DE2258561A1 - BASIC SUBSTITUTED PYRIMIDONE (4) DERIVATIVES, THE PROCESS FOR THEIR PRODUCTION AND THE MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

68 Int October'197e

■ - 1 ~

Byk Gutde η. Lomberg Chemical Factory Limited liability company, Constance

; Basically substituted pyrimidane (4) derivatives, Process for their preparation and containing them

Medicinal products.

The invention relates to therapeutically valuable basic substituted pyripidone ( k) derivatives with predominantly antihypertensive properties.

Quinazolone (^) derivatives with sedative (Therapy, Vol. 13 / J95 # 7Y ^s - 30 to ^ 5) and anticonvulsant properties (Journal of Pharmacy and Pharmacology, Vol. S5. 501) have been known for a long time. From those in the German Au

3Q9825 / 116T

68 Int October 1972!

Writings 1 231 7 <? 5 and 1 2 '* 9 281 described chinezolone-'l derivatives possesses the 2-dimethylaminoπlethyl-3-methyl-ö-ethoxyquinazolon-'i one of the known 4-dimethylamino-i-phenyl-2,3-dimethylpyrazolon-5 comparable analgesic effect.

The invention relates to basic substituted pyrimidone

\ 4) derivatives of the general formula I and their possible, '_

tautofflcre forms sode doren salts with inorganic or

organic acids.

In the general formula I:

Il is a hydrogen atom, a straight-chain or branched one Alkyl or alkenyl groups each with 1 to 6 carbon atoms, a cycloalkyl or cycloalkenyl group each with 5 to 6 carbon atoms, a Phenylre.st or a phenylalkyl group in which the alkyl radical is seradketiiig or branched and have 1 to 6 carbon atoms may own; ' ■.

A is a straight-chain or branched alkylene group having 1 to 6 carbon atoms;

09825/1167

68 Int October 1972 ' - 3-

- ■. 4 '- ■ ..- ■ - ■ 4 ^; ■■ · ■ ·· - .: ■■ ■ .-

X is the group -N (R) -, in which R is a hydrogen atom or a straight-chain or branched alkyl group having 1 to 6 carbon atoms, or a S clvwe fei atom; -

Y is an oxygen atom or a sulfur atom, with the measure "'indicating that Y is an oxygen atom when X is a sulfur atom;"' ^ ^; '_

Z is a hydrogen atom, one or more straight-chain or branched alkyl, alkoxy or alkyl mercapto. groups each having 1 to k carbon atoms, trifluoromethyl groups or fluorine, chlorine or bromate;

W a vinyl enre st. . ._j · '. ""'.

"■. - R ¹ R ² '■■■ ■"-'

- C == C

or exrre optionally · 1,2-phenylene or 1,2- or 2,3-naphthylene group substituted by one or more identical or different radicals R or by an alkylenedioxy group having 1 to 2 carbon atoms, where

1 2

R and R. are identical or different and are hydrogen atom, a straight-chain or branched alkyl, alkenyl, alkoxy or alkylraercapto group, each with 1 to 6 carbon a £ omen, a cycloalkyl or cycloalkenyl group with each

■ ν because 5 to 6 carbon atoms, a phenylalkyl group,

wherein rier straight-chain or branched alkyl radical 1 to 6

309825/1

May have carbon atoms, an aryl radical, a carboxy group or a carboxyalkyl group with up to 7 carbon atoms or a functional derivative thereof, eirc hydroxy or mercapto group, an amino, alkylamino or dialkylamino group, in which alkyl can contain up to k carbon atoms, a halogen atom , such as a fluorine or iodine atom, in particular a chlorine or brine atom, a nitro or nitroso group, an alkanoyl group with 2 to 7 carbon atoms, an aroyl or aralkanoyl group, in which the alkanoyl radical can contain 2 to 7 carbon atoms.

A straight-chain or branched alkyl group with up to 6 carbon atoms is, for example, a methyl, ethyl, Propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, pentyl, isopeiityl, 1- or 2-methyl-butyl, tert-pentyl, ilexyl, isohexyl, 1-, 2- or 3-methylpentyl, 1-, 2- or 3-ethyl-butyl, 1,2-, 1,3 ^ or 2,3-dimethyl-butyl group; an alkenyl group is, for example, vinyl, allyl, 2-methyl-allyl, propen-1-yl, butene-1- or 2-yl, Pcnten-1, 2- or 3-yl-, hexenyl or 2-ethyl-propen-1-yl group.

3 0 9 V 2 5/1 1 8 1

68 Int October 1972 - 5 -

A straight-chain or branched alkoxy or alkylcapto group up to 6 carbon atoms is, for example, one of the above-mentioned alkyl groups with up to 6 carbon atoms derived alkoxy group, such as a methoxy, ethoxy, Propoxy, isopropaxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy group, - -

or an alkylmercapto group derived therefrom, such as a Zuni Methylniercapto-, Äthylmercapto- group _R propylmercapto, Isopropylmercapto- or Butylmsrc ap tο "

ID a cycloalkyl or cycloalkenyl group with 5 to

6 carbon atoms is for example one: -

Cyciopentyl-, 2- or 3-methyl-cycloj> entyl-, cyclohexyl- or cyclohexenyl group. «* -

A straight-chain or branched alkylene group A with 1 to β carbon atoms - —— ~~ ~ ^r

is for example a methylene, 1,1-ethylene-j

1,2-ethylene, trimethylene, propylidene, 1- or 2-methyl

ethylene, tetramethylene, 1-, 2- or

3-methyl-trimethylene, butylidene, 1- or 2-ethyl-ethylene: pentylidene, P ent on the ethylene or H ex on the ethylene group, and also a 1-, 2-, 3- or 4-methyl -tetramethylene 1- or 2-propyl-ethylene-, 1- or 2-isopropylethylene-, 1-, 2- or 3-ethyl-trimethylene-, 1-methyl-2-ethyl-ethylene-, 2-methyl-1- ethyl-ethylene, I ₁ 3-dimethyl-

'tfrimethyXi & n-, · Hex3 ^r liden-, 1- or

SB-butyl-ethyl-vinyl, 1- or 2-isobutyl-ethylene, 1- or 2-

2258 (5: 6 Τ

68 Int October 1972 '«

sec-butyl-ethylene-, 1- or 2-tert-butyl-ethylcn-, 1-, 2- or 3-propyl trimethylene, 1-, 2- or 3-isopropyl trimethylene, 1-, 2-, 3- or 'i-ethyl-tetraniethylene-,

or 5-methyl-pentamethylene, 1,2-, 1,3-, 2,3-, 3 » - ¹ I- or 2, ^ - dimethyl-tramethylene, 1-methyl-3-ethyl-tri-methylene, 1,2,3- ^ rimethyl-trimethylene, 1-methyl-2-ethyl-trimethylene, 3-methyl-1-ethyl-trinicthylene, 2-methyl-1-ethyl-trimethylene

2-methyl-3-ethyl-trimethylene group. ;; ■

An aryl radical is optionally one or more the radicals indicated under Z are substituted, preferably but unsubstituted Phcnylrest.

In a phenylalkyl group, the alkyl group can be one of the mentioned above for a straight or branched chain alkyl group Have meanings. Is a phenylalkyl group

or., _Λ

for example a benzyl fexne or p-phenyl-ethyl

_i group. The phenyl group can be replaced by a

or more of the radicals given under Z may be substituted, but is preferably unsubstituted.

An alkylamino group with up to h carbon atoms is a methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylaniino or tert-butylamino group. Eincf. Dialkylamino groups, in which the alkyl groups ^{can contain up to 1} U carbon atoms, is a dialkyl amino group derived from the above-mentioned alkylamino groups by replacing the hydrogen atom with an alkyl group.

3 ρ .- ■ ■ -i r ι 4 * Λ ^rili

68 Int October 1972 - 7 -

rest and is, for example, a dimethylamino, diethyl , araino, N-methyl-N-ethylamino, N-methyl-N-propylamino, dipropylamino or diisopropylamino group. ,

A carboxyalkyl group of up to 7 carbon atoms is derived from one of the aforementioned straight-chain or branched alkyl radicals with up to 6 carbon atoms the replacement of a hydrogen atom by the carboxyl group from and is, for example, a carboxymethyl or an Ιο the 2-carboxyethyl group.

In a functional dex-ivate of a carboxy or carboxyalkyl group the carboxy group is replaced by a functionally modified carboxy group «A functionally treated one Carboxy group is, for example, an alkoxyaarbonyl group with up to 5 carbon atoms, one- cyano- or a carbamoyl group.

An AlkOXj ^1- carbonyl group with up to 5 carbon atoms is an alkoxycarbonyl group derived from one of the above-mentioned alkoxy groups with up to k carbon atoms, such as a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl group,

Sine carbamoyl group is preferably unsubstituiort, •• can also ibcjr by one or two glej.chc or different of the above alkyl groups which may contain up to Ί 'Kohlenstoffritonic entlialtcn, on the nitrogen atom or mono- dii · üb st i tu i s a place in.

3 O Γ-ΐ < ? B / 1 1 6 7

68 Int October 1972 - 8 -

Alkanoyl radicals with 2 to 7 carbon atoms are acyl radicals of straight-chain or branched alkanecarboxylic acids with 2 to 7 carbon atoms, in which the alkyl radical with 1 to 6 carbon atoms one of the above for a straight chain or branched alkyl group meanings given, has, preferably the remainder of the acetic or propionic acid.

An aroyl radical is an optionally substituted by one or more of the radicals given under Z, but preferably an unsubstituted benzoyl radical.

In an aralkanoyl group, the aryl radical and the alkanoyl radical with 2 to 7 carbon atoms have one of the aforementioned requirements. An aralkanoyl group is, for example, a phenylacetyl, 1- or 2-phenyl-propionyl-. ■ group. "

Is an alkylenedxoxy group of 1 to 2 carbon atoms a methylenedioxy or ethylenedioxy group.

The compounds according to the invention, dexgeneral, formula I have valuable pharmacological properties and can accordingly be used as medicaments. They, in contrast to known compounds with similar structure, \ never described in the German Auslegeschrift 1 231 and 1 2 ^ 9 2ü8l '. are described, especially for such a subsidiary group, novel antihypertensive and pronounced ariaJXgetic properties with low toxicity on \. The new compounds show a pronounced effect on anesthetized cats and rats when administered intravenously

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68 int October 1972

antihypertensive effect »This blood pressure lowering is not solely due to the peripheral inhibition of the adrenaline and noradrenaline effects, as some products, the weaker adrenolytic and noradrenolytic effects Possessing phentolamine than phentolamine will lower blood pressure more than phentolamine. It can also be administered orally a pronounced analgesic component in the mouse to be established. (Delay in the defense reaction in thermal irritation of the mouse tail) ■ \

The new compounds and the pharmacologically acceptable salts with inorganic or organic acids can therefore be valuable therapeutic agents - such as Anaigetika or preferably for the treatment of hypertension, and also as useful intermediates for example to ¹ the preparation of other, especially of pharmacologically active onnectivity find use. From this class of compounds, pyrimidone (4) derivatives of the general formula I * and their possible tautomeric forms and their salts with inorganic or organic acids have particularly good effects,

X * - A * - N

68 int October x9? 2

R *. a straight-chain or branched alkyl group with up to 6, preferably up to k carbon atoms, a cycloalkyl group with 5 to 6 carbon atoms, and in particular a methyl or ethyl group, or a hydrogen atom,

A * denotes a straight-chain or branched alkylene group with 2 to k carbon atoms, in particular an ethylene or trimethylene group,

X * the group -N (R) -, in which R is a straight-chain or branched alkyl group having 1 to h carbon atoms and in particular a ^c hydrogen atom, or is a sulfur atom, _m

Y * is an oxygen atom or a sulfur atom with which Provided that Y * is an oxygen atom when X * is a sulfur atom,

Z * is a hydrogen atom, a fluorine or chlorine atom, or an alkoxy group having 1 to k carbon atoms, preferably a methoxy or ethoxy group in particular

wine ortho position, means, forner also an alkyl,

preferably methyl group, with 1 to 4 carbon atoms,
W * is a vinylene residue

R ¹ * R ² '

or an o-phenylene radical

meansι

where R ¹ *! R ² * and R- * are identical or different and a Wassoretoffntom, oino alkyl or Alkoxygruppo wit 1 ' to 6, vbrzugwoiso with 1 to h carbon atoms,

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a "Fhienyl group, a carboxy, carboxymethyl,
Methoxycarbonyl, ethoxycarbonyl or Methoxycai'boKiylmethylgr'uppe, a preferably unsubstituted carbamoyl group, a cyano group, a
Hydroxy group, an amino, alkylamino or dialkylamino group in which the alkyl group can have 1 to 4 carbon atoms, a chlorine or bromine atom,
an alkanoyl group with 2 to 4 carbon atoms,
denote the benzoyl group or the benzyl group,

1 * 2 *
and in which in the vinylene radical R and R are preferably a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, a phenyl group, a carboxy, carboxymethyl, methoxycarbonyl, ethoxycarbonyl or methoxycarbonylniethyl group, an amino, alkylamino or dialkylamino group, in which the alkyl group 1 to 4
May have carbon atoms, a chlorine or bromine atom, an alkanesayl group with 2 to 4 carbon atoms, the benzoyl group or the benzyl group, and

ta, ι * a ** 3 *

■ wherein in the o-phenylx the substituents R, R and R preferably a hydrogen atom, an alkyl or alkoxy group with 1 to 4 carbon atoms, a chlorine or Bromine atom or two of these substituents together represent an alkylenedioxy group with 1 to 2 carbon atoms, and flex * o-PhonylJrest in particular by one or two Methyl, ethyl, methoxy or ethoxy groups, in the first place Lines in the 6- and / or 7-position, or by three methoxy groups., primarily in the 6-, 7- and 8-position, substituting Lt is, and especially the 2- [3- (1- [2-methoxy-rphenyl] -pipoinainyl-4) -i3ropylaiuino] -6-methyl-5-butyi'-4 [3Il] -pyrimidone, 2 ~ Cl3- (1- [2-methoxyphenylJ-piperazinyl-4) propylamino] - -4 [3Il] -pyrimidone, 2- [3- (l- [2-methoxyphenyl] -pipera-

309825/1167 - ^H ^.

68 int October 1972

zinyl- ^) -propylamino] -6-amino-4 [31l] -pyriraidone, 2- [3- (1- [2-methoxyphenyl] .piperazinyl-4) -propylaminoJ-6-propyl- ^ [3HJ -pyrimidone, 2- [3- (1-L2-methoxy-phenylJ-pip he azinyl- * έ) -propylmercapto ^J-3-c yclohexyl-5-acetyl- (l: [3HJ-pyrimidone, 2-L3- ( .1-L3-Methyl-phenyl] -piperazinyl-'t) -propylmercaptoJ-3-benzyl-5-ethoxycarbonyl-4 [3H] -pyrimidone and the 2- [2- (1- [2-Xthoxyphenyl] - piperazinyl -k) -äthylmercapto J-6, 7-dimethoxy-Ί [3HJ-quinazolone, 2- [3- (1- [2-methoxyphenyl] -piperazinyl- * i) -propylraercaptoJ-6,7-dimethoxy- 4 [3Hj-quinazolone, 2- [3- (ΐ ~ [2-ethoxy-phenyl] -piperazinyl- k) -propylamino] -7-methyl-4 [3Hjchxnazolinethione, 2- [2- (1- [2-methoxy -phenyl] -piperazinyl- (t) -äthylmercapto J-6, 7-dimethoxy-4 [3Il] -quinazolone, 2 - ['i- (1- [2-methoxyphenyl] -piperazinyl-4) -butylamino] -6,7-dimethoxy - ^ [3H] -quinazolone, 2- [3- (1- [2-methoxyphenyl] -piperazinyl-4) -propylamino] -6 ₁ 7-methylenedioxy- ^/ l [3H] - quinazolinthioni 2- [2- (1- [2-ethoxy-phenylJ-piperazinyl-4) -ethylamino] -6,7-dimethoxy-4 [3HJ-quinazolinthione, 2- [3- (1-L 2-methoxyphenyl J-piperazinyl-4) -propylamino] -6,7-dimethyl- k [3H] -chxnazolinethione, 2- [3- (1- [2-methoxyplienyl j-piperazinyl- 'i) -propylamino J-6, 7-dimethoxy- ^ [3H] -quinazolinethione, 2- [3- (1- [2-methoxyphenyl] -piperazinyl-4) propylamino] -6-bromo-7-methyl -4 [3H] -quinazolinethione and 2- [3- (1- [2-methoxyphenyl] -piperazinyl- (l) -propylmorcapto J-5-bxityl-6-methyl-4 [3Hj-pyrimidone and primarily 2- [3- (1- [2-Methoxyphenyl] -pipex "azinyl-4) -propylmercaptoJ-3-ethyl-6-methoxycarbonylmethyl- ^ [3H] -pyrimidone, 2- [3- (1- [ 2-MethoxyphenylJ-piperazinyl-4) -oropylaminoJ-5-chloro-6-methyl-4 [3Hjpyrimidon and 2- [2- (l-phenyl-p ^ perazinyl-4) -äthylaminoJ-6,7-dimethoxy- * l [3H] -ch: iniizolinthione and 2- [2- (l- [4-fluoro-phenyl] -piperazinyl-'i) -a'thylamino J-6, 7-dimethoxy- * [3n] -quinthione, the in doses of about 0.1 mg / kg to * · 5 niss / ks «* ⁿ anesthetized cats and rats, when administered intravenously, had a pronounced antihypertensive effect and

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68 int October 1972
- * 3 -

2 2 5 8J5 61

at doses from about 5 mg / kg to about 20 mg / kg when taken orally Administration to the mouse have a pronounced analgesic component.

The invention also relates to a method for Making connections of general. Formula I and their possible tautomeric forms and their salts with organic or inorganic acids, characterized in that one

a) a compound of the general formula II

where W, Y * and R have the preceding meanings and L represents a halogen atom, preferably a Chlorine or bromine atom, or for a SuIiPogruppe • stands with a compound of the general formula IV

HX-A-N "-K ~ \ _Ty

wherein. A, X and Z have the meanings given above, where, when X is a sulfur atom, the compounds of the formula IV are preferably in the form; their alkali or alkaline earth salts are used, or "

309825/1167

68 int October 1972
- Ik -

b) in the case of the preparation of compounds of the general formula I in which X is an -N (R) group and W, R, A, Z, Y and ¹ R have the aforementioned meanings, a compound of the general formula ITT,

III

wherein W, Y and R have the above meanings, V stands for the grouping -S-, -SO- or -SO - and R ^{5 stands} for an alkyl radical having 1 to k carbon atoms, preferably a methyl or ethyl group, or a carboxymethylene group, with a connection of the general

k mean formula IV, in which X is the group -N (R) -

' k

means and in which A, R and Z have the preceding meanings, converts, or

c) in the case of the preparation of compounds of the general formula I in which X is a sulfur atom and W, Y, R, A and Z have the aforementioned meanings, a compound of the general Börmel V

wherein V, Y and R have the preceding meanings, with a Vtrbunden of the general Pormei vi 309825/1167

68 int October 1972
- 15 -

E-A-N

■ where A and Z have the abovementioned meanings and E represents a reactive esterified hydroxyl group
or

d) in the case of the preparation of compounds of the general formula I, in which Y is a sulfur atom and X is a -N (R ^ i) group, and V, R, A, Z and

4th
R have the meanings given above, a compound of the general formula VII

C η = Ν

V VII + ■

C Y

wherein W has the above meaning and Y is a sulfur atom means having a connection of general

I ₁
Formula IV, wherein X is a -N (R) group and

h ib , A and Z have the above meanings, implemented, the reaction being preferably carried out in polar solvents or

e) fjffi case of the preparation of compounds of the general formula I in which X denotes an -N (R) group, and W _v Y, R, A, Z and R have the abovementioned meanings

309825/1187

68 Int October 1972 • - 16 -

own a compound of the general formula VIII,

C ns N

NlI-C

VIII

in which W, A, R and Z have the aforementioned meanings and Y is an oxygen atom or is a sulfur atom, wherein when Y is a

k "
Is sulfur atom, R is then different from a hydrogen atom, treated with alkali metal hydroxides, preferably in the presence of hydrogen peroxide, or

f) in the case of the preparation of compounds of the general formula I in which X is an -NH group and Y is a sulfur atom, and W, R _t A and Z have the aforementioned meanings, a compound of the general formula IX,

NH

Π-Ι.Α-Ν

IX

wherein W ₁ A and Z have the abovementioned meanings, with or without a solvent and preferably in the presence of basic substances

5/1167

68 int October 1972
- 17 -

Reagents for compound I rearranged, or

• -

g) in the case of the preparation of compounds of the general formula I in which X is an -NH-6 group and Y represents a sulfur atom, and W, R, A and Z have the abovementioned meanings, a compound of the general formula X

C ~ N

wherein W has the abovementioned meaning with a compound of the general formula XI,

N-V Λ> XI

wherein Y stands for a sulfur atom and A and Z have the meanings given above, converts, or

3Q982S71167

68 Int October 1972;

h) a compound of the general formula XII

XII

with a compound of the general formula XIII

HO - _22nd

^{2 2} ^ -. Q

HO - CH ₂ CH ₂

preferably in the form of its reactive ester is reacted, in each of which one of the symbols P or Q is the group

N ΧΙΙα XA-

Z and the other symbol for - (J ^ V stands,

309825/1 167

68 Int October 1,972 - 19 -

and in which W ₁ R ₁ A ₁ X ₁ Y and Z have the abovementioned meanings, or

i) a compound of the general formula XIV,

XIV Z

XA-NH-CH ₂ -CH ₂ -NH

wherein W ₁ Ii, A, X ₁ Y and Z have the aforementioned meanings, with I ₁ 2-dioxyethane XV

• HO - CH ₀ CII ₀ - OH XV

preferably in the form of its reactive esters, for example 1,2-dibroniethane, or

j) a compound of the general formula XVI

\ XVl

• N. ^ X-A-E

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- 20 -

where E is a reactive esterified hydroxyl group, preferably a chlorine or bromine atom, and W, Y ₁ R, X and A have the aforementioned meanings, * with a compound of the general formula XVII, ..

XVII

wherein Z has the abovementioned meaning, converts • or

k) in the case of the preparation of compounds of the general formula I in which W is the vinylene radical -Q (R) = C (R_) 32'- ■ means and the radicals X, Y, Z, A, R, R. and R have the meanings given above, a compound of the general formula ΧλΤΙΙ - Y

OR "XVIII

wherein R and R 'are an alkyl group with 1 to ^! k carbon atoms, preferably a methyl or ethyl

7th
group, and R also represents a hydrogen atom

1 2

and in which Y, R and R have the aforementioned meanings with a compound of the general formula XiX

309 8 25 / 116-7

f 68 int October 1972

R.
I.

HN

CV λ

HN

wherein R, A, X and Z have the abovementioned meanings, and, if desired, in one according to a) to k) obtained compound a thioxo group in an oexo group or an oxo group in converted a thioxo group and / or, if desired, in a compound obtained with a carboxy, Cyano, alkoxycarbonyl or carbamoyl group these within the definition by esterification, Transesterification, hydrolysis, alcoholysis, aminolysis or dehydration converted into one another, and / or, if desirable to have an alkenyl or cycloalkenyl group as a substituent in a compound obtained

1 2 ■ ■

R, R or R converted in a manner known per se by selective, preferably catalytic hydrogenation into an alkyl or cycloalkyl group, and / or, if desired, a free compound obtained into its salts or a salt obtained into the free compound or into another salt, in particular into a pharmacologically acceptable salt.

According to variants a) and b), the compounds of general formula II or III are combined with the compounds of the general formula IV either without a solvent or also in inert organic solvents, such as See example alcohols such as ethanol, isopropanol, Xäbtonen such as acetone, methyl ethyl ketone, strongly polar Fatty acid araids or nitriles, such as dimethylformamide, Acetonitrile, or mixtures thereof, at elevated levels

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Temperatures, in particular between 50 and 200 C or at the boiling point of the solvent it is appropriate in variant a) either an equivalent amount of an auxiliary sbase, such as, for example, dimethyl

· * Aniline or Athyldicyclohexylamxn, to add or the

· '
To carry out reactions with at least twice the equivalent amount of the arylpipcrazines of the general formula IV.

When reacting a compound of formula V with a Compound of the formula VI according to variant c) is preferably used an alkali metal derivative, in particular a sodium odor Potassium derivative, the compound V with VI. The implementation preferably takes place in anhydrous, inert solvents, for example in dimethylformamide or imo-ethyl sulfoxide or in high-boiling hydrocarbons λ \ Ίο Xylene or toluene at boiling point.

The conversion of a compound of the formula IV in which X is a sulfur atom or of the formula V into its alkali metal derivatives takes place in a known manner, for example by reaction with an alkali metal ", alkali metal" hydroxide, alkoxide, hydricl or amide in an anhydrous inert solvent.

In variant d), connections VII are made with connections IV In a non-polar organic solvent, for example a hydrocarbon such as benzene, toluene or xylene, or a halogenated carbon dioxide, such as chloroform,

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Int October 1972 - 23 -

or trichlorethylene or preferably in a polar one organic solvent, for example a ketone, such as acetone, or a strongly polar fatty acid amide, such as dimethylformamide, at temperatures between 0 C and 150 C, preferably at the boiling point of the solvent.

According to variant e), connections are d.2r general Formula VIII with alkali hydroxides at room temperature or preferably winter heating to 30 C to 120 C, in particular

o o "* special at 30 C to 50 C, preferably in organic solvents, such as in ethanol _} treated, preferably in the presence of at least the equivalent amount of hydrogen peroxide.

According to variant Jf), connections of the general Formula IX without or in the presence of a polar or non-polar solvent, preferably at 30 to 120.degree heated, preferably in the presence of a basic agent, such as a metal, preferably Alkali metal hydroxide or alcoholate, an ammonium hydroxide such as benzyltrimethylamraonium hydroxide, ammonia or an amine such as diniethylamine. It is it iai the presence of strongly basic reagents not necessarily required to heat «

The reaction according to variants g), Ix) ₁ i) and k) is ■ vorznygsweine in an inert organic solvent, yv as in the example of one of the aforementioned, optionally: -: / ^ 'at elevated temperature, preferably at boiling temperature Solvent.

3 0 9 8 2 5 / T 1 6 7

68 int October 1972

According to variant j) one sets the connections of the general Formula XVI preferably at elevated temperature, in particular between 50 and 150 C either in a ' inert solvents such as chloroform, benzene, Toluene or xylene, oder.auch without a solvent with the compounds of the general formula XVII. It can be expedient, either an equivalent amount of auxiliary base, such as, for example, triethylamine, to be added, or a corresponding one To use excess compounds of the formula XVII.

A reactive esterified hydroxyl group X is above all one through a strong inorganic or organic one Acid, especially a hydrohalic acid such as iodine, preferably hydrochloric or hydrobromic acid, furthermore .Sulfuric acid or a strong organic sulfonic acid, such as a benzenesulfonic acid, for example p-toluenesulfonic acid, esterified hydroxy group. "

An oxo group can be converted into a thioxo group by known methods, such as, for example, by reaction with P ₃ S _51. On the other hand, a thioxo group can also be converted into an oxo group in a known manner, for example by reaction with HgO ₁ Ag 0 or with alkaline hydrogen peroxide.

309825/1 167

A functionally modified carboxy group, like a Cyan *, alkoxycarbonyl or carbamoyl group, can by known methods in a free or another functional modified carboxy group can be converted, for example by hydrolysis (for example by treatment with a acidic or basic reagent), alcoholysis or transesterification (optionally in the presence of a catalyst, such as for Example of an alkali metal alcoholate), aminolysis (a Alkoxycarbonyl group by treating with, for example

Ammonia or an amine) * A free carboxy group can j

..ija_eixre. functionally modified carboxy group can be converted, for example into an alkoxycarbonyl group by esterification (such as, for example, treatment with alcohol in the presence of a catalyst, for example an acid, or with a diazo compound) or into a carbamoyl or cyano group, for example by dehydration of an ammonium salt . - * ■

The reaction conditions for the transformations described above are chosen taking into account all the rod substituents in the molecule »

According to process variants a) to Ic) according to the invention for example, the following connections can be represented »;

309825/1167

60 Int October 1972 - 26 -

2- / 5 · - (1- ^ 2-Mothoxy-phenyjL7-piperazinyl- ^) 3-phenyl-6,7-dimethoxy-'i / 3H7-quinazolone, 2- / 2- (1- / 2-methox ; y-pheny \ L / -pip er az.inyl -k) -ä thylmer ca ρ to7- VT] | 7-quinazolone, 2- / 2- (1-j / 2-mothoxy-phonyv7-piporazinyl-d) ethyl mercapto / -6, 7-dimethoxy-'i / 3_H / -quinazolon, 2- / 2- (1- / 2-ethoxy-phenyl ^ / - piperazinyl-4) -äthylmcrcapto7-6,7-dimethoxy- (t / 3ri / -chinazo.lon, 2- / 5- (l- / 2-methoxyphenyl / -pipernzinyl-'i) -propylmercapt ^ yG, 7-din-ethoxy- ^/ i / 3H7-chixiazolon, 2- / 3 - (i- / 3-Mcthyl-phcnyl7'-piporazinyl- (l) -propylmercapto7-6 ₁ 7-dimethoxy-4 / 3il7-quinazolone, 2- / 3- (1- / 2-Me thoxy-phenyl7 ~ pi per azinyl-'t) -prop y. ) .m or cap taj- 3-butyl-6,7-diraetlioxy-V "3 _i H7-quinazolone, 2- / 2- (1-phenylpipernzinyl-'l) -ethylaminoy- 6, 7-dii! Iethoxy-'j / 3] V ^r -quinazolinethione, 2- / 2- (! - / T-fluorophenylT-piporasinyl-'t) -ethylamine p ^ - 6 _i 7-diraethoxy- ^/ i / 3H7-quinazolinethione, 2- / 3- (1-m-tolyl-pipera- »ynyl-d) -propylamino7-6 _t 7-dimethoxy-'i / 32I7-quinazolinethione, 2- / 7Γ- (! - / a -Methoxy-phenylZ-piperazinyl-'i) -buty lainino / -6, 7-dimethoxy-4/3 £ l / -quinazolinthione, 2- / T- (l - ^ - chlorophenyl / -piporazinyl-'l) -butylainiaio] 7-6,7-dimethoxy- ^/ i / 3j | / -quinazolinthian, 2- / 3- (l-ZS-Äthoxy-phenylJ ^ -piperaziiiyl-'i) -propylaminoj ^ - e ^ -diiuethoxy - ^ / '^ T'-quinazolinthione, 2- / 3 - (l- / 2-Äthoxypheny_l / -pipei * azinyl-'t) -propyl amino - 7-methyl-'l / Jü / - quinazolinthione, 2- / 3- (l- / 2-Athoxy-phcny27- pipei * azinyl-4) -propylamiiio7-6,7-diethoxy- hfySJ- chinazolinthioη, 2- / T- (1 - / 2-Methoxy-pheny _i ly "-pip ^cr f ^l 2inyl- ^) -propylaminc ^ Zo- methoxy -? - but $ loxy-4 / 5ü7-quinazolinthione, 2- / 5 - (! - / Hethoxyphenyl / -pip «rirai« inyl- ^/ i) -propylnmin £ 7-7-chloro- ^/ i / 3li7 -chinazolinthion ₁ 2- / 5 * C !! - / ^ - ΜοίΙιοχ ^ '- ρΗοηγΙ ^ -ρχροΓβζίη ^ ΊΊ) -propylamino7-6, 7-mothylcÄdioxy - ^ / lilZ-chinazoIinthion, 2- / 2- (l- / "~ 2-ethoxy-

309825/116 7

68 Int October IS ¹ ? 2 - 27 -

phenyl7 ^r -pipera2ii-iyl-4) -äthylamino / -6,7-dimethoxy-4 / 3H / ~ quinazolinethione, 2- / 5- (l- / 2-methoxy ~ phenyJL7-piperazinyl-4) propylainino / -6, 7 ~ dimethoxy- ^/ i / 3Jtf / ~ quinazolinthione, 2 .- / _ '5- (l - / ^ 2-chloropheny \ L / ~ r> iperazinyl-4) -propylamine / -6,7-diinetlioxy- 4 / 3n7-quinazolinethione, 2- / 5- (1- / 2-methyl-phonyl / piperazinyl-d) -propylamino _ / - 6,7-dimethoxy- ^/ J; _J / 3XI / - ^c hi ¹¹ i ^{: iZO} lp- ⁿ thion, 2 - / ^ 3- (l- / 2-methoxy-i3henyl7-i3iperazinyl- ^z i) -propylami _s no / -6, 7-dimethyl- ^/ i _i / 3iI / -quinazolinthione, ² ~ /, 3- ( l- / ß ~ methoxy-pheny ^ / - piperazinyl-4) -propylamino _ / - 6-chloro-4 _J / 3ii / -quinazolinthione, 2- ~ f5 - (l -_ / 2-Methoxy-phenyJL / -piperazi: n.yl- (i :) propylamino_ "7-6 -br om-7-nte thyl- 4 / 3JH / - quinazolinthione, 2 - / ^ 3- (1-Phenyl-pi.perazinyl- ^) -proi) ylam, ino _ / '- 6, 7,8-trimethoxy- ^

- (l - / ^ - Fluor-pheny ^ 7-piperazinyl-4) -äthylamino / -6,7-

^ / pjV-chinazoloji, 2- / J- (l- / 2-chloro-phenyl / -piperazinyl-4) -propylarnino _ / - 6,7-diniethoxy- ^/ i / 3n / i * quinazolone, 2- / 2- (l- / 2-Xtlioxy-ph "cnyi / -p.ijperazinyr- ^/ i) -äthylainino / -6, 7-dimethoxy ~ ^/ i / 3n7-quinazolone, 2- / 5- (l- / 2-methylphenyl7- j) iperazinyl-4) -proj> ylanvino_ / ~ 6, 7-dimethoxy- ^ y3Π / -quinazolone, 2 - / ^ 3- (lm-tolyl-pipercEiiiyl-4) -propylamiiio / -6,7-diniethoxy-4 / 3H7-chinnzolone, 2- / 7Γ- ('! »■ / 2-MGt] voxyphen piperaziiyl-4) -butyl amino / - 6, 7 - dime thoxy-4 _J / 3] j [/ - china zo lon, 2- / Jl- (l - / ^ 2-chloro-phcny _< l7-piperaziiiyl-4 ) -butylamino / -6, 7-dimethoxy- ^/ i / 3il / -quinazolon, 2- / β- (! - /iT-Xtho'xy-phcnylT'-pj.pcrazinyl-4)-propylamiiio_/-6,7-diniethöxy-4 _i / 3j [l / -quinaziolon, 2- / 3- (l - / ^ 2-ethoxy- pheny ^ 7 ^r "Pipcrazinyl-4) -7- propyl" iothyl- ^/ l _J / 3] j (7-quinazolone, 2 ~ / _3- (l- / 2-phenyJ Xthoxy ~ ^ / - zinyl-4 ) -propylamine / -6, 7-dietlioxy-4 _J / 32l7 ^r -chi3iazolon,

309 8 25/1187

68 Int October I> 7! - 28 -

methoxy-7-butyloxy-4 / 3n / -quinazolone, 2- / 5- (l- / 2-methoxyphenyl / -piperazinyl-4) -propylamine ^ -7-chloro ~ 'i / 3H / -quinazolone, 2- / 3- (1- / 2-Methoxy-pheny \ L7-piporazinyl-4) -propyl-amine £ 7-6 t 7 ~ niethylcndioxy-4 / 3jV- ^c hinazolone, 2- / 2- (1-phenylpiperazinyl -4) ~ acylamino / ⁷ -6, 7 ~ diniethoxy- * i / 5.H7-quinazolone, ² ~ / 3- (l -, / 2-methoxy-phcnyl / -piperazinyl-'i) - propylamine ^ - ^ "7-dimethyl-'i / 3Jii7-chinazclon, 2- / 5- (1/2 * - methoxy-pheiiy _j l / -piperaziiiyl- (i) -propylaniinoZ-ö-chloro-il / 3 | IF7-Chinaz , olon _% 2 - / ^ 3- (l- / 2-methoxyphenyl / "- piperazinyl-4) -pr * opylaniiii £ / -6-broin-7-methyl- ^/ iy3 £ i / -cliiiiazolon, 2- / 3- (1-Plxenyl-pipcrazinyl -Ί) -propyla: nin £ 7 "-6, 7 18-trimethoxy- ^/ i / ^ 3] i7-quinazolone, 2 - / _ N-Xthyl-K- (2- / 1- (2-Methoxy-phenyl) -piperazinyl ^ y-ethy ^ -araino / '- 6, 7-dimethoxy- (l / 3n7-quin.azolone, 2- / ΪΤ-butyl-N- (3- /. 1- (2-methoxyphenyl) -piporaziiiyl-47-prop3'l) -amino / -3-

hj'-lG, 7-dimethoxy- ^/ i / 3n7-quinazolone, 2- / N-ethyl-N- (2- - (2-methoxy-phciiyl) -pii ") erazinyl - ^ / - ethyl) amine * 7-3-isoprt> pyl-6,7-dimethoxy- ⁱ / 3Ji / -quinazolon _l 2- / 1? -Ethyl-N- (2- ^ / f- (2-methoxyphenyl) -pipcrazinyl-J ^ Z-ethyl) -311111107-3-AlIyI-6 ₁ 7-dimethoxy-V5ii7-quinazolon, 2- / Ii-AtIIyI-N- (2- / T- (2-mctlioxy-phcnyl) -pipcrazinyl-JlZ-ethyl ) -amino - 3-t> utyl-6, 7-dlmothoxy-'l / ^ nZ-quinazolon, 2- / 5- (lj / 2-methoxy-phonyl / -piperazinyl-'i) -propylainino7-3- phonathyl-6,7-diniGthoxy-d / ^! / - chinazolon, 2- / 3- (l- / 2-Mctho?; y-phenyJL / -piperazinyl- (i) -prop ^ € ainin ^ / - 4 / 3jV ^r -quinazolinthione, 2- / 3- (l -_ / 2-Mcthoxyphtc uyiT'-piperazinyl- ^) -pr'opylamiiio _ / - ^/ l _j / 3jl7-quinazolone, 2- / 3- (l ⁱ -j / 2-methoxyphenyl _ / - pipcrazinyl-'l) -propylamiiio / -6-

zi nyJL- h ), -pr ο py 1 am i nöj- 5 - c 111 ο r - 6 -jii et hyl - ^l ^ / j}] \ / - pyr iini do η, 2 - / [5- (1 - / 2-Methoxy-phcnylT'-pipcraJiinyl-'i) -propylnmino7 - (> -

zinyl-'i) -

309825/1167

68. i _n t October 1972

amino7-6-benzyl- 4/311 / -Py ¹ * imidone, 2- / 3- (l "if2-

/.3H/-pyz*imidon, 2- / 3- ('1- / 2-Methoxy-phenyJ ^ / - piporazinyl-4) propyXamiaoT ^ -ß-propyX-A / JllT ^ -pyriniidQii, 2- / 3 - (1 ~ / 2-Me tlioxy-phenyl / -pip erazinyX- ^ i) -propyXantiiooT- 5--cya.no - k / 3Uf-T? Yrlmldon _% 2- / 2- (l - ^ - jChlor-phenj ^ T-piperaainyX-d) -

2- / N-EthyX-K- C 2- / T- (2-inethoxy-plienyX) -piperaz-inyX-Jt, / - * äthyX) -amine ^ T-6-methoxycarbonyXmd tliyX - ^ / 3iI / -pyi `` imidoxi, ₎ 2- / N-XthyX-N- (2- / Γ- (2-me tlio>; y-phenyX) -piporazinyX -Λ7- ^

(l-ra-ToXyX-p ± pei "azinyX-4) -propylajnino / - 3-phcnä-thyX- 5-

, 2- / 3- (! - / a-methoxy-pheiiyX / "
piperazinyX-4 ^ propylamino / ^r -'3'- (4-cliniQthyi amino «phenyl butyryl -4 / 3H7-pyrimidone, 2- / J- (1 - / 2-methoxy-ph enylj-

pyriraidon, 2- / 3- (l "jn-tolyl-'pxperazinyl-4) -propylmercapt ^ / 5r nitro-6-propyX-4 / 3jiF - pyi'i ^ iÖQ», 2- / 2- (! - / aphenyl7-piper asinyl - 4 } ^ a thyXmer c apt o? * ^ -ä tliyl -

^ K ^ (3-r / T- (2 «methoxy-phcinyl) -pi

68 Int October 1972 - 3α -

(3 - /, I- (2-methoxyphenyl) -piperazinyl- ^ Z-propyl) -amino / -3 ethyl-6-methyl-1 / 3H7-pyrinidone, 2- / 5- (1- / 2-methoxy- I pheny \ L / -piperasinyl-'i) -propylamino / -6-dimethyIainino-'i

The ones used in process variants a) to Ic)

Starting materials are started or are produced according to methods known per se. Process for the preparation of the starting materials of the general formula II, III and V are in DJ Brown, The Pyrimidines, ι Interscience Publ., J. Wiley & Sons, .New York-London 1962 , Suppl. I, 1970 and in RC Elderfielil, Heterocyclic Compounds, Vol. VI, Wiley & Sons, New York-London 1957, Chapters, VII and VIII. Compounds of .Formel IV can be obtained from the corresponding 1-aryl-pipcrazincn: if X is a sulfur atom by reaction with compounds HS-A-Hal, in which Hal is a halogen atom, if X = -K (R) - by reaction of i Bromoalkyl-phthalimides and elimination of the phthalic acid residue by glydrazinolysis and, if necessary, introduction of R by acylation and subsequent reduction of the acylamino obtained by means of a metal hydride.

The compounds of the general formula VI are obtained for example by reacting the corresponding 1-arylpiperazines with chlorine or bromohydrin and conversion of the l- (uT-hydroxyalkyD-t-aryl-piperazines into reactive esters, e.g. esters of the carbon dioxide

309825/1167

Int October 1972 - 31 -

acid, according to known methods, e.g. by Treat with thionyl chloride.

The compounds of formula VII are obtained, for example, by Phosgenation or thiophosgenation of compounds

The compounds of the formula VIII can be obtained by the process described below from a compound of the general formula VII by reaction with a compound IV _V in which X is an -N (R ^X ) - 'group. · ·

Compounds of the general formula X in which W denotes a vinylene radical can be selected from appropriately substituted / i- oxo-alkali carbonitrile and ammonia, those in which 17 denotes an o-plienylene or naphthylene group from the compounds NC-W-NO ₀ can be produced by reduction. _. -.

Isothiocyanates of the formula XI can be obtained by reacting Compounds of the formula IV, -wherein -X- an -NH- group means 'with carbon disulfide and oxidation' the obtained dithiocarbamic acids with ilypohalogenite, e.g. Sodium hypochlorite, obtained.

Compounds of the * formula XII, in which P has the meaning XIIa, are made by reacting compounds dex "formula XJ. With N-acetyl-alkylondinmines and subsequent cleavage of the acetyl group or by reacting compounds of the formula V with N- ( iv'-chloro-alkyl) acetamide and

309825/1167

⁶⁸ int October 1972

32.

subsequent cleavage of the acetyl group obtained Instead of the N-acetyl group, the N-bornylene (2y ~ radical can be used as protection group £> c (see DT-OS

1 770 557). ■ · '

The compounds of the general formula XIII rait Q in meaning XIIa can be obtained from amines of the formula XII with P ds XIIa and ethylene chlorohydrin

A compound of the general formula XIV can by Reaction of a compound XII, in which P has the meaning of XIIa, obtained with a 2-Arylaminoiräthylhalogenid will.

Compounds of the general formula XVI can, if X = O, analogously to method a) or b) from II or III and a compound IIO-A-OII, if X = S analogously to method c) from V and ΗΟ-Α-ΟΪΙ and subsequent Conversion of the Hydroxygrüppo in a reactive esterified hydroxy group can be obtained. The compounds of formula XIX, when X represents a -KH group from XI by reaction with _n RNII, subsequent Metiiylierung the SH group, for example with Mothyljodid place under alkaline conditions and reaction condition> the resulting compound with ammonia, for X = S, durclt) alkylation of thiourea with VI

The invention also relates to novel arylpiperazinyl alkylene glycol derivatives the general

Formula Will and their possible tautoincre forms, as well dcrcsn S'a-Τϋ ', ο with inorganic or organic acids,

309825/1 167

VIII

in which If one, if necessary, by one or more identical or different radicals R or by one Allcylenedioxy group substituted with 1 to 2 carbon atoms 1,2-phenylene or 1,2- or 2,3-naphthyl group means,

R is a hydrogen atom, a straight-chain or branched alkyl, alkenyl, alkoxy or alkyl mercapto group with 1 to 6 carbon atoms each, a cycloalkyl or cycloaflkenyl group with 5 to 6 carbon atoms each, a phenylalkyl group, in which the straight-chain or branched alkyl radical 1 to May have 6 carbon atoms, an aryl radical,

a carboxy group or a carboxyalkyl group with up to 7 Kottienstoffatomen or a functional 'derivative thereof, a hydroxy or mercapto group, an amino, alkylamino or dialkylamino group ^ in which alkyl can contain st » k carbon atoms, a Halotgena-tor, such as a fluorine or iodine »especially a chlorine or bromine atom,

-309825 / 11β7-

68 Int October 1972 2258581

- 3'i -

a nitro or nitroso group,

an alkanoyl group having 1 to 7 carbon atoms, an aryl or arallcanoyl group, in which the alkanoyl radical May contain 1 to 7 carbon atoms. A has a straight-chain or branched alkylene group Means 1 to 6 carbon atoms,

Y 'is an oxygen or sulfur atom,

4 '

R. a straight or branched alkyl group with 1 to 6 carbon atoms or, if Y is an oxygen atom, also a hydrogen atom, and Z is a hydrogen atom, one or more straight or branched alkyl, alkoxy, or alkyl mercapto groups each with 1 to k carbon atoms , Trifluoromethyl groups or fluorine, chlorine or Droniatotae Ιιοαβίΐίοί.

_{14 ~ '~ The substituents W 1} R, U, A and Z mentioned in the general formula VIII come with the

.Mentioned meanings about
«

The pre-compounds of the general formula VII, which are suitable for the invention, have valuable pharmacological properties, such as antihypertensive and analytical effects, which are comparable to the aforementioned properties of the pyrimidone derivatives of the general formula I. The new compounds and their pharmacologically acceptable salts with inorganic - ■ See or organic acids can therefore be used as valuable therapeutic agents. But they are also valuable intermediates for the preparation of other, in particular pharmacologically active compounds, such as, for example, the preparation of pyrimidone- (Ό-derivatives of the general formula I,

309 8 25/1 167

68 Int October 1972 - 35 -

! 258561

Are particularly preferred in this class of compounds Arylpipcrazinylalkyl urea derivatives of the general formula VIII * and their possible tautoinere Forms as their salts with inorganic or organic acids, ''

1*

CN

NH '- "C

N - Α - - N

wherein

A * denotes a straight-chain or vex * branched alkylene group with 2 to k _%, preferably with 2 to 3 carbon atoms,

4 *
R denotes a hydrogen atom or a straight-chain or branched alkyl group with 1 to 1 carbon atoms, ■ ·

Z * is a hydrogen atom, a fluorine or chlorine atom, a Alkyl, preferably methyl, or an alkoxy group

with 1 to k carbon atoms means 1 * "2 *":,., 3 *

2 *
, R and R ^{J are} identical or different and represent a hydrogen atom, an alkyl or alkoxy group with 1 to 6, preferably with 1 to k carbon atoms, a phenyl group, a carboxy, carboxymethyl,

309825/1167

68 October 1972

Mofthoxycarbonyl-, ethoxycarbonyl, before ^ zugsveisjo uiisub- ".tituierte carbamoyl or 'Cyanogrupi ^ e, a Ilydroxygrupi> c, cine amino, alkylamino or Dialkyla: ninogruppc in which the alkyl group 1 to h carbon atoms have kani, i, a chlorine or dromate atom, an alkanoyl group with 2 to h carbon dioxide, the ticmzoyl group, or the benzyl group, primarily compounds of the general formula VIII **

and their possible tautomeric forms as well as your salts with inorganic or organic acids,

• -

• - CN "''

^ N - A ** - N 1ί

I \ - J

R ¹ * is a hydrogen atom, 1 to 2 saturated alkyl and / or alkoxy groups with 1 to Λ carbon atoms, preferably methyl, ethyl, ethoxy and / or ethoxy groups, and / or chlorine or bromine atoms, in particular in 6 - and /: or 7-digit, or three methoxy groups in 6-, 7- and 8-position,

309825/1 1 67

R is an alkyl group with 1 to k carbon atoms, preferably a methyl or ethyl group, or a hydrogen atom,

A represents an ethylene or trimethylene group and ,

* *
> A fluorine or chlorine atom, preferably in ortho "or para abutment condition, a methyl group, preferably in meta abutment condition, or a methoxy or ethoxy group, a hydrogen atom, _t is preferably in the ortho position, also.

The invention also relates to a process for the preparation of compounds of the general formals VIII and their possible ent autonomous forms as well as their salts with organic or inorganic acids, marked thereby, that he

a) a compound of general. Formula VII

w - yii

wherein Y and Vi have the meanings given for formula VIII, with a compound of formula IV *

3Q9825 / 11Q?

6ff. International October 1972 ~ 38 ~

H-N-

wherein Λ and Z have the meanings given for formula VIII and R is a straight-chain or branched one Alkyl group having 1 to 6 carbon atoms or, if Y in formula VTI is an oxygen atom, also a Hydrogen atom means, converts, or

b) in the case of the establishment of connections of the general

k
Men formula VIII, in which R is a hydrogen atom <: i and the other radicals have the aforementioned meaning, a compound of the general formula X.

^ * Il .1 T | J "

W X ■ · -

wherein Vi has the meanings mentioned in Jpür.Fo.rmel VIII, with a compound of the formula XI ₁

Y = C = NA- ?! NC ⁷ ^ V

XI

wherein Y is an oxygen atom and A and Z are those for Formula VIII mentioned meanings ha ^ i converts, and if Desirably, a obtained free compound in their Salae or a obtained salt in the free compound or in another suI ^ c, especially in a pharinakolo ^ ircli compatible salts, transferred

vi

68 Int October 1972 - 39-

The reaction of VII with IV according to variant a) "is carried out in a non-polar organic solvent, such as, for example, a hydrocarbon such as benzene, toluene or xylene, or a halogenated hydrocarbon such as chloroform or trichlorethylene, or in a polar solvent, for example, a ketone such as acetone, or a strongly polar fatty acid amide, such as dimethylformamide, at temperatures between 0 C and 150 C, preferably, carried out at the boiling point of the solvent. the reaction according to Vari ante b) is preferably conducted in an inert organic solvent such as for example one of the aforementioned, optionally at elevated temperature, preferably at the boiling point of the solvent.

The invention also relates to new basic substituted ones 1,3-thiazines of the general Fox-mel IjX and "arene salts with inorganic or organic acids

WH

IX -:

'^ p. ■■ "■

W J - ·. ■ η-

^N ΝΓΙ-Λ-Ν

worj η

- ^Λ cine straight-chain or branched alkylene groups with Ά I ¹ XLS 6 carbon atoms,.

'Λ c: ui V / ajiscrstoiTatoin, one or more straight-chain odor vorawei & tti alkyl, alkoxy or alkyl mercapto- ~ ΕΠφροη each with 1 bir. ¹ I Carbon atoms, 'Trxfluoj'iiinthylKrajipoii odea "Fluorine, Chlorine or Brojnatome liodfiiitct,' i

68 int October 1972. - 40 -

W a vinylenre "st

I I

or one optionally by one or more of the same

or different radicals R ″ or through an alkylondioxo group 1,2-phenylene substituted with 1 to 2 carbon atoms or 1,2- or 2,3-naphthylene group,

12th
* where R and R are the same or different and are a hydrogen atom, a straight or branched alkyl, alkenyl, alkoxy or alkyl mercapto group each having 1 to 6 carbon atoms, a cycloalkyl or cycloalkenyl group each having 5 to 6 carbon atoms, a phenylalkyl group, in which the straight-chain or branched alkyl radical can have 1 to 6 carbon atoms , '■ an aryl radical, * "'. '" ■ a carboxy group or a carboxyalkyl group with up to 7 carbon atoms or a functional derivative thereof,

a hydroxyl or mercapto group, an amino, alkylaraino or dialkylamino group, in which alkyl can contain up to h carbon atoms, a halos.cnatoiii, such as a fluorine or iodine, iiisbesondex-e a chlorine or bronintone,
a nitn »or nitroso group,

an alkanoyl group with 1 to 7 carbon atoms, an aroyl or aralknnoyl group, in which the alkanoyl radical May contain 1 to 7 carbon atoms, represent, mean.

309825/1167

'. ϊ ■

68 int October l '> 7Li

.j. 12th

The in. The general formula IX under W ₁ R, Π.,

A. and Z mentioned Sufostitueiiten come here mentioned meanings.

The connections according to the invention of the 'general Formula IX have valuable pharmacological properties, such as antihypertensive and analgesic effects,

♦ *

those with the aforementioned properties of the pyrimidone Ci) derivatives the general formula I are comparable to »The new compounds and their pharmacological. tolerable Salts with inorganic or organic acids can therefore ■ be used as valuable therapeutic agents. she are! but also valuable intermediate products for manufacture other, especially pharmacologically active 'compounds, such as for the production of pyrimidones) derivatives of the general formula I.

Particularly preferred in this connection are 1.3 " Thiazines of the general formula IX * and the salts with ojrgavnisehen or inorganic acids

IX *

wherein

A * a straight or branched chain. Alkylene group with 2 to k _{t is} preferably with "2 to 3 carbon atoms,

309 8 25/1187 '.

68 Int October λ9? 2 - k2 -

Z * denotes a hydrogen atom, a fluorine or chlorine atom, an alkyl, preferably methyl, or an alkoxy group with 1 to h carbon atoms,

W * is a vinylene residue

R ¹ 'R ² *

ι ι ■ ·.

or an o-phonylene radical,, '

P *

R ³ *
-. means,

1 * 2 * 3 *
• where R, H and R are the same or different and are a hydrogen atom, an alkyl or "alkoxy group with 1 to 6, preferably with 1 to k carbon atoms, a" phenyl group, cine carboxy, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, preferably denote unsubstituted Cnrbomoyl- or cyano group, a Kydroxygruppe, an amino, alkylamino or Dialkylaininogruppe in which the alkyl group has 1 can have up k carbon atoms, a chlorine or bromine atom, a Alkaiioylgruppe having 2 to h carbon atoms, the Henzoylgruppe or Donzylgruppo . -1:

309825/1 167

68 int October 1972

The invention relates to a feigner etn process for the preparation of compounds of the general formula IX and their salts with organic or inorganic acids, characterized in that a compound of the general formula VII - "-

C ΞΞΞ N

N = C -. Y

wherein Y and W have the meanings given for formula IX have, with a connection of the formula IV ". /

IV »

wherein A- and Z have the meanings given for formula IX have implemented and, if desired, received one free compound into its salts or a obtained salt into the free compound or into another salt, in particular into a pharmacologically acceptable salt, convicted.

The reaction of VII with IV " is carried out in a non-polar Spanish solvent, such as, for example, some carbon fiber, such as benzene, toluene or xylene, or a halogenated hydrocarbon, such as chloroform or triclorethylene, at temperatures between 0 C and 150 C ₁ preferably at the boiling point of the "solvent, before-

3 0 9 8 2!) / 1 1 6 7

68 Int October 1972 - kk -

Depending on the reaction conditions, the "new ones" are obtained Compounds in free form or in the form of their salts,

. which forms can be converted into one another in a manner known per se are. The production of salts, especially pharmaceutically acceptable, non-toxic salts, with inorganic and organic acids can in the usual way, for example by treating the free bases with the required amount of * 'acid, or with suitable Anioncnaustauschern, are carried out. As inorganic acids come into consideration, for example: Halogemx'asscr-

: chemical acids, such as hydrogen chloride or: hydrogen bromide

• acid, also sulfuric acid, phosphoric acid or amido

'sulfonic acid. Examples of organic acids are. ^; called: vinegar, propion, milk, glycol, gl'ucon, oxal, • maleic, fumaric, amber, wine, lemon, acetate, benzoic, salicylic, pamoa -, methanesulphone, ß-hydroxy-ethanesulphone

• Polygalacturoji, polyvinylcarbonic or ethylenediaminetetraacetic acid. The salts of the compounds according to the invention

. can be easily or sparingly soluble in water, the sparingly soluble salts being especially useful for the production ■ used by sustained-release molds of the compounds according to the invention can be.

The invention also relates to those embodiments the procedure ι both of which one on any one Stage of the process available as an intermediate Connection goes out and the additional process stepc '· ■ carries out the procedure, or carries out the process at any stage

• breaks, or a compound used as a starting material under the Henktionsbodigungsch. forms or in the form of a functional derivative or salt used..

■ ·

309825/1167 .. · .- ■

68 Int October 1972 '* 2 5 0 5 ß 1

As starting materials for the process of the present Invention are preferably used those that lead to the connections described above as particularly valuable

Medicines can be produced which contain one or more of the compounds according to the invention in Form of the free bases or a pharmacologically acceptable acid addition salt as an active ingredient, given - if also in a mixture with other pharmacologically "effective" Substances included. These medicines can like

usually be prepared by combining the active ingredient with a pharmaceutical carrier such as a filler ^; ttel, a diluent, a cori-igenS and / or other common ingredients for pharmaceuticals. The .Mittel can be produced, for example, in the solid state as tablets or capsules or in liquid form as solutions or suspensions. The pharmaceutical carrier can also contain the usual diluents or tableting additives, such as cellulose powder, corn starch, lactose and talc, as are customary for such purposes.

The pharmaceutical preparations are produced in a manner known per se, for example by means of conventional mixing, granulating or coating processes. The pharmaceutical preparations contain about 0.1 % to about 75 %, preferably about 1 % to about 50%, of the active ingredient. Administration can take place enterally, for example orally, or parenterally, with the individual doses between! 1 and 100 mg, preferably 10 to 50 mg, of active ingredient. The specified doses can be 1 to k

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times a day, for example with meals and / or in the evening. The single dose that The frequency of administration and the duration of the treatment depend on the nature and the Severity of the disease.

The invention therefore also relates to medicaments, in particular for the treatment of hypertension, which are caused by the content of one or more of the compounds according to the invention in free form or in the form
pharmacologically acceptable salts are marked, as well as their production ..

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68 Int- October 1972

Example of an approach for the production of 75 tablets each with 20 mg of active ingredient

Components:.

1,500 kg 2- / 3- (l ~ / ^ - MGthoxy-.phenyl7-pipcrazinyl- ^z l:) · -

propylam ± no / -6,7-dimethoxy-4 _; £ 3H / - chinazolon 6,000 kg shark starch 4.875 kg lactose. . . . · '-0.225 leg amorphous silica · “. 0.300 kg sodium lauryl sulphate '0.375 kg polyvinylpyrrolidone. 1.200 kg of pectin. , Rs 0.375 talc
0.150 kg magnesium stearate

15,000 kg. /

The ■ active ingredient, the iiais starch, the milk sugar, the amorphous silica and sodium auryl sulfate are mixed and sifted. This mixture is made with a solution of Polyvinylpyirrolido'ns moistened in 2, ^ - 1 alcohol and through a sieve with a mesh size of. 1.25 mm granulated. The granulate is dried at ^ O C and with mixed with pectin, talc and magnesium stearate. These Misaimng is turned into tablets of 200 mg on a rotary machine ffi mm diameter pressed.

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Example of an approach for the production of 200 capsules a 20 mg active ingredient

Components:

4.000 kg 2- / J- (l- / 2-methoxy-phenyl7-piperazinyl-4) -

propylnmiiio7-6,7-dime thoxy-4 / _3H7-quinazolone 15 1990 kg of microcrystalline cellulose 0.010 kg of amorphous silica,. ,

20,000 kg '

The active ingredient in finely powdered form, the microcrystalline Cellulose and the uncompressed amorphous silica Averden are good mixed and filled into hard golatine capsules size Λ.

The following examples explain the invention in more detail, without restricting them.

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Game 1

2- / 3- (? R / ,. 2- ^ fc ^ fa-oxy · "P'henyl / '-» ■ pi-peraz.in-yl .-- 4) -propylamino / -3- · phenyl-6, .7-φ n-thoxy- * 4 / 3H / ~ quinazolone

5 g (0.0158 MoX) 2- ^ chinazolone and 111.8 g (0.047 mol). 1- (3-aminopropyl) -4-t2-methoxy-phe: nyl) -piper Azin are together with ÖO ml of ethanol for 8 hours in a shaking autoclave at 130 G heated. After cooling: the clear solution in vacuo concentrated,: de * · residue taken up with chloroforni and with 3N hydrochloric acid extracted exhaustively. The hydrochloric acid solution ... ' is adjusted to pH 8 with aqueous * i.gGr ammonia solution, λ · γο-bei the prodxj & t crystalline, accumulates and is sucked off «, after" ·

. Drying in vacuo and crystallization from "Acetic acid ethyl ester obtained" on 6.0 g of 2 ^ 3 - (! - / S-Mcthoxy-phenyiy-piporazin.yl-4) -propylzcraiiio7-3-phenyl-6,7- dimethoxy- ^/ i / ^ 3H, / irquinazolon Tfom Schmelzpuiikt 163-164 ° C. (Yield 72 % of theory) In an analogous manner by using the corresponding starting products 2 - / _ N-ethyl-2 - (! - / ^ -Methoxy-phenylZ-piperazinyl%) -äthylamino7 ~ 3-butyl-61 7-dimethoxy- ⁱ i / ^ 3H / -quinazolon obtained _.; Melting point of the hydrochloride: 221-222 C (from acetic acid

"Äih, yl ester / chloroform), yield: 15 % of theory.

Baxspiel 2

J don

3.12 g (0.02 mol) of 2-methylmercapto-6-methyl- ^/ i / 3 '] i7-pyrii: iidone and 6.24 g (0.025 mol) of 1- (3-aminopropyl) -4- (2 -methoxy-phenyl) pipöraziiii are intimately premixed with one another and heated to 180 ° C. for 30 minutes. heated. The clear melt Λίΐτύ decomposed after cooling to 80 C with ethanol, boiled again briefly and the product filtered off with suction after cooling. One receives after drying

68 int October 1972

- 50 -

in a vacuum 'i, 7 g 2 - / ^ - (l - / ^ 2-methoxy-pheny27-pipera _Z i _n yi_ / i) _ propyl-amine £ / -6-methyl- ^/ i ^ 3ü / -py ^r i'i'idan with a melting point of 198 ° C (yield 66 % of theory)

In an analogous way, inserting the corresponding Output products receive the following connections:

* '■ ■

2- / 3- (1- / 2-Methoxyphenyl / -piperazinyl-'i) -propylamino / -5-chloro-6-methyl -% / _i 3ri / ~ pyi "iniidone, melting point 155 ° C (from ethyl acetate / Petroleum ether. = 2/3) »yield 58.5 %

2- / ~ 3- (1- / ^ 2-Metlioxy-phenyl7-piperazinyl-'l) -propylamiiioy-oamino -% / ^ 3jl / -pyriniidon, melting point 170 ^ (from ethyl acetate / petroleum ether = 2/3), yield 83 % of the total

2- ^ / 3- (1- _J / 2-methoxy-phcnyJ ₁ / -piperazinyl- ^/ l) -propylamino _ / -5-carbethoxy- ^/ i / 3H / -pyriniidone, melting point 168 C (from acetone / ffetrolether = 1 / 4), yield 81 % of theory

¹ Si "/ Ji- (1- ^ 2-methoxy-phenyj _: / -piperazinyl- ^/ i) -propylamino / -6-benzyl-4 / 3il7-pyrimidone, melting point 132 C (from acetone), yield 82.5 % d.Th.

2- / 3 "- (! - / ^ - Methoxy-phenyiy-pipcraziriyl-'i) -propylαιηϊιΐ £ 7-6-ractliyl-5-butyl- ^/ i _j / 32l / -pyrimidone, melting point ΐΛθ C (from acetone) , Yield 86 % of theory

-4) -propylaiaiiio _ / - 6 pifopyl- (l ^ 3JX / -py ^r iniidon, Schmelzpunlct 132 C (from acetone / methanol = l / l), yield 85% of theory

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2- / ß- (l -, / 2-methoxyphenyl / -pip.crazinyl-T4) -propylamine / ~ 5-cyano ~ ü / 3H "7-pyrimidone, melting point l67 C (from chloroform / methanol = 2 / 3), yield 78 % of theory

2- / 2- (1- / 7 "3-chlorophenyl7-piperazinyl- ^z Jt) - ethyl amino / -3-allyl-5-ethoxycarbonyl-Vln7-py ** iniid ^o n, the salt with maleic acid; melt .t at 151 ° C (from ethanol), yield 91 % of theory ". 2- / ¥ - (l- / 2-chloro-phenyl7-iDiperazinyl- (l) -.butylamino / -3-phenethyl-5-ethoxycarbonyl- ^/ iy3H / -pyrimidone, oil, yield: 72.5 % of theory .: / -.

2-j / J- (1- / 2-XtHOXy-phenylT-piperazinyl- ^) -prop _x ylämino / - 3-ethyl- ^ - benzoyl-'l / Jji ^ -py ^ iniidon, melting point of the Ilydroohlorids: 179- 180 ° C., yield: 85 % of theory

Example 3 . · "

2 - / * 2- (1- / a-methoxyphenyiy-piperazinyl-4) ethyl mercapto / - ^ / * 3H / -quinazolone

3i56 g (0.02 mol) of 2-mercapto-V3n7-quinazolone are dissolved in 20 ml of anhydrous dimethylformamide and replaced with 1.2 g (0.02 mol) of a 50 suspension of Joigen Natr-iumhydrid in mineral oil \ ^r. After the evolution of hydrogen has ceased, a solution of 5.1 g (0.02 mol) of 1- (2-Chloi'äthyi) - ^/ Jt- (2-methoxyphenyl} -piperazine in 20 ml of diinothylformamide is added dropwise with stirring, and the mixture is then added dropwise The reaction mixture is diluted with 500 ml of water and extracted with chloroform, the extract is dried over flashed potassium carbonate and evaporated in vacuo. The residue is obtained from a mixture of cyclohexane / ethyl acetate 1: 1 crystallized,! -Fan obtained 3.9 g of 2- / 2- (1 - / ^ - methoxy-phenyjLZ-pi per * azinyl -% -) - ethylraorcap tj2 / - 'j / 3ll / -chinaz; olone with a melting point of 155 C. (yield 69.2 % of theory)

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In an analogous way, inserting the appropriate Starting products contain the following compounds:

6,7-dimethoxy-'i / 5n7-quinazolone, melting point 172-173 ° C (from methanol), yield: 36 % of theory

2- _< / J- (l-ni-tolyl-piperazinyl-d) -piOpylmercaptoT ^ -isopropyl-6 _f 7-dim6thoxy- ^/ i / 3H / -quinazjolon _f , melting point of the maleate:

168 C (from ethyl acetate / chloroform). Yield:

50 _t l % of the total

2- ^ 2- (1- ^ 2-methoxy-phenyJL / -piperazinyl- ⁱ 0 -äthylmcrcapto / -öfV-dimethoxy-'i / ^ T-quinazolone, melting point 196-197 ° C (from methanol), yield: k9 , k% of theory

2 »[3- (1- [2-methoxyphenyl] -piperazinyl-4) -propylmercapto] -6,7-dimethoxy-4 [3H] -quinazolone, Melting point 179-180 ° C

(from methanol), yield: 25.6 % of theory Th.. ■

2- I 3- (1- [3-methyl-phenyl] -piperazinyl- k) -propylmercapto] -6,7-dimethoxy- * i [3H] -quinazolone, melting point 230 * 231 ° C. (from methanol), yield : 29.4 % d. Th.

2-I3- (1- [2-methoxyphenyl] -piperazinyl- k) -propylmercapto] -3-butyl-6,7-dimethoxy- ⁱ i [3H] -quinazolone, oil, melting point of the oxalate 151 ° C ( from ethyl acetate / methanol = 95: 5) t yield: 27.1 % of theory . Th.

2- [3- (1- (2-Methoxyphenyl] -piperazinyl-d) -propylmercapto] -3-phenethyl-6,7-dimethoxy-4 [3H] -quinazolone, oil, melting point of the maleate ΙΊ9-15O ⁰ C (from ethyl acetate / chloroform = 95 * · 5) i Yield: ^ 2.2 % of theory

2 - [^ - (1- [2-methoxy-phenyl] -piperazinyl k) -propylmercapto] ^{-3-cyclehexyl-5-acetyl-i} i [3H] -pyrimidone, oil, melting point of the oxalate 181 - L82 ° C (from methanol), yield: 66.1 % of theory Th.

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■■ .. '- 53 -

2- [3- (1-C2-methaxy-phenyl] -piperazinyl-Λ) -propylmercapto] ■ 5-butyl-6-methyl-4 [3H] -pyrimidone, melting point 121 ° C. (from ethanol), yield; 70.5 % of theory, .... 2- [3- (1-C 2-methoxyphenyl] -piperazinyl-4) -propy! Mercapto] «3-butyl ~ 5"t> enzoyl- ^ [3H] -pyriniidone, oil, yield: 60.9 %

d. Th.

d. Th.

2- [3- (1- L 3-methyl-phenyl] -piperazinyl- 't) -pr opylmer cap t o] 3-benzyl-5-ethoxycarbonyl- ^ [3H] -pyrimidone, Oil, yield:

46.1 % d. Th.

2-E3-C1- [2-methoxyphenyl] -piperazinyl-4) -propylmercapto] 3-ethyl-6-methoxycarbonylmethyl-4 [3H] -pyrimidone, oil, yield: 53.4 % of theory . Th.

Example 4 ■. ,. '

2- / 2- (l ~ phenyl-piT> er% ynyl-4) ~ ethylainin oil 7-6, 7-dintethoxy-4

a) 12.9 g (0.0505 mol) of 2-isothiocyanato-4,5-dimethoxy-benzo-. nitrile and 12.0 g (0.0585 mol) l- (2-amino-ethyl) -4-phenyl-

: piperazine are dissolved in 100 ml of anhydrous benzene 30 Boiled under reflux for minutes. The reaction mixture

I is cooled to 20 ° C, the crystalline product is suctioned off, dried and with the Thiele-Pape attachment Methanol hot extracted. 21.3 g of 2- ^ 2- (l-phenyl-pipcrazinyl-4) are obtained ethylamino7-4-intino-6,7-disnethoxy-

_v 3,4-dihydro-benzo / 3ri7thiazine with a melting point of 185-16 ° C. (Yield 85- »5 % of theory)

0 9 8 2 5/1167

b) 5 £ des Z- / 2 ~ ( l-Phonyl-piperazinyl-4) -ethylamino7- ⁱ i - imino ~ 6,7-dimethoxy-3, ^ - dihydro-bcnzcj / 3 · i / thiazine are in. 50 ml of Ethylenglykolmonoäthyläthcr dissolved, treated with 10 ml of a 30 J ^ igon methanolic benzyltrimethylammonium hydroxide solution and 10 Hin. heated on the boiling water bath. The cooled solution is diluted with 100 ml of water, charged with activated charcoal, filtered and adjusted to pH 6.5 with acetic acid. The aqueous solution is extracted exhaustively with methylene chloride, the methylene chloride phase is dried over calcined sodium sulfate and concentrated in vacuo. The residue is extracted hot with acetone from a Thiele-Pape attachment. 3.5 g of 2- / 2- (l-phenyl-piperazinyl-4) -ethylamino7-6,7-dimethoxy-4/3-n / -quinazolinethione with a melting point of 213-21 ° C. are obtained (yield 70 . % of theory). '-

^c ) 5 μ of the denzo / 3. thiazine described under a) are dissolved in 50 ml of Ilexaiaethylphosphorsäurtrriamid, treated with 1.6 g of potassium hydroxyl in 10 ml of ethanol and heated to 100 ° C for 10 minutes. The solution is diluted with 100 ml of water and worked up as described under b)

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68 * Int October 1972 - 55 - ~

4.15 g of 2 .- / 2.- (1-phenyl-piperazinyl ~ 4) -ethylamino-S, 7-dimethoxy- ^ t _j / 3Ii / - ^c hinazolintliipii of melting point 212-214 ° C. (Atis loot 83? £ · d.Th.)

In an analogous manner, by inserting the corresponding starting products 2- / ß- (l - ^ / izinyl-4) -äthylamino / -6, 7-diineth ^ i with a melting point of 21 ° C (from methanol) with a yield. of 2 ^, 8 % of theory obtain.

Example 5 “ _v . . ·. *

2- / 5- (lr.i-tolyl-piperazinyl-4) -propylamino / '- G, 7-dimetho> ry-% / 3H / - clinazolinethione . '*

11.0 g (0.05 mol) of 2-isothiocyanato-4,5-dimethoxy-benz6-nitrile and 11.7 S (0.05 mol) of 1- (3-amino-propyl) - (tm-tolyl-piperazine are combined boiled under reflux in 150 ml of acetone for 20 min. After cooling the reaction mixture to -10 ° C., the crystalline precipitate is filtered off with suction and crystallized twice from ethanol. {l) -pro'-pyl "amino / -6, 7-dimethoxy- (i: / 3II / quinazolinethione from melting point 206-207 ^O C (excerpts 92 % of theory).

Outside analogous way aiorden by inserting the appropriate one Output products contain the following compounds:

2- / 5 ^ - ('S-V2-methoxyphenyl / -piperazinyl- ^/ l) -butylamiiioy-ö, 7- dimclÜia ^ y-'j / ^ jiZ-cliinazolinthion, melting point: 207-208 ° C (from H.etJhanol). , Yield: 90 ^χ ; ό d.Th ..

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⁶⁰ int October 1972

2- / ί- (! - / ^ - chlorophony-lZ-piper azxnyl-'l) -butylamino / -6, 7-dimothoxy - ^ / 3n7 ~ quinazoliithione, melting point: 217-2l8 ° C (from methanol) , Yield: 86 % of theory

2-V3- (l- _i / 2-ethoxy-pheny2- / ~ piperazinyl- (l) -propylamine / -6,7- »dimethoxy- ^/ l ^ 3j2 / ~ ^cnanazoxl " thioji, melting point: 203 ° C (from methanol ), Yield: 6 % d »th.

2- / 3- (1- / 2-ethoxy-phenyi / -pipera / iinyl-'l) -propylamino / -7 ~! ^nc "thyl · k / ßU / ~ ch ± nazol ± ni.l \ i on ',' melting point: lßB C (from chloroform), ... Yield:" 87 % '/ 1st th.

2- / 3- (l- / 2 ~ -ethoxy-pheny _i l] 7 '~ piperazinyl- (i) -propylamiiioy-6, 7-diethoxy-'i _J / 3] 2 / - ^c ' »i Nazol: i ntlij.on, melting point: 202 ° C. (from methanol), yield: 85 ¹ A of theory

2- / 3- (l - / _ 2-Mcthoxy-phejiyjlT'-piperaKinyl-'i) -

mm— Jim .. Γ)

Methoxy-7 ~ butoxy ~ 'l / 3H / -cliinazolinth: i.on, SchnelzpunJct: 189 C. (from acetone), yield: Ί3 ^ d.Th.

2- / 5- (l- / _p 2-methoxy-pheny _i l _- /-pipei*a7.inyl-'i) -propylamiiio./-7-chl'or- ^/ j / 3n7-chiniizolinth: i.on ₁ Scluaolr'.punlct: 198.5-199.5 ° C (from Ksisigsiüiriiäthylcster), yield: 66 / ί of theory

2 .- / 73 · -'Ί - / 2-I ¹ Ii; thoxy-phenyl / -piperazinyl-'l) -pj * opyla: n.injo / -6, 7-inctlly i] cii (Hoxy- ^/ i /3H/-chinai'-,olJnth.i on, Sclimelz point: 220 C (nui: i / Mhnnol / Chloroform - 3/1), Au;.; Bc; ute: 87.0 / ό d.Th. .

"i 0 9 8 2 r> / 1 1 6 7

68 int October 1972
- 57 - '

2 - ^ / 2- (l ~ / 2-ethoxy-pheriyl / ~ pipcrazinyl ~ 4) -a thylniiiiiio / -6, 7 dimethox3 ^r -'i / 3ir7-quinazoliiitl] tion, melting point: 189-190 C (from Acetone), yield: 78 »7 % of theory

2 - _ / 3- (l ~ ^ 2-Methoxy-phciayJ ^ / - piperaziiiyl - 4) -propylamine o / '- 6, 7- dime thoxy- ^ / Jj]} 7- quinazolin fchi011, Sclimelzpvüilct: 209- 2iO ° e (from methanol), yield: k 9 Ji of theory. ■ '

-'i) -propyliunino _ / - 6, 7-

^ jioii, melting point: '22 ^ C (from methanol), yield: 85 % of theory: '

2-V3- (l -_ / 2-methyl-pheny _# l7'-piporazinyl-4) -propylaniiioy-G, J- dimctlioxy - ^ / ^ HZ-chinazolinthioii, Sch
(from methanol), yield: 93 % of theory

, Melting point: 219-220 ° C

2 .- / 3-. (l- / 2 ^ -l-Iethbxy-x) hcnyl'7-piporaziny.l-4) -propylaminoy ~ 6, 7-, '- _o

dimoth3 '"l-4 / _i 32I / -quinazolinthione, melting point: 139 C (from methanol), yield: 87 % of theory

2r / 5- (I-V2-MG thoxy-phony ^ / Z-pip or azinyl- k) -propyl nmirto / - 6 clilor-VljlZ-quinazolinthione, melting point: 209-210 ° C
(from methanol), yield: 89 % of theory .

2 - ^ / 3- (l- / 2-methoxy-pheny_l ^ / - p.iperazinyl-4) -propylamino _ / - 6 bromo-7-methyl-V3H / -quinazolinethione, melting point: 212 C (from ethanol / chloroform = 3/1), yield: 92 % of theory .

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6Ö Itit October 1972 - 5 «-

2-j / 3- (1-Phciiy Lp Lperaz Lny LOf> ro [) yl.aiainc) / - 6, 7, 8-trimethoxy - '* / 3il /, - chinnzo I. LnLh Lon, melting point: 177 ° C (on methanol), yield: 75 % of theory

At game 6

2 - / 3- ( 1 - / 2-M o tho'.ry-phen y 17-pi tie raz iuy I. -h) - ρ ro η y 1 n; ni »p / -, 7- ^ in i e thoxy- ^/ t / 3H / -chJ.nazoloii

a) ^f i, 03 s (0.02 mol) 2-isocyanato- ^/ l, 5-dliiicthoxy-benzonitrile and Ί, 9δ g "(0.02 mol) i- O-amino-propyl ) -k- C2- nKithoxy-phenyl) -piperazine are cooked in 6θ ml anhydrous acetone for 20 minutes under reflux, the hot solution is abgsaugt- through kieselguhr and evaporated iin vacuo and the residue is treated with a mixture of chloroform / Mothtinol ^r).:. l to neutral Kiescigcl (0 , from 05 to 0.2). chromatographxort from the concentrated eluate was 8.1 g of residue which was further crystallized from Isopropimol 'ird *% is obtained. MtUi receives S ₁ IE 1- (2-Cyniio-'i, 5-dimcthoxy- phenyl) -3- ( "} - / _} ■ - (2-never thoxy-phonyl) -p Lperaainyl-Jl7-propyl) -urea from the melting point 151-15 ° C. The substance solidifies at 1 ^ 0-162 C and melts again at 230 ° C.

b) Ί.53 S (0.01 mol) of the urea obtained according to a) are mixed with 5.6 g (0.01 mol) of caustic potash iu 10 ml of ethanol and 1 ml of 10% Wanscrs tof fi) croxide-I, ösung . Stirred for 10 minutes at 10 ° C., a yellowish precipitate forming. The solution is poured onto 200 ml of ice water and mixed with 6 ml of glacial acetic acid to pII - 7-7i5.

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68 int October 1972

The aqueous solution is extracted exhaustively with chloroform, the extract is dried over sodium sulfate and evaporated in vacuo. The residue is crystallized from isopropanol. 31 '* S 2- / 3- (l ~ / 2-metho: xy-phenyjl _ / - piperazinyl- h ) -propylamino / -6,7- , diinethoxy-'l / 3n / ~ ^cn - ^ nazolone from Melting point 23 ° C. (yield 75.1 % of theory). · "·

In an analogous manner inserting vrerden dui'ch the corresponding Ausgangsprodulcte the following A ^r onnectivity condition:

2 .- / Ji- (lv / ^ - Fltior-phenyJ ^ -piporazinyl-'l) -äthylamino / - • 6,7-dimethoxy- ^/ l / 3U7-c ^> 'hinnzolon ₁ Melting point: 2'19-250 ⁰ C from Es.sxE.sätu ' ^v e < ^: ith3 ^r lestcr / dichloromethane = k / l) , yield 44.5 % of theory. ' +

2- / _ 3- (l ~ / n-chloro-phcnyJL / -piperazinyl-Ji) -propylainiiio _ / - 6,7-dimethoxy-V * 3li7-quinazolone, melting point: 227-228 ° C (from ethyl acetate / dichloromethane = 9/1) Yield: 45.9 % of theory

2- / 2- (l - / - 2- / ithoxy-] jhenyjL _ / - p3 pcrazinyl-'l) - ethyl araiiio / -6,7-dimet]] o>: y - / j / 3n7-quinazolone, Melting point: 202-203 ° C (from E ;; r - ;. i gäurä thylester / Dj clilormeihan. = 95/5) ι Yield: 72.9 Yo d.Th.

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68 int October 1972. . - 60 -

2- / ß- (l - / ^ 2-methyl-phenyiy-piperazinyl- ^) -propylamiii / -6,7-dimethoxy ~ 'i / 3J17-quinazolone, melting point: 228 C (from acetone), yield: 52 ? o d.Th ..

Example 7

2- / 5- (l-ni-Tolyl-piperazinyl-fr) -propylaminoy-G, 7 . 7 dimcthoxy ~ ^/ f / 3H / -chinazo.'lon

a) 2.0 g -propylamine (0,00ViMoI) of 2- / 3- (lm-tolyl-piperazinyl-4) / -6, 7-dimethoxy-4 _J / 3JJ [/ - cliinazolinthion A / ground in hO ml dimethylformamide , which contains 2.2 ml of 2N hydrochloric acid, dissolved and treated with 1 g of mercury (II) oxide. After stirring for one hour at 30 ° C., the light gray suspension is diluted with 200 ml of water and adjusted to pI = 7 with saturated sodium azotate solution. The aqueous suspension is extracted exhaustively with chloroform and, after drying over sodium sulfate, the extract is concentrated in vacuo. The residue is crystallized from ethanol / ethyl acetate 1: 1. One receives li 5 E 2- / 5r (1 -m-ToIyI -piporazinyl-Ό-propylamino / - '1 / .3JV-quinazolone with a melting point of 18'1 ⁰ C (yield 78-1% of theory)

b) 5 g (0.0011 mol) of the starting compound used under a) are in 8θ ml 80-i3roz. Acetic acid with 0.5 g (0., 01) 22 mol) silver-I-oxide stirred for 30 minutes at 50 ° C. The Rvcaktion.slösung is sucked through kieselguhr, with 2K sodium hydroxide solution adjusted to pI-7 and as under a)

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6g Int October 1972

described worked up. 0.5 S 2. "/ J} - (lm- .Tolyl-piperazinyl-4i-propyiami no] / - ^ 1 7 ~ dimethoxy-4 / ^ 11 / -quinazolone with a melting point of 1 & 3-1 / 4 ° C, (Atis yield 62.5 % of theory) ".

Example B.

(.? L ^^ * / 2 ^ ίe fehoxy-phenyl; l · ^7]; -Pip ■ βr;! ■ a ginyl · -4) ^ - b ^ ty ■ tamino7'-6, 7-dimethoxy- 4 / 3H / - chi nazolon '. .

It r 3 S (.0 * 0235 Hol) 2 ~ / ^ - (l - / ^ - Methoxyphenyl7-piperazinyl - 4) -butylaminjo / -6 _t 7- ' ^c Ii) 5isthoxy-4y32i / -chiiiiazoline. thiöii are sxisj> ended in 13 ml Ätliylenglykolmonomethyläther and mixed with 36 ml -IO Solger aqueous potassium hydroxide solution, whereby a clear solution is formed. 13 ml of 30% hydrogen peroxide solution are then slowly added with stirring, the temperature not being allowed to exceed fiO.degree. The mixture is stirred for a further 10 minutes

; o "· ■■" ·

FiO C, the solution almost decolorized, diluted with 200 ml of ice water and adjusts the solution to pH = 7 by adding glacial acetic acid. It is extracted exhaustively with methyl chloride, the extract is dried over potassium carbonate and concentrated in vacuo. The residue is crystallized from ethanol / ethyl acetate 1: 1. One obtains O ₁ O g 2 - /? - (1- / 2-Methoxyrph <myl / ~ pip er azinyl - 4) -butyl amino / - 6, 7 - diine thoxy-Z ^ i] T'r- quinazolone Schmelzpunlct from 185 ⁰ C (yield 73% of theory).

In an analogous manner, the following compounds are obtained by inserting the corresponding output products:

309825/1167

68 int October 1972 __- 62 -

2- / Jk- (l - / ^ - chlorophonyl7 '- piperazinyl-4) -butylaraino7-, 6,7-dimethoxy- (t _J / 3jJ / -quinazolone, melting point 208 C (from ethyl acetate / ethanol = 1 : 1), yield: 61 % of theory.

2_ / 3- (l- _J / 5-Äthoxy-pheny ^ / - piperazinyl-d:) - propylaniino7-6, 7 ditnethoxy-4 / ^ n7-chinazoloii _T Melting point: 195-196 C (from acetic acid ethyl ester), Yield: 76 % of theory

2- ^ 3- (l- ^ 2 ~ ethoxy-phenyjL / -piperazin.yl-4) -propylaraino / -? - roethyl- ^} i £ ^ 7 ~ ^: quinazolone, melting point of the monohydrate: 175 ° C (from Ethanol), yield: 30 % of theory

- (! - / ^ - Ethoxy-phcnylV-piperazinyl-fl) -propylamirio _ / - 6, 7 diätllOxy- ^/ i / ^ 3j ^ Z-cϊlinazolon, melting point: 183 C (from ethyl acetate), yield: 64t 5 »d .Th

"ίl - /, 2-methoxyphenyl7-piperazinyl-4) -propylamino7-6

.,in ". , Q

ittethoxy-7- * butyloxy- ^/ i / 3] l / ~ quinazolone, melting point: 15C (from ethyl acetate), yield: 69 % of theory

2- / J} - (l - ^^ - Mcthoxy-phcnyJLy-piperazinyl-'i) -propylamine ^ -7

, Melting point: 211-212 ° C (from ethanol),. ^ Yield: 86.6 ^C A of theory.

2- / fj- (l - / 2 ^ -Methoxy-phG] iyjL7-piperazinyl-'i) -propylaminoT ^ -6, 7-mst] ir _> ';lcndioxy-'l ^ 3ll / -quinazolone, melting point: 2 (ΐ7 »5 C (from ÄfiiCTiol / chloroform = 5/1). Yield: 69.2% of theory.

309825/1167

2258581

68 int October 1972 J- 63 -.

2- / 2- (1-phenyl-piperazinyl-4) -ethylamino / -6,7-dimethoxy-4 / ^ C ^ -quinazolone, melting point: 239 C (from ethyl acetic acid ester / ethanol "= l / l), yield: 52? 6d.Th ..

2-Y3 (l _J / 2-methoxy-phenyl7 ^r piperazinyl-4) -propylamine) / -; 6,7-dimethyl- ^/ V3 ^ I / -quinazolon, melting point: 187 C (from ethyl acetate = 1: 1), yield: 36 % of theory. . · *

2 - / ^ 3- (l- / _> 2->fetho'xy-plieny] L / -piperazinyl-4) -propylaniino7-6 chloro-dy3H / -quinazolone, melting point: 217 C (from ethyl acetate / acetonitrile 1: 1 ),. ^ Yield: 92 % of theory

2- / 3- (l - ^ - Methox ^ '- phenyl ^ Z-piperazinyl- ^) -propy3.amino / -6 ~ broni-7-methyl-4 / 3H ./- quinazolone, melting point: 225 C (from Acetonitrile / methanol = 6/4), yield: 87 % of theory

2- / 3- (1-Phenyl-pipcrazinyl-4) -propylamiiioy-6,7,8-trimethoxy-4 / ^ 3H, / ~ quinazolone, melting point: 193 C (from acetonitrile / methanol = 1/2), yield : 80 % of theory

30982 5/1167

Claims (1)

Claims in which. R is a hydrogen iitoin, a straight chain © odei ^. branched Alkyl or alkenyl groups each with 1 to 6 carbon atoms, a cycloalkyl or cycloalkenyl group each having 5 to 6 carbon atoms, a phenyl radical or a phenylalkyl group in which the alkyl radical straight-chain or branched and can have 1 to 6 carbon atoms, means A has a straight-chain or branched alkylene group 1 to G is carbon atoms, X is the group -N (R) -, in front of R a hydrogen atom or represents a straight or branched alkyl group having 1 to 6 carbon atoms, or a sulfur atom represents 309825/1167 68 Int October 197? - 65 - Y is an oxygen atom or a sulfur atom with which Provided that Y is an oxygen atom when X is Sulfur atom means Z represents a hydrogen atom, one or more straight-chain or branched alkyl, alkoxy or alkyl mercapto groups each with 1 to ¹ k carbon atoms, trifluoromethyl groups or fluorine, chlorine or bromine atoms, W is a vinylene residue R ¹ R ² '
IJ or one optionally by one or more identical or different radicals R or by one '. Alkyl endi oxy group with 1 to 2 carbon atoms substituted 1,2-phenylene- or 1,2- or ~ 2,3- . Represents naphthylene group, where R ¹ and R ^{2 are} identical or vex and a hydrogen atom, a straight-chain or branched alkyl, alkenyl,. Alkoxy or alkyl mercapto groups each with 1 to 6 carbon atoms, a cycloalkyl or cycloalkenyl group each with 5 to 6 carbon atoms, a phenylalkyl group in which the straight-chain or branched alkyl group can have 1 to 6 carbon atoms, an aryl group, a carboxy group or a carboxyalkyl group with up to to 7 carbon atoms or a functional derivative thereof, a hydroxy or mercapto group, 309 8 25/1187 68 int October 1972
- 66 - an amino, alkylamino or dialkylamino group, in which alkyl '" can contain up to k carbon atoms, a halogen atom, such as a fluorine or iodine, in particular a chlorine or dromotor, a nitro or nitroso group, an alkanoyl group 2 to 7 carbon atoms, an aroyl or aralkanoyl group, in which the alkanoyl radical can contain 2 to 7 carbon atoms. 2. Basically substituted pyrimidone ( h) derivatives of the general formula I * and their possible tautomeric forms and their salts with inorganic or organic acids, wherein R * is a straight-chain or branched alkyl group with up to 6 carbon atoms, a cycloalkyl group having 5 to 6 carbon atoms, or a hydrogen atom means, A * is a straight-chain or branched alkylene group with 2 to 4 carbon atoms, preferably an ethylene or Trimethylene group, means 309825/1167 X * the group -N (R) -, in which R is a straight-chain or branched alkyl group with ί to k carbon atoms and preferably a hydrogen atom or a sulfur atom,. J Y * is an oxygen atom or a sulfur atom, / with the proviso that Y * is an oxygen atom when X * is a sulfur atom, Z * is a hydrogen atom, a fluorine or chlorine atom, a Alkyl, preferably methyl, or an alkoxy group with 1 to k carbon atoms, W * denotes a vinylene radical . N ¹ * R ² * or an o-phenylene radical R ¹ * means, wherein R, R "and R are the same or different and are a hydrogen atom, an alkyl or alkoxy group having 1 to 6, preferably 1 to h carbon atoms, cine phenyl group, a carboxy, carboxy; ncthyl- _s Methoxycar-bonyl-, Xthoxycarbonyl -, or ethoxycarbonylinctliyl group, a preferably unsubstituted carbomyl group, a cyano group, a hydroxyl group, an amino, alkylamino or dialkylamino group, in which the alkyl group can have 1 to Ί carbon atoms, a chlorine or bromine atom, an alkanoyl group with 2 to k carbon atoms, the benzoyl group or represent the benzyl group. 3 0 H M? B / 1 1 6 7 2258581 68 Int October 197? - 68 - 3. Basically substituted pyrimidone ( k) - derivatives of the general formula I * according to claim 2 and their possible tautomeric forms and their salts with inorganic or organic acids, wherein R *, A *, X *, Y * and Z * are in Claim 2 have given meaning and W * is a vinylene radical " R ¹ * · R ^{2 #}
II ö __ means in which 1 * 2 * ■ R and R denote a hydrogen atom, an alkyl group with 1 to k carbon atoms, a phenyl group, a carboxy, carboxymethyl, methoxycarbonyl, ethoxycarbonyl or methoxycarbonylmethyl group, an amino, alkylamino or dialkylamino group in which the alkyl group has 1 to k carbon atoms can mean a chlorine or bromine atom, an alkanoyl group having 2 to k carbon atoms, the benzoyl group or the benzyl group. h * Basically substituted pyrimidone (4) derivatives of the general formula I * according to claim 2 and their possible tautomeric forms and their salts with inorganic or organic acids, wherein R *, A *, X *, Y * and Z * are the in Claim 2 have the meaning given and W * is an o-phenylene radical .1* 1 * 2 * 3 * means, in which R, R and R ^ are a hydrogen atom, 309825/1 167 68 Int October 1? 72 'f an alkyl or alkoxy group with 1 to k carbon atoms, a chlorine or bromine atom or two of these substituents together denote an alkylenedioxy group with 1 to 2 carbon atoms, and the o-phenylene radical in particular by one or two methyl, ethyl, methoxy or xthoxy groups , primarily in the 6- and / or 7-position, or by three methoxy groups, primarily in the 6- ,. 7- and 8-position, is substituted. 5 x 2-Ü3- (1- [2-Methoxyphenyl] -piperazinyl-4) -propylamino] -6-methyl-5-butyl-4 [3H] -pyrimidone. 6 x 2- [3- (1- [2-methoxyphenyl] -piperazinyl-%) -propylamino] -6-methyl-4 [3H] -pyrimidone. 7. 2- [3- (1- [2-Methoxyphenyl] -piperazinyl-4) -propylaraino] -6-amino-4 [jh] -pyrimidones 8. 2- [3- (i- [2-Methoxyphenyl] -piperazinyl- ^/ i) -prbpyl- - pyrimidone. 9 • 2- [3- (1- [2-Methoxyphenyl] -piperazinyl-4) -propyl nercapto] -3-cyclohexyl • 5-acetyl-4 [3H] -pyrimidone. 10. 2- [3- (1- [3-Methyl-phenyl] -piperazinyl-4) -propylmercapto] -3-benzyl-5-ethoxycarbonyl-4 [3H] -pyrimidones 11. 2- [2- (1- [2-Ethoxyphenyl] -piperazinyl-4) -ethylmercapto] -6,7-dimethoxy- ^ [3H] -quinazolone · 12. 2- [3- (1- [2-Methoxyphenyl] ~ piperazinyl-4) ~ propyl mercapto] -6,7-diroethoxy-4 [3H] -quinazolone " 309825/1167 68 Int October 1972 - 70 - 13 · 2- [3- (1- [2-Ethoxy-phenyl] -piperazinyl- ⁱ t) -propylamino] -7-nie thy l-'t [311] -china zol int hion. Ik. 2- [2- (1- [2-methoxyphenyl] -piperazinyl- ^z i) -ethylmercapto] -6,7-dimethoxy-'i [3H] -quinazolone. 15. 2 - ['i- (i- [2-Methoxyphenyl J -piperazinyl-O-butylaraino] -6,7-dimethoxy-4 [3H] -quinazolone. 16. 2- [3- (1- [2-Methoxyphenyl] -piperazinyl-'l) -propylamino] -6,7-methylenedioxy-4 [3Il] -quinazolinethione. 17-2 [2- (1- [2-Ethoxyphenyl] -piperazinyl-4) -ethy1amino] -6,7-diraethoxy- ⁱ l [3H] -quinazolinethione. 18. 2- [3- (1- [2-Methoxyphenyl] -piperazinyl- ^) -propylaraino] -6,7-dimethyl-4 [3H] -quinazolinethione. 19. 2- [3- (l- [2-methoxy-phenyl] -piperazinyl * * 0- propylaminoJ - &, 7-dimethoxy-k L3H] -chinazolinthion. 20. 2- [3- (1- [2-Methoxyphenyl] piperazinyl - '*) - propyl amino] -6-bromo-7-diethyl-'i [3H] -quinazolinethione. 1. 2- [3- (1- [2-Methoxyphenyl] -piperazinyl- **) -propylmercapto] -5-butyl-6-methyl-'i [3H] -pyrimidone. 22i 2- [3- (1- [2-Methoxyphenyl] -piperazinyl- ^) -propylmercapto] -3-ethyl-6-methoxycarboylmethylpyrimidone. 309825/1 167 23 x 2- [3 ~ (1- L 2- methoxyphenyl] - ^ piperazinyl-k ) propylamino] 5-chloro-6-methyl-4 [3H] -pyrimidone. 2k. 2- [2- (l-Phenyl-piperazinyl- ⁱ l) -äthylamino] -6,7- ! -quinazolinthion. . . 25 · 2-L2- (l-L'i-fluoro-phenylj-piperazinyl ^ O-äthylaniino] -6 ₁ 7-dimethoxy-4 [3H] -chinazolinthion. 26. Those described in Examples 1 to 8 are basic substituted pyrimidone (^) derivatives. 27 · Process for the preparation of basic substituted pyrimidone ( h) derivatives of the general formula I and their possible tautomeric forms and their salts with inorganic or organic acids. * - A r · NN wherein R is a hydrogen atom, a straight-chain or branched one Alkyl or alkenyl groups each having 1 to 6 carbon atoms, a cycloalkyl or cycloalkenyl group each with 5 to 6 carbon atoms, or a phenylalkyl group in which the alkyl ** est is straight-chain or branched and can have 1 to 6 carbon atoms, means 3 0 9 8 2 5/1167 68 int October 1972 - 72 - A is a straight-chain or branched alkylene group having 1 to 6 carbon atoms, X is the group -N (R) -, wherein R is a hydrogen atom or a straight-chain or branched alkyl group having 1 to 6 carbon atoms, or a Represents sulfur atom,
Y is an oxygen atom or a sulfur atom, with the proviso that Y * is an oxygen atom when X - means a sulfur atom,
Z is a hydrogen atom, one or more straight-chain or branched alkyl, alkoxy or alkyl mercapto groups each having 1 to k .carbon atoms, trifluoromethyl groups or fluorine, chlorine or Bromatoine represents
W is a vinylene residue R ¹ R ² or one optionally by one or more identical or different radicals R or by one Alkylenedioxy group with 1 to 2 carbon atoms substituted 1,2-phenylene or 1,2- or 2,3- 1 represents 2 naphthylene group, where R and R are the same or are different and a hydrogen atom, a straight-chain or branched alkyl, alkenyl, Alkoxy or alkyl mercapto group each with 1 to 6 carbon atoms, a cycloalkyl or cycloalkenyl group » each with 5 to 6 carbon atoms, a phenylalkyl group in which the straight-chain or preceded alkyl radical has 1 to 6 carbon atoms may have an aryl radical, a Cnrboxygruppe 309825/1 167 68 Int October 1972 - 73 - or a carboxyalkyl group of up to 7 carbon atoms or a functional derivative thereof, a hydroxyl or mercapto group, an amino, Alkylamino or dialkylamino group in which alkyl can contain up to 4 carbon atoms Halogen atom, such as a fluorine or iodine, especially a chlorine or bromine atom, a nitro or nitroso group, an alkanoyl group having 1 to 7 carbon atoms, an aroyl or aralkanoyl group, in which the alkanoyl radical May contain 1 to 7 carbon atoms, mean characterized in that one a) a compound of the general formula II • y · in which W, ..Y _: and R have the preceding meanings and L stands for a halogenator, preferably a chlorine or bromine atom, or for a sulfo group, with a compound of the general formula IV ία-an ν— ν -λΓ iv in which Λ, X and Z have the above meanings, where, if X eats a sulfur atom, the compounds of the formula IV are preferably in the form of their alkali metal or alkali metal salts ₁ or " 309825/1187 68 int October 1072 -X- b) in the case of the preparation of compounds of the allpreinoine formula T, \ iorin X a -N (R) - k group and W ₁ denotes R, A, Z, Y and R the Have the aforementioned meanings, a compound of the general formula TIT, Y III wherein W ₁ Y and R have the above meanings, V is the group -S-, -SO- or -SO -, and R is an alkyl radical having 1 to h carbon atoms, preferably a methyl or Attiylgriippe, or represents a Carboxyiiicthylengruppc, with a compound of the general formula IV, in which X is the flu -N (R) - and in which A, R and Z have the above meanings, or ** · '- c) in the case of the preparation of compounds of the general formula I ₁ in which X is a sulfur atom and W, Y, R, A and Z have the aforementioned meanings, a compound of the general formula V V S 309825/1167 68 int October 1972 Λί-orin Vi, Y and R the preceding Bedem ungen have, with a connection dsr general Formula VI E-A-N where A and Z have the aforementioned meanings and E is a reactive esterified hydroxyl « gruj> pe represents, implements or ' . in the case of the preparation of compounds of the general formula I ₁ in which Y is a sulfur atom and X is an -N (R) group, and W, R, A, Z and R are as defined above, a compound of the general formula VII W VII in which W has the above meaning and Y is a sulfur atom, with a compound of the general formula IV in which X is a -N (R *) - group and II · , Λ and Z have the above conditions
odter -. · 3093 2 5/1167 68 int October 1972
- 76 - e) in the case of the preparation of compounds of the general formula I in which X is an -N (R) group means, and W, Y, R, A, Z and R have the aforementioned meanings, a compound of general formula VIII VIII in which W, A, R and Z have the aforementioned meanings and Y is an oxygen atom or a sulfur atom, where, if Y is a sulfur atom, R is then different from a hydrogen atom, treated with alkali metal oxides,
or f) in the case of the preparation of compounds of the general formula I in which X is an —NH group and Y is a sulfur atom, and W ₁ R, A and Z have the abovementioned meanings, a compound of the general formula IX ₁ w I z ix wherein W ₁ Λ and Z have the abovementioned meanings, rearranged to give compound I, or 309825/1 167 68 Int October 1972 - 77 - g) in the case of the preparation of compounds of the general formula I ₁ in which X is an —NH group and Y is a sulfur atom, and W, R, A and. Z have the abovementioned meanings, a compound of the general formula X. ν * = JlN W X NH ₂ wherein W has the abovementioned meaning with a compound of the general formula XI, XI wherein Y stands for a sulfur atom and A and Z have the meanings given above, converts or
h) a compound of the general formula XiI P - NH ₂ XII with a compound of the general formula XIII • HO - CH ₂ CH ₂ . N-Q XIII HO - ^CH 2 ^CH 2 preferably in the form of their reactive esters, in which one of the symbols P or Q for the group Y-C = N-A 309825/1167 68 Int October 1972 - 78 - 225856t XIIa and the other symbol stands for V ____ /, and in which W, R, Λ, X and Z have the aforementioned meanings, or '
i) a compound of the general formula XIV ₁ Y. XIV XA-KH-CM ₀ -CH ₂ -NII wherein H ₁ R, A, X, Y and Z have the aforementioned meanings, with 1,2-lHhydroxyoxäthan XV HO - " ^0H XV preferably converts in the form of its reactive ester or 309825/1167 j) a compound of the general formula XVI ^ N ^^ X-A-E where E is a reactive esterified hydroxyl group, preferably a chlorine or bi atom, and W, Y, R, X and A have the aforementioned meanings, with a compound of the general formula XVII ₁ XVII wherein Z has the abovementioned meaning., converts or k) in the case of the preparation of compounds of the general formula I ₁ in which V7 is the vinylene radical -C (R) = C (R _? ) and the radicals X, Y ₁ Z, A, R, R ₁ and R _{3 have} the aforementioned meanings own a compound of the general formula XVIII XVIII 6 '7 wherein R and R are an alkyl group with 1 to ¹ k carbon atoms, preferably a Hcthyl- or ethyl 309825/1167 68 Int October 1972 - 80 - group, and 'R also oin a hydrogen atom 1 mean 2 and in which Y, R and R have the aforementioned meanings, with a compound of general formula XIX ■ '* ■ / TTy _ντγ - AT
1IN in which R, A _1, X and Z have the abovementioned meanings, and, if desired, in a compound obtained according to α) to k) converts a thioxo group into an oxo group or an oxo group into a thioxo group and / or, if desired, into of a compound obtained with a carboxy, cyano, alkoxycarbonyl or carbamoyl group, these are converted into one another within the definition by esterification, transesterification, hydrolysis, alcohol, aniinolysis or dehydration, and / or, if desired, an alkenyl or cycloalkenyl group in a compound obtained as a substituent 1 2
R, R or R converted into an alkyl or cycloalkyl group in a manner known per se by selective, preferably catalytic hydrogenation and / or, if desired, a free compound obtained into its salts or a salt obtained into the free compound or into another salt, in particular a pharmacologically acceptable salt, converted. 309825/1167 68 int October 1972 28 «The method according to claim 2? Ι characterized in that that in the variants c), h), i) and j) a reactive esterified hydroxy group represents a halogen atom, in particular a chlorine or bromine atom. 29 · The method according to claim 27 »characterized in that in variant d) the reaction is carried out in one polar organic solvent, such as a ketone or a strongly polar fatty acid amide » 30. The method according to claim 27 j, characterized in that that in .. variant e) the reaction with alkali metal hydroxide carried out in the presence of hydrogen peroxide. 3I method according to claim 27, characterized in that that in variant f) the rearrangement is carried out in the presence of basic reagents. 32. The method according to "Claim 3I1, characterized in that that the basic reagent used is potassium hydroxide or benzyltrimethylammonium hydroxide is used. 33 · The method according to claim 27t, characterized in that that one obtained free compound or a obtained salt in a pharmacologically acceptable Salt transferred. Method according to one of Claims 27 to 331 characterized in that one of one obtainable as an intermediate at any stage in the process Connection runs out and performs additional procedural steps, or the procedure on any one Level is canceled. 309825/1167 68 Int October 1972 - 82 - 225856 35 · Process according to one of Claims 27 to "} h, characterized in that a compound used as a starting material is selected from among the
Forms reaction conditions or in one
tautomeric form and / or in the form of a
reactive derivative or salt used. 36. The method according to any one of claims 27 to 351, characterized in that one is basic
substituted pyrimidone ( k ) derivatives of the general formula I * and their possible tautomeric forms and their salts with inorganic or organic acids, X * - Λ * .- ■ wherein R * is a straight-chain or branched alkyl group with up to 6 carbon atoms, a cycloalkyl group with 5 to 6 carbon atoms or a hydrogen atom, A * is a straight-chain or branched alkylene group with 2 to k carbon atoms, preferably an ethylene or tri-ethylene group, 309825/1167 68 Int October 1972 - 83 - X * is the group -N (R) -, in which R is a straight-chain "or branched alkyl group having 1 to k carbon atoms and preferably a hydrogen atom," or a sulfur atom Y * is an oxygen atom or a sulfur atom with the proviso that Y * is an oxygen atom when X * means a sulfur atom, Z * denotes a hydrogen atom, a fluorine or chlorine atom, 'an alkyl, preferably methyl, or an alkoxy group with 1 to k carbon atoms, W * a * vinylene residue ~ R ¹ ■. ir. or an o-phenylene radical
R ¹ * means, 1 * 2 * 3 *
wherein R, R and R are identical or different and a hydrogen atom, an alkyl or alkoxy group with 1 to 6, preferably with 1 to k carbon atoms, a phenyl group, a carboxy, carboxymethyl, methoxycarbonyl, ethoxycarbonyl or methoxycarbonylinethyl group, a preferably unsubstituted carbamoyl group, a cyano group, a hydroxy group, an amino, alkylamino or dialkylann no group, in which the alkyl group can have 1 to 1 IColil ojiiitof fatoine, a chlorine or 309 · ■: ■? ^r './ 1 1 6 7 68 Int October 1972 - 6k - Broniatom, an alkanoyl group with 2 to k carbon atoms, the benzjoyl group or the benzyl group, produces. 37 · The method according to any one of claims 27 to 35 »characterized in that base substituted pyrimidone (Ό derivatives of the general formula I * according to claim and their possible tautomeric forms and their salts with inorganic or organic acids, in which R *, A *, X *, Y * and Z * have the meaning given in claim 36 and W * is a vinylene radical 1 p R ¹ R ² ■ - ■ ■ ' 1 * 2 *
means in which R and R are a hydrogen atom, an alkyl group having 1 to k carbon atoms, a phenyl group, a carboxy, carboxymethyl, methoxycarbonyl,. Athoxycai'bonyl or methoxycarbonylmethyl group, an amino ·? . Alkylamino or alkylcimino groups, in which the alkyl group can have 1 to k carbon atoms, a chlorine or bromine atom, an alkanoyl group with 2 to k carbon atoms, the benzoyl group or the benzyl group. 38. The method according to any one of claims 27 to 35 »characterized in that basic substituted pyrimidone ( k ) derivatives of the general formula I * according to claim Jd and their possible tautomeric forms and their salts are mf.t inorganic or organic acids, in which R *, A *, X *, Y * and Z * have the meaning given in claim 36 and W is an o-nylon base 3 0 9 8 2 B / 1 1 6 7 68 int October 1972 1 * 2 * 3 * means in which R, R and R are a hydrogen atom, an alkyl or alkoxy group with 1 to k carbon atoms, a chlorine or bromatoin or two of these substituents together denote an alkylenedioxy group with 1 to 2 carbon atoms, and the o-phenylene radical in particular by one or two methyl, ethyl, methoxy or ethoxy groups, primarily in the 6- and / or 7-position, or substituted by three methoxy groups, primarily in the 6-, 7- and 8-position. 39 · Method according to one of Claims 27 to 351 characterized in that 2- [3- (1- [2-methoxyphenyl] -piperazinyl- ^/ i) -propylamino] -6-methyl-5-butyl-Ί [3Il] -pyrimidone, 2- [3- (1 - [2-Methoxyphenyl] -piperazinyl-'l) -propylamino] -6-methyl-4 [3H] -pyrimidone, 2- [3- (1- [2-methoxyphenyl] -piperazinyl- ¹ I) -propylamino] -6-amino-4 [3H] -pyrimidone, 2- [3- (1- [2-methoxyphenyl] -piperazinyl- ^ i) -propylamino] -6-propyl- k [3H] -pyrimidone , 2- (3- (1- [2-Methoxyphenyl] -piperazinyl- ^) -propylmercapto]. 3-cyclohexyl-5-acetyl- ^/ i [3H] -pyrimidone, 2- [3- (l- [ 3-methylfiaenyl] -piperazJ.nyl- ⁱ t) -propylniei * capto] -3- "ben7iyl-5-alkoxycarbonyl-'t [3II] -pyrimidone, 2- [.2- (1- [2-ethoxyphenyl ] - ^) -äthylmercapto] -6, 7-dimethoxy- 309825/1 68 int October 1972
- 86 - '225856] quinazolone, 2- {j- (1- [2-methoxy-phenyl] -piperazinyl-4) -propylniercüpto] -6, 7-u "imethoxy-'l [3II] -quinazolone, 2- [3- (1- L2-Λthoxy-phenyl - pipernz.inyl-'i) -propylamino] -7-methyl- ^/ l [3Il] -chinnzolinethione, 2- [2- (l- [2-methoxyphynyl J-piperazinyl-'i} - A thy liner cap to] -6, 7- «line thoxy-'i [31Ij-ClIiHaZOlOn, 2- [Ί- (1- L 2-Mo thoxy-phenyl j -piporaziiiyl ⁱ l) -butylamino] -6, 7 -flime thoxy-'l [3HJ-chinnzolon, 2- [3- (1- L 2-methoxy-phenyl] -piperazinyl- Ί) -propylain Lno-j -6,7-me tliyienclioxy-'lf 3Il] - chinazol.inthion, 2- [2- (l- [2-ethoxy-phenyl] -piperaz Lnyl-'l) -ä thyi.ainiiio] -6, 7-tliine thoxy- ^/ l [3Il] -quinazolinthioii, 2- [3- (1- [2-Methocy-phonyl] -piperaziiiyl-'l) -propy laniino] -6,7-climDthyl-'l [3II] quinazolinethione, 2-L3- (1-L 2-methoxy- phenyl] -piperazinyl-4) -propylainino] -6,7-tumethoxy- ^/ i [3H] -quinazolinethione, 2-L3- (1-L 2-methoxyphenylI-piperazinyl-'t) -propylaminoI-6-bromo -7-methyl- ^/ l [3Il] -quinazoliTithione and 2- [3- (l- [2 ~ methoxy-phenylJ-piperazinyl-'i) - propylmercapto] -5-butyl-6-methyl-'l [3H] -pyriraidon, produces, Method according to one of Claims 27 to 35 »thereby characterized in that 2- [3- (1-L2-methoxyphenyl] -piperazinyl-'i) -propylmercapto] -3-ethyl-6-methoxycarbonylraethyl-'i [3H] -pyrimidone manufactures 309825/1167 kl. Process according to one of claims 27 to 35 »characterized in that 2-L3- (1-l2-methoxyphenyl] -piperazinyl - ^) - propylaminoJ-5-chloro-6-methyl- ^z l [3H] -pyriinidon -produces. k2 * method according to one of claims 27 to 35 »2- (l-phenyl- piperazinyl- ⁱ l) -äthylamino] - 6,7-dimethoxy-4t [3H.] - quinazolinethione. 'l3 · method according to one of claims 27 to 35 » characterized in that 2- [2- (1- ['i-Fluoro-'phcnyl] -piperazinyl- * l) -ä ± .hylainino]' - 6 , 7-dimethoxy-cliiiiazolinthione produces. hh » The processes described in Examples 1 to 8 for the preparation of basic substituted. Pyriniidone ( h) derivatives. h3 * Medicines, characterized by the content of one or more of the pyriinidone - (^) - derivatives mentioned in claim 1 or of their pharmacologically acceptable salts. * i6. Medicines3., Denoted by the content of a or more of the pyrimidones mentioned in claim 2. ) - derivatives or of their pharmalcologically acceptable Salt. hj. Medicinal product, characterized by the content of one or more of the in claim 3 and ^ l goiiaimtcn i'yrimidon · ( h) -dori vat <; or from their pharinnkologd .sch ■ vert riig- 3 i r.licii f5a3 /.<■]). Int October 1972 48. Medicines, characterized by the content of one or more of the claims 5 to 25 pyrimidone (4) derivatives mentioned or of their pharmacologically acceptable salts 49. Medicaments according to one of claims 45 to 48, characterized in that they contain about 0.1% to about 75 %, in particular about 1 % to about 50 _{%% of} one or more of the compounds mentioned. Process for the production of 'medicaments, characterized in that one or more of the pyrimidone (4) derivatives mentioned in_Anspruch 1 or their pharmacologically acceptable. Salting, as Active ingredient components used 51. The method according to claim 50, characterized in that medicaments which contain about 0.1% to about 75%, in particular about 1% to about 50 Si, of one or more of the active ingredient components used are produced. 52. Arylpiperazinylalkyl urea derivatives of the general Formula VIII and their possible tautomcre forms, as well as their salts with inorganic or organic Acids 309825/1 167 68 Int. October 1972 C = N Y
NIIC ' NII-C N-A-N wherein W is an optionally by one or more identical or different radicals R or by an alkylenedioxy group having 1 to 2 carbon atoms substituted l, 2 ™ or phenylene ~ l _t represents 2- or 2,3-naphthylene group, ι · R is a hydrogen atom, a straight chain or branched alkyl, alkenyl, alkoxy or alkyl mercapto group each having 1 to 6 carbon atoms, a cycloalkyl or cycloalkenyl group each with 5 to 6 carbon atoms, a phenylalkyl group, wherein the straight-chain or branched alkyl radical can have 1 to 6 carbon atoms, an aryl radical, a carboxy group or a carboxyalkyl group with up to 7 carbon atoms or a functional one Derivative thereof, a hydroxyl or mercapto group an amino, alkylamino or dialkylamino group, wherein alkyl is up to h. May contain carbon atoms, a halogen atom, such as ei ^ra F ¹ IuOr- or iodine, in particular 309825/1 167 a chlorine or bromine atom, a nitro or nitroso group, an alkanoyl group with 2 to 7 carbon atoms, an aroyl or aralkanoyl group, in which the alkanoyl radical can contain 2 to 7 carbon atoms, A is a straight-chain or branched alkylene group with 1 to 6 carbon atoms, Y is an oxygen or sulfur atom, k " R is a straight-chain or branched alkyl group having 1 to 6 carbon atoms or, if Y is an oxygen atom, also a hydrogen atom, and Z is a hydrogen atom, one or more straight-chain or branched alkyl, alkoxy or alkyl mercapto groups each having 1 to k carbon atoms, trifluoromethyl groups or fluorine, chlorine or bromine atoms. , 53 »Process for the preparation of arylpiperazinylalkylurea derivatives of the general formula VIII W Y ^ NII-C ^ / —- λ ΛΤΤ \? VIII • N / A- ¹ k and their possible tautomcren forms as well as salts with inorganic or organic acids, wherein W is an optionally by one or more identical or different radicals II or by an alkylene 309825/1167 68 int October
- 91 - dioxy group having 1 to 2 carbon atoms substituted 1,2-phenylene or 1,2- or 2,3-Naph | hy- lengruppe means
R ^{1 is} a hydrogen atom, a straight-chain or branched alkyl, alkenyl, alkoxy or alkyl mercapto group with 1 to 6 carbon atoms each, a cycloalkyl or cycloalkenyl group with 5 to 6 carbon atoms each, a phenylalkyl group, in which the straight-chain or branched alkyl radical 1 to 6 May have carbon atoms,
an Ar y Ir es t, . a carboxy group or a carboxyalkyl group with up to 7 carbon atoms or a functional derivative thereof, a hydroxy or mereapto group, an amino, alkylamino or dialkylamino group, in which alkyl can contain up to 4 carbon atoms, a halogen atom, such as a fluorine or iodine atom, in particular a chlorine or bromine atom, a nitro or kitroso group, an alkanoyl group with 2 to 7 carbon atoms, an aroyl or aralkanoyl group, in which the alkanoyl radical contains 2 to 7 carbon atoms can, means, -A means a straight-chain or verwoigto alkylene group with 1 to 6 carbon atoms "means, -3 09825/1167 68 Int October 1972 - 92 - Y is an oxygen or sulfur atom, H
Π cine straight-chain © or branched alkyl group ¹ with • '' j up to 6 carbon atoms or, if Y is an oxygen atom is, also means a hydrogen atom, and Z is a hydrogen atom, one or more straight chain or branched alkyl, alkoxy or alkyl mercapto groups each having 1 to ^ t carbon atoms, trifluoromethyl groups, ο del · fluorine, chlorine or ßroinatome " means, characterized in that one a) a compound of the general formula VII C β = Ν ■ W '. VII N - C - Y wherein Y and V have the meanings given for formula VIII, with a prebond of formula IV. S. ^{1 Γ} Λ H-N-A-N N wherein A and Z have the meanings mentioned for formula VIII and 31 have a straight-chain or branched alkyl group with 1 to 6 carbon atoms or, when Y in formula VII is an oxygen atom, also denotes a Vnssor.stoffatom, converts, or 3 0 9325/1167 68 Int October 1972 - 93 - b} in the - Pail ο. 'of the production-of-interconnections of the - - general formula VIII, in which R is hydrogen atom and the other radicals have the aforementioned meaning, a compound of the general Formula X W X in which W has the meanings given for formula VIII, with a compound dpr formula XI ₅ Y = C = NAN N -if "V in which Y is an oxygen atom and A and Z have the meanings given for formula VIII, and, if necessary, a free compound obtained in its salts or a salt obtained in the free compound: or in an outer salt, in particular iji a pharmateologically acceptable salt, transferred. . > 68 int October 1972
- 94 - 5 ^ · Medicines, characterized by the content of a or more of the arylpipcrazinylalkyl urea derivatives mentioned in claim 52 or their pharmacologically acceptable salts. cc process for the production of pharmaceuticals, thereby- * characterized in that one or more of the in Arylpiperazinylalkyl »urea derivatives mentioned in claim 52 or their pharmacologically acceptable Salts used. 56. Basically substituted 1,3-thiazines of the general Pormol IX and their salts with inorganic or organic acids' NH IX ^r Γ * s wherein A denotes a straight-chain or branched alkylene group with 1 to 6 carbon atoms, Z denotes a hydrogen atom, one or more straight-chain or branched alkyl, alkoxy or alkyl mercapto groups each with 1 to k carbon atoms, tri- 309825/1167 68 int october i972 - 95 - fluoromethyl groups or fluorine, chlorine or broin atoms c means, * W is a vinylene residue R ¹ R ² I I · ■ ■ or one possibly dur, ch one or more 1 identical or different radicals R or by an alkylenedi oxo group with 1 to 2 carbon atoms substituted 1,2-phenylene- or-1,2- or 2,3- 1 means 2 naphthylene groups in which. R and R the same or are different and a hydrogen atom, a , straight-chain or branched alkyl, alkenyl, Alkoxy or alkyl mercapto group, each with 1 to 6 carbon atoms, a cycloalkyl or cycloalkenyl group each with 5 to 6 carbon atoms, a phenylalkyl group, wherein the straight-chain or branched alkyl radical can have 1 to 6 carbon atoms, an aryl radical, a carboxy group or a carboxyalkyl group with up to 7 carbon atoms or a functional derivative thereof,
a hydroxy or mercapto group, an amino, alkylamino or dialkylaniino group, in which alkyl can contain up to h carbon atoms, 3 0 9 fi? B / 1 1 B 1 68 Int October 1972 - 96 - an Ilalogenatom such as a fluorine or iodine, in particular a chlorine or bromine atom, a nitro or nitroso group, an alkanoyl group with 2 to 7 carbon atoms, an aroyl or aralkanoyl group in which the alkanoyl radical 2 to 7 carbon atoms can contain, represents, mean. 57 · Process for the preparation of basic substituted 1,3-thiazines of the general formula IX IX and their salts with inorganic and organic acids, vrox "in A is a straight-chain or branched alkylene group with 1 to 6 carbon atoms, Z is a hydrogen atom, one is several straight-chain or branched allyl, alkoxy or alkyl mercapto groups each with 1 to k carbon atoms, trifluoromethyl groups or fluorine, chlorine or bromine atoms, 30982 5/1167 68 int October 1972 j a vinyl rust I I c = 5 == s c or one optionally by one or more of the same or various radicals II or by an alkylenedioxo group 1,2-phenylene substituted with 1 to 2 carbon atoms or 1,2- or 2,3-naphthylon group, 12th
where R 'and R are the same or different' and a hydrogen atom j is a straight-chain or branched alkyl, alkenyl, alkoxy or alkyl mercapto group with 1 to 6 carbon atoms each, a cycloalkyl or cycloalkenyl group with 5 to 6 carbon atoms each, a phenylalkyl group ppe, in which the straight-chain or branched alkyl radical can have 1 to 6 carbon atoms, an aryl radical, ■ - * ■ a carboxy group or a carboxyalkyl group with up to to 7 carbon atoms or a functional derivative thereof, a hydroxy or mercapto group, an amino, alkylamino or dialkylamino group, in which alkyl can contain up to k carbon atoms, a halogen atom, such as a fluorine or iodine, in particular a chlorine or bromine atom,
represents a nitro or nitroso group, an alkanoyl group having 2 to 7 carbon atoms, an aroyl or aralkanoyl group in which the alkanoyl radical can contain 2 to 7 carbon atoms. 309825/1167 68 int October 1972 - 98 - dadtirch marked that you have a connection ι of the general formula VII -C S = N N = C = Y wherein Y and V / have the meanings given for formula IX, with a compound of formula IV " -A-K N-V 'Υ IV " wherein Λ and Z have the meanings given for formula 'IX, and, if desired, one obtained free connection in its salts or a received SnIz in the "free compound or in another salt, in particular into a pharmalcologically acceptable salt, convicted. . Medicines, characterized by the content of a or more of the basic substituted 1,3-thiazines mentioned in claim 56 or pharmacologically thereof compatible salts. en. Process for the manufacture of pharmaceuticals, thereby l'elconn notes that one or more of the in Basically substituted 1,3-thiazine according to claim 56 or their phariiialcologically acceptable Salts used. 309825/1167