DE2051013A1 - 1,2-Dihydropyrido square bracket to 2,3-square bracket to pyrimidin-2-one and process for their preparation - Google Patents

Description

Case 600-6251 / B

Patent attorneys

Dr. W. Schalk, Dipl.-Ing. P. Wirth Dipl.-Ing. G. Dar.nsnberg Dr, V. Schmted-Kowarzik

Dr. P. Weirsholcl, Dr. D. Gudel

6 Frankf urf / KV, Gr. Eschenheimer Str.

SANDOZ AG. Basel, Switzerland

l, 2 »-Dihydropyri do [2,3-d1pyrimidin-2-ones and processes for d e ren Her position

The invention relates to 1,2-dihydropyrido [2,3-d] pyrimidin-2-ones of formula I,

109849/1959

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wherein χ y stands for the group C = N or CH-N

- I '■' ■ ■ "■ · '■ -"

Rp Rp H

R, alkyl, with 1-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, allyl, methallyl or propargyl and R is phenyl or substituted phenyl of the formula II,

where Y is fluorine, chlorine, bromine, alkyl or alkoxy each denotes 1-4 carbon aljomes and Y "denotes hydrogen, Fluorine, chlorine, bromine, alkyl or alkoxy with 1 * 4 carbon atoms each, and B is a radical of the formula Ila,

Ha

denotes in which Z and Z are identical or different and in each case hydrogen, fluorine, chlorine, bromine or alkoxy with Mean 1-3 carbon atoms.

The inventive method is characterized in that one

a) 'for the preparation of compounds of the formula Ic,

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600-6251 / B

Ic

in which R and R _{p have the} above meaning "and Rj has the same meaning as R ,, but cannot represent tertiary alkyl bonded directly to the ring nitrogen atom with the tertiary carbon atom, compounds of the formula III,

M '

III

wherein R and R have the above meaning and M ^{1 is} alkali, with compounds of the formula IV,

IV

where RJ has the above meaning and X stands for chlorine, bromine or iodine stands, converts, or

b) for the preparation of compounds of the formula Ia,

R,

Yes

109849/1959

/ L «J vJ IUIO

- k - 6OO-625I / B

wherein R, R, and R have the above meanings, compounds of Formula V,

R-

^U * ^ N> NH R ₂

wherein R, R and Rp have the above meaning with the Carboxylic acid derivatives

1) phosgene,

2) C. ρ alkyl chlorocarbonate,

J>) C, "alkyl carbamate, or
4) Ι, Ι'-carbonyldiimidazole

cyclized, with the proviso that, for the preparation of compounds of the formula Ia in which R represents tertiary alkyl bonded directly to the ring nitrogen atom ψ via the tertiary carbon atom, the cyclization is carried out with phosgene or 1,1'-carbonyldiimidazole, and in the case of cyclization with C,,. Alkyl carbamate at temperatures of

1-5

works above 140 ° C, or

c) for the preparation of the aforementioned compounds of the formula Ic, 2-aminopyridylphenyl ketones of the formula VI,

VI

10 9 8 4 9/1 95 9

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where R, R 'and R _? have the above meaning with the connections

I) C,, _ alkyl carbamate,

2) urea or

3) isocyanic acid

cyclized, whereby for the cyclization with C. _r

Alkyl carbamate at temperatures above 140 ° C and in

The presence of catalytic amounts of Lewis acid works, or

d) for the preparation of compounds of the formula Ib,

R-,

Ib

wherein R, R ^ and Rp have the above meaning, compounds the formula Ia already mentioned reduced in an inert organic solvent.

The process a) is zweekmässigerweise in an inert organic solvent and at temperatures between ⁰ and 100 C, - preferably carried out room temperature. Suitable solvents are dimethylacetamide, diethylacetamide, dimethylforma-.Eidj methyl sulfoxide and dioxane. · The compound of formula III is preferably used

109 84 9 / 19S9

. ·. ■ ■. ■ ■ ι- / L U.tC I tf; 1

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a sodium or potassium salt, and as a compound of Formula IV is preferably an iodide used.

The variant (1) of the process b) is conveniently carried out at temperatures between 0 and 5O ⁰ C, preferably 10 and 5O ⁰ C ',. carried out. The reaction can be carried out in an inert organic solvent, conveniently an aromatic solvent such as toluene, xylene or, preferably, benzene. The molar ratio W ' of: phosgene to the compound "of the formula V is not particularly critical, but a considerable excess of phosgene is preferably used. The process is optionally carried out using an acid-binding third, for example an inorganic base , like: Näibriuiir> - or 'Kaliuracai'bojrat, or a tertiary aiäiins, like pyridine or -an amir:, _: preferably:

Variant (2) of the process b), after which a compound of formula V medium-methyl chlore ar carbonate or preferably Aethylchiorcarbonat is reacted is appropriately, -mässigerweise at temperatures between J50 and 150 ⁰ C, preferably 60 and 10jQ. ° C, carried out. You can work in the presence of an inert organic solvent. Suitable as an aromatic hydrocarbon.,; such as toluene, xylene or preferably benzene. As. Solvents: - Medium is also suitable: ¹ Dioxane. The Melvörhallennisdes Chlorca-rbOnait, for: connection ·· de.r ^v FormBl · V is. Not. Be-sorrders.- kritis-ch *, V (CfB ¹ ZUSS-WSiS ^ - aübeiüefe man; jedoich ^ with i ziemMIchiarr Uehfeaisroirassi

- 7 - 600-6251 / Β

time can be between 0.5 and 10 hours, and they is usually 1 to 4 hours. " The cyclization with chlorocarbonate can optionally be carried out in the presence of an acid binder, for example an inorganic one Base, such as sodium or potassium carbonate, or a tertiary amine, wit pyridine or a trialkylamine ^ preferably triethylamine.

Variant (3) of the method b) is conveniently carried out at temperatures between I ¹ IO and 20O ⁰ C, preferably I60 and 180 ⁰ C is performed. The molar ratio of the carbamate to the compound of formula V is not critical. Under preferred conditions, a substantial excess of carbamate is used, which at the same time serves as the preferred solvent for the reaction. Other suitable high-boiling inert organic solvents may optionally or additionally be used. Urethane in particular is used as the carbamate. The reaction time can be, for example, between 0.5 and 10 hours, and it is normally 1 to 4 hours. The cyclization with the carbamate is expediently carried out in the presence of a Lewis acid as the reaction catalyst. The Lewis acid is preferably used in amounts between about 5 and 20 % , based on the weight of the compound of the formula V in the reaction mixture. Zinc chloride is preferably used as the catalyst.

The variant (k) of process b) can, for example, at room temperature or at elevated temperature up to *

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- 8 - 6θΟ-β251 / Β

120 ⁰ G, for example 6θ to 90 ⁰ C, can be carried out. The reaction is preferably carried out in an inert organic solvent, conveniently an aromatic hydrocarbon such as benzene, toluene or xylene, or a cyclic ether such as tetrahydrofuran. The molar ratio of 1,1'-carbonyldijmidazole to the compound of the formula V is not particularly critical, but an excess of 1,1'-carbonyls is preferably used. .. diimidazole. «-, ■: ...,. ^: ,,

Process b) is preferably carried out according to variant (.1) carried out. .,:

The variant (l) of method c) is preferably arralogated for variant (* 5) of method b) carried out.

Variant (2) of process c) is a reaction known per se and can, for example, be carried out analogously to the process described in Japanese patent specification ^ 097/67. Suitably bulky enough, the reaction is carried out at temperatures between ² K I) and 220 ⁰ C, preferably 180 and 210 ° C, as well as in, the absence of a further solvent.

Variant (3) of process c) can be used, for example, at temperatures between 50 and 150 ^° C. preferably 100 and 140 ° C, and in an inert organic solvent .., .. · ,. be performed. Since isocyanic acid is known to be unstable, it is expediently produced in situ by

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the reaction in an acidic medium and using a salt of isoeyanic acid of the formula VII /

M-N = C = O VII

performs, where M is alkali, such as sodium or potassium, Alkaline earth, such as calcium, or ammonium, where sodium, Potassium and ammonium are preferred.

As an acid for the in situ production of isocyanic acid a lower carboxylic acid is expediently used, preferably acetic acid, which also acts as a solvent can serve for the reaction.

Process c) is preferably carried out according to variant (I).

The organic solvent used for process d) is usually a lower alkanol, such as methanol or, preferably, ethanol, or a cyclic ether, such as tetrahydrofuran. Optionally, additional solvents such as methylene chloride, chloroform or water can be used. The reduction can be carried out, for example, by means of borohydride, preferably an alkali borohydride such as sodium or borohydride, with lithium aluminum hydride or catalytically in the presence of Raney nickel, platinum or palladium. However, if you want to prepare compounds of the formula Ib j in which R _{1 is} an unsaturated radical, then

109849 / 19S9

Io *

an alkali borohydride should be used as a HödukfcionSffiittel - ,, which reduces the double mouth of the filing, the un-. saturated ^ f est R, j © döoh not affected in the Jteäktion ällgemeinen can, for example, at temperatures between + and -2Ö 8ö ^ö Ö vorgenoriMien. When using borohydride, the reduction is expediently carried out at temperatures between Io and So ⁰ C, preferably 20 and 40 ° C. For the reduction with lithium aluminum hydride räan zweokniM.sgigerw@iee carried out at temperatures between -20 and +80 ⁰ C, preferably I5 and 70 ° Ü * UeDliGherweise used.-Close about one equivalent of lithium aluminum hydride. The hydrogenation is katalytisohe 2 / V / eckniässigerweise carried out at temperatures between I5 and 6NC ° C / 20 and preferably 50 ⁰ C. The hydrogen drug can expediently be between 1 and 10 atmospheres, and palladium is preferably used as the catalyst.

The connections of the. Formula ί Ιίαηηβη in itself known Way to be isolated and purified.

In general, the variant (l) aeh process b) is preferred for the production of compounds of the formula Ia, in which the substituent on the Btiokatoff is a branched-chain alkyl, because of the fact that the carbon atom attached to the nitrogen atom occurs, while the Procedure &) in general aur M @ rit # lluil | d © rr © stliöh © n compounds of the formula Ia, preferably WIM «

109SA9 / 1959

- 11 - 6θΟ ~ β251 / Β

The alkali metal salts of the 1,2-dihydropyrido [2,> - <ä] pyrimidin-2-ones used as starting materials for process a) of the formula III can be prepared by adding appropriate, 1,2-dihydropyrido- [2,3 ~ d] pyrimidin-2-ones unsubstituted in position 1 of formula VIII,

R LIi VIII

where R and R "have the above meaning in for the preparation such alkali salts are treated in a known manner, for example with sodium hydride or an alkali alkoxide, such as sodium or potassium ethoxide or methoxide. The reaction is conveniently at room temperature in one inert organic solvents carried out, such as dimethylacetamide, diethylacetamide, dimethylformamide, dimethyl sulfoxide or dioxane. The same solvent is expediently also used for the subsequent preparation of the compound of the formula Ia is used.

The 1,2-dihydropyrido [2,3-d] pyrimidin-2-ones of the formula VIII can be prepared, for example, by 2-aminopyridylphenylketpne of the formula IX,

IX

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where R and R _{2 have the} above meanings, _{cyclized with C 1} alkyl carbamate at temperatures above 140.degree. The method may analogously to variant (l) of the process c) are performed, wherein one but suitably bulky enough, at temperatures up to about 22O ⁰ C.

The compounds of the formula IX are either known or can be prepared by processes described in the literature. (j.Med.Chem. 5, 722/1965).

> '~' ■■■■ ■■

The 2-aminopyridylphenylketoniinines of the formula V used as starting products for process b) can be prepared by adding 2-aminonicotinonitriles of the formula

S ^ ¹ X _05n xiii

where R and R. have the above meaning with organometallic Compounds of formula XIV,

where R has the above meaning and Q is lithium or < . the group -MgX, in which X has the above meaning, reacts and the reaction products are neutral in a manner known per se or alkaline hydrolyzed. ,

1 0 9849/195 t

u i | Pf »

'2 ^; O51O13

- 13 - 6OQ-6251 / B

The reaction of compounds of formula XIII with compounds of formula XIV is preferably carried out in an inert organic solvent, for example an acyclic or cyclic ether, such as diethyl ether, dioxane and tetrahydrofuran, preferably a cyclic ether. The reaction may for example at temperatures between 20 and 100 ⁰ C, preferably 40 ° C and 8o, are performed. In general, an aryl magnesium bromide is used as the compound of the formula XIV. However, if you want to prepare compounds of the formula V in which R is alkyl or phenyl in position ^ or 6 of the ring, a lithium aryl is preferably used as the compound of the formula XIV, the reaction time preferably being limited to a relatively short period of about 5 to 50 minutes, in particular 5 to 12 minutes, is limited, and the reaction is conveniently started at about room temperature. The subsequent hydrolysis can generally be carried out by neutral or alkaline hydrolysis in a manner known per se.

The compounds of the formula V can be isolated and purified in a manner known per se.

The 2-aminonicotinonitriles used as starting products of formula XIII can be prepared; be by one

p) 2-chloro- or 2-bromonicotinonitriles of the formula XI,

'-0C "

9/1969

wprin I above meaning · .has wnd.X 'for Chlop' , mi% QF $ mi§§h§n amines ä @ r formula · Χίϊ #

wherein R ₁ above B§4§wfe "img q) S ^ Aminpnieotirioriitrilf i

XXI

XY

R above Be4 XVI,

h ^, raifc prganiSQhen. ■

xind X

οθϊ »Porwel 5EVII,

R ₄ S ₁ and 5ξ 'Qb4i§ gäeu ^ ung

^ with K

implements,

- 15 - 600-6251 / B

The process ρ) represents a customary exchange reaction and is expediently carried out at elevated temperature, in particular at 100 to 150 ^° C. The reaction can be carried out in an inert organic solvent, although normally an excess of compounds of the formula XIlI is simply used as the solvent .

The method q) is conveniently carried out at elevated temperature, preferably at 60 to 150 ⁰ C, particularly at 80 to 130 ⁰ C is performed. It is expedient to work in an inert organic solvent, such as benzene, dioxane or toluene. Optionally, an excess of compounds of the formula XVI can also be used as the solvent medium. In this case, the process can also be carried out under pressure, if this is necessary in order to skin the compound of the formula XVI in the liquid state under the selected temperature conditions. The operation is preferably carried out in the presence of an acid binder, for example an inorganic base such as an alkali hydroxide, a tertiary amine, or preferably an inorganic carbonate such as an alkali carbonate, for example sodium or potassium carbonate.

Customary techniques for the alkylation of amines can also be used to make process q) particularly special to make advantageous. So you can, for example, the amino group before the reaction with the compound of formula XVI tosylate and remove the tosyl group after this reaction

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columns. A direct reaction between the compounds of the formula XV and XVI is preferred \ if the desired amino substituent is a branched alkyl.

In the method r), the reaction with cuprous cyanide conveniently effected at an elevated temperature, for example between about 6o and 200 ⁰ C, preferably 80 to l80 ° C, in particular? at the reflux temperature of the reaction mixture carried out. The procedure is, as indicated, in the presence

™ made of an inert organic solvent. As a solvent are those that boil within the preferred temperature range, such as dimethylformamide, or, preferably, dimethylacetamide. The molar ratio of Copper-I-cyanide to connect the. Formula XVII is not ■ particularly critical. It is expedient to work with the stoichiometrically required amount or a small one Excess of copper cyanide. The reaction time can be about 1 to 20 hours. As a compound of the formula XVII a bromine-substituted compound is preferably used. The decomposition of the formed copper complex can in itself

t done in a known manner.

The compounds of the formula XIII can be known per se Way to be isolated and purified,

The compounds of the formula XI are either known or can be prepared by processes described in the literature (Org.Synth., Anthology IV, pages 166 and 704 ff, Bull.Sog.Chitn. (France), 1966, 2387; and ti Am. Chem. Soc, 69 , 2574). The compounds de: · Formula XI, wherein R is a

1 09849 / 19S9 · ■■. ? - _; r \ f

is phenyl in position 4 or 6 of the ring, are preferably prepared by reacting the corresponding 3-cyano-2-pyridone with phosphorus oxychloride or -oxybroraid in the absence of large amounts of phosphorus pentachloride or pentabromide, as explained in more detail in Example 1. -

To the starting materials used for process q) of the formula XV can be obtained by reacting compounds of the formula XI with ammonia.

The process is conveniently carried out at temperatures between 60 and 120 ⁰ C, preferably 80 and 100 ⁰ C is performed. It is advisable to work in an inert organic solvent, for example a mixture of dioxane and water.

The compounds of the formula XV can be isolated and purified in a manner known per se.

Those used as starting materials for process r) Compounds of Formula XVII can be prepared by

<x) compounds of the formula XXII,

XXII

109843/1959

2ÖS1013

18 · «■ 6θθ-βδ5ΐ / β

where H and X 'above have a meaning,

(3) connections ά ^ ρ formul MtIt

where Ft and Λ, the above Ba &gutung'besitain, reacts with oder * bromine. ■.

The process is usually carried out using conventional procedures for the alkylation of amino solids, for example by tosylation, alkylation and detosylation, or by direct alkylation and subsequent separation of undesired by-products in a manner known per se. If the substance R büi defi compounds of the formula Χνϊί is branched, where

the branching at which a «the Ütiöksfcoffät appear on the carbon atom, - wiM the direct alkyiierlin free operations between. #twa 60 and 12 NC ^ C preferred tftFstihdiiGh see refers to the * Irae VÖI "ferry en ~ ä) called Se gi'iff" alkylation "on eifrfaohö ÄlkyligrUfti - Cyelöälky allylation ^ ^ Metöäli Üei'üflg: scrWiö alkyl ieruaftgsnfifetsel äina on P§t & bmmn

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The compounds of the formula XXII are either known or can be prepared in a manner known per se. (j.Am.Chem. Suction 71, 1186)

Process β) represents a halogenation known per se (E. & F. Berliner, JACS 71, 1195-1220 (19 ^ 9). It is preferably carried out at temperatures between 0 and 20 ° C. and in an acidic, aqueous medium A strong acid, for example sulfuric acid, is preferably used to create the acidic conditions.

The compounds of the formula 5QCIII are either known or can be produced in a manner known per se. .

The compounds of the formula XVII can be isolated and purified in a manner known per se.

The compounds of the formula VI used as starting materials for process c) can be prepared by the same process be prepared as the compounds of formula V, the last stage instead of a neutral or alkaline hydrolysis, however, represents acid hydrolysis and compounds of the formula are used as starting materials

1 09 849/19 59

XIIIx,

Ti

Χίϊίχ

used, wherein S and R 'have the above meaning.

The boiling hydrolysis could be done in a way be carried out, for example by means of 2 to 5N Hydrochloric acid in ethanol and water as well as at temperatures' ^ Wipe 15 and 60 ° C.

The compounds of the formula I are valuable drugs. They have an anti-inflammatory effect in particular. A suitable daily dose is about 35 to 1ÖÖÖ.

Administered in fimhP & P & n Te'iiiiieiigeti 9 and 500 mg, 2 to -4töäi daily ödöi * in

Öie vörbindüßgeil the formula

Fi and R have the above meaning> sliÜeti pharmaceuticals dar vihd Wifkefi in§tei © «d # fi

" ^: i! ^ll '!! ljljj | l | j! | j | ίlj! ^{|| I} !! ^| Ίll! ■ :: !! jljl! j | ll | jllll |! l! ιηιΓ: ^{ι |} !.: ιι: i; ι ^{| ί} !: l! l!: μili | j:!: H ■ ι! l ■ ιι ■! ;;! ιιι:!:;! i!

anti-ignition. Suitable daily doses are between about 35 and 1000 mg, preferably administered in several partial amounts of about 9 to 500 mg, 2 to H times a day or in sustained release form.

The compounds of the formulas I and XIIIa can optionally processed with pharmaceutically acceptable carriers and other common additives and in the form of tablets, • Capsules, elixirs, suspensions or solutions are administered orally or parenterally.

A suitable tablet contains, for example, 50% by weight of a compound of the formula I, such as 1-isopropyl-4,6-diphenyl, 2-dihydropyrido [2,3-d] -pyrimidin-2-one, or a compound of the formula XIIIa such as 5-phenyl ~ 2-isopropylaininonicotinonitril, 2 wt .- $ tragacanth, 39 * 5 wt .- ^ lactose, 5 wt -.% corn starch, 3 wt .- ^ talc and 0.5 wt -. $> magnesium stearate.

One of the compounds of the formula I is l-isopropyl-4,6-diphenyl-1,2-dihydropyrido [2,2-d] pyrimidin-2-one preferred, and of the compounds of the formula XIIXa, 5-phenyl-2-isopropylaminonicotinonitrile.

109849/1959

Example 1 ; l-Isopropyl-4,6-diphenyl- 1,2-dihydropyrido - [2,3-d] pyrimldin-2-one [method a]

A mixture of 6.6 g of 3- (2-amino-5-phenyl) pyridylphenylketon, 18.4 g Aethylcarbamat and 500 mg of zinc chloride is 45 minutes for 210 - 220 ⁰ C heated. The resulting mixture is cooled, the resulting solid with hot

Treated P chloroform and filtered off the insoluble material. ■. ■■. . ■ · ■ ■ ... The chloroform solution is extracted three times with water, dried over sodium sulfate and evaporated in vacuo. The residue is dissolved in methylene chloride and recrystallized therefrom to give the title compound. ■;

k) 1. Isopropyl-4,6-diphenyl-1,2-dihydropyridote 2,3-d2-pyrimidin-2-one

0.468 g of sodium hydride (57% in mineral oil) are added to a suspension of 2.7 g of 4,6-diphenyl-1,2-dihydropyrido [2,3-d] pyrimldin-2-one in 25 ml of dimethylacetamide. After P 5 minutes, a precipitate forms and 10 ml of dimethylacetamide are added. The mixture is stirred for 60 minutes at room temperature, 1.9 ml of isopropyl iodide is added, the mixture is heated to 50 ^° C. for two hours, the precipitate formed is filtered off and washed with water. The precipitate is taken up in methylene chloride, the solution is dried over sodium sulfate, treated with activated charcoal, filtered and concentrated in vacuo. The residue is dissolved in ethyl acetate / diethyl ether / pentane and recrystallized therefrom, the title compound having a melting point of 45-148 ° C.

1098A9 / 1959

Example 2 : [method a]

In a manner analogous to Example 1 and using suitable starting materials in approximately equivalent amounts you get to the following connections:

1-Isopropyl-4,7-diphenyl-1,2-dihydropyrido [2 _J 3-d] pyrimidin-2-one

i-isopropyl - ^ - ^phenyl-1 ö-O, 4'-diraethoxyphenyl) -l, 2-dihydro-pyrido [2, 3-d3pyriinidin-one 2-

EXAMPLE J l-Isopropyl-4, 6-diphenyl-l, 2-dihydropyridof2 -dlpyrimldin ^ ^ -one [Process b) (I) J

a) 2-Phenyl-3- ^< iimethylaininoacrolein

Ij8o g of phosphorus oxychloride are added over a period of 810 g of dimethylformamide were added dropwise for 1.5 hours, the temperature being kept below 150 ° C. by ice cooling holds. The mixture is for one hour with 404 g Phenylacetic acid was added in 292 g of dimethylformamide. Man then slowly heated to 70 - 75 ° C and maintained at this temperature for 16 hours. The mixture is then cooled Poured 10 kg of ice and with external cooling with 4 kg Potassium carbonate added. 2 l of benzene are then added and the mixture is refluxed for 12 hours. in the

109849/1359

It is then cooled, the organic phase is separated off and the aqueous phase is extracted with 2 l of benzene. The combined organic phases are washed with water and under high vacuum (0.005 to 0.05 mg Hg) Distilled at 120-160 ° C., an oil of the title compound receives.

b) 3-cyano-5-phenyl-2 (1H) -pyridone

A solution of 64 g of 2-CyanoaoetaTud and 132 g of P-phenyl-J-dimethylaminoacrolein in 200 ml of methanol is added to a solution of sodium methoxide prepared from a mixture of 35 g of sodium in 800 ml of methanol. The mixture is heated under reflux for 4 hours and cooled, whereupon the resulting precipitate is filtered off, washed with ethanol, dissolved in hot water and the solution acidified. After the precipitate formed has been filtered off and washed with water, the title compound has a melting point of 4

c) 2-chloro-5-phenylnicotinonitrile

A solution of 105 S j5-cyano-5-phenyl-2 (1H) -pyridone in 210 ml of phosphorus oxychloride is mixed with 110 g of phosphorus pentachloxide added and the resulting mixture heated to reflux for 48 hours. The phosphorus oxychloride is evaporated

109849/1959

and the residue is treated with a large amount of ice and made alkaline with 50% sodium hydroxide solution in order to destroy excess phosphorus pentachloride and some phosphorus oxychloride. The yellowish precipitate formed is filtered off and dissolved in chloroform. The chloroform solution is extracted with V / ater, dried and evaporated in vacuo to give the title compound, mp. 129-143 ⁰ C.

d) 5-phenyl ~ 2-isopropylaminonicotinonitrile

[Compound XIIIa, method p) j

A solution of 15 g of 2-chloro-5-phenylnicotinonitrile in βθ ml iscpropylamine is kept at 130-140 ° C. in an autoclave for 4 hours. The mixture is cooled, transferred to a flask using chloroform and evaporated to dryness. The residue is dissolved in 250 ml of chloroform, extracted twice with water, the organic phase is dried over sodium sulfate and evaporated in vacuo. The residue is dissolved in 250 ml of pentane and the solution is ^{kept at 0} ° C. overnight to crystallize out, giving the title compound with a melting point of 78-80 ° C. »

e) [5-Phenyl ~ 3- (2-isopropylamino) pyrldyl] -pnenylketonimine

A solution of 13 g of S-phenyl ^ -isopropylaminonicotinonitrile in 100 ml of tetrahydrofuran is converted into a phenylmagnesium bromide solution in tetrahydrofuran at room temperature given, which consists of 4.0 g of magnesium and 27 g of broinbenzene in

1098AÖ / 1959

150 ml of tetrahydrofuran was prepared. The mixture will Heated under reflux for 7 hours, cooled and poured into 500 ml of water. It is then steamed to remove Tetrahydrofuran in vacuo, the aqueous phase extracted twice with methylene chloride, whereupon the organic Combined extracts, dried over sodium sulfate and concentrated in vacuo to give the title compound as crude oil to obtain.

^f ) i

pyrimidin-2-one

A solution of 17 g of [5-phenyl-3- (2-isopropylamino) pyridyl] phenylketonimine and 50 ml of triethylamine in 200 ml of benzene is added dropwise with 85 ml of a 12.5 % strength phosgene solution in benzene while cooling with ice. The mixture is stirred for minutes at room temperature, then poured into water and made alkaline with 2N sodium hydroxide solution. After P extraction with benzene, washing the extract once with water, drying over sodium sulfate and evaporation in vacuo, a solidifying crude product is obtained which, after recrystallization from ethyl acetate / diethyl ether / pentane (2: 1: 1), the title compound from 145-148 ° C yields.

Example 4 : 1-Isopropyl-6-p-chlorophenyl- »4-phenyl» 1,2 · »dihydropyridof2,3-d3pyrimldin-2-one

[Method b) (I)]

109349/1969

At a temperature between 20 and 50 ⁰ C 1J58 g of phosphorus oxychloride under external cooling dropwise with 8l g of dimethylformamide was added. Bas mixture is stirred for 15 .Minuten at room temperature, then treated with a solution of 50 g p-chlorophenylacetic acid and 20 hours at 65 - 75 ⁰ C heated. The reaction mixture is cooled, poured onto 1 kg of ice and adjusted to pH 12 with 5 # sodium hydroxide solution while cooling with ice. The mixture is then heated on the steam bath for 1 hour. The resulting precipitate is filtered off and washed with a fair amount of water. The moist material is dried in vacuo and, after recrystallization from ethyl acetate to give the title compound, mp. 117-120 C. ^Q

t>) 3-Cyano-5-p-chlorophenyl-2 £ 1H) pyridone

A solution of 7 ß sodium in J500 nil methanol is under Stir with a solution of 16 g of 2-cyanoacetamide and 37 g of 2 ~ p-chlorophenyl-; 5-dimethylarainoacrolein in 100 ml Methanol added. The mixture is refluxed for one hour, the precipitate obtained is filtered off, with ethanol washed, dissolved in hot water and the solution acidified. After filtering off the precipitate and washing the title compound with a melting point of 278-280 ° C. is obtained.

c) 2-chloro-5-p-chlorophenyl nicotinonitrile

A solution of 17 g of j5-cyano-5-p-chlorophenyl-2 (lK) -pyridone in 40 ml PhosphoroxycMorid is mixed with 18 g phosphorus

109849 / 19S9

Pentachloride was added and the mixture was refluxed for 48 hours. The phosphorus oxychloride is evaporated and the residue is treated with a fair amount of ice to remove the excess of phosphorus pentachloride and some phosphorus oxychloride to destroy. The yellowish precipitate obtained is filtered off and dissolved in chloroform. The chloroform solution is extracted with water, dried and evaporated in vacuo, the title compound having a melting point of 176-180 ° C. receives.

d) 2-isogropylamino-5-p-chlorophenylnicotinonitrile

[Compound XIIIa, author p)]

A mixture of 5 g of 2-chloro-5-p-chlorphenylnicotinonitril and 6o ral Isopropylarain is heated in a sealed tube for 4 hours at 120 ⁰ C. The bomb tube is then cooled in a dry ice bath and opened. The reaction mixture is diluted with ethanol and evaporated in vacuo. The residue is dissolved in chloroform, washed once with f IN sodium hydroxide solution and twice with water, dried and concentrated in vacuo. The solid residue is filtered through silica gel with benzene to give an oil which solidifies on standing. After recrystallization of the solid from methylene chloride / pentane (2: 1), the title compound is obtained with a mp.

l} i} ir? ri? zi 52Γ2? ί: §ϊ-ί} 22ϊ-phenyl ketonimine

In a manner analogous to Example 3e) and using suitable starting products in corresponding

109849/1959

Quantities lead to the title compound.

f) l-isopropyl-ö-p-chlorophenyl - ^ - phenyl-lig-dihydropyrido [2,3-d] pyrimidin-2-one

In a manner analogous to Example 3f) and using Appropriate amounts of suitable starting materials lead to the title compound.

Example 5: [method b) (I)]

In a manner analogous to Example 5 or 4 and using suitable starting materials in appropriate quantities lead to the following compounds:

2-t-butylaraino-5-phenylnicotinonitrii; M.p. 72-75 ° C (Uracrystallization from petroleum ether) [compounds XIIIa, Method p)]

[5-Phenyl-3- (2-t-butylamino) pyridyl] phenyl ketone imine [Compound V]

l-t -Butyl-4,6-diphenyl-1,2-dihydropyrido [2,3-dlpyrimidin-2-one

o-Phenyl-a-isopropylaminonicotinonitril ^ mp. 78-80 ⁰ C [Compound XIII, method p)]

[6-phenyl -; 5- (2-isopropylamino ) pyriclyl ] -phenylketonimine [compound V}

109849/1959

1-isopropyl- '! , 7-diphenyl-1,2-dihydropyrido [2,3-ci] pyrimialri-2-one

5- (3 ' A * -dimethoxyphenyl) -2-isopropylaminonicotinonitrile \ mp 102-106 ° C (recrystallization from Aechanol / pentane) [compound XIIIa, method p)]

[5- (3 ', V-dimethoxyphenyl) ~ 3- (2-isopropylamino) pyridyl] phenyl ketone imine [Compound V]

l-Isopropyl-4-phenyl-6- (3 ', 4'-dimethoxyphenyl) -l, 2-dihydro ■ - · pyrido [2,5-d] pyrimidin-2-one.

Bei Piel 6: l-propyl-4,6-dl Isc phenyl-l j 2-dJhyriropyr1.do

[2 _I 3 ~ dlpyrimidin-2-one [method b) (2)]

A mixture of 6.7 g of [fT-phenyl-3 ~ (2-isopropylamino) pyridyl] iJhenylketonimin (prepared according to Example 3), 5 ml of ethyl chlorocarbonate, 6 ml of triethylamine and 1> 0 ml of benzene is refluxed for 2.5 hours . The mixture is diluted with 70 ml of benzene and extracted twice with water. The organic phase is dried and concentrated in vacuo to give a crude product which is purified by column chromatography using silica gel and chloroform as the eluent. After recrystallization of the purified product from methylene chloride / diethyl ether, the title compound is obtained with a mp.

Example 7 : 1-Isopropyl- ^, 6- dljOhepylrjl ^ 2-dihydrQpyrido

'EVer'faawen b) (3)]

UIh mixture of 6.7 S

- 31 - 2 O 51 01 3 6C0-6251 / 8

pyridyl] phenyl octonimine (prepared according to Example 3) and 10 g of urethane are heated to 175 ° C. for 2.5 hours. After cooling, the mixture is taken up in 50 ml of methylene chloride, insoluble material is filtered off and the filtrate is extracted with 50 ml of water. The organic phase is dried, evaporated in vacuo \ ma the residue of ethyl acetate / r.-'- äth / liithoi '(1: 1) uN.kriotä.ll.iijjc-rt, wofc-ji m & n the titanium compound from Snip. 145-148 ⁰ C.

DeJjsj;

[2,3- Qlpyriinidin-2-one [method b)

A] solution of 2.8 g of [5-phenyl-3- (2-isuprony3.a: nino) pyridyl J-phenylcetoninine (prepared according to Example 3) in 4C ml of v.'aisser-free tetx'aliydrofuran is mixed with 1, J g 1,1 '-Ctirbonyldj imidazole is added and the GeiniGC? I is stirred for 2 hours at room temperature. The solvent is removed in vacuo, the residue is dissolved in methylene chloride and the mixture is extracted three times with water. After drying, the solvent is evaporated and the residue is recrystallized from methylene chloride / diethyl ether, the title compound having a melting point of 145-1 ^ f ¹⁰ ° C.

Example 9: [method b) (2), (3) and (k)]

In a manner analogous to Examples 6, 7 or 8 and using suitable starting materials in the appropriate manner Quantities one obtains the following compounds:

1098A9 / 1959

l-Isopropyl-e-fp-ühlorphenylJ - ^ - phenyl-l ^ -dihydropyrido [2,2-d] pyrimidin-2-one

l-t-Butyl-4,6-diphenyl-1,2-dihydropyrido [2,; 5-d] pyrimidine 2-on (analogous to example 8).

Example 10 : l-Isopropyl - ^^ e-diphenyl-l ^ -dihydropyrido [2,3-d] pyrimidin-2-one [method c) (I)]

[Compound VI]

A solution of IjJ g of 5-phenyl-2-isopropylarainonicotinonitrile in 100 ml of tetrahydrofuran is added to a phenylmagnesiurabromide solution in tetrahydrofuran at room temperature, the one from 4.0 g of magnesium and 27 g of bromobenzene in 150 ml Tetrahydrofuran was produced. The resulting mixture is refluxed for 7 hours, cooled and poured into 100 ml of 2N Poured hydrochloric acid solution. The mixture is stirred for 15 minutes and adjusted to pH 8.5 to 9.0 with the addition of 2N sodium hydroxide solution. The mixture is three times with 50 ml P extracted methylene chloride, the organic extracts are combined, extracted with water, dried and in vacuo evaporated to give the title compound as OeI.

A mixture of 65 mg [5-phenyl-3- (2-isopropylaraino) pyridyl] phenyl ketone, 200 mg urethane and a trace of zinc chloride

109849 / 19S9

heated to 160 ° C. in an oil bath. The resulting melt solidifies, is dissolved in methylene chloride, filtered, washed with water, dried and concentrated in vacuo, whereupon the product obtained is purified by chromatography using methylene chloride as the eluent. The purified product is then recrystallized from diethyl ether, the title compound having a melting point of 145-148 ° C receives.

Example 11 : l-Isopropyl-4,6-diphenyl-1,2-dihydropyrido ~ [2,3-d] pyrimidin-2; -one [method c) (2)]

A mixture of 6.3 g of [5-phenyl-; 5- (2-isopropylamino) pyridyl3-phenylketone and 10g urea is on for 2 hours Heated between 180 and 200 ° C. The solid residue is with ICX) ml Treated 50 # aqueous ethanol, and after filtering off a crystalline residue is obtained Title compound of m.p. 145-148 ° C.

Example 12 ; l-Isopropyl-4 ₁ 6-diphenyl-1,2-dihydropyridof 2,3-d1pyrimidin-2-one [method c)

A solution of 2.65 g of [5-phenyl-3- (2-isopropylaraino) pyridyl J-phenyl ketone in 2 ml of glacial acetic acid is treated with 1.5 S. Potassium cyanate is added and the mixture is heated to 100 ° C. for 20 hours. Ice is added to the mixture and 2N sodium hydroxide solution is added made alkaline. After extraction with methylene chloride, drying of the organic phase, evaporation

109849/1 959

, ^ 051013

The title compound with a melting point of 145-148 ° C. is obtained in vacuo and the residue is recrystallized from diethyl ether.

Example 1? : [Method c) (l), (2) and (5)]

In a manner analogous to Examples 10, 11 or 12 and. using suitable starting materials in appropriate Quantities lead to the following compounds:

[5-P-chlorophenyl-3- (2-isopropylamino) pyridyl) phenyl ketone [Connection VE]

1-Isopropyl-6- (p-chlorophenyl) -4-phenyl-1,2-dihydropyrido- [2,5-d] pyrimidin-2-one

[6-phenyl-5- (2-isopropylamino) pyridyl] phenyl ketone [Compound VI)

l-isopropyl ~ 4,7-diphenyl-1,2-dihydropyrido [2,3-d) pyrimidin-2-one

[5- (5 ' $ ^' - dimethoxyphehyl) -5- (2-isopropylaraino) pyridyl] phenyl ketone [compound VI]

1-Isopropylamino-4-phenyl-6- (3 ^f , 4'-dimethoxyphenyl) -1,2-dihydropyrido [2,3-d] pyrimidin-2-one

Example 14 : 1-Isopropyl-4,6-dlphenyl-1 _J 2 _f 3j4-tetrahydropyrido [2,3 ~ dlpyrlmldin-2'On [method d)]

A solution of 5 * 1 ß l-Isoprcpyl-4,6-diphenyl-l _# 2 ~ dihydro-

109849/1959

35 - 6ΌΟ-6251 / Β

pyrido [2,3-d] pyrittidin-2-one in 200 ml of 95 # ethanol 2.4 g of sodium borohydride are added in portions with stirring at Ratini temperature. The mixture is then Stirred for 50 minutes at room temperature, with 200 ml v / ater added and evaporated in vacuo to remove ethanol. After extracting the residue twice with methylene chloride, washing the combined extracts with water, Drying, evaporation in vacuo and recrystallization of the obtained crude solid from ethyl acetate / petroleum ether the title compound is obtained with a melting point of 158-161 ° C.

Example 1 ^: g-Phenyl-2-isopropylaminonieotinonitrile

[Method q)]

a) 5-Phenyl-2-aminonicotinonitrile

A mixture of 5 g of S-phenyl - ^ - chlornieotinonitril, 50 ral of dioxane and 100 ml of concentrated aqueous ammonia in a sealed tube 15 hours at 80 - 100 ⁰ C heated. The whole is then allowed to cool and the resulting mixture is evaporated in vacuo. The residue is dissolved in 150 ml of methylene chloride, whereupon it is filtered off and extracted twice with 100 ml of water. The solution obtained is dried and evaporated in vacuo, giving 5-phenyl-2-aminonicotinonitrile, which can be recrystallized from diethyl ether / pentane (1: 2) and purified.

b) 5-phenyl-2-isopropylaminonicotinonitrile

A mixture of 10 g of S-phenyl-S-atninonicotinonitrile, 10 g Isopropyl iodide, 8 g of triethylamine and 50 ml of dimethylformamide

10 9349/1959

is heated to 6O to 100 ° C for n8 hours. The mixture is evaporated in vacuo, the residue is dissolved in chloroform, filtered, extracted twice with water, dried and evaporated in vacuo. The residue is dissolved in I50 ml of pentane, the solution was kept at 0 to 5 ⁰ C to give the title compound, mp. 78-8O ⁰ C crystallizes.

Example l6 : ^ -Phenyl - ^ - isopropylaminonico t inon itril Ψ [method r)]

a) 3-Bromo-2-isopropylamino-5 * -phenylpyridine

A mixture of 21.2 g of 2-isopropylamino ~ 5 ~ phenylpyridine and 50 ml 20 # sulfuric acid is cooled in an ice water bath and treated dropwise during 2 hours at a temperature between 0 and 5 ⁰ U 18.7 g of bromine. The mixture is then made slightly alkaline by adding 10% aqueous sodium hydroxide solution, taken up in 500 ml of methylene chloride, whereupon the organic phase is washed three times with 200 ml of water each time, dried and evaporated in vacuo. The crude oil obtained is filtered through silica gel using methylene chloride, and after evaporation of the solution obtained in this way, an oil of 3-broin-2-isopropyl8mlno-5-phenylpyridine is obtained.

109849/1959

b) 5-Pheiij ^r 1-2-isopropylaminonicotinonitrile

A unit of 5 g of 3-bromine-5-phenyl-2-isopropylaminopyridine, 6 g of copper (I) cyanide and 100 ml of dimethylformamide is ^{heated to 120 °} C. for 10 hours. The mixture is evaporated in vacuo and the residue is treated with 2N hydrochloric acid at room temperature for 30 minutes while stirring. Subsequently, the mixture is made slightly alkaline with 2N sodium hydroxide and the mixture is extracted with 200 ml of methylene chloride. The organic phase is washed twice with 100 ml of water each time, dried and concentrated in vacuo. After recrystallization of the residue from pentane to give the title compound, mp. 78-8O ⁰ C.

Example 17; [Method q) and r)]

In analogous procedure to Examples 14 or 15 and under Using suitable starting materials in appropriate amounts leads to the following compounds:

2-isopropylamino-5-p-chlorophenylnicotinonitrile; M.p. II9-C (Recrystallization from methylene chloride / pentane (2: 1))

2-t-butylamino-5-phenylnicotinonitrii; M.p. 72-75 ° C (Recrystallization from petroleum ether)

2-isopropylamino-6-phenylnicotinonitrii; Mp. 78-80 ⁰ C

2 ~ isopropylamino-5- (j5 ', V-dimetho: x: yphenyl) nicotinonitrile Mp. 1O2-1O6 ° C (recrystallization from ethanol / pentane)

109849/1959

Example 18 ; ! -Methyl- 4,6-dipheny l-l, 2-dih.y dropy rido- [2,3-d] p yrimid in-2-one [method a)]

a) 4 ^ 6-Diphenyl- 1,2-dihydropyrido [2, ~ *> ~ d] pyriniidin-2-one

A mixture of 5 g of f5 ~ phenyl-3- (2-amino) pyridylj-phenyl ketone, 18 g of Aethylcarbaraat and 500 mg of tin chloride is Heated to 210-220 ° C for 1 hour. The mixture is cooled treated with hot chloroform and filtered off from the solid matter. After the chloroform solution is extracted twice with water, dried and evaporated in vacuo, one obtains a crude oil of 4,6-diphenyl-1,2-dihydropyrido [2,3-d] pyrimidin-2-one.

A suspension of 20 g of ^, o-diphenyl-l ^ -dihydropyrido- [2,3-djpyrimidin-2-one 0.35 g of sodium hydride ($ 57 in mineral oil) is added to 25 ml of dimethylacetamide. The resulting 10 ml of diraethylacetamide are added to the precipitate, the mixture is stirred for one hour at room temperature, 1.4 ml of methyl iodide are then added, and the resulting solution is stirred for 2 hours at room temperature. After adding water and ice, a crystalline precipitate forms, which is filtered off and washed with water. The precipitate is taken up in methylene chloride and the solution is dried, treated with activated charcoal, filtered and concentrated in vacuo.

109849/1959

After recrystallization of the residue from ethanol, l-methyl-4,6-diphenyl-1,2-dihydropyrido [2, 5-d] pyrimidine is obtained. 2-on.

109849/1959

Claims (13)

Claims: £ L / Process for the preparation of l, 2-dihydropyrido [2, j5-dJ pyrimidiri ~ 2-ones of the formula I, where χ y for the group C = N or CH-N RTD TT 2 2 ßtoht, R, Alkyl with 1-6 carbon atoms, cycloalkyl with 3-6 carbon atoms, allyl, methallyl or propargyl and Rp for phenyl or substituted phenyl of the formula II, Y, where Y is fluorine, chlorine, 3rom, alkyl or alkoxy with 1- 4 denotes 4 carbon atoms and Y1 denotes hydrogen, fluorine, chlorine, bromine, alkyl or alkoxy each with 1-4 carbon atoms, and R denotes a radical of the formula Ha, 109849/1959, in which Z and Z are identical or different and are each hydrogen , Fluorine, chlorine, bromine or alkoxy with 1-5 carbon atoms, characterized in that a) for the preparation of compounds of the formula Ic, Ic in which R and R2 have the above meaning and R 'has the same meaning as R1, but not for the tertiary bonded directly to the ring nitrogen atom with the tertiary carbon atom Can be alkyl, compounds of the formula III, M 'in 109849/1959 in which R and Rp have the above meaning and M1 is alkali, with compounds of the formula IV, R- [X IV in which RJ has the above meaning and X is Ciilor, bromine or iodine, reacts, or b) for the preparation of compounds of the formula Ia, R, Ia in which R, R1 and R? Have the above meaning, compounds of the formula V,, NH OC in which R, R and Rp have the above meaning, with the carboxylic acid derivatives 1) phosgene, 2) C. ρ alkyl chlorocarbonate, 3) C _{1 c} alkyl carbamate, or 1-5 4) Ι, Ι'-carbonyldiimidazole 109849/1959 cyclized, with the condition that one for the preparation of compounds of the formula Ia, wherein R, for over the tertiary carbon atom is tertiary alkyl bonded directly to the ring nitrogen atom, the cyclization with Phosgene or!, L'-carbonyldiimidazole, and at Cyclization with C, ._ alkyl carbamate at temperatures of lt?
works above 140 ° C, or c) for the preparation of the above-mentioned compounds of the formula Ic, 2-aminopyridylphenyl ketones dei formula VI, VI wherein R, RJ and R _{2 have the} above meanings with the compounds 1) C-ic alkyl carbamate, 2) urea or 3) isocyanic acid cyclized, in which case one works for the cyclization with C _{1 ς} alkyl carbamate at temperatures above 140 ° C. and in the presence of catalytic amounts of Lewis acid, or 109849/1959 600-6251 / B d) for the preparation of compounds of the formula Ib, Ib in which R, R ₁ and R_ have the above meaning, compounds of the formula Ia already mentioned are reduced in an inert organic solvent. 2. Process for the preparation of 2-aminopyridylphenyl ketone imines of the formula V, in which R, IL and R _{2 have} the meaning given in claim 1, characterized in that »2-aminone / cotino nitriles of the formula XIII, ■ OC NH XIII 109849/1959 wherein R and R _{1 have the} above meaning with organometallic compounds of the formula XIV, R ₂ Q XIV in which R _{2 has the} above meaning and Q is lithium or the group -MgX, in which X is chlorine, bromine or iodine, and the reaction products are hydrolyzed in a manner known per se in a neutral or alkaline manner. 3. Process for the preparation of 2-aminopyridylphenyl ketones of formula VI, VI wherein R, R 'and Rp have the meaning given in claim 1 have, characterized in that 2-aminonicotinonitriles of the formula XIIIx, NH XIIIx 109849/1959 wherein R and Rj have the above meaning with organometallic compounds of the formula XIV, XIV where R _{2 has the} above meaning, Q is lithium or the fc group -MgX and X is chlorine, bromine or iodine, * converts and acid hydrolyzes the reaction products in a manner known per se. 4. Process for the preparation of 2-arainonicotinonitriles of formula XIII, ^xm wherein R and R. have the meaning given in claim 1, characterized in that one p) 2-chloro- or 2-bromoniootinonitriles of the formula XI, xi 109849/1959 where R has the above meaning and X 'is chlorine or bromine, with organic amines of the formula XII, R ₁ NH ₂ XII wherein R, has the above meaning, converts, or q) 2-aminonicotinonitriles of the formula XV, wherein R has the above meaning with organic halides of the formula XVI, R ₁ X XVI in which R ₁ and X are as defined above, converts, or r) 2-amino-5-chloro- or bromopyridines of the formula XVII, XVII wherein R, R ₁ and X ^{1 have the} above meaning, reacts with copper-I-cyanide in an inert organic solvent and decomposes the copper complex obtained. 109849/1959 5. Process for the preparation of 1,2-dihydropyrido- [2,3-d] pyrimidin-2-ones of formula VIII, VIII wherein R and R have the meaning given in claim 1, 2
characterized in that 2-aminopyridylphenyl- ketones of formula IX IX in which R and R «have the above meaning, with C« -alkyl carbamate cyclized at temperatures above 140 ° C. 109849/1959 6. l _i 2-dihydropyrido [2,3 ~ d] pyrimidin-2-ones of the formula I according to claim 7. 2-Arainopyridylphenylketonimine of the formula V according to Claim 2. 8. 2-aminopyridylphenyl ketones of the formula VI according to Claim 5 9. 2-aminonicotinonitriles of the formula XIII Claim 4. 10. 2-aminonicotinon triles of the formula XIIIa, XIIIa wherein R and R have the meaning given in claim 1, 11. l _J 2-DihydrQpyrido [2 _i 3-d] pyrimidin-2-ones of the formula VIII according to claim 12. Pharmaceutical preparation * marked by a content of compounds of the formula I as active ingredient. 109849/1959 13. Pharmaceutical preparation, labeled durofi a content of compounds of the formula XIIIa as active ingredient. f ** r ~ SANDOZ AO.