such as ethanol, propanediol or glycerol; furthermore sugar solutions, such as glucose or mannitol solutions, or a mixture of the aforesaid sol~ents.
The following examples illustrate the invention.
E X A M P L E 1:
6,?-Dimethoxy-1-carbamoYlmethylene-1,2,3,4-tetrahYdroisoquino-1_ Polyphosphoric acid (10.0 g) is heated to 100 C and 1.0 g of 6,7-dimethoxy-1-cyanomethylene-1,2,3,4-tetrahydroisoquinolj.n~
is added under mech~nical stirring. The reaction mixture is heated for 1 hour, poured into crushed ice and made basic with 30 % sodium hydroxide. The mixture is extracted with chloro-form and the extract dried over anhydrous sodium sulfate. The solvent is evaporated under xeduced pressure to give a white solid, yield 0.7 g, mp. 156 - 158 C~
E X A M P L E 2:
-2~ 9,10-Dlmethoxy-3,4,6,7-tetrahydro-2H pyrimido(6,1-a)isoquinolin-1 163B~9 A solution of 6,7-dimethoxy-1-car~amoylmethylene-1 t 2,3,4-tetrahydroisoquinoline (5.0 g) and an excess of sodium ethoxide (prepared from 12.0 g of sodium metal and 600 ml of ethanol) 5 in ethanol is heated~ To the solution 150.0 ml of diethyl carbonate is added. The reaction mixture is refluxed *or an additional 2.5 hr. The solvent is removed under vacuum and the residue is acidified to give a white pre~ipitate, yield 4.80 g.
The pr~duct crystallizes from dimethylforma~ide, mp. 323 - 325C.
E X A M P L E 3: `
9,10-Dimethoxy-3-methyl-3,4,6,7-tetrahydroA2H-pyrimido-(6 r 1-a)-isoquinolin-2,4-dione A mixture of 9,10-dimethoxy-3,4,6,7-tetrahydro-2~-pyrimido-(6,1-a)isoquinolin-2,4-dione (4011 g), oilfree sodium hydride (0.75 g) and dimethylformamide (100 ml) is heated for 15 minutes to 100 C and then cooled to room temperature. Methyl iodide (10 ml) is added and the reaction mixture is heated for 12 hours to ~00~ C. The sol~ent is removed under reduced pressure and - the residue treated with cold water. The solid matter is fil-tered off and recrystallized from ethyl acetate/methylene chlo-ride. Yield 4.0 g, melting point 260 - 262 C.
E X A M P L E 4:
.
9,10-Dimethoxy-3-isopropyl-3,4,6,7-tetrahydro-2H-pyrimido-(6~1-a)iso~uinolin-2,4-dione In a manner analogous to that of Example 3, 9,10-dime~hoxy-3,4,6,7-tetrahydro--2H-pyrimido(6,1-a)isoquinolin-2,4-dione is reacted with isoPropYl iodîde. Yield 50 %; melting point 190 - 192 C.

.

,i~ ' .
.. . . . .
. ' ' ' ' , .

HOE ?7/P 091 1163~29 -9,10-Dimethoxy-2-thio-2,3,6,7-tetrahydro-4H-pyrimido(6,1-a)isO-_ _ .. . .. . ... _ . .
quinolin-4-one -~ A mixture of 9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido(6,1-a)isoquinolin-2,4-dione (10.0 g) and phos-phorus pentasulfide (9.0 g) in 200 ml o~ pyridine is refluxed for 5 hours. Pyridine is xemoved under pres-sure. The residue is treated with dilute hydrochloric acid and then extracted with methylene chloride. The methylene chloxide extract is dried over anhydrous so-sium sulfate and evaporated to dryness leaving a white powder which is crystallized from chloroform-ether mix-ture, yield 10.0 g, m.p. 236 - 237 C.
E X A M P L E 6:
-~5 9,10-Dimethoxy-3-methyl-2-thi~ 2r3~6~7-tetrahydro-4H-pyrimido-_ _ .. . . .
(6 " -a)isoquinolin-4-one Phosphorus pentasulfide (1.0 g) is added to a solution or 9,10-dimethyl-3-methyl-3,4,6,7-tetrahydro-2H-pyrimido(6,1-a)iso-quinolin-2,4 dione (0.5 g) in pyridine (10 ml~. The mixture is ~ 29 -.~,. , ,, - ' '' ' -HOE 77~F 0~1 refluxed for 15 hours, the solvent removed under reduced pressureand th~ residue re~eatedly extracted with methylene chloride.
The combined methylene chloride extracts are washed with dilute hydrochloric acid and with water, dried over sodium sulfate and evaporated to dryness. The residue is chromatographed to yield the desired compound. Yield 0.25 g, m.p. 230 ~ 231 C.

9,10-Dimethoxy-2-chloro-6,7-dihyro-4~-pyrimido(h,1-a)isoquinolin-_ . . .. . . .
4-on~
_ . , .,, _ . . .
A mixture of 30.0 g of 9,10-dimethoxy-3,4,6,7-tetrahydr~2H-pyrimido(6,1-a)isoquinolin-2,4-dione and 300 ml of pho~phorus oxy-chloride is heated on a steam bath for 4 hours. The excess of phosphorus oxychloride is distilled under reduced pressure. The residue is poured into a cold solution of sodi~m hydroxide. A
yellow solid precipitates which is collected by filtration. The product is purified by passage thro~gh a silica gel column using chloroform as eluent. Yield 28.0 g, m.p. 235 - 236 C~
E X A M P L E 8:
.. . _ . .
9,~0-Dimethoxy-2-butoxy-6,7-dihydro-4H-pyrimido(6,1-a)isoquinolin-_ .
4-one To a mixture of sodium hydroxide (l.0 g) and n-butanol (50.0 ml) is added 9,10-dimethoxy-6,7-dihydro-2-chloro- ~pyrimido(6,1-a~
isoquinolin-4-one (1.46 g~. The reaction mixture is refluxed for ~ hours. The solvent is removed under reduced pressure. The re-sidue is treated wi~h water and extracted with chloroform. The - extract is dri~d over a~hydrous Na ~ 04 and e~parated to give a whlt ~: solid. After crystallization ~rom chloroform-ether m~xture, O.7 g^
.
~~~~~~~~~ ~~ of the l:itle ~compoùnd is obtained, m.p. 158 - 159 C.
.. ... . . .. ... . . . . . . .

.. . ..
~ -- 30 -- -.
~ . , 1 1~3~29 E X A ~1 P L E 9:
9,10-Dimethoxy-2-ethoxy-6,7-dihydro-4H-pyrimido(6,1-a)-isoqui-.
nolin-4-one A mixture o 3.0 g of 9,10-dimethoxy-3,4,6,7-tetrahydro- .
2H-pyrimido(6,1-a)isoquinolin-2,4-dione and 15.0 g of triQthyl-oxonium fluoroborate in 100 ml of dichloromethane is stirred overnight. The reaction mixture is washed with a solution of sodium carbonate. The organic layer is separated and dried o~rex anhydxous sodium sulfate. Evaporation of the solven~ gives the title compound, yield 1.8 g.
E X A M P L E 10:
9,10-Dimethoxy~2-methylmercapto-6,7-dihydro-4H-pyrimido(6,1-a)-. _ iso~uinolin-4-one hydroiodide To a suspension of 10.0 g of 9~1o-dimethoxy-2-thio-2~3~6~7- -tetrahydro-4H pyrimido(6,1-a)isoquinolin 4-one in 200 ml of tetrahydrofuran, 20 ml of methyliodide is added and the reaction mixture refluxed for 4 hours. A white solid precipates and is collected by filtration. It is crystallized from chloroform methanol mixture, yield 10.50 g, m.p. 220 - 225 C. (dec.) E X A M P L E 11:
General procedure for the preParation of comPounds of the qene-ral formula I_from com~ounds of formula III or IV:
Compound III (X = ~) or any one of the compounds IV (Y = Cl, SCH3,OBu) is heated with an about equimolar amount of the appro-priate amine of the general formula HNR2R3. The reaction is carried out in the presence of a base or an acid scavenger.
The base is preferably the reacting amine itself, used in ex-cess of that re~uired for the reaction. The reaction is alsQ
29 prefer~bly carried out in the presence of a suitable solvent ~ - i1 -as defined in the te~t. The reaction mixture may be heated to refluxing temperatures for 2 - 10 hours. Tlle solvent is eva-porated under reduced pressure. The residue is treated with water and e~tracted with an organic solvent. The extract is allowed to stand over anhydrous sodium sulate and evaporated to dryness. The residue is purified by chromatography and/or crystallized to give the desired compound, wllich, if desired, is converted to its salt.
E X A M ~ I, E 12:
9,10-Dimethoxy-2-tert-butylamino-6,7-dihydro-4H-pyrimido(6,1~a~-, isoquinolin~ -one hydrochloride A solution of 9,10-dimethoxy-2-chloro-6,7-dihydro~4H-py-rimido(6,1-a)isoquinolin- ~one (3.0 g) and tert.-butylamine (10.~ ml) in chloroform (75 ml) is heated under reflux or 16 15 hours. The solvent is evaporated under reduced pressure and the residue triturated with a dilute solution of sodium hydro~i-de to give a white precipitate. The precipitate is filtered, dried and converted into its hydrochloride by '~reating it in solution in ethanol with hydrochloric acid. The hydrochlori~e 20 is crystallized from ethanol-ether mixture, yield 3.0 g, m.p.
265 ~ 270 C.
E X A M P L E 13:
g,10-Dimethoxy-2-sec-butylamino-6,7-dihydro-4H-pyrimido(6,1-a)-; ~ iso~uinolin~ -one hydroc~loride A solution of 9,10-dimethoxy-6,7-dihydro-2-chloro-4H-pyri-mido(6,1 a)isoquinolin-`~one (2.5 g) sec-butylamine (10 ml) and dimethylformamide (2 ml~ is heated under reflux for 5 hours.
The sol~ent and excess amine are distilled under reduced pres-29 sure. ~he residue is treated with water. A white solid preci-! ~ .' ., : . , HOE 77~F 091 cipitates and is collectea by filtration. The precipitate is crystallized from methylene chloride-ether mixture, yield 2.10 g.
The crystals are dissolved in dichloromethane and treated with a solution of etheral hydrochloric acid. The hydrochloride is cry-stallized from ethanol-ether mixture, m.~. 218 - 225~ C.
X A M P L E 14:
9,10-Dimethoxy-~-(2,6~dimethylanilino)-6,7-dihydro-4H~pyrimido-. . ~ ._ __ ~L~a isoquinolin-4-one . _ A solution of 9,10-dimethoxy-2-chloro~6,7-dihydro~ H-pyri-mido(6,1-a)isoquinolin-4-one (2.5 g), 2,6-dimethylaniline t5.0 ml) in butanol 120.0 ml) is heated under reflux for 10 hours.
The solvent is evaporated under reduced pressure to give a gummy mass. Chromatography of the gummy mass over silica sel using benæene-ethyl acetate as eluent g~ves the requi_ed pr^duc~.
The compound is crystallized from methanol, yield 2.0 g, m.p.
297 - 2g9~ C.
E X A M P L E 1~:
. .
9,10-Dimethoxy- ~(2,4-dimethylanilino)-6,7-dihydro~ H-pyrimido-(6L1_a)isoquinolin- ~one The procedure described in Example 14 is followed by using 2,4-dimethylaniline in place of 2,6-dimethylaniline. Yield: 75 ~, m~p. 239 - 241 C.
E X A M P L E 16:
9,10-Dimethoxy-2- ~2-chloroanilino)-6,7-dihydro- ~-pyrimido(6,1-a)-~, . . .
~

The proceduxe described in Example 14 i5 followed, using 2-chloroaniline in place of 2,6-dimethylaniline. The hydrochloride is prepared as described in Example 12. Yield 70 %, m.p. 182 -29 186 C.

... .
",". ~ , HOE 77~F 091 E X A M P L F.` 17~
~r1o-Dimetho~y-~-(2~4~6-trimethylanilino!-6r7-dihydro~ H-pyri-... ..
mido(6,1-a)isoquinolin-4-one hydrochlori~e dihydrate -The procedure described in Example 14 is followed using S 2,4,6-trimethylaniline in place of 2,6-dimethylaniline- . The hydrochloride is prepared as described in Example 12.
Yield 70 ~, m.p. 167 - 169 C.
E X A M P L E 18:
.
9,10-Dimethoxy-3~methyl-2-mesitylimino- ~ 3,6,7-tetrahydro-4H-py-~ ,. _ _ . .
rimido(6,1-a)isoquinolin-4-one A mixture of 9,10-dimethoxy-3-methyl-2-thio~2,3,6/7-tetra-hydro-4H-pyrimido(6,1-a)isoquinolin-4- one (0.1 g) and methyl iodide (2 ml) in tetrahydrofurane (10 ml~ is refluxed for 2 hours. The solid matter is filtered off and heated for 3 hours to 100 to 110 C together with 2,4,6-trimethylaniline (0.4 g).
The excess trimethylaniline is remo-~ed by trea~ing the reaction mIxture with petroleum ether, The residue is worked up to gi~e X

. .

1163~29 HOE 77/F 091 the desired compound, which is recrystallized from ethyl acetate/
pe~roleum ether. Yield 80 mg, m.p. 151 - 152 C.
The s~me compound can also be obtained by direct reaction of 9~lo-dimethoxy-3-methyl-2-thio-2~ 6, 7-tetrahydr~- 4~-pyrïmido -(6,1-a)isoquinolin-4- one with 2,4,6-trimethylaniline.
E X A M P L E 19:
9.10-Dimethoxy-3-methyl- ~n-butylimino-2,3,6,7-tetrahydro-~H-.. . . ..
pYrimido(6,1-a)isoquinolin- ~one In a manner analogous to that of Example 18 th-e compound is prepared from 9~1o-dimethoxy-3-methyl-2-thi~3~4~6~7-tetxa-hydro-4H-pyrimidot6,1-a)isoquinolin-4- o-ne and n-butylamine.
Yield 100 %, m.p. 120 - 121 C.
E X A M P L E 20:
General procedure for the preParation of compounds of the formula I from compoun& of formulae Ia and Ib ~ The compound of formula Ia or Ib, in which ~3 preferably represents aryl is reacted, in the presence of a base, an acid scavenger, or a salt with a halide of the formula R~ or R X.
The halide can be used in equimolar amounts or in an excess.
The reaction is preferably carried out in the presence of a solvent as defined above. The reaction mixture may be refluxed - for 2 to 50 hours~ The solvent i5 evaporated under reduced pressure. The residue is treated with water and extracted with an organic solvent. The extract is dried over anhydrous sodium sulate and the filtrate is evaporated to dryness. The residue is purified by chromatography and/or recrystalliæed to give the desired compound whi~h can be transformed into its salt, if desired.

1 I63~29 HOE 77/Y 091 a) 9llo-Dimethoxy-3-methyl-2-mesitylimino-2~3~6~7-tetrahydro-4H-pyrimido~6,1-a)iso~uinolln-4-one, its h~drochloride and meth-iodide and b) 9,10-Dimethoxy-2-(N~meth~Ll-2,4~6-trimethYlanilino)-6l7-dihy-dro- ~-pyrimido(6,1-a)isoquinolin-4-one and its hydrochloride . . _ _ A suspension o~ 9,10-dimethoxy-2-(2,4,6-trimethylanilino)- -6,7-dihydro-4H~pyrimido(6,1-a)isoquinolin~ -one (3.0 g), anhy-drous potassium carbonate (15.0 g) and methyl iodide (45.0 ml) in acetone (300.0 ml) is heated under ~eflux for 15 hours. The reaction mixture is cooled and filtered. The filtrate is con-centrated under reduced pressure whereby a residue is obtained.
Chromatography of the residue o~er silica gel using benz~ne-chlo roform (1:1~ as eluent ~ives the desired free bases a) 2.3 g.
m.p. 151 - 1~2 C and b) 0.15 g, m.p. 175 - 176 C. Further elution of the chromatography column with chloroform gives 0.35 g of the methiodide of base a) of m.p. 221 - 222 C. The hydrochlorides are prepared from the bases by the procedure described in Example 13. $~ynr~crystallized from dichloro-methane/petroleum ether (b.p. 60 - 80 C~ or dichloromethane~
ethyl acetate or ethanol~diethyl ether. M.p. o~ hydrochloride a) 198-200~C, m.p. of hydrochloride b) 139 - 191 C.

a) 9/1o-Dimethox~-2-(N-isopropyl-2r4f6-trimethylanilino)-6t7-di h ~ and b) ~ methoxy-3-isoProPyl-2-mesityllmino-2~3r6~7-tetrahydr 4`H-pyrimido(6,1-a)isoquinolin-4 one . .
9,10-Dimethoxy-2-(2,4,6-trimethylanilino)-6,7-dihydro- ~-py-29 rimido(6,1-a)isoquinolin-4-one (5.85 g) and dimethylformamide s~ . .... ..
,.~, .
.. - ~ ' ,.

HOE 7~/F Oq 1 1 163~;2g (30 ml) are added to oil-free sodium hydride (1.5 g). The mixture is heated for 5 minutes to 110 C and then cooled to room temperature. Isopropyl iodide (2.55 g) is added and the whole is heated to 110 C for 40 hours. After cooling, met~a-nol is added to the reaction mixture and the solvents are re moved under reduced pressure. The residue is extracted with chloroform, the extract washed with water, dried over sodium sulfate and evaporated to dryne.ss. The residue is chromato-graphed to gi~e the bases a) m.p. 182 - 183 C and b) m.p.
178 - 179 C.
E X A M P L E 23:
_ a) 9,10-Dimetho~v-2-(N-ethyl-2 ! 4,6-trimeth~lanilino)-6~7-dihYdro-4.H-pyrimido(6,1-a)isoquinolin-4-one and b) 9,10-dimethoxy-3-ethyl-2-mesitylimino-2,3,6,7-tetrahydro-4H-.. .. _ pyrimido(6,1-a)isoquinolin-4-one PROCEDURE A:
Example 22 is repeated with the exception that ethyl iodide is used instead of methyl iodide.
PROCEDURE B:
.
9,10-Dimethoxy- ~(2,4,6-trimethylanilino)-6,7-dihydro~ H-py-rimido(6,1-a~isoquinolin-4-one (0.5 g) and potassium rluoride (0.5 ~) are added to dimethylformamide (10 ml). The ~ixture is heatPd to ~00 C for 1 hour and then cooled. Ethyl iodide (0.2 g~ is added and the whole is heated to ~00 C for 40 hours. The solvent is removed under reduced pressure and the residue worked up as described in Example æ
The procedur~ A and B yield the two isomers in dif~erent proportions. Free base a~ m.p. 164 - 165 C; free base b~
29 m.p. 142 ~ ~43 C.
. 5~ ............................... . .... . .

IIOE 77/F ~!, ' 1 ~B3629 E X A M P L E ~ 4:
....
9,10-Dimethoxy-2-(N-acetvl-2,4,6-trimethylanilino)-6,7- :
.
dihydro-4H-pyrimi.do-(6,1-a)isoquinolin-4-one To an ice-coid solution o~ 9,10-dirnethoxy-2-(2,4,~ ri- ;
methyl-anilino)-6,7-dihydro-4.H-pyrimido(6,1-a)isoquincl~ -4-one (1.6 g) in chloro~orm ~40.0 ml) is added first tri_ ~ylamine (1.2 ml) and then dropwise a solution of acetyl chlori-- (0.64 ml~ in chlorofol~ (10.0 ml)~ The mixture is stirred le- 2 hours.
The chloroform solution is washed successively with wa.~~, so-dium carbonate solution and water, and is then driea o~-r anhy-drous sodium sulfate. The solution is filtered and the ~ rate evaporated to dryness in vacuo. The residue is triturc_ed ~ith diethyl ether to yield the desired compound in solid ~m.
Yield 1.6 ~, m.p. 210 - 212 C (dichloromethane-petrole~m e-~er b.p. 60 - 80 C~.

~ " .

.. . .. . . . . .

X ` 1.

Claims (8)

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

1. A process for the preparation of a compound of the formula III or IV

III IV

wherein R1, R4 and R5, which may be the same or different, represent hydrogen, hydroxy, lower alkoxy, dialkylphosphinylalkoxy, acyloxy or halogen, two of the radicals R1, R4 or R5, when in adjacent positions and taken together, may form a methylenedioxy or an ethylene-dioxy group, R6 represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl, alkoxy-alkyl, dialkoxyalkyl, haloalkyl, dialkylaminoalkyl, aralkyl, heterocyclically substituted alkyl, dialkylphosphinylalkyl, acyl and aryl which may be substituted one or several times by halogen, C1-C3 alkyl, C1-C3 alkoxy, haloalkyl, amino or hydroxy and in the hydroxy group the hydrogen may be replaced by an alkali metal, X is oxygen or sulfur and Y is halogen, alkoxy, or alkylthio, with the exception that in the compound of formula III, R1, R4, R5 and R6 are hydrogen and X is oxygen or sulfur in which (a) to prepare a compound of the formula III or IV a compound of the formula v V

wherein R1, R4, R5 and R6 have the meaning as defined above is reacted with a compound of the formula Rx - ? -Ry wherein X is oxygen, Rx and Ry are amino, halogen or alkoxy, or Rx is alkoxy and Ry is halogen, a compound of the formula III in which X is oxygen may be transformed into a compound of the formula IV in which Y is halogen and the latter compound alkoxylated to a compound of the formula IV in which Y is alkoxy or a compound of the formula III wherein X is oxygen may be alkylated with a trialkyloxonium fluoroborate to obtain a compound of the formula IV in which Y is alkoxy, or a compound of the formula III in which X is oxygen may be converted into a compound of the formula III in which X is sulfur and the latter compound may be alkylated to obtain a compound of the formula IV wherein Y is alkylthio; or (b) to prepare a compound of the formula III, wherein R1, R4, R5 and R6 are as defined above, and X is oxygen, a compound of the formula III in which X is oxygen and R6 is hydrogen is alkylated or acylated; or (c) to prepare a compound of the formula III, wherein R1, R4 and R5 are as defined above, X is sulfur and R6 is acyl, a compound of the formula III in which X is sulfur and R6 is hydrogen is acylated.

2. A compound of the formula III or IV as defined in claim 1, whenever obtained according to a process as claimed in claim 1 or by an obvious chemical equivalent thereof.

3. A process as claimed in claim 1 for the preparation of a compound of the formula III or IV as defined in claim 1 in which the preparation is carried out according to reaction (a).

4. A compound of the formula III or IV as defined in claim 1, whenever obtained according to a process as claimed in claim 3 or by an obvious chemical equivalent thereof.

5. A process as claimed in claim 1 for the preparation or a compound of the formula III as set forth in claim 1 wherein R1, R4, R5 and R6 are as defined in claim 1, X is oxygen in which the preparation is carried out according to reaction (b).

6, A compound of the formula III as defined in claim whenever obtained according to a process as claimed in claim 5 or by an obvious chemical equivalent thereof.

7. A process as claimed in claim 1 for the preparation of a compound of the formula III as set forth in claim 1 wherein R1, R4 and R5 are as defined in claim 1, X is sulfur and R6 is acyl in which the preparation is carried our according to reaction (c).

8. A compound of the formula III as defined in claim 7 whenever obtained according to a process as claimed in claim 7 or by an obvious chemical equivalent thereof.