DE2406930A1 - NEW HETEROCYCLIC COMPOUNDS AND METHODS FOR THEIR PRODUCTION - Google Patents

Description

CIBA-GEIGY AG, BASEL (SWITZERLAND)

Case 4-865 ^ 1 + 2

DR. ERLEND DINNg

PATENT ADVERTISER 28 BREM E-N

UHLANDstrasse 25

New heterocyclic compounds and processes for their preparation

The invention relates to new heterocyclic compounds of the general formula

CH ₅

₉ p (Ι),

wherein Het optionally substituted pyridazinyl,

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Means pyrimidinyl, pyrazinyl or substituted pyridil, R is hydrogen or methyl and

Rp lower alkyl, optionally substituted Is phenyl-lower alkyl, carboxy-lower alkyl or functionally modified carboxy-lower alkyl, their condensation products with aldehydes, ketones or carbonic acid, their N-oxides and processes for their production.

Before and below, under a lower remainder

especially such a radical having up to 7 C atoms, especially up to 4 carbon atoms understood.

Lower alkyl radicals are radicals with preferably up to 7 carbon atoms, especially up to 4 carbon atoms and are e.g. methyl, Ethyl, n-propyl, i-propyl or unbranched or any Place bound or branched butyl, pentyl, hexyl or heptyl.

Optionally substituted lower alkyl groups are Phenylniederalkylreste with up to 7 C atoms, especially up to 4 carbon atoms, which are substituted in any position by optionally substituted phenyl groups. Particularly suitable phenyl substituents are lower alkyl, lower alkoxy groups, the trifluoromethyl radical and halogen atoms. Examples are 3-phenyl-n-propyl or above

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especially benzyl and 2-phenylethyl.

Carboxy-lower alkyl radicals are lower alkyl radicals with preferably up to 7 carbon atoms, especially up to 4 carbon atoms, which are substituted in any position by carboxy, such as e.g. 3-carboxy-n-propyl, 4-carboxy-n-butyl and above all Carboxymethyl and 2-carboxyethyl.

Functionally modified carboxy-lower alkyl is, for example, refined carboxy-lower alkyl, amidated carboxy-lower alkyl or cyano-lower alkyl.

Esterified carboxy-lower alkyl is, for example, carboxy-lower alkyl esterified with an aliphatic alcohol. The lower alkyl part of the esterified carboxy-lower alkyl preferably has up to 7 carbon atoms, especially up to 4 carbon atoms. Aliphatic alcohols are those in which the hydroxyl group is bonded to a carbon atom which is not a member of an aromatic S3'stems. Suitable aliphatic alcohols include cycloalkanols such as those having 3-7, in particular 5 -7 ring members, for example Cyclopropanols cyclopentanol, cycloheptanol Cyclohexanolund, Cycloalkylniederalkanple that ^^ _ eg above cycloalkyl moieties include groups such as cyclopentyl-methanol, cyclohexyl methanol, 2 ~ cyclohexyl ethanol and cycloheptyl methanol, phenyl lower alkanols, such as 2-phenylethanol and benzyl alcohol, with phenyl radicals also being replaced by halogen, lower alkyl and or lower alkoxy, such as those mentioned above

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may be substituted, and in particular lower alkanols, such as n-propanol, iso-propanol, straight-chain or branched Butanol, pentanol, hexanol or heptanol, and in particular Methanol or ethanol. Esterified carboxy-lower alkyl is mainly methoxycarbonylmethyl, 2-methoxycarbonyl-ethyl, Ethoxycarbonylmethyl and 2-ethoxycarbonylethyl. '.

Amidated carboxy-lower alkyl is substituted or unsubstituted carbampyl-lower alkyl. The lower alkyl part of the aminated carboxy-lower alkyl preferably has up to 7 carbon atoms, in particular up to 4 carbon atoms. Substituted carbamoyl has, for example, the formula -CONRrRg, where R ₁ - is hydrogen or _{lower alkyl, R fi} is lower alkyl or R ₅ and Rg together are lower alkylene, oxane-lower alkylene, thi-lower alkylene or aza-lower alkylene. Lower alkylene is branched or, in particular, straight-chain lower alkylene with in particular 3-7, especially 4-6, carbon atoms in the alkylene chain. Oxane-lower alkylene is branched or, in particular, straight-chain oxane-lower alkylene with in particular 4 or 5 carbon atoms in the oxaalkylene chain. -Thian-lower alkylene is branched or, in particular, straight-chain thian-lower alkylene with, in particular, 4 or 5 carbon atoms in the thiaalkylene chain. Azaniederalkylen is branched or straight-chain azanieder-

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alkylene with in particular 2-6, especially 4-6 carbon atoms in the azaalkylene chain. Araid carboxy-lower alkyl is therefore above all carbamoylmethyl, 2-carbamoylethyl, N, N-dimethj ^T lcarbamoylmethyl, 2- (N, N ~ dimethylcarbamoyl) -ethyl, N, N-diethylcarbaraoylmethyl, 2- (N, N-diethylcarbamoyl) -ethyl, pyrrolo · lidinocarbonylmethyl, 2-ethyl-pyrrolidinocarbonyl, piperidinocarbonylmethyl, 2-Piperidinocarbonyläthyl, morpholinocarbonylmethyl, 2-Morpholinocarbonyläthyl, Thiomorpholinocarbonylmethyl, 2-Thiomorpholinocarbonyläthyl, 2,6-Dimethylthiomorpholinocarbonylmethyl, 2- (2 ^1, o'-Dimethylthiomorpholinocarbonyl) ethyl, Piperazinocarbonylmethyl, 2-piperazinocarbonylethyl, N'-methylpiperäzinocarbonylmethyl, 2- (N'-methylpiperazino) carbonylethyl, N ¹ - (β-hydroxyethyl) piperazinocarbonylmethyl or 2- [N '- (β-hydroxyethyl) piperazino ] carbonyl ethyl.

In the lower alkyl part, cyano-lower alkyl preferably has up to 7 carbon atoms and, above all, up to 4 carbon atoms and is, for example, 3-cyano-n-propyl, 4-cyano-n-butyl, 5-cyano-n-pentyl and especially 2-cyanoethyl and cyanomethyl.

Het is optionally substituted pyrazinyl of the formula

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N 4

N
or the same optionally substituted pyrimidinyl der

^R 4

formula

N
or the same optionally substituted pyridazinyl

formula

R_ hydrogen, halogen, cyano, hydroxy, lower alkyl, Lower alkoxy lower alkyl, amino lower alkyl, lower alkoxy lower alkenyl, Lower alkylamino, di-lower alkylaraino, acylamino, acylamino lower alkyl, acylamino lower alkenyl or lower alkylsulfonyl is and

R ₂ , hydrogen, halogen, lower alkyl, hydroxy-lower-alkyl, lower alkenyl, optionally substituted phenyl, hydroxy, lower alkoxy, lower alkoxy-lower alkyl, amino-lower alkyl, lower alkoxy-lower alkoxy, lower alkenyloxy, lower-alkylthio, lower-alkylthxo-lower alkoxy, azo-lower-alkylthio-lower alkyl, azo-lower-alkylthio-lower alkyl, lower alkylene-amino-lower, thio-lower-alkyl, lower-alkylenamino, hydroxy-lower-alkylene-lower-alkyl, lower alkylenamino, hydroxy-lower alkylene-lower-alkyl, lower alkyleneamino, hydroxy-lower alkylene-lower-alkyl, lower alkyleneamino, hydroxy-loweralkylene Carbaraoyl, lower alkylamino, di-lower alkylamino / optionally substituted phenylthio, acylamino, lower alkyl

sulfonyl or lower alkoxycarbonyl.

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or identical substituted pyridyl of the formula

in which.

R, halogen, cyano, nitro, lower alkyl, hydroxy lower alkyl, Lower alkenyl, optionally substituted phenyl, hydroxy, lower alkoxy, lower alkoxy-lower alkyl, Lower alkoxy lower alkenyl, lower alkoxy lower alkoxy, lower alkylthio lower alkyl, Lower alkenyloxy, lower alkylthio, lower alkylthio lower alkoxy, lower alkylenamino, hydroxy lower alkylenamino, Oxaniederalkylenamino, Thianiederalkylenamino, Azaniederalkylenamino, Niederalkylamino, Diiederalkylamino, Acylamino, acylamino lower alkyl, acylamino lower alkenyl, Amino-lower alkyl, optionally substituted carbamoyl, optionally substituted carbamoyl-lower alkyl or lower alkylsulfonyl and

η is 1, 2 or 3, where η is 2 or the substituents R 1 can also be of different types. Condensation products of compounds of the formula I with an aldehyde or ketone are those of the formula Iy

Het - 0 - CH - CH - CH (I),

Il

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where Het, R , R - have the above meanings and X is the divalent radical of an aldehyde or ketone. Suitable ketones are, for example, lower alkanones, such as acetone. Suitable aldehydes are, for example, lower alkanals, such as those with up to 7 carbon atoms, in particular up to 4 carbon atoms, such as acetaldehyde or especially formaldehyde, also aryl lower alkanals, such as phenyl lower alkanals, which are optionally substituted in the phenyl part by lower alkyl, lower alkoxy, Halogen or trifluoromethyl groups are substituted, but are preferably unsubstituted and in which the lower alkanal part has in particular the above meaning, such as benzaldehyde. -

Condensation products of compounds of the formula I with carbonic acid are those of the formula Iz.

Het - O - CH - CH - CH (Iz),

OR.
• · 1

wherein Het, R ₁ ; R _g ^ have the above meanings.

The new compounds have valuable pharmacological properties. The main effect of the substituted pyridines, pyrazines '

and pyrimidine consists in a blockade of adrenergic f1 receptors, which can be demonstrated, for example, as a hemispherical effect against the effects of known β-receptor stimulators in various organs: inhibition of isoproterenol tachycardia in isolated guinea-pig hearts and the Isoproterenol relaxation at the j

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isolated guinea pig trachea at concentrations of 0.001 to 3 μβ / ml, inhibition of isoproterenol tachycardia and vasodilation in the anesthetized cat with intravenous administration of 0.01 to 30 mg / kg IV. The compounds mentioned either belong to the class of non- cardioselective β-receptor blockers, ie they block the β-receptors on the vessels or in the trachea at doses or concentrations that are similar or even smaller than those. ß-receptors in the heart, or they belong to the class of so-called cardioselective ß-receptor blockers, i.e. they block the ß-receptors of the heart in a dose or concentration range that does not yet block the ß-receptors in the vessels or causes in the trachea. As an additional property, some of these compounds have a so-called "intrinsic sympathominetic activity (ISA) ¹¹ , that is, these compounds cause, in addition to the ß-blockade (= main effect), a partial ß-stimulation. The main effect of unsubstituted pyrazine and pyrimidine consists in one Stimulation of the adrenergic ß-receptors, which can be demonstrated as positive inotropic and positive chronotropic effects on the heart, for example. The compounds mentioned increase the heart rate and myocardial contraction force in isolated guinea pig atria in concentrations of 0.01 to µg / ml and in the anesthetized cat when intravenous Administration of 0.001 to 0.1 mg / kg IV. In concentrations that are significantly higher than those required for ß-stimulation, these compounds also have ß-receptor-blocking properties

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on "2- (2'-Hydroxy-3'-isopropylarainopropoxy) -pyrimidine and 2- (2'-Hydroxy-3'-ispropyl-aminopropoxy) -pyrazine differ qualitatively clearly from known ß-receptor stimulators in that they are at the Anesthetized cats can only lower the arterial blood pressure at a dose of 1 mg / kg iv, i.e. in a dose range that is significantly higher than that required for an increase in myocardial contraction force and heart rate. In the isolated guinea pig chentrachea, the compounds in a concentration of 10 μg / inl do not yet have a relaxing effect. Because of this property, these compounds can be referred to as cardioselective R- receptor stimulators. The new compounds can therefore be used for the treatment of diseases of the cardiovascular system. The ft receptor blockers can be used, for example, for the treatment of angina pectoris, hypertension and cardiac arrhythmias. The cardioselective preparations have the advantage over the non-cardioselective ones that in the doses which are required to block the α-receptors of the heart, no blockage of β-receptors in other organs is to be expected. The risk of causing undesirable side effects, such as bronchospasm, is therefore very low. In contrast to the cardioselective preparations, the non- cardioselective preparations either block the ß-receptors - somewhat equally in all organs, or preferentially in certain organs (such as in the blood vessels).

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The ß-Re2, eptorenstimulatoren can be used as cardiotonics for the treatment of heart muscle insufficiency (alone or in combination with other preparations such as cardiac glycosides). Compared to known β-receptor stimulators, these compounds have the following advantages: Due to the pharmacologically proven cardioselectivity, it can be expected that the myocardial contraction force will be increased without an undesired decrease in blood pressure at the same time. Furthermore, only an insignificant increase in heart rate is to be expected because the reflex tachycardia that occurs as a result of a drop in blood pressure is eliminated. However, they can also be used as valuable intermediates for the production of other useful substances, in particular pharmaceutically active compounds.

ι ι

For compounds of formula I in which Het is optionally substituted pyrazinyl, formula I represents, for example, compounds of the general formula Ia

CH.

0-0H ₂ -CH (OH) -CH ₂ -MCR ₂ "(Ia)

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and their condensation products with aldehydes, ketones or Carbonic acid and the corresponding N-oxides in which

R, and Rp have the same meanings as above, R-, hydrogen, halogen, cyano, hydroxy, lower alkyl, Lower alkoxy lower alkyl, amino lower alkyl, lower alkoxy lower alkenyl, Lower alkylamine, di-lower alkylamino, acylamino, acylamino lower alkyl, acylamino lower alkenyl or Is lower alkylsulfonyl and

Rjl hydrogen, halogen, lower alkyl, hydroxy lower alkyl, Lower alkenyl, optionally substituted phenyl, hydroxy, lower alkoxy, lower alkoxy-lower alkyl, amino-lower alkyl, Lower alkoxy lower alkoxy, lower alkenyloxy, lower alkylthio, lower alkylthio lower alkoxy, lower alkylthio lower alkyl, Lower alkylenamino, hydroxy-lower alkylenamino, oxaniederalkylenamino, thianiederalkylenamino, aza-loweralkylenamino if substituted carbamoyl, lower alkylaminOi di-lower alkyl

-*1

amino, optionally substituted phenylthio, acylamino, lower alkylsulfonyl or lower alkoxycarbonyl.

Above and below, a lower radical is in particular a .solcher radical with up to 7 carbon atoms, especially understood up to 4 carbon atoms.

Lower alkyl radicals are radicals with preferably up to. 7 carbon atoms, especially up to 4 carbon atoms and are e.g. methyl, ethyl, n-propyl, i-propyl or unbranched or any Place bound or branched butyl, pentyl, hexyl

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or heptyl.

In the lower alkyl part, hydroxy-lower alkyl preferably has up to 7 carbon atoms, especially up to 4 carbon atoms, and is e.g. 3-hydroxy-propyl, 2-hydroxy-propyl, 1-methyl-2-hydroxyethyl or hydroxybutyl, hydroxypentyl, hydroxyhexyl, unbranched or bound or branched at any point, Hydroxyheptyl and especially hydroxymethyl and 2-hydroxyethyl.

Lower alkenyl preferably has up to 7 carbon atoms and especially up to 4 carbon atoms, such as vinyl, 2-methylvinyl, methallyl and especially allyl.

Suitable substituents for optionally substituted phenyl are halogen, trifluoromethyl, lower alkyl, Lower alkenyl, lower alkoxymethyl, lower alkoxy and lower alkenyloxy. Optionally substituted phenyl is thus primarily phenyl, chlorophenyl, bromophenyl, trifluorraethylphenyl, Tolyl, methoxymethylphenyl, methoxyphenyl, ethoxyphenyl and allyloxyphenyl.

Lower alkoxy radicals preferably have up to 7 carbon atoms, especially up to 4 carbon atoms, such as ethoxy, propoxy, i-propoxy, straight or branched butyl, pentyl, hexyl or heptyloxy bonded at any point or above especially methoxy.

Lower alkoxy-lower alkyl preferably has up to 7 carbon atoms in the lower alkyl part of the lower alkoxy part, in particular up to 4 carbon atoms, such as iso- or n-propyl, straight or branched, Butyl, pentyl, hexyl bound in any position

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or heptyl, especially ethyl and especially methyl. The den Lower alkyl part bearing lower alkoxy part preferably has up to 7 carbon atoms, in particular up to 4 carbon atoms. For example lower alkoxy lower alkyl is methoxymethyl, 2-ethoxyethyl, 3-methoxy-n-propyl, 3-ethoxy-n-propyl, 4-methoxy-n-butyl or especially 2-methoxyethyl and ethoxymethyl.

Niederalkoxyniederalkenyl are lower alkenyl radicals with preferably up to 7 carbon atoms and especially up to 4 carbon atoms, which are substituted at any point by lower alkoxy. Lower alkoxy has preferred in the lower alkyl part up to 7 carbon atoms and especially up to 4 carbon atoms. Lower alkoxy-lower alkenyl is therefore preferably 2-methoxyvinyl, 2-ethoxyvinyl and especially 3-methoxyallyl and 3-ethoxyallyl.

Lower alkenyloxy radicals are radicals with preferably up to 7 carbon atoms, in particular with 3 or 4 carbon atoms, such as the methallyloxy or especially allyloxy radical.

Lower alkoxy-lower alkoxy has in each of the lower alkyl parts up to 7 carbon atoms, especially up to 4 carbon atoms and is e.g. methoxymethoxy, ethoxymethoxy, 2-methoxy-ethoxy, 4-methoxy-n-butoxy and especially 3-methoxy-n-propoxy.

Lower alkylthio radicals preferably have up to 7 carbon atoms, especially up to 4 carbon atoms, such as ethylthio, n-propylthio, n-butylthio, i-propylthio or especially methylthio. .

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Lower alkylthione have lower alkoxy radicals in the two Lower alkyl parts preferably each have up to 7 carbon atoms all up to 4 carbon atoms, such as methylthiomethoxy, Ethylthiomethoxy, propylthiomethoxy, 3-methylthiopropoxy, 3-ethylthiopropoxy, 3-propylthiopropoxy and especially 2-methylthioethoxy, 2-ethylthioethoxy and 2-propylthiopropoxy.

Lower alkylthio lower alkyl has each in the lower alkyl parts up to 7 carbon atoms, especially up to 4 carbon atoms and is e.g. methylthiomethyl, ethylthiomethyl, 3-methylthiopropyl, 4-methylthiobutyl and especially 2-methylthioethyl, 2-ethylthioethyl or 2- (n-propylthio) ethyl.

Lower alkylamino radicals are radicals with preferably up to 7 carbon atoms, in particular up to 4 carbon atoms, such as ethyl, propyl, i-propyl, straight or branched butyl, pentyl, hexyl or bonded at any point Heptylamino or especially methylamino.

Di-lower alkylamino radicals are radicals with preferably up to 7 carbon atoms, in particular up to 4 carbon atoms, in each of the lower alkyl moieties. The two lower alkyl radicals are independent of one another and, together with the nitrogen atom, form radicals such as, for example, diethyl, methylethyl, diethyl, dipropyl, dibutylamino or, in particular, dimethylamino.

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Lower alkyleneamino radicals are radicals with, for example, 4 to 8 ring members, the lower alkylene part being branched or in particular straight-chain lower alkylene is with particular 3-7, especially 4-6 carbon atoms in the alkylene chain. Examples are pyrrolidino or piperidino.

Hydroxy-lower alkyleneamino radicals are radicals with, for example, 4-8 ring members, the hydroxy-substituted lower alkylene part is branched or, in particular, straight-chain lower alkylene, with in particular 3-7, especially 4-6, carbon atoms in the alkylene chain. Examples are 4-hydroxypiperidino or 3-hydroxypyrrqlidino.

Oxaniederalkylenamino is branched or in particular straight-chain oxaniederalkylenamino with in particular 4 or 5 carbon atoms in the oxaalkylene chain. Morpholino, in particular, should be mentioned as an example.

Thianiederalkylenamino is branched or, in particular, straight-chain thianiederalkylenamino with in particular 4 or 5 carbon atoms in the thiaalkylene chain. As examples are in particular thiomorpholines and 2,6-dimethylthiomorpholino to call. - -

Azaniederalkylenamino is branched or in particular straight-chain azaniederalkylenamino with in particular 2-6, especially 4-6 carbon atoms in the azaalkylene chain. Examples are piperazino, N'-methylpiperazino or N '- (ß-HydroxyMthyl) -piperaz ± no. ·

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Acylamino is e.g. lower alkanoylamino with up to 7 carbon atoms and especially up to 4 carbon atoms in the lower alkyl part or optionally substituted aroylamino, such as optionally substituted benzoylamino or optionally substituted aryl-lower alkanoylamino or lower alkoxycarbonylamino.

Lower alkanoylnminor groups are e.g. n-propionylamino, n-butyrylamino, n-valerylamino, n ~ hexanoylamino, n-heptanoylamino or especially acetylamino. Optionally substituted benzoylamino radicals are, for example, benzoylamino or Lower alkoxybenzoylamino, v? Ie n-propoxybenzoylamino and above all methoxy and ethoxybenzoylamino, or lower alkylbenzoylamino, such as n-propyl, straight or branched, butyl, pentyl, hexyl or bonded in any position Heptylbenzoylamino and especially methyl- and ethylbenzoylamino, or trifluoromethylbenzoylamino or halobenzoylamino, many fluoro-, bromo- and very particularly chlorobenzoylamino. Optionally substituted aryl lower alkanoylamino radicals are Niederalkanoylaminpreste, which at any Place of the lower alkyl part e.g. carry optionally substituted phenyl groups. The phenyl groups can be the same As mentioned above for optionally substituted benzoylamino radicals, they carry substituents. As examples of Optionally substituted aryl-lower alkanoylamino are especially phenylacetyiamino, 3-phenyl-n-propionylamino, 4-phenyl-n-butyrylamino, chlorophenylacetylamino and

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Bromophenylacetylamino to be mentioned. Lower alkoxycarbonylamino In the lower alkyl part of lower alkoxy, it preferably has up to 7 carbon atoms and especially up to 4 carbon atoms and is, for example, n-propoxycarbonylamino, n-butoxycarbonylaniino, i-propoxycarbonylamino, tert-butoxycarbonylamino and above especially methoxycarbonylamino and ethoxycarbonylamino.

-Acylamino lower alkyl radicals are lower alkyl radicals

with preferably up to 7 carbon atoms and especially up to 4 carbon atoms, which are in any place by acylamino radicals are substituted. Acylamino is, for example, lower alkanoylamino with up to 7 carbon atoms and especially up to 4 carbon atoms in the • lower alkyl part or optionally substituted aroylamino, such as optionally substituted benzoylamino or optionally substituted aryl-lower alkanoylamino or Lower alkoxycarbonylamino. ';' · - ·

Lower alkanoylamino radicals are, for example, n-propionylamino, n-butyrylamino, n-valerylamino, n-hexanoylamino, n-heptanoylamino or, above all, acetylamino. Optionally substituted benzoylamino radicals are, for example, benzoylamino or ^{lower alkox3 T} benzoylamino, such as n-propoxybenzoylamino and especially methoxy- and ethoxybenzoylamino, or lower alkylbenzoylamino, such as n-propyl, straight or branched butyl, or pentyl, hexyl, attached in any position Heptylbenzoylamino and especially methyl and ethylbenzoylamino, or trifluoromethylbenzoylamino or halobenzoylamino. amino, such as fluorine, bromine and especially chlorobenzoylamino. Optionally substituted aryl lower alkanoylamino radicals are lower alkanoylamino radicals attached to any

IB

Position of the lower alkyl part ζ.Έ>. - optionally carry substituted phenyl groups. The phenyl groups can have the same

carry chen substituents, V7ie mentioned above for optionally substituted benzoylamino radicals. Examples of optionally substituted aryl-lower alkanoylamino are especially phenylacetylamino, 3-phenyl-n-propionylamino, 4-phenyl-n-butyrylamino, chlorophenylacetylamino and bromophenylamino . Lower alkoxy carbonylatnino preferably in the lower alkyl lower alkoxy of up to 7 carbon atoms, and especially up to 4 carbon atoms and is, for example, n ~ propoxycarbonylamino, n-butoxycarbonylamino, i-propoxy carbonylamino, tert .- * butoxycarbonylamino and before allera methoxycarbonylamino and Ethoxycarbonylamino. As examples of Acylaminoniederalkylreste are therefore especially acetylaminomethyl, 2-acetylamino-a'thyl, benzoylaminomethyl, 2-Benzoylaminoäthyl, Methoxybenzo} ^T l ~ aminomethyl, 2-Methoxybenzoylaminoäthyl, Aethoxybenzoyl- aminomethyl, 2-Aethoxybenzoylaminoäthyl, methylbenzoyl aminomethyl, 2-Methylbenzoylaminoäthyl , Ethylbenzoyl aminomethyl, 2-ethylbenzoylaminoethyl, chlorobenzoylaminomethyl, 2-chlorobenzoylaminoethyl, phenylacetylaminomethyl , 2-phenylacetylaminoethyl, chlorophenylacety1-

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aminomethyl, 2-chlorophenylacetylamioethyl, kethoxycarconylaminoraethyl, Ethoxycarbonylaminomaühyl, 2-methoxycarbonylaminoethyl, Mention should be made of 2-ethoxycarbonylaminoethyl, 3-acetylaminopropyl and 3-methoxycarbonylaminopropyl.

Acylamino lower alkenyl preferably carries up to 7 carbon atoms and especially up to 4 carbon atoms in the lower alkenyl part while acylamino e.g. lower alkanoylamino, optionally substituted benzoylamino or optionally substituted Is phenyl lower alkanoylamino or lower alkoxycarbonylamino. As examples of acylamino-lower alkenyl are above all 2-acetylaminovinyl, benzoylaminovinyl, phenylacetylaminovinyl, 3-acetylaminoall yl, 3-benzoylaminoallyl, 3-phenylacetylaminoall yl and 3-methoxycarbonylaminoallyl.

Optionally substituted phenylthio is, for example, phenylthio or by halogen, trifluoromethyl, lower alkyl or lower alkoxy substituted phenylthio and is therefore mainly phenylthio, chlorophenylthio, bromophenylthio, trifluoromethylphenylthio, Methylphenylthio, methoxyphenylthio or ethoxyphenylthio.

Lower alkoxy carbonyl preferably has up to in the lower alkyl part to 7 carbon atoms and above all up to 4 carbon atoms and is above all Methoxycarbonyl and ethoxycarbonyl. ' Amino lower alkyl preferably has up to 7 carbon atoms and especially up to 4 carbon atoms in the lower alkyl part and is above all Aminomethyl, 2-aminoethyl and 3-aminopropyl. Halogen is fluorine, bromine and especially chlorine.

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Lower alkylsulfonyl radicals are radicals with preferably up to 7 carbon atoms, in particular up to 4 carbon atoms, such as ethyl, propyl, iso-propylsulfonyl, straight or branched Butyl, pentyl, hexyl or heptylsulphonyl or, in particular, methylsulphonyl bound at any point. Carbamoyl which is optionally substituted is, for example, carbamoyl, N-lower alkylaminocarbonyl with preferably up to 7 carbon atoms in the lower alkyl part, especially with up to 4 carbon atoms, N, N-di-lower alkylaminoearbonyl with preferably up to ζμ 7 carbon atoms in each of the lower alkyl parts, especially with up to 4 carbon atoms in each of the lower alkyl moieties, lower alkylenaminocarbonyl with preferably 4 to 8 ring members, especially with 5-7 ring members, hydroxy lower alkylenaminocarbonyl with preferably 4-8 ring members, especially with 3-7 ring members, oxaniederalkylenaminocarbonyl with preferably 4 or 5 carbon atoms in the oxaalkylene chain, Thianiederalkylenaminocarbonyl with preferably 4 or 5 carbon atoms in the thiaalkylene chain, aza-loweralkylenaminocarbonyl with 4 or 5 carbon atoms in the azaalkylene chain. Optionally substituted carbamoyl is therefore above all carbamoyl, methylaminocarbonyl, Ethylaminocarbonyl, n-propylaminocarbonyl, n-butylaminocarbonyl, tert-butylaminocarbonyl, N, N-dimethylaminocarbonyl, Ν, Ν-diethylaminooarbonyl, N, N- (di-n-propylamino) -carbonyl, Pyrrolidineafbonyl, piperidinocarbonyl, 4-hydroxypiperidinocarbonyl, Morpholinocarbonyl, thiomorpholinocarbonyl, 2,6-dimethylthiomorpholinocarbonyl, piperazinocarbonyl, N'-methylpiperazinocarbonyl or N '- (ß-hydroxyethyl) piperazinocarbonyl.

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Pur compounds of the formula I in which Het optionally is substituted pyridazinyl, formula I represents z.3. Compounds of the general formula Ib

R "-h -14-C-CH-CH (OH) -CH -M-3 Γ ΪΓ 2 2

and their condensation products with aldehydes, ketones or carbonic acid and the corresponding N-oxides, wherein

R, Rp, R, and R _{1 have} the same meanings as above.

For compounds of the formula I in which Het is optionally substituted pyrimidinyl, formula represents I e.g. compounds of the general formula Ic

^R l

and their condensation products with aldehydes, ketones or carbonic acid and the corresponding N-oxides, wherein

Rp R ₂ , RJ and R, the same meanings as

have up.

For compounds of formula I in which Het is substituted pyridyl, formula I represents, for example, compounds the general formula Id

-CH (OH) -CH-HH-CR ( _Id )

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()H

409834/1110

and their condensation products with aldehydes, ketones, or

Carbonic acid and the corresponding N-oxides, in which R- and Ry have the above meanings,

Ro halogen, cyano, nitro, lower alkyl, hydroxy lower alkyl, Lower alkenyl, optionally substituted phenyl, hydroxy, lower alkoxy, lower alkoxy-lower alkyl, Lower alkoxy lower alkenyl, lower alkoxy lower alkoxy, lower alkylthio lower alkoxy, Lower alkenyloxy, lower alkylthio, lower alkylthio lower alkyl, lower alkylenamino, hydroxy lower alkylenaraino, Oxaniederalkylenamino, Thianiederalkylenatnino, Azaniederalkylenamino, Niederalky3.amino, Diniederalkylamino, Acylamino, acylamino lower alkyl, acylamino lower alkenyl, Amino-lower alkyl, optionally substituted carbaraoyl, optionally substituted carbamoyl-lower alkyl, or lower alkylsulfonyl and

η is 1, 2 or 5, with η being 2 or 3 the substituents FL · also being different can.

Above and below, a lower radical is understood to mean, in particular, such a phase with up to 7 carbon atoms, especially up to 4 carbon atoms.

Lower alkyl radicals are radicals with preferably up to 7 carbon atoms, especially up to 4 carbon atoms and are e.g. methyl, Ethyl, n-propyl, i-propyl or unbranched or any Place bound or branched butyl, pentyl, hexyl or heptyl.

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Hydroxy lower alkyl has preferably in the lower alkyl part up to 7 carbon atoms, especially up to 4 carbon atoms and is e.g. 3-hydroxypropyl, 2-hydroxypropyl, 1-methyl-2-hydroxyethyl or hydroxybutyl, hydroxypentyl, hydroxyhexyl, unbranched or bound or branched at any point, llydr'oxyheptyl and especially hydroxymethyl and 2-hydroxyethyl.

Lower alkenyl preferably has up to 7 carbon atoms and especially up to 4 carbon atoms, such as vinyl, 2-methylvinyl, methallyl and especially allyl,

Suitable substituents for optionally substituted phenyl are halogen, trifluoromethyl, lower alkyl, Lower alkenyl, lower alkoxymethyl, lower alkoxy and lower alkenyloxy. Optionally substituted phenyl is thus especially phenyl, chlorophenyl, bromophenyl, trifluoromethylphenyl, tolyl, methoxymethylphenyl, methoxyphenyl, ethoxyphenyl and allyloxyphenyl,

Lower alkoxy radicals preferably have up to 7 carbon atoms, especially up to 4 carbon atoms, such as ethoxy, propoxy, i-propoxy, straight or branched, bonded at any point Butyl, pentyl, hexyl or heptyloxy or above especially methoxy. ■

409834/1136

Lower alkoxy-lower alkyl has in the lower alkyl part of the lower alkoxy part preferably up to 7 carbon atoms, especially up to 4 carbon atoms, such as iso ~ or n-propyl, straight or branched, Butyl, pentyl, hexyl or Ileptyl bound in any position, especially ethyl and especially methyl. The den Lower alkyl part bearing NiederalkoxytGil preferably has up to 7 carbon atoms, especially up to 4 carbon atoms. For example is lower alkoxy-lower alkyl, methoxymethyl, ethoxymethyl, 3-methoxy-n-propyl, 3-ethoxy-n-propyl, 4-methoxy-n-butyl or especially 2-methoxyethyl and 2-ethoxyethyl.

Lower alkoxy-lower alkenyl are lower alkenyl radicals with preferably up to 7 carbon atoms and especially up to 4 carbon atoms, which are substituted at any point by lower alkoxy are. Lower alkoxy preferably has up to 7 carbon atoms in the lower alkyl part. and above all up to .4 carbon atoms, lower alkoxy-lower alkenyl is therefore preferably 2-methoxyvinyl, 2-ethoxyvinyl and especially 3-methoxyallyl and 3-ethoxyallyl. "

Lower alkenyloxy radicals are radicals with preferably up to 7 carbon atoms, in particular with 3 or 4 carbon atoms, such as the methallyloxy or especially allyloxy radical.

Lower alkoxy-lower alkoxy has up to 7 carbon atoms in each of the lower alkyl parts, especially up to 4 carbon atoms and is e.g. methoxymethoxy, ethoxymethoxy, 2-methoxy-ethoxy,

4-methoxy-n-butoxy and especially 3-methoxy-n-propoxy.

409834 / 113G

Lower alkylthio-lower alkoxy has in the lower alkyl parts each up to 7 carbon atoms, especially up to 4 carbon atoms and is e.g. methylthiomethoxy, ethylthiomethoxy, 3-methylthiopropoxy, 4-Methyithiobutoxy and especially 2-Methylthio-

ethoxy, 2-ethylthioethoxy or 2- (n-propylthio) ethoxy.

Niedcralkylthiorestc preferably have up to 7 C atoms, especially up to 4, carbon atoms, such as ethylthio, n-propylthio, n-butylthio, i-prop3 ^r lthio or, in particular methylthio.

Lower alkylthio has lower alkyl in the lower alkyl portions each up to 7 carbon atoms, especially up to 4 carbon atoms and is e.g. mathylthiomethyl, ethylthiomethyl, 3-mathylthiopropyl, 4-methylthiobutyl and especially 2-methylthioethyl, 2-ethylthioethyl or 2- (n-propylthio> -ethyl.

Lower alkylamino radicals are radicals with preferably up to 7 carbon atoms, in particular up to 4 carbon atoms, such as e.g. Ethyl, propyl, i-propyl, straight or branched, on Any point bound butyl, pentyl, hexyl or lleptylamino or especially methylamines

Di-lower alkylamino radicals are radicals with preferably up to 7 carbon atoms, in particular up to 4 carbon atoms in each of the Lower alkyl parts. The two lower alkyl radicals are independent of one another and form together with the nitrogen atom Residues such as diethyl, methylethyl, dipropyl, dubutylamino or especially dimethylamino.

409834/1130

Lower alkyleneamino radicals are radicals with, for example, 4 to 8 ring members, the lower alkylenecile being branched or in particular straight-chain lower alkyl is particularly

their 3-7, especially 4-6 carbon atoms in the alkylene chain. Examples are pyrrolidino or piperidino.

Hydroxynicderalkylenamino radicals are radicals with, for example, 4-8 ring members, the hydroxy-substituted lower alkylene moiety branched or especially straight-chain "^ .._ Kiedcralkylen has in particular 3-7, especially 4-6 carbon atoms in the alkylene chain. Examples are 4-hydroxypiperidino or 3-hydroxypyrrolidino.

Oxaniederalkylenamino is branched or in particular straight-chain oxaniederalkylenamino with in particular 4 or 5 carbon atoms in the oxaalkylene chain. As an example is to mention in particular morpholino.

Thianiederalkylenami.no is branched or particular straight-chain thiane-lower alkyleneamino with in particular 4 or 5 carbon atoms in the thiaalkylene chain. As examples are in particular thiomorpholines and 2,6-dimethylthiomorpholino to call.

Aza-lower alkylenamino is branched or, in particular, straight-chain aza-lower alkylenamino with in particular 2-6, especially 4-6, carbon atoms in the azaalkylene chain. Examples are piperazino. N ¹ -methylpiperazino or N '- (ß-hydroxyethyl) -piperazino.

409834/1130

Acylamino is e.g. lower alkanoylamino with up to 7 carbon atoms and especially up to 4 carbon atoms in the lower alkyl part or optionally substituted aroylamino, such as optionally substituted benzoylamino or optionally substituted aryl-lower alkanoylamino or lower alkoxycarbonylamino.

Lower alkanoylnminor groups are e.g. n-propionylamino, n-butyrylamino, n-valerylamino, n ~ hexanoylamino, n ~ lleptanoylamino or especially acctylamino. Optionally substituted benzoylamino radicals are, for example, benzoylamino or Lower alkoxybenzoylami.no, such as n-propoxyb.enzoylamino and above all methoxy and ethoxybenzoylamino, or lower alkylbenzoylamino, such as n-propyl, straight or branched butyl, pentyl, llexyl or Heptylbenzoylamino and especially methyl- and ethylbenzoylamino, or trifluorotethylbenzoylamino or llalobenzoylamino. like fluorine. Bromo- and especially chlorobenzoylamino. Optionally substituted aryl lower alkanoylamino radicals are lower alkanoylamine radicals which. at any Instead of the lower alkyl part, for example, carry optionally substituted phenyl groups. The Pheny! Groups can do the same Carry substituents, as above for optionally sub-

409834/1130

-ν-

substituted benzoylamino radicals mentioned. Examples of optionally substituted Arylniecicralkanoylamino are especially phenylacetylamino, 3-phenyl-n-propionylamino, 4-phenyl-n-butyrylamino, chlorophenylacetylamino and Bromophenylacetylamino to be mentioned. Lower alkoxycarbonylarai.no preferably has in the lower alkyl part of lower alkoxy up to 7 carbon atoms and especially up to 4 carbon atoms and is e.g. n ~ Propoxycarbonylann.no, n-Butoxycarbonylamino, i-Propoxycarbonylamino, tert-Butoxycarbonylainino and above especially Hethoxycarbonylamino and Aethoxycarbonylamino.

Acylamino lower alkyl radicals are lower alkyl radicals with preferably up to 7 carbon atoms and especially up to 4 carbon atoms in any position by acylamino radicals are substituted. Acylamino is e.g. lower alkanoylamino with up to 7 carbon atoms and especially up to 4 carbon atoms in the • lower alkyl part or optionally substituted aroylamino, such as optionally substituted benzoylamino or optionally substituted aryl-lower alkanoylamino or Lower alkoxycarbonylarrd.no. ■

Lower alkanoylamino radicals are e.g. n-propionylamino, n-butyrylamino, n-valerylamino, n-hexanoylamino, n-heptanoylamino or especially acetylamino. Optionally substituted benzoylamino radicals are, for example, benzoylamino or

409834/1130

Lower alkoxybenzoylaiTri.no, like n ~ propoxybenzoylamino and above especially methoxy and aethoxybenzoylamino, or lower alkyl. benzoylamino, such as n-propyl, straight or branched, in Any point attached butyl, pentyl, ilexyl or Heptylbenzoylamino and especially methyl- and ethylbenzoylamino, or Trifluorniethylbenzoylamino or Jlalobcnzoylainino, V7ic fluoro-, bromo- and especially chlorobenzoylamino. Optionally substituted aryl lower alkanoyl groups are lower alkanoylamino groups In place of the lower alkyl part, for example, optionally substituted phenyl groups. The Pheny! Groups can do the same Wear substituents, as mentioned above for optionally substituted benzoylamino radicals. As examples for optionally substituted Arylniederalkanoylami.no are especially phenylacetylamino, 3-phenyl-n-propionylamino, 4-phenyl-n-butyrylamino, chlorophenylacetylamino and Bromophenylacetylamino to be mentioned. Lower alkoxycarbonylamino has vorzugswcise in the lower alkyl part of lower alkoxy up to 7 carbon atoms and especially up to 4 carbon atoms and is e.g. n-propoxycarbonylamino, n-butoxycarbonylamino, i-propoxycarbonylamino, tert-butoxycarbonylamino and above especially methoxycarbonylamino, and ethoxycarbonylamino. as

409834/1130

Examples of acylamino-lower alkyl radicals are acmnach especially acetylamino-ethyl, 2-acetylamino-ethyl ,. Benzoylaminomethyl, 2-benzoylaminoethyl, kethoxybenzoylarainomethyl, 2-methoxybenzoylaminoethyl, ethoxybenzoylaminomethyl, 2-ethoxybenzoylaminoethyl, methylbenzoyl-

• aminomethyl, 2 ~ _l Methylbenzoyl.arainoäthyl Aethylbenzoylaminomethyl, 2-Aethylbenzoylaminoäthyl, Cblorbenzoylaminomethyl, 2-Chlorbc? Nzoj ^r laminoiithyl, Phcnylacctylaminomethyl, 2-Phenylacetylaminoäthyl, 3-acetylaminopropyl, 3-Methoxycarbonylaminopropyl, methoxycarbonylaminomethyl, Aethoxycarbonylaminomethyl, 2 ~ Methoxycarbonylaminoäthyl and 2-Aethoxycarbonylaminoäthyl to call.

Acylamino lower alkenyl carries in the lower alkenyl part preferably up to 7 carbon atoms and especially up to 4 carbon atoms ^ while acylamino e.g. lower alkanoylamino, optionally substituted benzoylamino or optionally substituted Phenyl lower alkanoylamino or lower alkoxycarbonylamino is. As examples of acylamino-lower alkenyl are above all 2-acetylaminovinyl, benzoylaminovinyl, phenylacetylarainovinyl, 3-acetylaminoall yl, 3-benzoylaminoallyl, 3-phenylacetylaminoallyl and 3-methoxycarbonylaminoallyl.

In the lower alkyl part, amino lower alkyl preferably has up to 7 carbon atoms and especially up to K carbon atoms and is above all aminomethyl, 2-aminoethyl and 3-aminopropyl.

Optionally substituted carbamoyl, e.g.

Carbamoyl, N-lower alkylaminocarbonyl with preferably up to

ΔΩ9834/1130

7 carbon atoms in the lower alkyl part, especially with up to 4 carbon atoms, Ν, Ν-di-lower alkylaminocarbonyl with preferably up to 7 carbon atoms in each of the lower alkyl parts, especially with up to 4 carbon atoms in each of the lower alkyl parts, lower alkylenaminocarbonyl with preferably 4 to 8 ring members, especially with 3-7 ring members, hydroxy lower alkylenaminocarbonyl with preferably 4-8 ring members, especially with 3-7 ring members, oxaniederalkylenaminocarbonyl with preferably 4 or 5 carbon atoms in the oxaalkylene chain, thianiederalkylenaminocarbonyl with preferably 4. or 5 carbon atoms in the thiaalkylene chain, aza-lower alkylenaminocarbonyl with 4 or 5 carbon atoms in the azaalkylene chain. Optionally substituted carbamoyl is accordingly above all carbamoyl, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, n-butylaminocarbonyl, tert-butylaminocarbonyl, Ν, Ν-dimethylaminocarbonyl, N, N "diethylaminocarbonyl, N, N- (di-n-propylamino) - carbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, 4-hydroxypiperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, 2,6-dimethylthiomor.pholinocarbonyl, piperazinocarbonyl, N ¹ -methylpiperazinocarbonyl or N * - (ß-hydroxyMthyl) -plperazinocarbonyl.

Optionally substituted carbamoyl lower alkyl preferably carries up to 7 carbon atoms in the lower alkyl part, and above all up to 4 carbon atoms and, as the carbamoyl part, the carbamoyl given above for any -Q if substituted and is e.g. *

CD -

co carbamoylmethyl, 2-carbamoylethyl, methylamlnocarbonylmethyl,

^ 2-methylamine / carbonylethyl, dimethylaminocarbonylmethyl,

- »2-dimethylaminocarbonylethyl ₃ piperazinocarbonylmethyl,

° 2-piperazinocarbonylethyl, N ^f -methylpiperazinoearbonylmethyl

or 2- [l \ r'-Methyl-piperazinoearbonylj-ethyl.

Lower alkylsulfonyl radicals are radicals with preferably up to 7 carbon atoms, in particular up to 4 carbon atoms, such as ethyl, Propyl-, iso-propylsulfonyl, straight or branched, on Butyl-, pentyl-, hexyl- or heptylsulfonyl or, in particular, methylsulfonyl bound at any point.

Halogen is fluorine, bromine and especially chlorine.

Of the compounds of type Ia, pyrazines are the Formula Iaa

O-CH ₂ -CH (0H) -CH ₂ -KH-ö-R _2a (Iaa)

and to highlight their condensation products with aldehydes, ketones or carbonic acid and their corresponding pyrazine-N-oxides, wherein R ₁ and R ₇ . have the above meaning, R means lower alkyl with up to 4 carbon atoms, benzyl, halobenzyl, trifluoromethyl

409834/1130

benzyl, lower alkylbenzyl with up to 7 carbon atoms in the lower alkyl part, Lower alkoxytenzyl with up to 7 carbon atoms in the mederalkyl part, Carboxy-lower alkyl with up to 4 carbon atoms in the lower alkyl part, lower alkoxycarbonyl-lower alkyl with up to to 4 carbon atoms in the lower alkyl parts, carbamoyl lower alkyl with up to 4 carbon atoms in the lower alkyl part, lower alkylaminocarbonyl lower alkyl each with up to 4 carbon atoms in the lower alkyl parts, di-lower alkylaminocarbonyl lower alkyl with each up to 4 carbon atoms in the lower alkyl parts, pyrrolidinocarbonyl lower alkyl, Piperazinocarbonyl lower alkyl, N'-methylpiperazinocarbonyl lower alkyl, N '- (ß-hydroxyethyl) piperazinocarbonyl lower alkyl, morpholinocarbonyl lower alkyl, thiomorpholinocarbonyl lower alkyl, 2,6-dimethylthiomorpholinocarbonyl lower alkyl with up to 7 carbon atoms in the lower alkyl part or cyano-lower alkyl with up to 4 carbon atoms in the lower alkyl part, R means hydrogen, hydroxy, lower alkyl with up to 7 carbon atoms, lower alkenyl with up to 7 carbon atoms, halogen, Lower alkylamino with up to 7 carbon atoms, di-lower alkylamino with up to 7 carbon atoms in each of the lower alkyl parts, pyrrolidino, piperidino, 4-hydroxypiperidino, morpholino, thiomorpholino, 2,6-dimethylthiomorpholino, lower alkoxy with up to 7 carbon atoms, lower alkenyloxy with up to 7 carbon atoms, lower alkoxy-lower alkyl with up to 4 carbon atoms each in the lower alkyl parts, Lower alkoxy-lower alkoxy with up to 4 carbon atoms in each of the lower alkyl parts, lower alkylthio with up to 7 carbon atoms, lower alkylthio lower alkoxy with up to

409834/1130

7 carbon atoms in each of the lower alkyl parts, lower alkanoylatnino with up to 7 carbon atoms in the lower alkyl part or lower alkoxycarbonylamino with up to 7 carbon atoms in the lower alkyl part.

Compounds of the formula lab should also be emphasized

0-CH ₂ -OH (OH) -OH ₂ -IiH-OK _b (lab),

and their condensation products with aldehydes, ketones. or Carbonic acid, where R ,, PL · and R ^ have the above meanings, R ",

means .ι

Lower alkyl with up to 4 carbon atoms, benzyl, carbamoylmethyl, lower alkylaminocarbonylmethyl with up to 7 carbon atoms in the lower alkyl part, di-lower alkylaminocarbonylmethyl with up to 7 carbon atoms each in the lower alkyl parts, pyrrolidino * carbonylmethyl, piperidinocarbonylmethyl, piperazinocarbonylmethyl methyl, N'carbonocarbonyl methyl N ¹ - (β-hydroxy-ethyl) -piperazinocarbonylmethyl, morpholinocarbonylmethyl, thiomorpholinocarbonylmethyl, 2,6-dimethylthiomorpholinocarbonylmethyl or cyanomethyl.

Compounds of the formula Iac should also be emphasized

"0-CH ₀ -CH (OH) -CH-NH-OR ₀ (Iac)

409834/1130

and their condensation products with aldehydes, ketones or Carbonic acid, in which R has the above meaning, R means lower alkyl with up to 4 carbon atoms, benzyl, carbamoylmethyl or cyano-

methyl. R means hydrogen, halogen, cyano, lower alkyl with up to 7 carbon atoms, lower alkoxy-lower alkyl with up to 7 carbon atoms in each of the lower alkyl parts, lower alkoxy-lower alkenyl with up to 4 carbon atoms in the lower alkyl part and up to 4 carbon atoms in the lower alkenyl part, Lower alkanoylamino with up to 7 carbon atoms in the lower alkyl part, lower alkoxycarbonylamino with up to 7 carbon atoms in the lower alkyl part, lower alkanoylamino-lower alkyl with up to 4 carbon atoms in each of the lower alkyl parts, lower alkoxycarbonylamino-lower alkyl with up to 4 carbon atoms in each of the lower alkyl parts, lower alkanoylamino-lower alkenyl with up to 4 carbon atoms in the lower alkyl part and up to 4 carbon atoms in the lower alkenyl part, lower alkoxycarbonylamino-lower alkenyl with up to 4 carbon atoms _; in the lower alkyl part and up to 4 carbon atoms in the lower alkenyl part, R ,, means hydrogen, hydroxy, lower alkyl with up to 4 carbon atoms, lower alkenyl with 3 or 4 carbon atoms, lower alkylamino with up to 4 carbon atoms, di-lower alkylamino with each up to 4 carbon atoms in the lower alkyl parts, pyrrolidino, piperidino, 4-hydroxypiperidino, morpholino, thiomorpholines, 2,6-dimethylthiomorpholino, piperazino, N'-methylpiperazino, chlorine, bromine, lower alkoxy with up to 4 carbon atoms, lower alkenyloxy with 3 or 4 carbon atoms in the lower alkenyl part, Nie deralkoxyniederalkyl with up to 4 carbon atoms in each of the lower alkyl parts, Niedereikoxyniederalkoxy with up to 4 carbon atoms in each of the lower alkyl parts, lower alkylthio with up to

409834/1130

to 4 carbon atoms, lower alkylthio-lower alkoxy with up to 4 carbon atoms in each of the lower alkyl parts, lower alkanoylamino with up to 4 carbon atoms or lower alkoxycarbonylamino with up to 4 carbon atoms in the lower alkyl part.

Pyrazines of the formula lad should also be emphasized

0-0H ₂ -Cm (OH) -OH ₂ -KH-OS ₂₄ (lad)

where R and R have the above meanings, R ₂ ^ means methyl, Rg. means hydrogen, bromine, chlorine, lower alkyl with up to 4 carbon atoms, lower alkoxy-lower alkyl with up to 4 carbon atoms in each of the lower alkyl parts, lower alkoxy-lower alkenyl with up to 4 carbon atoms in the lower alkyl part and up to 4 carbon atoms in the lower alkenyl part, lower alkanoylamino with up to 4 carbon atoms in the lower alkyl part, lower alkoxycarbonylamino with up to 4 carbon atoms in the lower alkyl part, lower alkanoylamino-lower alkyl with up to 4 carbon atoms each in the lower alkyl parts, lower alkoxycarbonylamino-lower alkyl with up to 4 carbon atoms each in the lower alkyl parts. Pyrazines of the formula Iae should also be emphasized

ι. *

C-CH-CH (OH) -CH-In [HOR (Iae) 2 ί j Λ

^ß la

409834/1130

wherein R is hydrogen or methyl, R p is lower alkyl having 1-4 C atoms or phenyl-lower alkyl having up to 4 carbon atoms in the lower alkyl, R is hydrogen, halogen, lower alkyl having 1-4 carbon atoms, 2- (C ₁ _ ₄ ) -Loweralkoxy3thyl or 2- (C ₁ ,) - Niederalkoxycarbonylaminoäthyl and R, hydrogen, halogen, lower alkoxy with 1-4 C-atoms, lower alkoxy-lower alkoxy with up to 4 C-atoms each in the lower alkyl parts, lower-kenyloxy with up to 4 C- Atoms, lower alkylthio with up to 4 carbon atoms, lower alkylenamino with 4-6 carbon atoms in the lower alkylene chain, hydroxy lower alkylenamino with 4-6 carbon atoms in the alkylene chain, oxaniederalkylenamino with 4-5 carbon atoms in the oxan lower alkylene chain, lower alkylamino with up to to 4 carbon atoms, di-lower alkylamino with up to 4 carbon atoms each in the lower alkyl parts, phenylthio or N'-lower alkylazaniederalkylenamino with 4-6 carbon atoms in the lower alkyl parts and

in particular R _{n is} hydrogen or methyl, R ₀ is methyl xa cQ

or 2-phenylethyl, R, hydrogen, bromine, methyl, 2-

or ^ ⁰
Methoxyäthyly ^ -Methoxycartionylaminoäthyl and R ₁ , V / hydrogen, chlorine, methoxy, 2-methoxyethoxy, allyloxy, ethylthio, morpholino, 4-hydroxypiperidino, dimethylamino, isopropylamino, phenylthio or N ¹ -methylpiperazinoist and especially the compounds mentioned in the examples.

In all of the above groups, the substituent R, R_, R or R ^ is preferably in the para position to the 3-amino-2-hydroxy-propoxy group, but can also be in the meta position.

40983A / 1130

Of the type J compounds, are pyridazines

of formula I,

Aa 'CH.,

_R _L_ η -0-CH ₂ -CH (OH) -CH ₂ -MI-CR ^ (

N ^R l

and to highlight their condensation products with aldehydes, ketones or carbonic acid and their corresponding pyridazine-N-oxides, wherein R ,, Rp, R ^ and R ^ have the above meanings. Also to be emphasized are pyridazines of the formula I,

CH "

I ³

-0-CH ₂ -CH (0H) -CH ₂ -NH-CR _2b (I),

^R i

and their condensation products with aldehydes, ketones or carbonic acid, in which R ₁ , R _2fe , R-, and R ^ have the above meanings.

Also to be emphasized are pyridazines of the formula I,

CH 0-CT ₀ HJH (OH) -OH ₀ -HH-CHr ₀₀ (L),

where R ^, Ky » ^R 3 _a ^un ^ ^ u have the above meanings.

Also to be emphasized are pyridazines of the formula I ,

0-CHo-

409834/1130

MO

where R ₁ , Ro ₁ * R-or and R ,, above SeJ £ uUur »£; ei :. to have.

Particularly noteworthy are the pyridazines

Formula I,
be

CH ₇ 3

CH ₀ -OH (OH) -CH -KiI-CH

IL

la

and their condensation products with aldehydes, in which R _{1 is} hydrogen or methyl, R _{p is} hydrogen or lower alkyl with up to 4 carbon atoms, R is hydrogen and R _{2 is} hydrogen, lower alkoxy, halogen, oxaniederalkylenamino with up to 6 carbon atoms Is lower alkylene moiety or hydroxy and in particular R. is hydrogen, R "is methyl, R ^

la. 2e ^J * 5c

Is hydrogen and R. is hydrogen, methoxy, chlorine, morpholino or hydroxy and very particularly the compounds mentioned in the examples. Condensation products with aldehydes are preferably those with aryl lower alkanals, such as, for example, benzaldehyde.
I-. In all of the above groups the substituent is

R_, R, R_, or R preferably in the para position to the 3-amino j j> a yo jq,

2-hydroxy-propoxy group, but can also be in the meta or ortho position stand.

Of the compounds of type I are pyrimidines

of formula I.

approx

4a

Γκ Γ ³

₃ -ζ f— o-0H ₂ -rai (0H) -c: -i ₂ -UH-CHR _2a (i _oa )

-L ₁

A09834 / 1130

and their condensation products with aldehydes, ketones or Highlight carbonic acid and its corresponding pyrimidine-N-oxides, wherein R, R, R and R, have the above meanings.

Also to be emphasized are pyrimidines of the formula I,

CH

and their condensation products with aldehydes, ketones or Carbonic acid,

where R ,, Rok » ^R 3 ^unc * ^R 4a ° kiS ^{e have} meanings. Pyrimidines of the formula I should also be emphasized

CH

where R ", R", R- and R "have the above meanings.

Also to be emphasized are pyrimidines of the formula I,

^R 3b | "-tf 0-CH-CH (OH) -CH-IiH-CR ₀ , (I,),

\\ χ 2 2. ι 2d cd

^R l

wherein R.- ,, L ,, R-i and R ,, have the above meanings.

Particularly noteworthy are pyrimidines of the formula I

CH

0H) -CH ₂ -3IH-OH _2e

409834/1130 R

la

kl

and their condensation products mi.'c aldehydes in which R is water

.Lei

is substance or methyl, R is hydrogen or lower alkyl with

CZ. t-

up to 4 carbon atoms in the lower alkyl part, R, hydrogen, Cyano, di-lower alkylamino with up to 4 carbon atoms in each of the lower alkyl parts, lower alkoxycarbonylamino-lower alkyl with .up to 4 carbon atoms in each of the lower alkyl parts or lower alkyl with up to 6 carbon atoms and R ^ is hydrogen, lower alkanoylamino with up to 4 carbon atoms in the lower alkyl part. Lower alkoxy lower alkyl with up to 4 carbon atoms in each of the lower alkyl parts, Phenyl, lower alkylthio-lower alkyl with up to 4 carbon atoms in each of the lower alkyl parts, lower alkylaminocarbonyl with up to 7 carbon atoms in the lower alkyl part or lower alkoxycarbonyl with up to 5 carbon atoms in the lower alkyl part and in particular R is hydrogen, R is methyl, R Hydrogen, cyano, dimethylamine, 2-methoxycarbonylaminoethyl, Methyl or ethyl 1st and R. hydrogen, acetylamino, 2-methoxyethyl, Phenyl, methylthiomethyl, n-hexylaminocarbonyl or Is ethoxycarbonyl and especially those mentioned in the examples. Links. Condensation products with aldehydes are preferably those with aryl lower alkanals, such as benzaldehyde.

In all of the above groups, the substituent ^R 3 * ^R 3a ' ^R 3b ^{or # R} 3c is ^preferably in the para position to the 3-amino-2-hydroxypropoxy group, but can also be in the meta or ortho position.

409834/1130

Of the compounds dr ^j i> type I, are pyridines

of Formula 1

aa

CH C-CH --CH (OK) -CH ₀ -SH-

c. C. ι approx

R 1

• and iha? E condensation products with aldehydes, ketones and carbonic acid and their corresponding pyridine-N-oxides to be emphasized, where R, R and η have the above meaning, R means ₀

-L s approx

Lower alkyl with up to 4 carbon atoms, benzyl, halobenzyl, trifluoromethylbenzyl, lower alkylbenzyl with up to 7 carbon atoms in the lower alkyl part, lower alkoxybenzyl with up to 7 carbon atoms in the lower alkyl part, carboxy-lower alkyl with up to 4 carbon atoms in the lower alkyl part, lower alkoxycarbonyl-lower alkyl each with up to 4 carbon atoms in the lower alkyl parts, carbamoyl lower alkyl with up to 4 carbon atoms in the lower alkyl part, lower alkylatninocarbonyl lower alkyl with up to 4 carbon atoms each in the lower alkyl parts, di-lower alkylarninocarbonyl-lower alkyl with up to 4 carbon atoms each in the lower alkyl parts, N ^{1-methyl-piperazinocarbonylniederalkyl,} N ¹ - (beta-hydroxyethyl) piperazino-carbonylniederalkyl, Morpholinocarbonylniederalkyl, Thioraorpholinocarbonylniederalk3 ⁷ 'l, 2,6-Dimethylthiomorpholinocarbonylniederalkyl with up to carbon atoms in the lower alkyl oderCyanoniederalkyl having up to 4 carbon atoms in the lower alkyl.

409834/1130

Ai'o'r compounds of the formula I are to be emphasized

-0-CH ₂ -CH (OK) -CH ₂ -MI-GR

_{2 B}

^R l

where R _{1 has the} above meaning and η is 1 or 2.

R _3a means ilalogue, cyano, nitro, lower alkyl with up to 4 carbon atoms, lower alkenyl with up to 4 carbon atoms, phenyl, halophenyl, trifluoromethy! Phenyl, lower alkylphenyl with up to 7 carbon atoms in the lower alkyl part, lower alkoxyphenyl with up to 4 C atoms in the lower alkyl part, hydroxy lower alkyl with up to 7 C atoms in the lower alkyl part, lower alkoxy with up to 7 C atoms in the lower alkyl part, hydroxy, lower alkoxy lower alkenyl with up to 4 C atoms in the lower alkyl part and up to 4 C atoms in the lower alkenyl part , Lower alkoxy lower alkyl with up to 4 carbon atoms each in the lower alkyl parts, lower alkoxy lower alkoxy with up to 4 carbon atoms each in the lower alkyl parts, lower alkenyloxy with up to 4 carbon atoms in the lower alkenyl part, lower alkylthio lower alkoxy with up to 7 carbon atoms each, 'lower alkylthio with up to 7 carbon atoms in the lower alkyl part, lower alkylthio-lower alkyl with up to 7 carbon atoms each, lower alkanoylamino with up to 7 carbon atoms in the lower alkyl part, lower alkoxycarbonylamino with up to 7 carbon atoms in the N lower alkyl part, lower alkanoylamino-lower alkyl with up to 4 carbon atoms each in the lower alkyl parts, lower alkoxycarbonylamino-lower alkyl with up to 4 carbon atoms. in the lower alkyl parts, lower alkylamino with up to 7 carbon atoms in the lower alkyl part, di-lower alkylamino with up to 7 carbon atoms each in the lower alkyl parts, pyrrolidino, piperidino, 4-hydroxypiperidino, morpholino, thiomorpholines

409834 / 113Ö

or 2,6-dimethylthiomorpholino or ge {"; cbanenialls substituted carbamoyl, R _2b means lower alkyl with up to 4 carbon atoms, benzyl, carbamyl line thy 1, lower alkylaminocarbonylmethyl with up to 7th carbon atoms in the lower alkyl part, di-lower alkylaminocarbony! methyl with each up to 7 carbon atoms in the lower alkyl parts, pyrrolidinocarbony! methyl, piperidinocarbonylmethyl, piperazinocarbonylmethyl, N ^{1 -methylpiperazinocarbonylmethyl, N 1} - (β-Hydroxyηthyl) -piperazinocarbonyl methyl, morpholinocarbonylmethyl, thiomorpholinocarbonylmethyl, 2,6-carbonomorpholine-dimethylocarbonylmethyl,.

Also to be emphasized are pyridines of the formula I,

CH

where R and η have the above meanings, R means chlorine, χ a pb

Bromine, cyano, nitro, hydroxy, lower alkyl with up to 4 carbon atoms,

Lower alkenyl with 3 or 4 carbon atoms, phenyl, chlorophenyl, bromophenyl, Trifluoromethylphenyl, lower alkylphenyl with up to 4 carbon atoms in the lower alkyl part, lower alkoxyphenyl with up to to 4 carbon atoms in the lower alkyl part, hydroxy lower alkyl with up to 4 carbon atoms, lower alkoxy with up to 4 carbon atoms, lower

alkoxyalkonyl with up to 4 carbon atoms in the lower alkyl part and 3 or 4 carbon atoms in the lower alkenyl part, lower alkoxy lower alkyl with up to 4 carbon atoms in each of the lower alkyl parts, lower alkoxy lower alkoxy with up to 4 carbon atoms each in the lower alkyl parts, lower alkenyloxy with 3 or 4 carbon atoms, lower alkylthio with up to 4 carbon atoms, lower alkanoylamino with up to 4 carbon atoms in the lower alkyl part, lower alkoxycarbonylamino with up to 4 carbon atoms in the lower alkyl part, lower alkanoylamino lower alkyl with up to 4 carbon atoms each in the lower alkyl parts, Lower alkoxycarbonylamino-lower alkyl with up to 4 carbon atoms each in the lower alkyl parts, lower alkylamino with up to 4 carbon atoms in the lower alkyl part, di-lower alkylamino with up to 4 carbon atoms each in the lower alkyl parts, pyrrolidino, piperidino, 4-hydroxypiperidino, morpholino, thiomorpholine or 2 , 6-dimethylthiomorpholino _/ carbamoyl, lower alkylaminocarbonyl with 1-4 carbon atoms in the lower alkyl part, di-lower alkylaminocarbonyl with 1-4 carbon atoms each in the never deralkylteile, lower alkylenaminocarbonyl with 5 carbon atoms in the alkyleneamino chain, oxa-, thia- or aza-lower alkylenaminocarbonyl with 4 carbon atoms each in the rings or carbamoyl- _{lower alkyl with up to 4 carbon atoms in the lower alkyl part, R 2c} means lower alkyl with up to 4 carbon atoms Atoms, 3enzyl, carbamoylmethyl or cyanomethyl. Pyridines of the formula I should also be emphasized

dd

409834/113

_CH

C-CH-CH (OH) -CH -KH-C-R .2 2, 2d

where R
Methyl.

formula

and n _{& have the} above meanings. R means _2d

Particularly noteworthy are also pyridines

0-GH ₂ -CH (0H) -CH ₂ -ini-CR _2e

la

and their corresponding pyridine-N-oxides and their coridensation products with aldehydes, where η is 1,2 or 3, R _{1 is} hydrogen or methyl, R _? Lower alkyl with up to 4 carbon atoms or phenyl-lower alkyl with up to 5 carbon atoms in the lower alkyl part, R is halogen, nitro, cyano, lower alkyl with up to 4 carbon atoms, lower alkoxy with up to 4 carbon atoms, optionally substituted phenyl, Di- (C, _ _i .) -Lower alkylamino, (C, ^) - lower alkylamino, lower alkoxy-lower alkyl with up to 4 carbon atoms in each of the lower alkyl parts, lower alkanoylamino 'with up to 5 carbon atoms in the lower alkanoyl part, lower alkenyloxy with up to 4 C atoms in the lower alkyl part ^ ■ -

Lower alkanoylamino lower alkyl with up to 5 carbon atoms in the lower alkanoyl part and up to 4 carbon atoms in the lower alkyl part, hydroxy, hydroxy lower alkyl with up to 4 carbon atoms in the lower alkyl part,

(Ct ι.) -Loweralkoxycarbonylaminoniederalkyl with up to 1-4

4 carbon atoms in the lower alkyl part, amino lower alkyl with up to 4 carbon atoms in the lower alkyl part, lower alkylaminocarbonyl with up to

409834/1130

to 6 carbon atoms in the Niederalkylueii, Niederalkylenaminocarbonyl with up to 5 carbon atoms in the lower alkyl chain or aminocarbonyl lower alkyl with up to 4 carbon atoms in the lower alkyl part and condensation products with aldehydes are preferred Condensation products with optionally substituted benzaldehyde and in particular η is 1, 2 or 3, R is hydrogen

a J.S.

or methyl, R is methyl or 2-phenylethyl, R is chlorine, Nitro, methyl, ethyl, n-propyl, η-butyl, cyano, methoxy, ethoxy, allyloxy, phenyl, methylamino, dimethylamino, 2-aminoethyl, Aminomethyl, 2-methoxyethyl, hydroxy, hydroxymethyl, Ethylamino, acetylamino, acetylaminomethyl, 2-methoxycarbonylaminoethyl, Methoxycarbonylaminomethyl, 2-ethoxycarbonylaminoethyl, n-butyloxycarbonylaminomethyl, 2- [n-butyloxycarbonylamino] ethyl, Methylamine carbonyl, n-butylaminocarbonyl, n-hexylamino carbonyl, pyrrolidinocarbonyl, aminocarbonylmethyl and condensation products with benzaldehyde and especially the compounds mentioned in the examples.

The 3-amino-2-hydroxypropoxy radical can be used in all of the above groups occupy positions 2, 3 or 4 of the pyridine ring, but preferably takes position 3 or especially position 2.

In all of the above groups, the substituents R "for η equal to 2 or 3 can be identical or different be from each other.

One of the substituents Ro> is in all of the above groups Rq, R01 or R-, preferably in the ortho position or especially in the para position to the 3-amino

40983A / 1130

2-hydroxy-propoxy radical.

The new connections v7-ir-: l:; n after a »i were known Methods received.

So you can use a compound of formula II

X ₁

(II)

with a compound III

) R ₁ R ₂ (III)

implement, in which Het, R, and R ~ have the above meanings and one of the radicals Z-, and Z ~ is amino and the other one is reactive, esterified hydroxyl group and X-. Is hydroxy, or Z-, together with X, forms an epoxy group, when Z ~ is amino.

Compounds of type Ia, Ib or Ic can be prepared, for example, by the following methods.

For example, a compound of the formula Ha, or the corresponding pyrazine-N-oxide

N / A

X.

^N ^ C-CH ₂ -CH-CH ₂ -Z ₁ (Ha)

or of the formula Hb, or the corresponding pyridazine N-oxide

ι ¹

C-CH -CH-CH -Z (Hb)

² 2 1

409834/1130

or of the formula lic, or the corresponding pyriinidine-N-oxide

R,

with a compound of the formula III

Z ₂ -C (CH ₃ ) R ₁ R ₂

(nc)

(III)

implement, where R ₁ , R ₂ , R ₃ , R ^, Z ₁ and Z _{2 have the} above meanings.

So you can get a compound of the formula Ilaa

or the formula Ilba

bzv ?. the formula Ilca

(Ilaa)

(Ilba) (Ilca)

where R ₃ and R have the above meanings, X, for the hydroxyl group and Z ₁ for a reactive, esterified hydroxyl group, or X ₁ and Z, together form an epoxy group, with an amine of the formula NH ₀ -C (CH ₀ ) R _n R ₀ , where i η R ₁ and

£ ■ OL /. JL

R "have the above meanings, implement.

403834/1130

A reactive, esterified hydroxyl group is in particular one by a strong inorganic or organic acid, especially a hydrohalic acid, such as hydrochloric acid, hydrobromic acid or iodine water chemical acid, also sulfuric acid or a strong organic sulfonic acid, such as benzenesulfonic acid, 4 ~ bromobenzenesulfonic acid, 4-toluenesulfonic acid or methanesulf onic acid, esterified hydroxyl group. For example, Z stands for chlorine, bromine or iodine.

This reaction is carried out in the usual way. When using a reactive ester as Starting material is preferably in the presence of a basic condensing agent and / or with an excess worked on amine. Suitable basic condensing agents are e.g. alkali hydroxides such as sodium or potassium hydroxide, alkali carbonates such as potassium carbonate, and alkali alcoholates, e.g. alkali lower alkanolates such as sodium methylate, potassium ethylate and potassium tertiary butylate.

You can also use a compound of the formula Hab

or Ilbb

O-CH ₂ -CH (OH) -OH ₂ -EH (Hab)

R.
/

_J_ 41 0-CiHp-CH (OH) -OHp-IIHp

3 N

V 409834/1130

^R 4

-If 0-CII-OH (OH) -CII-Kh (Heb),

YY 2 2 2

in which Ro and R have the above meanings with a compound of the formula Z ₂ -C (CH ₃ ) R .-! R ₂ , in which R and R _{2 have the} above meanings and Z _{2 is} a reactive esterified hydroxyl group.

This reaction is carried out in the usual way, preferably carried out in the presence of a basic condensing agent and / or with an excess of amine. Suitable basic condensing agents are, for example, alkali metal alcoholates, in particular sodium or potassium lower alkoxides, e.g. sodium methylate or alkali metal carbonates such as sodium or potassium carbonate.

You can also use a compound of the formula IV

Het - Z (IV),

where Z is a nucleophilically cleavable radical and Het has the above meaning with. a compound of formula V

CH ₃

HO-CH-CH (Oh) -CH-MI-C-R (V)

C. egg. j C _|

^R l

or react with the corresponding condensation products with aldehydes, ketones or carbonic acid, in which R and R _{p have the} above meanings.

409834/1130

A nucleophilically removable group Z is e.g. a halogen atom, such as a chlorine, bromine or iodine atom, a nitro group, a lower alkylsulfonyloxy group, such as the methylsulfonyloxy group, a lower alkylsulfonyl group, such as the methylsulfonyl group, a lower alkylsulfinyl group, such as the methylsulfinyl group, a lower alkoxy group, such as the methoxy or ethoxy group, or an ammonium group, such as the trimethyl or triethylammonium group. Has in the above terms Lower alkyl preferably up to 7 carbon atoms and in particular up to 4 carbon atoms.

So you can use a compound of the formula IVa, or a corresponding pyrazine-N-oxide

(IVa)

or of the formula IVb, or a corresponding pyridazine N-oxide

A. L. / R.
'4 X < R ~ \\ X —Z * 3 N N /

(IVb)

wherein Z is preferably the 3 or 6 position of the pyridazine nucleus occupied, or of the formula IVc, or a corresponding pyrimidine-N-oxide

(IVc),

409834/1130

wherein Z is preferably the 2, 3 or 6 position of the pyrimidine ring occupied and R- and R, have the above meanings, with a connection of Formula V

HO-OH ₂ -OH (OH) -OH ₂ -JiIi-OH ₂ (V)

H.

or with the corresponding condensation products with aldehydes, ketones or carbonic acid, in which R 1 and R 2 are above Have meanings, implement.

This reaction is carried out in the usual way, preferably in the presence of a basic condensing agent. Suitable basic condensing agents are e.g. alkali hydroxides, such as sodium or potassium hydroxide,

409834/1130

Alkali hydrides, such as sodium or Xaliumh, ydriä and alkali alcoholates, such as sodium methylate, potassium ethylate and in particular Potassium tertiary butylate.

Furthermore, one can in a compound of the formula I, or in a corresponding N-oxide, wherein Het, R- and R have the above meanings and which one can be split off on the nitrogen atom of the amino group and / or on the hydroxyl group Have remainder, split off this (s) remainder (s).

Such cleavable residues are in particular

residues which can be split off by solvolysis or reduction.

Residues that can be split off by solvolysis are, in particular, radicals that can be split off by hydrolysis or ammonolysis.

Residues which can be split off by hydrolysis are, for example, acyl radicals, as may have been functionally modified Carboxyl groups, for example oxycarbonyl radicals, such as alkoxycarbonyl radicals, e.g. the tert-butoxycarbonyl radical or the ethoxycarbonyl radical, aralkoxycarbonyl radicals, such as phenyl-lower alkoxycarbonyl radicals, e.g. a carbobenzoxy radical, halocarbonyl radicals, e.g. the chlorocarbonyl radical, also arylsulfonyl radicals, such as toluenesulfonyl or bromobenzenesulfonyl radicals, and optionally halogenated, such as fluorinated, lower ones Alkanoyl radicals, e.g. the formyl, acetyl or trifluoroacetyl radical, or a benzoyl radical, or cyano groups or silyl radicals, such as tri-lower silyl radicals, e.g. the trimethylsilyl radical.

409834/1130

As residues on the hydroxyl group which can be split off by hydrolysis come from those mentioned in particular oxycarbonyl radicals and lower alkanoyl groups or benzoyl groups such as E.g. the above are considered.

As residues on the amino group which can be split off by hydrolysis In addition to those mentioned, double-bonded radicals can also be used, e.g. an alkylidene or benzylidene radical or a phosphoranylidene group, such as the triphenylphosphoranylidene group, in which case the nitrogen atom is a positive Charge.

Residues that can be split off by hydrolysis on the Ilydroxy-

group and the amino group are also divalent radicals, such as optionally substituted methylene. Any organic radicals can be used as substituents on the methylene radical in. Consideration, it being irrelevant for the hydrolytic cleavage what kind of a substituent of a methylene radical is. Possible methylene substituents are, for example, aliphatic or aromatic radicals, such as lower alkyl, e.g. as mentioned above, aryl, e.g. phenyl or pyridyl. The hydrolysis can be carried out in a customary manner, in particular in a basic or, preferably, in an acidic medium, for example with mineral acids such as hydrochloric acid.

Compounds with radicals which can be split off by hydrolysis are, for example, also compounds of the formula VIa

0-CH ₀ -CH-CH ₀ CH_

0 N C R (VIa)

409834/1130 ^γ r

s>

or the formula VIb

or the formula VIc

^U 3 I jj 0-CH ₂ -CH-CH ₀ CH,

₂ CH

(VIc),

wherein R- ,, R ₂ , R ₃ and R, have the above meanings and Y stands for a thiocarbonyl radical.

The hydrolysis is carried out in the usual way;

e.g. in the presence of hydrolyzing agents, e.g. in the presence of acidic agents such as aqueous Mineral acids, such as sulfuric acid or hydrohalic acid, or in the presence of basic agents, e.g. alkali hydroxides, like sodium hydroxide. Oxycarbonyl radicals, arylsulfonyl radicals and cyano groups can be used in an advantageous manner by acidic agents, such as by hydrohalic acid, especially hydrobromic acid. Particularly For example, splitting off by means of aqueous hydrobromic acid, optionally in a mixture with, is suitable for this Acetic acid. Cyano groups are replaced in particular by hydrogen bromide acid at elevated temperature, as in boiling hydrobromic acid, according to the cyanogen bromide method (v. Braun) from ge spa J from.

409834/1130

A tert-butoxycarbonyl radical, for example be cleaved under anhydrous conditions by treatment with a suitable acid, such as trifluoroacetic acid.

Particularly in the hydrolysis of compounds of the formula Via, VIb or VIc, suitable ones are used Wise acidic means.

Du]; ch reduction cleavable residues are for example cc-arylalkyl radicals, such as benzyl radicals, or a-aralkoxycarbonyl radicals, such as benzyloxycarbonyl radicals, which can be split off in the customary manner by hydrogenolysis, in particular by catalytically excited hydrogen, such as by hydrogen in the presence of a hydrogenation catalyst, for example Raney-Niekel. More through reduction Removable radicals are, for example, 2-haloalkoxycarbonyl radicals, like the 2,2 ^ -Trichloräthoxy-carbonylrest or the 2-iodoethoxy or 2,2,2-tribromoethoxycarbonyl radical, which are split off in the usual way, in particular by metallic reduction (so-called nascent hydrogen) can. Nascent hydrogen can be caused by the action of metal or metal alloys, such as amalgams, agents that provide hydrogen, such as carboxylic acids, alcohol

409834/1130

oil or water can be obtained, in particular zinc or zinc alloys together with acetic acid. The reduction of 2-halo-alkoxycarbonyl radicals can also by chromium (II) compound Gn, such as chromium (II) chloride or chromium (II) acetate. A radical which can be split off by reduction can also be an arylsulfonyl group, such as the toluenesulfonyl group, which is carried out in the usual way Reduction with nascent hydrogen, e.g. by a Alkali metal, such as lithium or sodium, can be split off in liquid ammonia or else electrolytically, in particular can be split off from an N atom. When performing the reduction, it must be ensured that other collapsible groups are not attacked.

You can also use one of the formula I corresponding

Compound or a corresponding pyrazine, pyridazine or pyrimidine N-oxide, in which the nitrogen of the propoxy chain connected to one of its substituents with a double bond or in which one of the carbon atoms bonded to the nitrogen atom bears a hydroxyl group.

409834/1130

For example, one can use a Schiff's base of the formula VIIa

R.

R * -

CiL

O-CH ₂ -CH (OH) -GH = NCR

(VIIa)

or the formula VIIb

R,

CH,

0-CH ₂ -CH (OH) -CH-FCR ₂ (VIIb)

R.

or the formula VIIc

CH

-Jf 0-CH ₂ -CH (OH) -CH = Ii-CR ₂ (VIIc),

wherein R ₁ , R 2, Ro and R, have the above meanings, or a Schiff base of the formula Villa

N Λ

0-CH ₂ -CH (OH) -CH

(Villa)

409834/1130

or the formula VIIIb

-H-O-CH-OH (OH) -CH -2T =

or the formula VIIIc

(VIIIb)

I 0-CH ₂ -CH (OH) -

(VIIIc),

wherein R 1 and R 1 have the above meanings and _{-X 9 is H, where R 9 has the} above meaning, or a ring tautomer of the formula IXa corresponding to the formula Villa

R,

s \

Q._ _CH - _{0H CH}

2 ι ι ti

IiH

(IXa)

or a formula IXb corresponding to formula VIIIb

409834/1130

0-CH ₀ -OH-CH

O MH (IXb)

or a formula IXc corresponding to formula VIIIc

^R 4

-H 0-CH ₀ -CH CH ₀

W 7 2 ι ι 2

II

^N 0 KH (IXc),

V.

in which R- and R, and -XpH have the above meanings and where compounds of the formulas Villa and IXa ₅ or VIIIb and IXb, or VIIIc and IXc can also be present next to one another, reduce.

This reduction is done in the usual way, for example with a di-light metal hydride such as a Alkali metal borohydride or aluminum hydride, e.g. lithium

aluminum hydride, with an alkali metal cyanoborohydride, e.g. Sodium cyanoborohydride, with a hydride such as diborane, with hydrogen in the presence of a hydrogenation catalyst, for example Platinum, palladium or nickel, such as Raney nickel. When reducing, it must be ensured that other collapsible groups are not attacked.

409834/1130

You can also use a compound of the formula X or the corresponding Pyrimidine-N-oxide

wherein R "and R" have the above meanings with a compound of the formula Xa

fi I ³

Z - CH ₀ - CH - CH ₀ - NH - C - R ₀ (Xa), 2 2 j 2

^R l

where Z stands for a reactive, esterified hydroxyl group, and X- denotes the hydroxyl group and R and R _{0 have the} above meanings, or where X ₁ and Z together form an epoxy group or with the corresponding ring-closed compound of the formula Xb

-> R ₀

j V cn »)

HO
realize.

409834/1130

A reactive, esterified hydroxyl group is in particular one through a strong inorganic or organic Acid, especially a hydrohalic acid such as hydrochloric acid, hydrobromic acid or hydrogen iodide acid, also sulfuric acid or a strong organic sulfonic acid, such as benzenesulfonic acid, 4-bromobenzenesulfonic acid, 4-toluenesulfonic acid or methanesulfonic acid, esterified hydroxyl group. For example, Z stands for chlorine, bromine or iodine.

This reaction is carried out in the usual way. If reactive esters are used as starting material, the compound of the formula X can preferably be used in Form of their metal alcoholate, such as alkali metal alcoholate, for example Sodium alcoholate, can be used, or one works in the presence of an acid-binding agent, in particular a condensing agent which can form a salt with the compound of the formula X, such as an alkali metal alcoholate. When using starting compounds of the formula Xb, the basic condensation agent is preferably an alkali metal hydroxide, such as potassium or sodium hydroxide used.

409834/1130

Compounds of the formula I in which Het is fyridyl and R- and R _{9 have the} above meanings can be represented, for example, by the following methods:

For example, a compound of the formula XI or the corresponding pyridine-N-oxide

ί Ι C-CH -CH-CH -2

N
with a compound of the formula III

) R, R ₀ (III)

react, where R-, R ₉ and R "have the above meanings and one of the radicals Z-, and Z _{9 is} amino and the other is a reactive, esterified hydroxy group and X ^ is hydroxy, or Z-, together with X- , forms an epoxy group when Z _{9 is} amino.

So you can use a compound of the formula XIa or the corresponding pyridine-N-oxide

-O-CH-CH-CH-Z

2 1

where R ^ and η have the above meanings, X-, for the hydroxy

409834/1130

group and Z, represents a reactive, esterified hydroxyl group, or X-, and Z-. together form an epoxy group with an amine of the formula NL ^ -C (CHo) R-, R ^, in which R, and R "have the above meanings _; realize.

A reactive, esterified hydroxyl group is in particular one by a strong inorganic or organic acid, especially a hydrohalic acid, such as hydrochloric acid, hydrobromic acid or hydrogen iodide acid, also sulfuric acid or a strong organic sulfonic acid, such as benzenesulfonic acid, 4-bromobenzenesulfonic acid, 4-toluenesulfonic acid or methanesulf onic acid, esterified hydroxyl group. For example, Z stands for chlorine, bromine or iodine.

This reaction is carried out in the usual way. When using a reactive ester as Starting material is preferably in the presence of a basic condensing agent and / or with an excess worked on amine. Suitable basic condensing agents are e.g. alkali hydroxides, such as sodium or potassium hydroxide, Alkali carbonates, such as potassium carbonate, and alkali alcoholates, e.g. alkali lower alkoxides, such as sodium methylate, potassium ethylate and potassium tertiary butylate.

409834/1130

So you can also use a compound of the formula XII

-0-0H-CH (OH) -CH-EH ₉ (XIl), -N

in which R ~ and η have the above meanings with a compound of the formula Z ₂ -C (CH ₃ ) R ₁ R ₂ , in which R ^ and R _{2 have the} above meanings and Z _{2 is} a reactive esterified hydroxyl group.

This reaction is carried out in a customary manner, preferably in the presence of a basic condensing agent and / or carried out with an excess of amine. Suitable basic condensing agents are, for example Alkali alcoholates, in particular sodium or potassium alcoholates, or also alkali carbonates, such as sodium or potassium carbonate.

A compound of the formula XIII or the corresponding pyridine-N-oxide can also be used

(XIII),

409834/1130

where R “and η have the above meanings, and Z is a nucleophile is removable radical, where the group Z is in the 2-, 4- or 6-position of the pyridine ring, with a compound of Formula XIV

CH ₃ HO-Ch ₂ -CH (OH) -CH ₂ -NH-CR ₂ (XIV),

or with the corresponding condensation products with aldehydes, ketones or carbonic acid, in which R 1 and R above Have meanings, implement. A nucleophilically removable group Z is, for example, a halogen atom, such as a chlorine, bromine or Iodine atom, a nitro group, a lower alkylsulfonyloxy group such as the methylsulfonyloxy group, a lower alkylsulfonyl group, such as the methylsulfonyl group, a lower alkylsulfynyl group, such as the methylsulfinyl group, a lower alkoxy group, such as the methoxy or ethoxy group or an ammonium group such as the trimethyl or triethylammonium group. In the above terms, lower alkyl preferably has up to 7 carbon atoms and in particular up to 4 carbon atoms.

This reaction is carried out in the usual way, preferably in the presence of a basic condensing agent. Suitable basic condensing agents are.

409834/1130

E.B. Alkali hydroxides, such as sodium or potassium hydroxide, alkali hydrides, such as sodium or potassium hydride and alkali alcoholates, in particular sodium or potassium alcoholates, e.g. sodium methylate, Potassium ethylate and especially potassium tertiary butylate, A compound of the formula XV can also be used

or the corresponding pyridine-N-oxide

\ tforin Ro and η have the above meanings with a connection of formula XVI

CH.,

Z-CH-GH-CH ₀ -MGR ₀ 2 2. ι ά

(XVI),

wherein Z, X ₁ , R ₁ and R "have the above meanings, or with the corresponding ring-closed compound of the formula XVIa

H (T

CH,

1 ^:

C.

(XVIa)

409834/1130

realize.

This conversion is carried out in the usual way. If reactive esters are used as starting material, the compound of the formula XV can preferably be used in Form of their metal alcoholate, such as alkali alcoholate, for example Sodium alcoholate, can be used, or one works in the presence of an acid-binding agent, in particular a condensation agent which can form a salt with the compound of the formula XV, such as an alkali metal alcoholate. When using output connections of the Formula XVIa is preferably an alkali hydroxide, such as potassium or sodium hydroxide, as the basic condensing agent used.

Furthermore, one can in a compound of the formula I, or in the corresponding pyridine-N-oxide, wherein R-, R ^, R »and η have the above meanings and which on the nitrogen atom of the Have an amino group and / or a removable radical on the hydroxyl group, these radical (s) split off. Such detachable Residues are, in particular, residues which can be split off by solvolysis or reduction.

409834 / 1.130

Residues that can be split off by solvolysis are, in particular, radicals that can be split off by hydrolysis or ammonolysis.

Residues that can be split off by hydrolysis are, for example, acyl radicals, such as, if appropriate, functionally modified Carboxyl groups, for example oxycarbonyl radicals, such as alkoxycarbonyl radicals, e.g. the tert-butoxycarbonyl radical or the AetliDxycarbonylrest, Aralkoxycarbonylreste, such as Phenylniederalkoxycarbonylreste, e.g. a carbobenzoxy radical, halocarbonyl radicals, e.g. the chlorocarbonyl radical, also arylsulfonyl radicals, such as toluenesulfonyl or bromobenzenesulfonyl radicals, and optionally halogenated, such as fluorinated, lower ones Alkanoyl radicals, e.g. the formyl, acetyl or trifluoroacetyl radical, or a benzoyl radical, or even cyano groups or silyl radicals, such as tri-lower alkylsilyl radicals, e.g. the trimethylsilyl radical.

As radicals on the hydroxyl group which can be split off by hydrolysis, there are in particular oxycarbonyl radicals and lower alkanoyl groups or benzoyl groups such as those mentioned above.

As radicals on the amino group that can be split off by hydrolysis, there are also double-bonded radicals in addition to those mentioned

409834/1130

Radicals into consideration, e.g. an alkylidene or benzylidene residue or a phosphoranylidene group, such as the triphenylphosphoranylidene group, in which case the nitrogen atom carries a positive charge.

Se by Hydrol3 ^T removable radicals at the hydroxy group and the amino group are ferner'zweiwertige radicals, such as optionally substituted methylene. Any organic radicals can be used as substituents of the methylene radical, the type of substituent of a methylene radical being irrelevant for the hydrolytic cleavage. Suitable methylene substituents are, for example, aliphatic or aromatic radicals, such as lower alkyl, for example as mentioned above, aryl, for example phenyl or pyridyl. The hydrolysis can be carried out in the usual way, in particular in a basic or preferably in an acidic medium, for example with mineral acids such as hydrochloric acid.

Compounds with radicals which can be split off by hydrolysis are, for example, also compounds of the formula XVII

(XVII),

409834/1130

2A06930

where R ,, R _? , R- and η have the above meanings and Y stands for a thiocarbonyl radical.

The hydrolysis is carried out in a conventional manner, for example in the presence of hydrolyzing agents, for example in the presence of acidic agents such as aqueous mineral acids such as sulfuric acid or hydrohalic acid, or in the presence of basic agents, e.g. alkali hydroxides such as sodium hydroxide. Oxycarbonyl radicals, arylsulfonyl radicals and cyano groups can advantageously by acidic means, such as by hydrohalic acid, especially hydrobromic acid. Particularly For example, splitting off by means of aqueous hydrobromic acid, optionally in a mixture with, is suitable for this Acetic acid. Cyano groups are particularly acidified by hydrobromic acid at elevated temperatures, such as in boiling Hydrobromic acid, according to the cyanogen bromide method (v. Braun) cleaved.

Furthermore, for example, a tert-butoxycarbonyl radical can be produced under anhydrous conditions by treating with a suitable acid, such as trifluoroacetic acid, are split off.

Particularly in the hydrolysis of compounds of the formula XVII, satire Mit-

409834/1 130

Residues that can be split off by reduction are, for example, oc-arylalkyl residues, such as benzene residues, or oc-aralkoxycarbonyl residues, like BenzyloxycarbonylrestG, which in usual Wise cleaved by hydrogenolysis can, in particular by catalytically excited hydrogen, such as by Hydrogen in the presence of a hydrogenation catalyst, for example Raney nickel. More through reduction Removable radicals are, for example, 2-haloalkoxycarbonyl radicals, like the 2,2 ^ -Trichloräthoxycarbonylrest or the 2-Jodäthoxy- or 2,2,2-Tribroraäthoxycarbonylrest, which are split off in the usual way, in particular by metallic reduction (so-called nascent hydrogen) can. Nascent hydrogen can · thereby through action from metal or metal alloys, such as amalgams, to hydrogen-supplying agents, such as carboxylic acids, alcohols or water, in particular zinc or zinc alloys together with acetic acid come. The reduction of 2-haloalkoxycarbonyl radicals can also be caused by chromium (II) compounds, such as chromium (II) chloride or chromium (II) acetate take place. A radical which can be split off by reduction can also be an arylsulfonyl group, v / ie the toluenesulfonyl group, which is carried out in the usual way

409834/1130

Reduction with nascent hydrogen, e.g. by a Alkali metal, such as lithium or sodium, can be split off in liquid ammonia or else electrolytically, in particular can be split off from an N atom. When performing the reduction, it must be ensured that that other reducible groups are not attacked. You can also use one of the formula I corresponding

Compound, or the corresponding pyridine N-oxide, in which the nitrogen of the propoxy chain with one of its substituents is linked to a double bond, or wherein one of the carbon atoms bonded to the nitrogen atom carries a hydroxyl group, reduce.

For example, one can see a Schiff ¹ base of the formula XVIII

Γ 4-CHCH ₂ -CH (OH) -CH = MR ₂ (XVIII),

NO

wherein R ₁ , R2 »Ro and η have the above meanings, or of the formula XIX

-0-CH-CH (OH) -CH-N = X ( _XIX ),

O O O

409834/1130

wherein R ~ and η have the above meanings and ^ H is -CH (CHo) R ^, where R _{0 has the} above meaning, or a ring tautomer of the formula XX corresponding to formula XIX

O-CH -CH CH,

0 HH (XX),

^X 2
in which R ₃ and η have the above meanings and -XoH is -CH (CHn) Ro, in which R _{2 has the} above meaning and where compounds of the formulas XIX and XX can also be present next to one another, reduce.

This reduction is carried out in the usual manner, for example with a di-light metal hydride, such as an alkali metal borohydride or aluminum hydride, e.g., lithium aluminum hydride, with a hydride such as diborane, with hydrogen carried out in the presence of a hydrogenation catalyst, for example platinum, palladium or nickel, such as Raney nickel. During the reduction, care must be taken that other reducible groups are not attacked.

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In the compounds obtained, in the context of the end products, substituents can be modified in the usual way or split off or compounds obtained can be converted into other end products in the customary manner.

Thus, in compounds obtained with a C-C double bond this double bond in the usual way by catalytic hydrogenation, such as by hydrogen in the presence of a hydrogenation catalyst, for example platinum, palladium or nickel, such as Rane} * "- nickel, in a C-C single bond can be converted. Care must be taken that other reducible groups are not attacked will. Particularly when reducing with Raney nickel and hydrogen, it is important to ensure that any halogen atoms bonded to aromatic rings are not replaced by hydrogen. In addition is in all reductions, especially catalytic hydrogenations, to take thioether fluids into consideration.

40983A / 1130

men. Sulfur-fast catalysts are preferably to be used and hydrogen uptake is optional to be followed volumetrically and to terminate the hydrogenation after the calculated amount has been taken up.

In the compounds obtained with one or more phenyl nuclei, these can be halogenated. This can done in the usual way, especially at not elevated temperature or with cooling and in the presence of a Catalyst, such as iron, iodine, ferric chloride, aluminum chloride or the corresponding bromides.

Free carboxyl lower alkyl groups on R can esterify in the usual way, for example by reaction with a corresponding alcohol, advantageously in the presence an acid such as a mineral acid, e.g. sulfuric acid or hydrochloric acid, or in the presence of a water-binding one By means such as dicyclohexylcarbodiimide or by reaction with an appropriate diazo compound, e.g. a diazoalkane. The esterification can also be carried out by reacting a salt, preferably an alkali salt, of the acid with a reactive esterified alcohol, e.g., a halide such as chloride, of the corresponding alcohol.

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Free carboxy-lower alkyl groups can be amidated in the usual way, for example by reaction with ammonia, a primary or secondary amine, advantageously in the presence of a water-binding agent such as dicyclohexylcarbodiimide.

In compounds which carry an esterified carboxy-lower alkyl group R ₂ , this can be carried out in the usual way, for example by hydrolysis, preferably in the presence of strong bases such as an alkali hydroxide, for example sodium or potassium hydroxide, or strong acids, for example a strong mineral acid such as a hydrohalic acid , for example hydrochloric acid or sulfuric acid ,, can be converted into the free carboxyl lower alkyl _{group R 2.}

In compounds that form an esterified carboxy-lower alkyl group R can contain this in the usual way by aminolysis with a primary or secondary amine or with ammonia into the corresponding carbamoyl lower alkyl compound be transferred.

Compounds which carry a carbamoyl lower alkyl group R- can be formed in a conventional manner, for example by the action dehydrating agents such as phosphorus pentoxide or phosphorus oxychloride, preferably dehydrated at higher temperatures to give the corresponding cyano-lower alkyl compounds will.

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Compounds which carry a cyano-lower alkyl group R ₉ can be saponified in a customary manner, for example in the presence of concentrated aqueous acids or alkali metal hydroxides, to give the corresponding carbamoyl-lower alkyl compounds or directly to give the carboxy-lower alkyl compounds.

Compounds which have a cyano-lower alkyl group R « • can be carried in the usual way, e.g. by adding alcohols in the presence of anhydrous hydrogen chloride and subsequent decomposition of the resulting imidoester, e.g. saponified in water to give the corresponding esterified carboxy-lower alkyl groups R.

_{Furthermore, in compounds obtained in which R 1} and / or R 1 is lower alkylamino, the lower alkylamino group (s) can be converted into a di-lower alkylamino group R 3 and / or R in the customary manner. This reaction is carried out with a reactive ester of a corresponding alcohol, such as Z-lower alkyl, where Z has the above meaning, preferably in the presence of a basic condensing agent. Suitable basic condensing agents are nitrogen bases, alkali metal hydroxides, alkali metal carbonates and alkali metal alcoholates, such as pyridine, triethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methylate, potassium methylate, sodium methylate or potassium ethylate. Furthermore, in compounds obtained in

409834/1130

where R ~ uiid / or R, is halogen, the halogen group (s) in Usually with a corresponding amine by lower alkylamino, Di-lower alkylamino, lower alkylenamino, hydroxy-lower alkylenamino, Oxaniederalkylenamino, Thianiederalkylenamino, Azaniederalkylenamino or with a corresponding one Alcohol by lower alkoxy, lower alkenyloxy, lower alkoxy-lower alkoxy, Replace hydroxy or with a corresponding mercaptan with lower alkylthio. It is useful to use it a basic condensing agent such as nitrogen bases, Alkali hydroxides, alkali carbonates and alkali alcoholates, xtfie e.g. pyridine, triethylamine, sodium hydroxide, potassium hydroxide, Sodium methylate, potassium methylate, sodium ethylate or potassium ethylate.

Furthermore, one can in the compounds obtained which are substituted on the heterocycle by halogen and / or halogen-substituted Carry phenyl groups that catalytically hydrogenate away the halogen atoms. The reaction takes place with hydrogen and the usual hydrogenation catalysts such as Raney-Ni.ckel or palladium carbon.

It can also be used in a compound of the formula XXIIIa _} or in a corresponding pyrazine-N-oxide

(XXIIIa)

^R l

4 0.98 34/1 130

or of the formula XXIIIb, or in a corresponding one Pyridazine N-oxide

T ³

0-0H _o -CH (OH) -CH-MCR (XXIIIb) Ή ^Z I.

N 1

or of the formula XXIIIc, or in a corresponding Pyrimi din ~ N-oxide

P -L_ ^N I

3 ~ T "Η C-CH ₂ -CH (OH) -CH ₂ -IWi-CR ₂ (XXIIIc)

the primary amino group by reaction with a compound of formula XXIV

Z - lower alkyl (XXIV),

where Z is a reactive, esterified hydroxyl group, into a lower alkylamino or lower alkylamino group convict.

This reaction is carried out in the usual way, preferably in the presence of a basic condensing agent. Suitable basic condensing agents are Nitrogen bases such as pyridine or triethylamine, alkali hydroxides such as sodium or potassium hydroxide, alkali carbonates such as sodium or potassium carbonate and alkali metal alcoholates, such as sodium methylate, sodium ethylate, potassium methylate or potassium ethylate.

409834/113 0

You can also use a compound of the formula XXVa, or a corresponding pyrazine-N-oxide

0-CH ₂ -CH (OU) -OH ₂ -HB-OH ₂ (XXVa),

^R l

wherein R-. and R _{2 have the} above meanings and Xo is amino or equal to Ro and X, amino or equal to R, is, or of the formula XXVb, or in a corresponding pyridazine-N-oxide

X.

4- CH ₃

-0-OH ₀ -OH (OH) -OH-KH-CR- (XXVb),

-N N

X ^ l V ₁ LJ. γ wltL / VlJi - ^ J.ii.J «V / JLk - ^

where R, and R _? have the above meanings and Xg is amino or Ro and X is amino or R, or of the formula XXVc, or in a corresponding pyrimidine-N-oxide

CH "I 3

^E l

where R ₁ and R _{n have the} above meanings and X «is amino or equal to Ro and X is amino or equal to R, or of the formula XXVd or in a corresponding pyridine-N-oxide

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-H

where η, R, and R "have the above meanings, the primary (n) Convert amino group (s) into acylamino group (s).

The reaction is carried out with a customary acylating agent, such as a reactive derivative of a carboxylic acid, in particular an optionally substituted one
Benzoic acid or a lower alkanecarboxylic acid, for example the
Acetic acid, or an aryl-lower alkanecarboxylic acid, for example phenylacetic acid. Particularly suitable for acylation is the anhydride or the ketone of one of the acids mentioned or the mixed anhydride thereof with a strong inorganic acid, such as a halogen, in particular hydrochloric or hydrobromic acid, or an organic acid, or an activated amide or an activated ester of the acids mentioned.

Activated esters are, for example, esters with electron-withdrawing structures, such as esters of phenol, thiophenol,
p-nitrophenol, cyanomethyl alcohol and the like. Activated amides are, for example, the N-acyl derivatives of pyrazoles, such as 3,5- dimethylpyrazole, or imidazoles, such as imidazole itself.

409834/1 130

Suitable acylating agents are also activated formic acid esters such as, for example, haloformic acid esters, in particular chloroformic acid esters. Depending on the nature of the acylating component, the use of a condensing agent may be expedient be. For example, disubstituted carbodiimides favor the reaction of acids, bases, such as tertiary amines, e.g. Tri-lower alkylamines, N, N-di-lower alkylanilines or aromatic tertiary nitrogen bases, such as pyridine or quinoline, or inorganic bases, such as alkali or alkaline earth hydroxides, carbonates or bicarbonates, e.g. sodium, potassium or Calcium hydroxide or sodium, potassium or calcium (bi) carbonate, or acylate ions the reaction of acid anhydrides, acid halides and activated formic acid esters.

Furthermore, in a compound of the formula XXVd, or in a corresponding pyridine-N-oxide, the primary (n) Amino group (s) by reacting with a compound of the formula XXVI

Lower alkyl - Z (XXVI),

where Z is a reactive, esterified .hydroxy group, convert into a lower alkylamino or di-lower alkylamino group.

This implementation is carried out in the usual way.

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performed, preferably in the presence of a basic condensing agent. Suitable basic condensing agents are nitrogen bases, such as pyridine or triethylamine, and alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal carbonates such as sodium or potassium carbonate and alkali alcoholates such as Sodium methylate, sodium ethylate, potassium methylate or potassium ethylate.

Furthermore, in compounds of the formula I obtained which are substituted on the heterocycle by alkylthio, the Hydrogenate away alkylthio group (s). The hydrogenation is preferably carried out in the presence of Raney nickel and preferably in a lower alkanol such as methanol or ethanol. The reaction is preferably carried out at an elevated temperature, for example at the reflux temperature of the solvent.

Furthermore, in compounds of the formula I obtained in which R 1 and / or R 1 denotes lower alkylsulfonyl, the lower alkyl sulfonyl group (s) against hydroxy, lower alkoxy, lower alkoxy-lower alkoxy, Lower alkenyloxy, lower alkylthio lower alkoxy, lower alkylthio, phenylthio, lower alkylamino, Di-lower alkylamino, lower alkylenamino, oxaniederalkylenamino, Aza-lower alkyleneamino. or replace thiane lower alkyleneamino.

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The exchange takes place in the usual way, preferably in Presence of a basic condensing agent such as alkali, hydroxides, for example sodium or potassium hydroxides or alkali metal alcoholates, for example sodium methylate, Sodium ethylate, potassium methylate or potassium ethylate. Further can be obtained in compounds of the formula Ia which have a di-lower alkylamino group in the 3-, 5- or 6-position carry or in compounds of the formulas Ic and Id obtained which have a di-lower alkylamino group in the 2-, 4- or 6-position carry or in compounds of the formula Ib obtained which carry a di-lower alkylamino group in the 3- or 6-position, exchange this for the hydroxyl group. The exchange takes place in the usual way, preferably in the presence an acidic condensing agent, such as aqueous mineral acids, for example dilute sulfuric acid or hydrohalic acids such as hydrochloric acid.

Furthermore, in compounds of the formula I obtained,. which carry an amino lower alkyl group, these Acylate amino lower alkyl group. The acylation is carried out in the usual manner with a suitable acylating agent, e.g. appropriate. Acid halide, such as an acid chloride or a corresponding anhydride or a corresponding haloformic acid ester, e.g. a chloroformic acid ester.

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Furthermore, in compounds of the formula Id, in which R "denotes a nitro group, this nitro group can be used Reduce amino group .. This reduction is carried out in the usual way Manner, for example with catalytically excited hydrogen and preferably in a high-boiling solvent such as dimethylformamide or dioxane. The hydrogenation catalysts are the customary catalysts, such as Raney nickel, palladium-carbon, platinum etc., in question.

Condensation products of the formula Iy can be obtained by an amine of the formula I with a Aldehyde or ketone of the formula X = O, in which X has the above meaning, or with a reactive carbonyl derivative thereof, implements.

Reactive carbonyl derivatives are mainly acetals, Ketals, hemithioketals, thioketals, in particular dimethyl or diethyl acetals, ketals or thioketals, or acylals, especially those with acetic acid or with a halogen water st off acid, for example compounds of the formulas XCl ^ or XBr-, in which X has the above meaning.

This reaction is carried out in a customary manner, in the presence or absence of a solvent, at room temperature

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or preferably at elevated temperature, if necessary in the presence of a condensing agent, in particular one acidic condensing agent.

Condensation products of the formula Iz can be obtained by adding an amine of the formula I with carbonic acid or one of its reactive derivatives.

Reactive carbonic acid derivatives are e.g. Carbonyl halides, such as, in particular, phosgene or carbonyl bromide, and also carbonic acid mono- or diesters, such as lower alkyl esters, e.g. dimethyl carbonate and methyl chloroformate.

This reaction is carried out in the usual way, preferably in the presence of a solvent and at a reduced temperature, room temperature or elevated temperature, if necessary carried out in the presence of a condensing agent, in particular a basic condensing agent.

In a corresponding manner, a condensation product of the formula Iy or Iz can be converted into a condensation product in a conventional manner by hydrolysis Amine of the formula I can be converted, for example in a basic or preferably an acidic medium.

In compounds of the formula I obtained in which R " Means cyano, the cyano group can be converted into the aminomethyl group in the usual way. Preferably done

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the conversion by hydrogenation using catalytically excited hydrogen and in the presence of ammonia. As hydrogenation catalysts the customary noble metal catalysts, such as palladium-carbon or platinum, are possible and also occur especially Raney nickel.

It is also possible to obtain mono- or di-N-oxides Convert in the usual way into the corresponding non-oxidized compounds. The implementation can e.g. with sulphurous Acid at room temperature or slightly elevated temperature, with phosphorus oxychloride or especially by catalytic Hydrogenation take place. Examples of suitable hydrogenation catalysts are noble metal catalysts such as platinum or palladium carbon, also Raney nickel.

Furthermore, non-N-oxidized compounds can be converted into the corresponding N-oxides in the usual way. The oxidation is carried out using one of the customary oxidizing agents, such as organic peracids, for example peracetic acid or perbenzoic acid or m-chloroperbenzoic acid or with hydrogen peroxide, e.g. a hydrogen peroxide / glacial acetic acid mixture. The reaction takes place at room temperature or at an elevated temperature. When using perbenzoic acid or m-chloroperbenzoic acid takes place

409834/1130

- ar -

the reaction is preferably carried out in a chlorinated hydrocarbon such as methylene chloride or chloroform.

The reactions mentioned can optionally be carried out simultaneously or in succession and in any order be performed.

The reactions mentioned are carried out in the usual way se in the presence or absence of diluents, condensation and / or catalytic agents, with reduced, more common or at an elevated temperature, optionally carried out in a closed vessel.

Depending on the process conditions and starting materials, the end products are obtained in free form or in the form of their acid addition salts also included in the invention. For example, basic, neutral or mixed salts, optionally also hemi-, mono-, sesqui or polyhydrates thereof, can be obtained. the Acid addition salts of the new compounds can be converted into the free compound in a manner known per se,

409834/1130

• - «β -

e.g. with basic agents such as alkalis or ion exchangers. On the other hand, the obtained free bases Form salts with organic or inorganic acids. For the production of acid addition salts, in particular those acids are used which are suitable for the formation of therapeutically useful salts. As such acids are named for example: hydrohalic acids, sulfuric acids, Phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic Carboxylic or sulfonic acids, such as formic, vinegar, propionic, amber, glycol, milk, apple, wine, lemon, Ascorbic, maleic, fumaric or pyruvic acid; Phenylacetic, benzoic, anthranil, p-hydroxybenzoic, salicylic acid, Embonsäure, Methanesulfon-, Aethansulfon ^ Hydroxyäthansulfon-, Ethylene sulfonic acid; Halobenzenesulfone, toluenesulfone, Naphthalenesulfonic acid, sulfanilic acid or cyclohexylaminesulfonic acid.

These or other salts of the new compounds, such as the picrates or perchlorates, can also be used for cleaning serve the free bases obtained by converting the free bases into salts, separating them and removing them from the Salting in turn releases the bases. As a result of the close relationships between the new connections in free form

40 9 8 34 / 113Ό

and in the form of their salts are preceding and following the free compounds meaningfully and appropriately also mean the corresponding salts, if appropriate.

The invention also relates to those embodiments of the process according to which one obtainable from one at any stage of the process as an interim product The connection goes out and the missing procedural steps are carried out, or the procedure is terminated at any stage, or in which a starting material is formed under the reaction conditions, or in which a reaction component is optionally present in the form of its salts.

For example, an amine of the formula Hab, Ilbb, Heb or XII can be reacted with an aldehyde or ketone of the formula O = X ₉ , where X has the above meaning, in the presence of a suitable reducing agent, such as one of the abovementioned ones. A compound of the formula Villa, VIIIb, VIIIc or XIX or the formula IXa, IXb, IXc or XX, which is then reduced according to the invention, is obtained as an intermediate product.

409834/1130

- S * s -

Depending on the choice of starting materials and working methods, the new compounds can act as optical antipodes or racemates or, provided they are at least two asymmetric Carbon atoms also contain mixtures of isomers (Racematgeraische) are present.

Isomer mixtures obtained (mixtures of racemates) can be due to the physico-chemical differences of the Components are separated in a known manner into the two stereoisomeric (diastereomeric) pure racemates, for example by chromatography and / or fractional crystallization.

Obtained racemates can be by known methods, for example by recrystallization from a optically active solvent, with the help of microorganisms or by reacting with one, with the racemic Compound optically active acid forming salts and separation of the salts obtained in this way, e.g. due to their different solubilities, into the diastereomers,

A09834 / 1130

from which the antipodes can be released by the action of suitable means, disassemble. Particularly common ones optically active acids are e.g. the D- and L-forms of Tartaric acid di-o-toluy! Tartaric acid, malic acid, mandelic acid »

^ Glutamic acid, aspartic acid ' Carnphersulfonic acid; or quinic acid. Advantageously isolated

the more effective of the two antipodes.

Appropriately one uses for the implementation. the reactions according to the invention are those starting materials, those relating to the groups of end products particularly mentioned at the beginning and especially those specifically described or emphasized End materials lead.

The starting materials are known or can, if so they are new, can be obtained by methods known per se.

Compounds of the formulas Ha, Hb, Hc or XI can be obtained, for example, if (Ro) (R /) - pyrazinols, or -pyridazinols, or -pyrimidinols, or (Rg) -pyridinols with epichlorohydrin. Compounds Via, VIb, VIc or XVII can be obtained, for example, by adding a (Ro) (R /,) " Halopyrazine or halopyridazine or halopyrimidine or a (Ro) halopyridine with a compound XXIII

409834/1130

-9Z-

HO-CH ₀ -CH CH ₀ CH

2 ι ι 2 ι

ο ΐί σ ε _ο (XXIII)

Y
¹

converts, in which R ,, R ₂ and Y have the above meanings. Compounds of the formulas Xa, Xb, Xc or XXI can be obtained, for example, if (Ro) (R ^ ) -Pyrazinole, or -Pyridazinole, or -Pyrimidinole, or (R ₀ ) -Pyridinole with Ver compounds of the formula XXIV

I ³

Halogen-CH ₂ -CO-CH ₂ -NH-CR ₂ (XXIV)

^R l

converts, in which R, and R "have the above meanings.

The starting materials can also be present as optical antipodes.

The new compounds can be used as medicaments, for example in the form of pharmaceutical preparations, which contain them or their salts in a mixture with a pharmaceutical, organic or inorganic, solid or liquid carrier material suitable for enteral or parenteral administration, for example. For the formation of the same substances come into question that do not react with the new compounds, such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl

4098 34/1 130

alcohols, gums, polyalkylene glycols, petrolatum, cholesterol, or other known excipients. The pharmaceutical Preparations can be e.g. as tablets, coated tablets, capsules, suppositories, ointments, creams or in liquid form in the form of solutions (e.g. as an elixir or syrup), suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliaries, such as preservatives, Stabilizing agents, wetting agents or emulsifying agents, salts for changing the osmotic pressure or buffers. she can also contain other therapeutically valuable substances. The preparations which are also used in veterinary medicine Can be used, are obtained by conventional methods.

The daily dose is about 40-150 mg in the case of a warm-blooded animal weighing about 75 kg.

The following examples illustrate the invention without, however, restricting it. The temperatures are in Degrees Celsius.

A0983A / 1130

example 1

39.7 g of 5-bromo-3-morpholine) ^r l-2 ~ (3 '~ bromo-2' -hydroxypropoxy) ~ pyrazine were refluxed with 41 g of isopropylamine in 500 ml of methanol for 15 hours. The reaction mixture is then evaporated in a water jet vacuum. The residue is between 2-n. Hydrochloric acid and ether distributed. The aqueous phase is made alkaline with concentrated sodium hydroxide solution and extracted with ether. The combined ether extracts are dried over sodium sulfate and evaporated in a water jet vacuum. One obtains the crude base and therefrom with ethereal hydrochloric acid in methanol, the 5-bromo-3-morpholinyl-2- (3'-isopropylamino-2 ^l -hydroxy - propox30-pyrazine hydrochloride, m.p. 202-203 °.

The 5-bromo-3-morpholinyl-2- (3'-bromo ~ 2 '~ hydroxy-propoxy) -pyrazine used as starting material can be produced as follows:

la) 149 g of 2,3-dichloropyra2ine are mixed with 300 g

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Morpholine and 400 ml of water were stirred at 40 ° for 16 hours. Then the reaction mixture is extracted with ether. The ether extracts are washed neutral with water, dried over sodium sulfate and evaporated in a water jet vacuum. The residue is distilled in a water jet vacuum. The 2-chloro-3 "inorpholinyl-pyrazine, boiling point 162-165 ° / 15 Torr, is obtained in this way.

Ib) 120 g of 2 ~ chlorine - 3 ~ morpholinyl-pyrazine and 70 g Allyl alcohol are dissolved in 640 ml of Ilexamethylphosphorsäuretriamid. In this solution are at 0 ° for 30 minutes 28.8 g of sodium hydride entered. The mixture is then stirred for a further 1 hour at 0 °, then left until the Stir the reaction for 1 hour at 30 ° and for 15 hours at room temperature. Then the reaction mixture is added to 2 liters of ice water poured. After the existing excess of sodium hydride has been decomposed, it is shaken out with ether, The ether extracts are washed neutral with water, dried over sodium sulfate and in a water jet vacuum evaporated. The residue is distilled in a high vacuum. This gives 2-allyloxy-3-morpholinyl-pyrazine, bp. 105-106 ° / 0.03 torr. - ·

Ic) 32 g of 2-allyloxy-3-morpholinyl-pyrazine become

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dissolved in 350 ml of dimethyl sulfoxide and 2.7 ml of water. In this solution becomes 52 g with stirring for 30 minutes N-bromosuccinimide entered. The reaction temperature rises to 35 °. The mixture is stirred for a further 30 minutes and diluted then with about 500 ml of water and shakes the reaction mixture with ether. The ether extracts are mixed with water washed, dried over sodium sulfate and in a water jet vacuum evaporated. This gives the 5 ~ bromine ~ 3 ~ mor ~ pholinyl-2- (3'-bromo-2'-hydroxypropoxy) pyrazine.

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404 24Ü6930

Example 2

71 g of 5 "bronv-3-dimethylamino- ^{2-(3 l} -bromo-2-hydroxypropoxy) -p3 ⁷ razine are refluxed with 71 g of isopropyl araine in 1 liter of methanol for 15 hours. The reaction mixture is then evaporated in a water-jet vacuum The residue is partitioned between 2N hydrochloric acid and ether. The aqueous phase is made alkaline with concentrated sodium hydroxide solution and extracted with ether. The combined ether extracts are dried over sodium sulfate and evaporated in a water jet vacuum. This gives the crude base and, from it, fumaric acid 5-bromo-3-dimethylamino-2- (3 ^f -isopropylamino-2'-hydroxy) pyrazine hydrogen fumarate in methanol ether, mp 146-147 °.

The 5-bromo-3-diethylamino - 2- (3 ' -bromo-2'-hydroxy-propoxy) -pyrazine can can be produced as follows:

- 2a) To 350 ml of a 40% aqueous solution of

409834/1130

-Wr-

74 g of 2,3-dichloropyrazine are added to dimethylamine with stirring added dropwise within 15 minutes. The reaction temperature is thereby peraüur kept at 30 ° by cooling. After the exothermic reaction has subsided, a further 15 hours at room temperature touched. Then the reaction mixture is extracted with ether. The ether extracts are mixed with water washed neutral, dried over sodium sulfate and evaporated in a water jet vacuum. The residue is in a water jet vacuum distilled. This gives 2-chloro-3-dimethylamino-pyrazine, boiling point 100-102 ° / 10 Torr.

2b) 47 g of 2-chloro-3-dimethylamino ~ pyrazine and 35 g of allyl alcohol are dissolved in 300 ml of hexamethylphosphoric acid triamide solved. 14.4 g of sodium hydride are introduced into this solution at 0 ° over a period of 30 minutes. Then leaves the mixture is stirred for a further 1 hour at 0 ° and 15 hours at room temperature. Then the reaction device is added to 2 liters of ice water poured. After the decomposition of excess sodium hydride, it is extracted with ether. The ether extracts are washed neutral with water, dried over sodium sulfate and evaporated in a water jet vacuum. The residue is distilled under reduced pressure. You get so the 2-allyloxy-3 ~ dimathylamino-pyrazine, boiling point 110-115 ° /

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2c) 45 g of 2-allyloxy ~ 3 ~ dimethylamino ~ pyrazine become dissolved in 600 ml of dimethyl sulfoxide and 9 ml of water. In these 89 g of K-brorasuccinimide are added to the solution with stirring for 30 minutes registered. The temperature is increased by external cooling held at 35 °. Then stir 1 hour at room temperature, then diluted with 2 liters of ice water and shaken out with ether. The ether extracts are washed with water, dried over sodium sulfate and evaporated in a V7asserstrahlvakuuin. That's how you get it .5-Bromo-3 ~ d5.methylamino-2 ~ (3 '-bromo-2' -hydroxy-propoxy) pyrazine. . ■.

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Example 3

7.5 g of 5-bromo-3 ~ inorpholin3 ^r l-2- (3 '~ isopropylainino-2'-hydroxypropoxy) pyrazine are dissolved in 80 ml of methanol and dried in the presence of 0.4 g of palladium carbon (5% strength ) hydrogenated at 20-30 ° under normal pressure. After 10 minutes the reaction is taking up the calculated amount of hydrogen
completed. The catalyst is then filtered off
and evaporated in a water jet vacuum. The residue is partitioned between water and ether. The "aqueous phase
is made alkaline with concentrated sodium hydroxide solution and extracted with ether. The ether extracts are with
Washed water, dried over sodium sulfate and evaporated in a water jet vacuum. This gives 3-morpholinyl.2- (3 ^f -isopropylamino-2'-hydroxypropoxy) pyrazine, mp 74-76 °.

The methyl chloride prepared therefrom crystallizes from methanol-acetone, mp 136-137 °.

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Example 4

In an analogous way v. ^T he described in Example 3, are obtained from 6.7 g of 5-bromo-3-dimethylamino-2- (3 ^l -isopropylamino-2 '-hydroxy-propoxy) -pyrazine the 3 ~ Dimathylamino-2- (3'- isopropylaraino - ^ - hydroxy-propoxy) pyrazine hydrochloride, m.p. 130-131 °. · ·.

40 98 34/11 30

Example 5

53 g of 2- (3'-bromo-2'-hydroxypropoxy) -3-chloropyrazine are boiled with 59 g of isopropylamine in 500 ml of methanol for 15 hours under reflux. The reaction mixture is then evaporated in a water jet vacuum. The residue is between 2-n. Hydrochloric acid and ether distributed Phase is made alkaline with concentrated sodium hydroxide solution and extracted with ether. The ether extracts are washed with water, dried over sodium sulfate and evaporated in a water jet vacuum. The residue crystallizes from ether. This gives 3-chloro-2- (3'-isopropylamino-2'-hydroxypropoxy) pyrazine, 99-100 °.

The hydrochloride produced therefrom crystallizes from methanol-ether, mp 183 °.

The 2- (3 * -Brom-2 ¹ -hydroxy-propoxy) -3-chloropyrazine used as starting material can be prepared as follows:

5a) 59.6 g of 2,3-dichloropyrazine and 92.8 g of allyl

40 9834/1130

alcohol v / earth dissolved in 400 ml dimethyl sulfoxide. 9.6 g of sodium hydride are added to this solution with stirring at 0-5 ° entered for 30 minutes. Then 15 hours stirred at room temperature. The reaction mixture is then poured onto 2 liters of ice water and extracted with ether. The ether extracts are washed with water, dried over sodium sulfate and in a water jet vacuum

evaporated. The residue is distilled in a high vacuum. This gives the 2-AlIyIoXy-S-ChIOr-PyTaZIn, bp. 42-44? 0.03 torr.

5b) 34 g of 2-allyloxy-3-chloro-pyrazine and 7.2 ml of water V7erden dissolved in 500 ml of dimethyl sulfoxide. With stirring, 71 g of N-bromosuccinimide are introduced over a period of 30 minutes, the reaction temperature being kept at 30 ° by cooling. The mixture is then stirred for a further 30 minutes at room temperature and then diluted with 1 liter of water. Then the reaction mixture is extracted with ether. The ether extracts are washed with water, dried over sodium sulfate and evaporated in a water jet vacuum. The crude 2- (3'-bromo-2 ¹ -hydroxypropoxy) -3-chloropyrazine is obtained in this way.

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Example 6

In a manner analogous to that in Example 1, 5-bromine is obtained from 39.7 g of 5-bromo-3-morpholinyl-2- ( ^{3'-bromo-2 f} -hydroxirpropoxy) pyrazine and 51 g of tert-butylamine -3-morpholinyl-2- (3'-tert-butylamino-2'-hydroxypropoxy) pyrazine, m.p. 104-105 °.

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Example 7

(- propoxy ^l 3 -tert-butylamino-2 ^I hydroxy) pyrazine 3-morpholinyl-2 (in an analogous manner as in Example 3 is obtained from 3.9 g of 5-bromo-3-morpholinyl ~ 2- 3'-tert-butylamino-2'-hydroxypropoxy) pyrazine hydrochloride, mp 175-176 °.

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Example 8

7.5 β 3-chloro: -2- (3 '~ isoprop3 ^r lamino-2 ^l -hydroxypropoxy) pyrazine and 3.2 g of sodium diethylate are refluxed in 150 ml of methanol for 10 hours. The reaction mixture is then evaporated in a water jet vacuum. The residue is between 2-n. Hydrochloric acid and ether distributed. The acidic, aqueous phase is made alkaline with concentrated sodium hydroxide solution and extracted with ether. The ether extracts are washed with water, dried over sodium sulfate and evaporated in a water jet vacuum. This gives the crude base and, with ethereal hydrochloric acid in methanol, 3-methoxy-2- (3'-isopropylamino-2 ^! -Hydroxy-propoxy) -pyrazine hydrochloride, melting point 152-153 °,

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444

Example 9

In a manner analogous to that described in Example 1, 37 g of 5-bromo-3-isopropylamino-2-(3'-bromo-2'-hydroxy-1-propoxy) pyrazine give 5-bromo-3-isopropylamino- 2- (3'-isopropylamino-2 ^1- hydroxy-1-propoxy) pyrazine, mp 108-109 °, crystallized from ether.

In a manner analogous to that described in Example 1, the 5-bromo-3-isopropylamino-2- (3'-bromo-2 ^1- hydroxy-propoxy) pyrazine used as starting material can be prepared as follows:

. , 9a) From 149 g (1.0 mol) of 2,3-dichloropyrazine and 1.4 liters of an aqueous, 40% strength solution of isopropylamine, 2-chloro-3-isopropylaminopyrazine, b.p. 120 °, is obtained - 121 ° / 12 torr.

9b) Obtained from 86 g of 2-chloro-3-isopropylamino-pyrazine the 2-allyloxy-3-isopropylamino-pyrazine, b.p. 121-123 ° / 12 Torr.

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9c) From 39 g of 2-allyloxy-3-isopropylamino-pyrazine, 5-bromo-3-isopropylamino-2- (3 ^f -bromo-2'-hydroxypropoxy) pyrazine is obtained.

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Example 10

In an analogous manner to that described in Example 3, 3-isopropylamino-2 ~ (3 ¹ ) is obtained from 7 g of 5-bromo-3-isopropylamino-2- (3 ^{l -isopropylamino-2'-hydroxypropoxy) pyrazine} -isopropylamino-2'-hydroxy-propoxy) -pj'razin-di-hydrochloride, m.p. 198-200 °. ■

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Example 11

10.7 g of 2-chloro-3-morpholinyl-5-nisthyl-pyrazine and 16.6 g of 2-phenyl-3-isopropyl-5-h3 ^r- hydroxynethyl-oxazolidine are yellowed in 130 ml of hexamethylphosphoric acid triarnide. 3.6 g of a 50% suspension of sodium hydride in paraffin oil are introduced into this solution with stirring at 0-5 ° over a period of 30 minutes. The mixture is then stirred for 1 hour at 0-5 ° and for 24 hours at room temperature. The reaction mixture is then poured onto 500 ml of ice water and extracted with ether. The ether extracts are washed with Piasser and evaporated in a water jet vacuum. The residue is in 200 ml of 1-n. Sulfuric acid was added and the mixture was stirred at room temperature for 15 hours. Then the reaction mixture is extracted with ether. The acidic, aqueous phase is made alkaline with concentrated sodium hydroxide solution and then extracted with ether. The ether extracts are washed with water, dried over sodium sulfate and evaporated in a water jet vacuum. The residue crystallizes from ether-pentane. This gives 2- (3 ^f -isopropylamino-2'-hydroxypropoxy) -3-morpholiny1-5-methyl-pyrazine, mp 77-78 °. The hydrogen fumarate prepared therefrom with fumaric acid crystallizes from methanol-ether, mp 183-184 °.

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The 2-chloro-3-morpholyl-5 "m & thyl-pyrazine used as starting material can be made as follows;

16.3 g of 2,3-dichloro-5-methyl-pyrazine and 100 ml
Morpholine are heated to 100 ° for 6 hours. Then the reaction mixture is diluted with 200 ml of ether and again
shaken out with water. The ethereal phase is dried over sodium sulfate and evaporated in a water jet vacuum. The residue is distilled in a water jet vacuum. This gives 2-chloro-3-morρholinyl-5-methyl-pyrazine, boiling point 166-167 ° / 15 Torr.

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Example 12

In a manner analogous to that described in Example 3, from 4.9 g of 3-chloro-2- (3'-isopropylamino-2 ^! -Hydroxypropoxy) pyrazine, 2- (3 ^c -isopropylamino-2'-hydroxypropoxy) - pyrazine. The fumarate produced therefrom with fumaric acid crystallizes from isopropanol, mp 136-137 °.

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Example 13

In a manner analogous to that described in Example 11, 2- (3 ^! Isopropylamino-2'-hydroxypropoxy) -3-allyloxypyrazine is obtained from 8.5 g of 2-chloro-3-allyloxypyrazine.

The fumarate prepared therefrom with fumaric acid crystallizes from methanol-acetone, mp 149-150 °.

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Example 14

A solution of 15.0 g of 3-chloro-2- (2 ', 3 ¹ -epoxypropoxy) pyridine in 100 ml of isopropanol is mixed with 20 g of isopropylamine and then refluxed for 3 hours. The reaction mixture is evaporated in vacuo, dissolved in 300 ml of ethyl acetate and with 100 ml of 2-n. Hydrochloric acid extracted. The hydrochloric acid extract is made alkaline with 30 ml of concentrated sodium hydroxide solution and extracted 3 times with 100 ml of ethyl acetate each time. The organic phase is washed with 10 ml of brine, combined and dried over magnesium sulfate. This gives 2- (3 '~ isopropylamino-2 ^I- hydroxy-propoxy) -3-chloropyridine, which is recrystallized from ether-petroleum ether and melts at 71-73 °. The hydrochloride melts at 167-169 ° (from methanol-acetone).

The 3-chloro-2- (2 ¹ , 3'-epoxy-propoxy) -pyridine used as starting material can be produced in the following manner

40983A / 1130

be asked:

14a) 108 g of 2,2-diinethyl-4-hydroxymethyl-dioxolane are added dropwise to a suspension of 16.5 g of sodium hydride in 600 ml of 1,2-dimethoxyethane in such a way that the reaction remains under control. The mixture is then stirred for 1 hour at a bath temperature of 50-60 °. 100.0 g of 2,3-dichloropyridine are added in portions under reflux to the resulting suspension in the form of a gall. The reaction mixture, which has become thinner again, is stirred under reflux for a further 3 hours after the addition has ended. The solvent is evaporated off in vacuo and the residue is distributed between 2 liters of ether and 200 ml of water. The ether phase is dried over magnesium sulfate. The product remaining after evaporation of the ether is distilled in a high vacuum. The 3-chloro-2- [2 ', 2'-dimethyl-1 ¹ , 3'-dioxolanyl- (4') I-methoxypyridine boils at 95-100 ° / 0.01 Torr.

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14b) A solution of 157 g of 3-chloro-2- [2 ', 2'-dimethyl-1 ¹ , 3'-dioxolanyl- (4 ^f )] - methoxypyridine in 100 ml of ethanol is mixed with 320 ml of 2-n . Hydrochloric acid is added and the mixture is stirred at room temperature for 2 hours. After the ethanol has evaporated, the product is dissolved in a minimum of water (approx. 100 ml), washed with 100 ml of ether and the aqueous phase is made alkaline with concentrated sodium hydroxide solution. The oil which separates out is extracted 3 times with 200 ml of ethyl acetate each time. The extracts are washed with 20 ml of brine, dried and evaporated. The 3-chloro-2- (2 ^f , 3'-dihydroxypropoxy) pyridine obtained boils at 142-145 ° /

0.015 torr.

14c) To a solution of 40.6 g of 3-chloro-2- (2 ', 3'-dihydroxypropoxy) pyridine 25.2 g of methanesulfonic acid chloride are added to 100 ml of pyridine with stirring and cooling at 0-5 ° added dropwise over the course of 1 hour. Thereupon the reaction mixture Stirred for a further 5 hours at room temperature and then poured onto 200 ml of ice water. That I

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separating oil is isolated as in Example Ib). This gives the crude 3-chloro-2- (3 ^r- methanesulfonyloxy-2'-hydroxypropoxy) pyridine, which is further processed in the raw state.

14d) 67 g of crude 3-chloro-2- (3'-methanesulfonyloxy-2'-hydroxypropoxy) pyridine, 400 ml of methylene chloride, 240 ml of 1-n. Sodium hydroxide solution and 5 g of tetrabutyl ammonium chloride are stirred for 15 hours at room temperature. The methylene chloride phase is separated off, washed twice with 40 ml of water each time, dried and evaporated. _{The 3-chloro-2- (2 '>} 3'-epoxy-propoxy) -pyridine is isolated as a pale yellow oil from the evaporation residue by distillation at 115-130 ° / 0.03 Torr.

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Example 15

22 g of crude 2-methoxy-3- (3'-methanesulfonyloxy-2'-hydroxy-propoxy) -pyridine, 50 ml isopropylamine and 150 ml isopropanol V7 are heated under reflux for 16 hours. To Working up analogously to Example 14 gives 3- (3'-isopropylamino-2'-hydroxypropoxy) -2-methoxypyridine, much of it melts after recrystallization from ether-pentane at 50-65 °. After reaction with half the equivalent amount of fumaric acid, the neutral fumarate with a melting point of 146-147 ° (recrystallized from acetone).

The 2-methoxy-3- (3'-methanesulfonyloxy-2'-hydroxypropoxy) pyridine used as starting material is obtained in the following way:

15a) 26 g of 3-il ', 3'-dioxolan-2'-on-yl- (4 ^l )] methoxy-2-nitro-pyridine are mixed with a solution of 7.5 g of sodium in 500 ml of absolute methanol 15 Heated to boiling under reflux for hours. The solution is cooled with

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ν * -

2-n. Hydrochloric acid neutralized and evaporated in vacuo. The residue is boiled with 500 ml of chloroform, the solution is filtered and evaporated. The evaporation residue contains the crude 3- (2 ^!, 3'-dihydroxypropoxy) -2-methoxypyridine as a yellowish oil.

15b) 14.8 g of 3- (2 ', 3'-dihydroxypropoxy) -2-methoxypyridine yellow in 100 ml of anhydrous pyridine are added dropwise at -10 to -15 ° with stirring with 9.0 g of methanesulfonyl chloride. The reaction mixture is then stirred for a further 3 hours at -10 °. The pyridine is then evaporated off as completely as possible on a rotary evaporator at 10 torr and the crude 2- ^{methoxy.3- (3 l} -raethanesulfonyloxy-2'-hydroxypropoxy) pyridine thus obtained is reacted with isopropylamine without further purification.

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Example 16

A solution of 6.5 g of 2- [3'-isopropyl-2'-phenyloxazolidinyl- (5 ^l )] - methoxy-6-methoxypyridine in 40 ml of ethylene glycol dimethyl ether and 10 ml of ethanol are mixed with 20 ml of 2-n . Hydrochloric acid is added and the mixture is stirred at room temperature for 2 hours. The solution is then evaporated in vacuo and the residue is distributed between 30 ml of water and 50 ml of ether. The aqueous phase is made strongly alkaline with concentrated sodium hydroxide solution and extracted 3 times with 100 ml of ethyl acetate each time. After drying and evaporation, 2- (3'-isopropylamino-2 ^l -hydroxypropoxy) -6-methoxypyridine is obtained, the neutral fumarate of which melts at 140-141 ° (recrystallized from methanol / acetone).

, 409834/1130

- did -

Example 17

7.4 "g of 2- [3 ^f -isopropyl-2'-phenyl-oxazolidinyl- (5 ')] -methoxy-4-phenyl-pyridine are hydrolyzed as in Example 16 and give the 2- (3'-isopropylinino-2 ¹ -hydroxy-propoxy) -4-phenyl-p3 ⁷ ridin, the neutral furarate of which melts at 171-173 ° (recrystallization from methanol / acetone) *

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Example 18

6.8 g of crude 2- [3'-isopropyl-2'-phenyl-oxazolidinyl- (5 ¹ )] -methoxy-5-nitropyridine are hydrolyzed as in Example 16, then brought to pH 9 with saturated soda solution and the product Vieiter V7ie isolated in Example 16. This gives 2- (3'-isopropylavnino-2 '~ hydroxy-propoxy) -5 ~ nitropyridine with a melting point of 117-123 ° (recrystallized from isopropanol)

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- YES" ·

Example 19

33 g of crude 3- (2 ^f , 3'-epoxy-propoxy) ~ 6-methylpyridine, 350 ml of isopropanol and 75 ml of isopropylamine are refluxed for 12 to 14 hours. Working up is carried out as in Example 14. The 3- (3'-isopropylamino-2'-hydroxypropoxy) -6-methyl-pyridine thus obtained boils in a bulb tube at 135-150 ° / 0.2 Torr. Its neutral fumarate melts at 171-173 ° (recrystallized from methanol / acetone) «

The 3- (2 ', 3'-epoxypropoxy) -6-methyl-pyridine required as starting material is made in the following way:

19a) 22 g of 6-methyl-3-pyridinol, 50 g of potassium carbonate and 80 ml of epichlorohydrin are dissolved in 500 ml of acetone with stirring and reflux heated to boiling for 18 to 20 hours. The undissolved parts are sucked off and that The filtrate was concentrated in vacuo at a bath temperature of 30 to 40 °. The 3- (2 *, 3'-epoxy-propoxy) -6-methyl-pyridine obtained in this way is processed further without further purification.

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Example 20

a) 4.9 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine are added to a suspension of 0.5 g of sodium hydride in 40 ml of ethylene glycol dimethyl ether. The reaction mixture is stirred for 2 hours at 40-50 °, then 2.9 g of 2-chloro-6-methoxypyridine are added and the mixture is refluxed for 14 hours. The solution of 2- [3 ¹ -isopropyl-2 ¹ -phenyl-oxazolidinyl- (5 ') j -methoxy-6-methoxypyridine thus obtained can, as indicated in Example 16, be hydrolyzed without isolating the product. The following connections can also be represented in a manner analogous to that described above:

b) 2- [3'-Isopropyl-2'-phenyl-oxazolidinyl- (5 ')] -methoxy-4-phenyl-pyridine from 2-bromo-4-phenyl-pyridine.

c) 2- [3 "'-Isopropyl-2 ¹ -phenyl-oxazolidinyl- (5')] -methoxy-5-nitropyridine from 2-chloro-5-nitro-pyridine.

d) 2- [3'-Isopropyl-2 ¹ -phenyl-oxazolidinyl- (5 ¹ )] - methoxy-3-methyl-pyridine from 2-chloro-3-methyl-pyridine,

409834/1 1'3OT

e) 2- [3 ¹ -Isopropyl-2 ¹ -phenyl-pxazolidinyl- (5 ')] -methoxy-5-raethylaminocarbonyl-pyridine from 6-chloro-N-methylnicotinic acid amide.

The starting material for example 20e) can be represented as follows:

42 g of 6-hydroxynicotinic acid are added over the course of 1 hour to a suspension of 126 g of phosphorus pentachloride in 300 ml of toluene registered. The reaction mixture is heated to boiling for 3 hours and then at reduced Evaporated pressure. The crude, crystalline evaporation residue is dissolved in 200 ml of chloroform and, with ice cooling, in 300 ml of a 16% solution of methylamine in absolute ethanol were added dropwise. After the addition, the reaction mixture becomes Stirred for a further 3 hours, then filtered and evaporated under reduced pressure. The evaporation residue is in Dissolved ethyl acetate, with 2-n. Washed sodium carbonate solution and recrystallized from ethanol-ether. The 6-chloro-N-methylnicotinamide isolated in this way melts at 149-151 °.

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Example 21

40 of crude 2- [3 ¹ ~ ^r l Isoprop3-2'-phenyl-oxazolidinyl (5 ')] g-methoxy-3-raethylp3 ridi.n ^7, dissolved in 150 ml of ethanol
are with 30 ml 6-n. Hydrochloric acid hydrolyzed for 3 hours at 20 ° and worked up analogously to Example 16. This gives 2- (3 '~ isoprop3 ^T lamino-2 ^l -hydroxypropoxy) -3-methylpyridine, which distills in a bulb tube at 130-140 ^o / 0.03 Torr and whose fumarate melts at 153-155 ° ( recrystallized from methanol-acetone).

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Example 22

22 g of 2- [3 ^l -isopropyl ~ 2 ^l ~ phenyl ~ oxazdlidinyl- (5 ^t )] methoxy-S-methyl-aminocarbonyl-pyridine earth dissolved in 200 ml of ethanol and mixed with 30 ml of 6 ~ n. Hydrochloric acid trydrolyzed at 20 ° for 3-4 hours and worked up analogously to Example 16. This gives 2- (3'-isopropylamino-2 ^1- hydroxy-propoxy) -5-niethylaminocarbonyl-pyridine with a melting point of 118-120 °.

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Example 23

25 g of crude 3- (2 ', 3 ^f -epoxy-propoxy) ^ - pyrrolidinocarbonyl-pyridine, dissolved in 350 ml of isopropanol, are refluxed with 150 ml of isopropylamine for 3 hours. After evaporation and work-up of the residue as in Example 14, 3- (3'-isopropylamino-2'-hydroxypropox3 '-) - 2-pyrrolidinocarbonylpyridine _f, which melts at 108-111 °, is obtained (recrystallized from ethyl acetate-ether).

The starting material is obtained by reacting 2-pyrrolidinocarbonyl ~ 3 ~ hydroxypyridine with epichlorohydrin analogous to example 19a).

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Example 24 '

4.2 g of sodium hydride dispersion (55%) are placed in 150 ml of dimethoxyethane and stirred and introduced of nitrogen dropwise with a solution of 24.3 g of 2-phenyl-3-isopropyl-5-hydroxymethyl-oxazolidine in 50 ml of dimethoxyethane are added. The mixture is stirred at 45 ° for 1.5 hours. After adding 19.96 g of 3-chloro-6-morpholinopyridazine the reaction mixture is refluxed for 24 hours, then acidified with hydrochloric acid (15%) at 20 ° and during Stirred well for 2 hours. At 40 °, the dimethoxyethane is evaporated in vacuo and the hydrochloric acid residue is extracted with ether. The acidic phase is denoted by 5-n. Sodium hydroxide solution made alkaline and extracted with chloroform. The one with saturated The extract, which has been washed with sodium chloride solution and filtered through cotton wool, is evaporated in vacuo and the residue is filtered through Purified chromatography on silica gel (eluent: chloroform / methanol = 9/1).

After recrystallization from methylene chloride / ether the 3- (3'-isopropylamino-2'-hydroxypropoxy) -6-morpholinopyridazine obtained melts at 112-113 °.

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Example 25

12.5 g of 2- [3'-isopropyl-2'-phenyl-oxazolidinyl- (5 ¹ )] -methoxypyrimidine are taken up in 60 ml of 1-N-sulfuric acid. The mixture is heated to the boil for half an hour, cooled, the benzaldehyde which has separated out is extracted with ether, the separated aqueous phase is treated with the amount of barium hydroxide solution necessary to neutralize the sulfuric acid and filtered. The filtrate is evaporated in vacuo. The oil obtained is distilled in a bulb tube. After a slight forerun, the 2- (3'-isopropylamino-2'-hydroxypropoxy) pyrimidine is obtained at 140 ° / 0.05 Torr as a colorless oily distillate. Its hydrogen oxalate melts at 181-182 ° (from acetone).

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Example 26

13.3 g of 2- (3'-p-toluenesulfonyloxy-2 ^l -hydroxypropoxy) pyrimidine are dissolved in 100 ml of isopropanol and 22 ml of isopropylamine and stored for 48 hours at room temperature. The volatile components are then distilled off in vacuo, the oily residue is taken up in acetone and a solution of 4 g of oxalic acid in acetone is added. The 2- (3'-isopropylamino-2 ^1- hydroxy-propoxy) -pyrimidine hydrogenoxalate is obtained, which is recrystallized from methanol-acetone. 181-182 °.

The 2- (3'-p-toluene-bulfonyloxy-2'-hydroxypropoxy) pyrimidine required as starting material can be made as follows:

26a) 6.6 g of 2,2-dimethyll, 3-dioxolane-4-methanol are added to a suspension of 1.2 g of sodium hydride in 50 ml of dimethoxyethane and stir for 2 hours at room temperature. Then 5.7 g of 2-chloro-pyrimidine are added. That The reaction mixture is heated to boiling for 2 hours and then evaporated in vacuo. The residue will

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distilled in a bulb tube. After a slight forerun, the 2- [2 ', 2'-dimethyl-1', 3'-dioxolane (4 ')] methoxypyrimidine distills at 200 ° / 19 torr as a colorless oil.

25b) 16 g of 2- [2 ', 2'-dimethyl-l ^l , 3 ^l -dioxolane (4')] - methoxypyrimidine are mixed with 20 ml of water and 2 ml of 2-n. Sulfuric acid heated to boiling for 15 minutes. It is then cooled, the amount of barium hydroxide solution necessary to neutralize the acid is added and the mixture is filtered. The filtrate is evaporated and the remaining oil is distilled in a bulb tube, the 2- (2 ', 3'-dihydroxypropoxy) pyrimidine being obtained as a colorless oily distillate at 180-190 ° / 0.4 Torr.

25c) In a solution of 11.8 g of 2- (2 ', 3'-dihydroxypropoxy) pyrimidine in 18 ml of pyridine which is cooled to -10 °, 13.6 g of p-toluenesulfonyl chloride are carried with stirring for 15 minutes. The reaction mixture is kept at 0 ° for 15 hours. Then ice is added and, under Stir, 20 ml 6-n. Hydrochloric acid. It is then extracted twice with 150 ml of methylene chloride each time. The extracts are washed with sodium bicarbonate solution, over sodium sulfate dried and evaporated. The 2- (3'-p-toluenesulfonyloxy-2'-hydroxypropoxy) pyrimidine is obtained as a yellowish oil. . .

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ί ο a . _

Example 27

In an analogous manner, V7ie is described in Examples 1-13 the following connections can also be made:

1) 2- (3'-Isopropylamino-2'-hydroxy-propoxy) -3-morpholino-5- (2 ¹ -methoxyethyl) pyrazine,

2) 2- (3 ¹ -Isopropylamino-2 ^f -hydroxy-propoxy) -3-morpholino-5- (2 ¹ -methoxycarbonylaminoethyl) pyrazine,

3) 2- (3'-Isopropylamino-2 ^1- hydroxy-propoxy) -5-hydroxy-pyrazine.

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. Example 28

In a manner analogous to that described in Examples 14 to 14, the following compounds can also be prepared:

a) 3- (3'-Isopropylamino-2'-hydroxy-propoxy) -2- (n-butylaminocarbonyl) pyridine, m.p. 65-67 °,

b) 2- (3 '"isopropylamino-2'-hydroxy-propoxy) -3-propy1-pyridiη,

c) 2- (3'-Isopropylamino-2'-hydroxypropoxy) -3-nitro-pyridine,

d) 3-dimethylamino-2- (3'-isopropylamino-2'-hydroxypropoxy) -pyridine,

e) 2- (3 ¹ -Isopropylamino-2 ¹ -hydroxy-propoxy) -5-methoxypyridine,

f) 2- (3'-Isopropylamino-2 ^1- hydroxy-propoxy) -5- (2'-methoxyethyl) -pyridine,

g) 5-acetylaminomethyl-2- (3'-isppropylamino-2 ^f hydroxypropoxy) pyridine,

h) 2-chloro-3- (3'-isopropylamino-2 ^r -hydroxy-propoxy) -pyridine,

409834 / 113D

i) 2- (3'-Isopropylamino-2'-hydroxypropoxy) -3,5-dimethyl-pyridine,

j) 2- (3'-Isopropylamino-2'-hydroxy-propoxy) -3-chloro-5- (2'-methoxyethyl) pyridine,

k) 2- (3 * -Isopropylamino-2'-hydroxy-propoxy) -5-carbanylmethyl-pyridine,

1) 2- (3'-Isopropylamino-2'-hydroxy-propoxy) -3-allyloxypyridine,

m) 3- (3'-Isopropylamino-2 ^1- hydroxy-propoxy) -6-hydroxy-pyridine,

n) 2- (-3 ¹ -Isopropylamino-2'-hydroxy-propoxy) -5-hydroxypyridine.

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' ²⁴⁰⁶⁹³ °

Example 29

The following compounds can also be synthesized in a manner analogous to that described in Examples 24-26:

1) 2- (3'-Isopropylamino-2'-hydroxy-propoxy) -4-acetylamino-5-cyano-pyriraidin,

2) 2- (3'-Isopropylamino-2'-hydroxy-propoxy) -5- (2'-methoxycarbonylamino-methyl) -pyrimidine,

3) 2- (3 ^f -Isopropylamino-2'-hydroxy-propoxy) -6-methy1-pyrimidine,

4) 2- (3'-isopropylamino-2'-hydroxypropoxy) -5-phenyl-pyrimidine,

5) 3- (3'-Isopropylamino-2 ^1- hydroxy-propoxy) -6-methoxypyridazine, mp 115-116 °,

6) 3- (3'-Isopropylamino-2'-hydroxypropoxy) -6-chloropyridazine, 98-99 °,

7) 3- (3'-Isopropylamino-2'-hydroxy-propoxy) -pyridazine, 91-93 ° F.

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Example 30

Tablets containing 50 mg of active substance are produced in the usual way in the following composition:
Composition: ■

Z- (3. ¹ -tert. ~ Butylamino-2'-hydroxy-propoxy) - , - 50 mg 3 -morpholinopyrazine 59 mg Wheat starch 70 mg Lactose 10 mg Colloidal silica 10 mg Talk ". · 1 mg Magnesium tearat. 200 mg '. . -

Manufacturing:

2- (3'-tert "-Butylamino-2'-hydroxypropoxy) -3-morpholinopyrazine is mixed with part of the wheat starch, with lactose and colloidal silica and the mixture driven through a sieve, obtaining a powder mixture will. Another part of the wheat starch is gelatinized with five times the amount of water on the water bath and the Powder mixture kneaded with this paste until one

409834/1130

weak plastic mass has arisen.

The plastic mass is pressed through a sieve with a mesh size of about 3 mm, dried and the resulting dry granules driven through a sieve again. The remaining wheat starch, talc and magnesium stearate are then placed on top xu mixed and the mixture is pressed into tablets weighing 200 mg with a break line.

The daily dose is about ½ to 4 tablets in the case of a warm-blooded animal of about 75 kg body weight, with the appropriate dose of active ingredient can also be administered in a single, appropriately composed tablet can. ■ -

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Example 31

A solution of 34 g of 2- [3'-isopropyl-2'-phenyloxazolidinyl- (5 ^f )] - methoxy-4-methyl-pyridine in 200 ml of ethanol is mixed with 60 ml of 4-n. Hydrochloric acid is added and the mixture is left to stand at room temperature overnight. The solvent is evaporated off in vacuo and the residue is dissolved in approx. 200 ml of water. This solution is extracted with 100 ml of ether. The aqueous phase is separated off, made strongly alkaline with concentrated potassium hydroxide solution and extracted with methylene chloride. After drying and evaporation of the solvent, a dark oil is obtained, which is distilled in a bulb tube at 120-130 ° / 0.1 Torr. Half the equivalent amount of fumaric acid, dissolved in methanol, is added to the 2- (3 ¹ -isopropylamino-2 ^1- hydroxy-propoxy) -4-methyl-pyridine obtained, the solution is evaporated in vacuo and acetone is added. The neutral fumarate with a melting point of 136-139 ° crystallizes in this way.

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Example 32

A solution of 40 g of 2- [3 ^f -isopropyl-2'-phenyloxazolidinyi- (5)] - methoxy-5-methyl-pyridine in 200 ml of ethanol is mixed with 60 ml of 4-n. Hydrochloric acid is added and the mixture is left to stand at room temperature overnight. The solvent is evaporated off in vacuo and the residue is dissolved in approx. 200 ml of water. This solution is extracted with 100 ml of ether. The aqueous phase is separated off, made strongly alkaline with concentrated potassium hydroxide solution and extracted with methylene chloride. After drying and evaporation of the solvent, a dark oil is obtained which is distilled in a bulb tube at 120-130 ° / o.1 Torr. The 2- (3'-isopropylamino-2 ^l -hydroxy-propoxy) -5-methyl-pyridine thus obtained crystallizes: mp 62-67 °. Half the equivalent amount of fumaric acid, dissolved in methanol, is added, the solution is evaporated in vacuo and acetone is added. The neutral fumarate with a melting point of 149-151 ° crystallizes in this way.

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Example 33

A solution of 35 g of 2- [3'-isopropyl-2'-phenyloxazolidinyl- (5 ')] - methoxy-6-methyl-pyridine in 200 ml of ethanol is mixed with 60 ml of 4-n. Hydrochloric acid is added and the mixture is left to stand at room temperature for 1 hour. The solvent is evaporated off in vacuo and the residue is dissolved in approx. 200 ml of water. This solution is extracted with 100 ml of ether. The aqueous phase is separated off, made strongly alkaline with concentrated potassium hydroxide solution and extracted with methylene chloride. After drying and evaporation of the solvent, a dark oil is obtained, which is distilled in a bulb tube at 130 ° / 0.04 Torr. Half the equivalent amount of fumaric acid, dissolved in methanol, is added to the 2- (3'-isopropylamino-2 ^1- hydroxy-propoxy) -6-methyl-pyridine obtained, the solution is evaporated in vacuo and acetone is added. The neutral fumarate with a melting point of 164-165 ° crystallizes in this way.

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Example 34

A solution of 40 g of 2- [3'-isopropyl-2'-phenyloxazolidinyl- (5 ')] - methoxy-3-ethoxypyridine in 200 ml of ethanol is mixed with 60 ml of 4-n. Hydrochloric acid is added and the mixture is left to stand at room temperature over night. The solvent is evaporated off in vacuo and the residue is dissolved in approx. 200 ml of water. This solution is extracted with 100 ml of ether. The aqueous phase is separated off, made strongly alkaline with concentrated potassium hydroxide solution and extracted with ethyl acetate. After drying and evaporation of the solvent, a dark oil is obtained, which is distilled in a bulb tube at 130-140 ° / 0.03 Torr. Half the equivalent amount of fumaric acid, dissolved in methanol, is added to the 2- (3'-isopropylamino-2 ^l -hydroxypropoxy) -3-ethoxy-pyridine obtained, the solution is evaporated in vacuo and methyl-ethyl-ketone is added. The neutral fumarate with a melting point of 142-144 ° crystallizes in this way.

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Example 35

A solution of 30 g of 2- [3'-isopropyl-2 ¹ -phenyloxazolidinyl- (5 ')] - methoxy-S-chloro-S- (methylaminocarbonyl) -pyridine in 260 ml of 2-n. Sulfuric acid is stirred for 4 hours at room temperature. This solution is extracted with 100 ml of ether. The aqueous phase is separated off, made strongly alkaline with concentrated potassium hydroxide solution and extracted with ethyl acetate. After drying and evaporation of the solvent, a dark oil is obtained which crystallizes from ether. The 2- (3'-isopropylamino-2 ^1- hydroxy-propoxy) -3-chloro-5- (methylaminocarbonyl) pyridine thus obtained melts at 130-132 °. Half the equivalent amount of fumaric acid, dissolved in methanol, is added, the solution is evaporated in vacuo and acetone is added. The neutral fumarate with a melting point of 133-136 ° crystallizes in this way.

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Example 36

A solution of 32 g of 2- [3'-isopropyl-2'-phenyl-oxazolidinyl- (5 ')] -methoxy-1-chloro-S-n-hexylaminocarbonyl-pyridine in 260 ml 2-n. Sulfuric acid is stirred for 4 hours at room temperature. This solution is extracted with 100 ml of ether. the aqueous phase is separated off, made strongly alkaline with concentrated potassium hydroxide solution and extracted with ethyl acetate. After drying and evaporation of the solvent, a dark oil is obtained which crystallizes from ether. That so obtained 2- (3'-isopropylamino-2'-hydroxypropoxy-S-chloro-S-nhexylaminocarbonylpyridine melts at 131-132 °. It is mixed with half the equivalent amount of fumaric acid dissolved in methanol, added, the solution evaporated in vacuo and mixed with acetone. In this way the neutral fumarate crystallizes from M.p. 170-172 °.

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Example 37

A solution of 28 g of 2- [3 ^l -isopropyl-2'-phenyloxazolidinyl- (5 ')] - methoxy-5-cyano-pyridine in 260 ml of 2-n. Sulfuric acid is left to stand for 4 hours at room temperature. This solution is extracted with 100 ml of ether. The aqueous phase is separated off, made strongly alkaline with concentrated potassium hydroxide solution and extracted with methylene chloride. After drying and evaporation of the solvent, a dark oil is obtained which crystallizes from methylene chloride-ether. The 2- (3'-isopropylamino-2 ^1- hydroxy-propoxy) -5-cyano-pyridine thus obtained melts at 124-126 °.

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Example 38

12.5 g of 2- (3'-isopropylamino-2 ^1- hydroxy-propoxy) -5-cyano-pyridine are dissolved in 100 ml of methanol. The solution is mixed with 5-7 g of ammonia and, with the addition of 3 g of Raney nickel, hydrogenated at 70-80 ° and 40 bar initial pressure of hydrogen until the hydrogen uptake stops. The catalyst is filtered off, the solution is evaporated and the residue is distilled in a bulb tube at 140 ° / 0.01 Torr. This gives 5-aminomethyl-2- (3'-isopropylamino-2'-hydroxypropoxy) pyridine as a pale yellowish oil .

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Example 39

28.7 g of 2- (3'-isopropylamino-2'-hydroxy-propoxy) -5-nitropyridine are dissolved in 300 ml of methanol and, with the addition of 3 g of Raney nickel, at room temperature and atmospheric pressure until the theoretical amount of hydrogen is absorbed hydrogenated. The catalyst is filtered off under nitrogen and the filtrate is evaporated. The crude 5-amino-2- (3'-isopropylamino-2 ^1- hydroxy-propoxy) -pyridine obtained in this way is yellowish in 150 ml of dichloromethane and 14.3 ml of acetic anhydride are added dropwise while stirring. The solution is heated to reflux. After the anhydride has been added dropwise, the reaction mixture is stirred for a further 20-30 minutes. After shaking out the solution with 90 ml of 2-n. Sodium carbonate solution is the organic phase with a total of 200 ml of 2-n. Hydrochloric acid extracted, the acidic, aqueous extract treated with activated charcoal (approx. 10 g) and evaporated in vacuo. The dark oil obtained is dissolved in the smallest amount of water required and made alkaline with concentrated sodium hydroxide solution. The crude base is isolated by extraction with dichloromethane. 5-Acetamido-2- (3 ¹ -isopropylamino-2 ¹ -hydroxy-propoxy) -pyridine with a melting point of 138 ° -141 ° crystallizes from butanone. It forms a hydrochloride with a melting point of 204-206 ° (from methanol-acetone)

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Example 40

A solution of 25 g of crude 2- [3'-isopropyl-2'-phenyloxazolidinyl- (5 ')] methoxy-5- (2'-aminoethyl) pyridine in 150 ml of 4-n. Sulfuric acid is reacted and worked up analogously to Example 35. Crude 5- (2'-aminoethyl) -2- (3'-isopropylamino-2 ^1- hydroxy-propoxy) pyridine of sufficient purity for further reactions is obtained in this way. Pure product is obtained by bulb tube distillation at 140-150%), 005 Torr.

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Example 41

12.4 g of 5- (2 ^f -aminoethyl) -2- (3 ^l -isopropylamino-2 ^I -hydroxy-propoxy) -pyridine, dissolved in a mixture of each ml of isopropanol and water, are stirred at a temperature of 20 -35 ° with 5.4 ml of methyl chloroformate added dropwise, cooling with ice water if necessary. The reaction mixture is stirred for a further hour at room temperature, evaporated in vacuo and the evaporation residue is dissolved in about 30 ml of water. This solution is extracted with 20 ml of ethyl acetate and the acidic, aqueous phase is made alkaline with concentrated sodium hydroxide solution. The precipitated oil is extracted with dichloromethane. After drying the solution over magnesium sulfate and evaporation of the solvent, the 2- (3'-isopropylamino-2'-hydroxypropoxy) -5- (2 ^f -methoxycarbonyl-aminoethyl) -pyridine is obtained, which after recrystallization from a little butanone at 97- 99 ° melts.

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Example 42

Using 8.9 ml of n-butyl chloroformate instead of 5.4 ml of methyl chloroformate gives 5- (2'-n-butoxycarbonylaminoethyl) 2- (3'-isopropylamino-2 ^1- hydroxy-propoxy) pyridine analogously to Example 41, which, after crystallization from butanone, melts at 93-95 ° and forms a neutral fumarate with a melting point of 145-147 °.

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Example 43

Analogously to Example 41, using 14.1 g of 5- (2 ^l -aminoethyl) -3-chloro-2- (3'-isopropylamino-2 ^{l of} hydroxypropoxy) pyridine is obtained instead of 5- (2'-atninoethyl ) -2- (3'-Isopropylamino-2-hydroxy-propoxy) -pyridine 3-chloro-2- (3'-isopropylamino-2'-hydroxypropoxy) -5- (2'-methoxycarbonylaminoethyl) -pyridine of m.p. 99-101 ° (from ether). It forms a neutral fumarate with a melting point of 179-180 ° (from ethanol). The raw material can be produced in the following ways:

a) The crude S ^ -dichloronicotinic acid chloride, which is obtained from 279 g 2-Hydroxy-5-pyridinecarboxylic acid is obtained analogously with 185 g of sodium borohydride in 3.2 liters of water F.E. Ziegler and J.G. Sweeny, J. Org. Chem. 34, 3545 (1969) reduced to 2,3-dichloro-5-hydroxymethylpyridine, m.p. 72-75 °.

b) The 2,3-dichloro-5-hydroxymethyl-pyridine is known in Way with thionyl chloride to 5-chloromethyl-2,3-dichloropyridine reacted and this reacted with sodium cyanide without further purification (e.g. analogous to L.A. Carlson et al., Acta Pharm. Suecica J9, 411 (1972). The 5,6-dichloropyridine-3-acetonitrile thus obtained melts after recrystallization from ether at 72-75 °.

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c) 85.5 g of (5,6-dichloro-3-pyridine) acetonitrile in 200 ml of methanol are reduced analogously to Example 40 a) with 18.5 g of sodium borohydride in 65 ml of concentrated sodium hydroxide solution and 20 g of Raney nickel. ^{The 5- (2!} -Aminoethyl) -2,3-dichloropyridine is obtained from the crude product thus obtained by Kugelrohr distillation at a bath temperature of 95-115 ° and 0.08 torr.

d) 44 g of 5- (2'-aminoethyl) -2,3-dichloropyridine and 55 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine, dissolved in 500 ml of 1,2-dimethoxyethane are cooled with ice at 0-10 ° 12 g of sodium hydride dispersion (55%) are added in portions. The reaction mixture is then 2 hours at Room temperature and stirred under reflux for 16 hours.

Working up gives the crude 5- (2'-aminoethyl) -3-chloro-2- [3'-isopropyl-2'-phenyl-oxazolidinyl- (5 ') 3-methoxypyridine, which without further purification analogous to Example 37) to 5- (2'-aminoethyl) -3-chloro-2- (3'-isopropylamino-2'-hydroxypropoxy) pyridine is hydrolyzed (bp 165-185%), 06 torr.

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Example 44

6 g of 5-aminomethyl-2- (2 '-hydroxy-3' -isopropylamino-propoxy) -pyridine Dissolved in 25 ml each of isopropanol and water are analogous to Example 41) with 2.3 ml of methyl chloroformate reacted and worked up and give the 2- (2'-hydroxy-3'-isopropylamino-propoxy) -5-methoxycarbonylaminomethyl-pyridine of m.p. 96-97 ° (from ether). Its neutral fumarate melts at 138-140 °.

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Example .45

Analogously to Example 44), using 3.7 ml of n-butyl chloroformate instead of the methyl ester is obtained 2- (2 '-Hydroxy-3' -isopropylamino-propoxy) -5- (n ~ butoxycarbonyl aminomethyl) pyridine of m.p. 85-87 ° (sinters from 79 °), after recrystallization from dichloromethane ether.

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Example 46

A solution of 24 g of 2- [3'-tert-butyl-2'-phenyloxazolidinyl- (5 ')] - methoxy-3-ethoxypyridine in 100 ml of ethanol is mixed with 60 ml of 4-n. Hydrochloric acid is added and the mixture is left to stand at room temperature for 2 hours. The solvent is evaporated off in vacuo and the residue is dissolved in approx. 100 ml of water. This solution is extracted with 100 ml of ether. The aqueous phase is separated off, made strongly alkaline with concentrated potassium hydroxide solution and extracted with ether. After drying and evaporation of the solvent, a dark oil is obtained, which is distilled in a bulb tube at 130 ° / 0.03 T. Half the equivalent amount of fumaric acid, dissolved in methanol, is added to the 2- (3 ¹ -tert.Butylamino-2'-hydroxypropoxy) -3-ethoxy-pyridine obtained, the solution is evaporated in vacuo and butanone is added. The neutral fumarate with a melting point of 170-172 ° crystallizes in this way, crystal transformation at 161-163 °.

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Example 47

19.5 g of crude 3- (2 ', 3'-epoxypropoxy) -2-nitro-pyridine _; dissolved in 300 ml of isopropanol, are refluxed with 100 ml of isopropylamine for 4 hours. After working up as in Example 14), 3- (2'-hydroxy-S'-isopropylaminopropoxy) -2-nitro-pyridine is obtained, which, after crystallization from ether, melts at 99-101 °.

The starting material is obtained in the following way: a) 28 g of 2-nitro-3-pyridinol, 200 ml of epichlorohydrin and 60 g Potassium carbonate are refluxed for 8 hours with stirring in 500 ml of acetonitrile. Filtration and evaporation of the reaction mixture give the crude 3- (2 ', S'-epoxy-propoxy) · 2-nitro-pyridine as a yellow oil.

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Example 48

5.2 g of 2 - [(3'-isopropyl-oxazolidin-2 ^I -one-5 ^! -Yl) -methoxy] -4-phenyl-pyridine are added to a mixture of 70 ml of ethanol and 20 ml of 2-n. Sodium hydroxide solution boiled under reflux for 16 hours. The reaction mixture is evaporated in vacuo and then partitioned between 100 ml of ether and 20 ml of water. The organic phase is separated and with 40 ml of 2-n. Hydrochloric acid extracted. The hydrochloric acid extract is made alkaline with concentrated sodium hydroxide solution and the separated oil is extracted again with ether. The 2- (2'-hydroxy-3'-isopropylamino-propoxy) -4-phenyl-pyridine isolated in this way forms a neutral fumarate with a melting point of 171-173 °.

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Example 49

A solution of 48 g of 2- [3 * -Isopropyl-2'-phenyloxazolidinyl- (5 ')] - methoxy-S-chloropyridine in 200 ml of ethanol is mixed with 60 ml of 4-n. Hydrochloric acid is added and the mixture is left to stand at room temperature for 3 hours. The solvent is evaporated off in vacuo and the residue is dissolved in approx. 200 ml of water. This solution is extracted with 100 ml of ether. The aqueous phase is separated off, made strongly alkaline with concentrated potassium hydroxide solution and extracted with methylene chloride. After drying and evaporation of the solvent gives an oil from which by adding a solution of hydrochloric acid in methanol until pH 2-3 2- (3 ^t 2 ^t -Isopropylamino-hydroxy-propoxy) -3-chloro-pyridine hydrochloride is isolated. After recrystallization from methanol-acetone, it melts at 167-169 °.

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Example 50

A solution of about 35 g of 4- [3'-isopropyl-2'-phenyloxazolidinyl- (5 ')] - methoxy-3-methyl-pyridine in 100 ml of ethanol is mixed with 60 ml of 4-n. Hydrochloric acid is added and the mixture is left to stand at room temperature for 2 hours. The solvent is evaporated off in vacuo and the residue is dissolved in approx. 100 ml of water. This solution is extracted with 100 ml of ether. The aqueous phase is separated off with concentrated potash. lye made strongly alkaline and extracted with .Methylene chloride. After drying and evaporation of the solvent, a yellow oil is obtained which is distilled in a bulb tube at 145 ° / 0.02 Torr. The 4- (3'-isopropylamino-2'-hydroxypropoxy) -3-methyl-pyridine thus obtained is treated with the equivalent amount of fumaric acid dissolved in methanol, the solution is evaporated in vacuo and isopropanol is added. The acidic fumarate with a melting point of 167-169 ° crystallizes in this way.

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Example 51

5.3 g of 5- (2 '-aminoethyl) -3-chloro-2- (3' isopropylamino-2 ' Hydroxy-propoxy) pyridine are analogous to Example 41) with 2.2 g of ethyl chloroformate in a mixture of 25 ml each Isopropanol and water reacted and, after recrystallization from acetone - ether, give 5- (2'-ethoxycarbonylaminoethyl) -3-chloro-2- (3'-isopropylamino-2'-hydroxypropoxy) pyridine from m.p. 120-122 °. It gives a neutral fumarate with a melting point of 149-151 ° (from ethanol-acetone).

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Example 52

32 g of crude 2 - [(3 ¹ -Isopropyl-2 ^f -paenyl-oxazolidin-5 * -yl) methoxy] -3-ChIOr-S - [(tetrahydropyran-2'-yloxy) -methyl] -pyridine is dissolved in 250 ml 2-n. Dissolved sulfuric acid, the solution left to stand for 4 hours at room temperature and then extracted with 100 ml of ether. The aqueous phase is evaporated to approx. 50 ml in vacuo, made alkaline with cone sodium hydroxide solution and extracted three times with 150 ml of methylene chloride each time. The 3-chloro-2- (2'-hydroxy-3'-isopropylamino-propoxy) -5-hydroxymethyl-pyridine obtained after drying and evaporation of the solvent distills in a bulb tube at 170-180 ° / 0.04 Torr as a colorless oil and forms a neutral fumarate with a melting point of 205-207 ° (from methanol).

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Example 53

A solution of .45 g of crude 3-Methyl-2- S [2-phenyl-3 ~ (4-phenyl-2-butyl) -oxazolidin-5-yl] -methoxyl-pyridine in 200 ml of ethanol with 120 ml 4-n. Hydrochloric acid hydrolyzed and worked up analogously to Example 31 for 3 hours at 20 °. Kugelrohr distillation at 140-150 ° / 0.04 torr gives 2- [2'-hydroxy-3'- (1-methyl-3-phenyl-propylamino) -propoxy] -3-methyl-pyridine as a light yellow OeI.

The raw material can be produced in the following ways:

a) 31.1 g of 2-phenyl-3- (l-phenyl-3-butyl) -5-hydroxymethyloxazolidine, dissolved in 150 ml of dimethylformamide, with 6.5 g of sodium hydride dispersion (55%) and then with 34.4 g of 2-bromo-3-methyl-pyridine reacted for 18 hours. This gives the crude 3-methyl-3-ί [2-phenyl-3- (4-phenyl-3-butyl) oxazolidin-5-yl] methoxy ^ pyridine.

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Example 54

A mixture of 6.1 g of 6-methyl-3-pyridinol, 5.5 g of 1-isopropyl-3-azetidinol, 0.3 g of potassium hydroxide and 25 ml of benzyl alcohol is stirred under nitrogen in a bath at 150 ° for 16 hours. After cooling, the reaction mixture is diluted with 50 ml of ether and treated with 30 ml of 4-n. Hydrochloric acid extracted. The aqueous phase is separated off, made alkaline with concentrated sodium hydroxide solution and extracted with 100 ml of methylene chloride. ^{The 3- (3 f} -isopropylamino-2'-hydroxypropoxy) -6-methyl-pyridine is isolated from the crude product thus obtained by Kugelrohr distillation at a bath temperature of 130-140 ° and 0.04 torr. Its properties are identical to the product obtained in Example 19.

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Example 55

14.8 g of 3-benzyloxy-2- (2 ^f -hydroxy-3'-isopropylaminopropoxy) -6-methyl-pyridine, dissolved in 150 ml of dioxane, are hydrogenated with the addition of 1.5 g of palladium-carbon catalyst. After the theoretical amount of hydrogen has been absorbed, the hydrogenation comes to a standstill. The catalyst is filtered off, the filtrate is evaporated and the remaining oil is treated with a solution of 2.6 g of fumaric acid in approx. 50 ml of methanol. This solution is filtered, evaporated to an oil in vacuo, and 50 ml of isopropanol are added to the residue. The neutral fumarate of 2- (2'-hydroxy-3'-isopropylamino-propoxy) -6-methyl-3-pyridinol with a melting point of 198-200 * crystallizes in this way.

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Example 56

Analogously by catalytic debenzylation of 6-benzyloxy-2- (2'hydroxy-3'-isopropylamino-propoxy) -pyridine
Example 55 is obtained 6- (2'-hydroxy-3 ¹ -isopropylarainopropoxy) -2-pyridinol, mp. 177-178 ° (from methanol (ether).

The starting material can be obtained in the following ways:

a) 2,6-dichloropyridine is mixed with 1 equivalent of sodium benzylate reacted in dimethylformamide to give 2-benzyloxy-6-chloropyridine (bp 95-100 ° / O, Ol Torr.).

b) 2-Benzyloxy-6-chloropyridine is in the usual way in
2-Benzyloxy-6- (2'-hydroxy-6'-isopropylamino-propoxy) -pyridine converted (bp. 140-150 ° / 0.02 Torr in the bulb tube, m.p.
57-64 °).

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Example 57

By catalytic debenzylation of 3-benzyloxy-2- (2'-hydroxy-3'-isopropylamino-propoxy) -pyridine analogously to Example 55, 2- (2'-hydroxy-3'-isopropylaminopropoxy) is obtained -3-pyridinol.

The starting material can be from 3-benzyloxy-2-nitro-pyridine can be obtained in the usual way.

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Example 58

15.6 g of 3- (2 ^! -Hydroxy-S'-isopropylamino-propoxy ^ ö-methylpyridine, dissolved in 75 ml of dioxane, are in the presence of 8 ml of 2,6-lutidine at 5-10 ° with stirring dropwise with a A solution of 10 g of phosgene in 40 ml of toluene is added. The reaction mixture is stirred overnight at room temperature and then evaporated in vacuo. The evaporation residue is made alkaline with a little concentrated sodium hydroxide solution and extracted with 200 ml of ethyl acetate. The organic phase is evaporated, first at approx 20 Torr, then at 0.1 Torr / 60 ° bath temperature. The remaining residue is mixed with about 50 ml of ether and thus gives crystalline 3-isopropyl-5 - [(6-methylpyridin-3-yloxy) methyl] oxazolidine- 2-on from m.p. 86-88 °.

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Example 59

A solution of 4.8 g of 3-isopropyl-5 - [(6-methylpyridin-3-yloxy) methyl] oxazolidin-2-one in 50 ml of dichloromethane is stirred within 10 minutes with a solution of 4.1 g of m-chloroperbenzoic acid in 30 ml of dichloromethane added and left to stand overnight at room temperature. After diluting with 50 ml of dichloromethane, the Reaction mixture extracted with 20 ml of saturated potassium bicarbonate solution, dried over sodium sulfate and im Evaporated in vacuo. The crystalline residue is recrystallized from dichloromethane ether. The thus obtained 3-f (3-Isopropyl-oxazolidin-2-on-5-yl) methoxy] -6-methylpyridine-1-oxide melts at 137-139 °.

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Example 60

To a solution of 3.6 g of 2- (3 ^T -amino-2'-hydroxypropoxy) -3-methyl-pyridine and 1.5 g of sodium cyanoborohydride in 70 ml of methanol, after adding 4 ml of a 2-n. A solution of hydrogen chloride in methanol was added dropwise to 12 ml of acetone over the course of about 30 minutes while stirring. The reaction mixture is stirred at room temperature overnight, then evaporated in vacuo and treated with 2-n. Hydrochloric acid acidified. The aqueous solution is extracted once with 30 ml of ether. The hydrochloric acid phase is separated off and made alkaline with concentrated sodium hydroxide solution. The 2- (2'-hydroxy-3 ^L isopropylamino-propoxy) -3-methyl-pyridine is isolated by extraction with ethyl acetate and is identical to the substance described in Example 21.

The raw material can be produced in the following ways:

a) Glycerine glycide and benzylamine are converted in a known manner to 3-benzylamino-1,2-propanediol (bp. 160-170 ° / 0.01 Tor

b) 3-Benzylamino-1,2-propanediol is treated with benzaldehyde by aze < tropical distillation with benzene in a known manner in the 3-benzyl-5-hydroxymethyl-2-phenyl-oxazolidine over-

ΔΠ983Λ / 1130

led (bp 168-171 ° / O, 005 torr).

c) By using 2-bromo-3-methyl-pyridine and 3-benzyl-5-hydroxymethyl-2-phenyl-oxazolidine, the 2- (3-benzylamino-2 ^r -hydroxy-propoxy) - 3-methyl-pyridine obtained. After recrystallization from ethyl acetate-cyclohexane, it melts at 77-82 °.

d) Catalytic debenzylation of a solution of 28.3 g of 2- (3 ^L benzylamino-2 ^L hydroxypropoxy) -3-methyl-pyridine in 300 ml of ethyl acetate with the addition of a total of 12 g of palladium / carbon (5%) leads to the 2nd - (3 ^L amino-2'-hydroxypropoxy) -3-methylpyridine, bp 120-130%), 07 Torr in a bulb tube.

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Example 61

27 g of crude 2,3-dichloro-5 - [(tetrahydropyran-2-yloxy) methyl] pyridine are mixed with 25 g of 5-H3 ^ droxymethyl-3-isopropyl-2-phenyl-oxazolidine and 4.5 g of sodium hydride Dispersion (55%) in 250 ml of 1,2-dimethoxyethane boiled under reflux for 16 hours and worked up in the usual way. The crude 2 - [(3 ¹ -isopropyl-2'-phenyl-oxyzolidin-5'-yl) -methoxy] -3-chloro-S - [(tetrahydropyran-2-yloxy) -methyl] -pyridine is obtained in this way.

The starting material can be prepared as follows: 2,3-dichloro-5-hydroxymethyl-pyridine is used in a known manner with 2,3-dihydropyran into 2,3-dichloro-5 - [(tetrahydropyran-2-yloxy) methyl] pyridine transferred (bp 115-123 ° / 0.08 torr).

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Example 62

While stirring and cooling, a solution of 16.0 g of 2,3-dichloro-5-methylaminocarbonyl-pyridine and 18.5 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine in 250 ml of hexamethylphosphoric acid triamide is added in the course of 1 Hour 4.25 g of sodium hydride dispersion (55%) entered. The reaction mixture is stirred overnight at room temperature, then poured onto 250 ml of ice water and extracted three times with 200 ml of ether each time. The combined ether extracts are evaporated and give crude 2- [3 ^! -Isopropyl-2 ¹ -phenyl-oxazolidinyl- (5 ')] - methoxy-S-chloro-S-methylaminocarbonyl-pyridine.

The starting material can be divided into the following stages represent.

a) To a suspension of 210 g of 2-hydroxypyridine-5-carboxylic acid in 1.5 liter cone. Hydrochloric acid is added dropwise to a solution of 63 g of potassium chlorate in 750 ml of water at 80-85 °. During the dropping creates a yellow solution from which gradually crystals separate out again. After the dropwise addition (1.5-2 hours), the reaction mixture is removed with an ice bath.

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cools and the crystallized 2-hydroxy-3-chloropyridine-5-carboxylic acid sucked off (m.p. 318-322 °).

b) To a suspension of 108 g of phosphorus pentachloride in 300 ml of toluene, with stirring over a period of about 30 45 g of 2-hydroxy-3-chloro-pyridine-5-carboxylic acid were added in minutes. The reaction mixture is refluxed for 2 hours and then thoroughly on a rotary evaporator in vacuo evaporated, last at a bath temperature of 70-80 °.

The crude Sjo-dichloro-nicotinic acid chloride thus obtained is reused raw.

c) A solution of 30 g is added to a solution of 50 g of methylamine in 250 ml of ethanol with stirring and cooling at 10-15 ° coarse Sjö dichloronicotinic acid chloride in 150 ml of chloroform dripped. The reaction mixture is stirred for a further 2 hours at 20-30 ° and then evaporated in vacuo. The evaporation residue is taken up in ethyl acetate, with 2-n. Washed soda solution, dried over magnesium sulfate and evaporated. The residue is recrystallized from ethanol-ether. The 2,3-dichloro-5-methylaminocarbonylpyridine thus obtained melts at 134-138 °.

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Example 63

A solution of -46.8 g of 5-hydroxymethyl-3-isopropyl ~ 2-phenyl-oxazolidine in 300 ml of 1,2-dimethoxyethane is used in At 20-40 °, 6.1 g of sodium hydride dispersion (55%) were carefully added in portions and, after the foaming stopped, added Stirred for 1-2 hours at 40 °. 11.0 g of 5- (2'-aminoethyl) -2-chloro-pyridine are then added added and the reaction mixture stirred at 80 ° for 18 hours. After evaporation of the solvent the evaporation residue is taken up in ether in vacuo, washed with water, the ether solution dried over magnesium sulfate and evaporated in vacuo. You get so the crude 2- [3'-isopropyl-2'-phenyl-oxazolidinyl- (5 ')] -methoxy-5- (2-aminoethyl) -pyridine.

The starting material can be represented as follows: To a solution of 30.4 g of (6-chloro-3-pyridine) acetonitrile in 90 ml of methanol is added after adding about 10 g of Raney nickel suspension at 50-60 ° a solution of 7.6 g of sodium borohydride in 25 ml of 8-n. Caustic soda dripped. By cooling becomes the temperature kept at 50-60 °. After the dropwise addition, the reaction mixture is stirred for a further 20 minutes at about 50 °.

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It is then cooled, the nickel filtered off and the The filtrate was evaporated in vacuo. The remaining dark red oil is stirred with 15 g of solid potassium hydroxide for 1 hour and the resulting suspension extracted with a total of 200 ml of dichloromethane. After drying and evaporation of the solvent an oil is obtained from which the 5- (2'-aminoethyl) -2-chloropyridine at 76-80 ° / 0.02 Torr is isolated as a colorless oil.

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Example 64

A solution of 27.5 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine in 100 ml of dimethylformamide is carefully mixed with 4.8 g of sodium hydride dispersion (55%) at 20-40 ° and after foaming has stopped stirred for another 1-2 hours at 40 °. Then 12.7 g of 2-chloro-4-methyl-pyridine are added and the reaction mixture is stirred at 80 ° for 2 hours.
After evaporation of the solvent in vacuo, the
Evaporation residue taken up in ether, washed with water, the ethereal solution dried over magnesium sulfate and evaporated in vacuo. The crude 2- [3'-isopropyl-2'-phenyloxazolidinyl- (5 ')] - methoxy-4-methyl-pyridine is obtained in this way.

The following can also be used in an analogous manner
Synthesize compounds:

2- [3'-Isopropyl-2'-phenyl-oxazolidinyl- (5 ') j-methoxy-5-methylpyridine,

2- [3'-Isopropyl-2'-phenyl-oxazolidinyl- (5 ')] - methoxy-3-ethoxypyridine,

2- [3'-Isopropyl-2'-phenyl-oxazolidinyl- (5 ')] -methoxy-6-methyl-pyr id in,

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2- [3'-Isopropyl-2 ^1- phenyl-oxazolidinyl- (5 ')] - methoxy-3-ethoxypyridine,

2- [3'-Isopropyl-2'-phenyl-oxazolidinyl- (5 ')] - methoxy-5-cyanopyridine,

2- [3'-Isopropyl-2'-phenyl-oxazolidinyl- (5 ')] - methoxy-3-chloropyridine,

4- [3'-Isopropyl-2'-phenyl-oxazolidinyl- (5 ')] -methoxy-3-methylpyridine.

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Example 65

Analogously to Example 62, using 15.6 g of 2,3-dichloro-5-n-hexylaIninocarbonyl-pyridine, 13.6 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine and 3.15 g of sodium hydride dispersion (55% in oil) in 250 ml of hexamethylphosphoric acid triamide 2- [3'-Isopropyl-2'-phenyl-oxazolidinyl- (5 ')] -methoxy-3-chloro-5-n-hexylaminocarbonyl-pyridine getting produced.

The starting material can be produced analogously to Example 62c).

Using 30 g of n-hexylamine, 2,3-dichloro-5-n-hexylamino-carbonylpyridine is produced, which after recrystallization from ether / η-hexane at 87-89 ° melts.

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Example 66

In a manner analogous to that described in Example 11, 9.4 g (0.05 mol) of 2-chloro-3- (2-methoxyethoxy) pyrazine 3- (2 ^l -methoxyethoxy) -2- (3 '- isopropylamino-2'-hydroxypropyloxy) pyrazine. The fumarate produced therefrom with fumaric acid crystallizes from methanol acetone, melting point 120-121 °.

The 2-chloro-3- used as starting material

(2'-methoxyethoxy) pyrazine can be prepared as follows: 14.9 (0.1 mol) 2,3-dichloropyrazine and 30 g (0.5 mol) ethylene glycol monomethyl ether are dissolved in 150 ml hexamethylphosphoric acid triamide and at 0- At 5 ° C., 4.8 g (0.1 mol) of a 50% suspension of sodium hydride in paraffin oil are added in portions. The mixture is then stirred for 15 hours at room temperature. The reaction mixture is then poured onto 1 liter of ice water and extracted with ether. The ether extracts are washed with water, dried over sodium sulfate and evaporated in a water jet vacuum. The residue is distilled in a high vacuum. This gives 2-chloro-3- (2'-methoxyethoxy) pyrazine boiling point 74 ° / 0.003 Torr,

: 1.5118.

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Example 67

In a manner analogous to that described in Example 8, one obtains from

7.5 (0.03 mol) 3-chloro-2- (3 * -isopropylamino-2'-hydroxy-propyloxy) -pyrazine, 2.8 g (0.045 mol) of ethyl mercaptan and 2.4 g (0.045 mol) of sodium methylate in 150 ml of methanol after 30 hours Reflux the crude base and from it 3-ethylthio-2- (3'-isopropylamino-2'-hydroxypropyloxy) pyrazine fumarate with 1.74 g of fumaric acid, Mp. 158-160 °, crystallized from methanol-ether.

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Example 68

9.8 grams (0.04 moles) of 3-chloro-2- (3'-isopropylamino-2'-hydroxypropyloxy) pyrazine are heated to 130 ° C. for 1 hour with 12.1 g (0.12 mol) of 4-hydroxypiperidine. To After cooling, the reaction mixture is taken up in chloroform-ether 1: 3 and washed with 2N sodium hydroxide solution and water, The organic phase is dried over sodium sulfate and vacuum evaporated in the water jet. 3- (4'-Hydroxy-1 ' -piperidyl) -2- (3 '-isopropylainino-2' -hydroxypropyloxy) -piperazine, m.p. 88-91 ° from ether-pentane. The cyclamate prepared therefrom with cyclohexylaminosulfonic acid crystallized from acetone; M.p. 90-92 °.

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- 1 B?

Example 69

In a manner analogous to that described in Example 68,
obtained from 9.8 g (0.04 mol) of 3-chloro-2- (3'-isopropylamino-2 ^f -hydroxy-propyloxy) pyrazine and 12.0 g (0.12 mol)
N-methylpiperazine 3- (4-methyl-1-piperazinyl) -2- (3 ^f -isopropylamino-2'-hydroxypropyloxy) pyrazine, m.p. 62-64 ° from petroleum ether. The fumarate produced therefrom with fumaric acid crystallizes from methanol, m.p. 200-201 °.

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-tn

Example 70

In a manner analogous to that described in Example 11, one obtains from

10.7 g (0.05 mol) of 2-chloro-3-morpholinyl-5-methyl-pyrazine and 15.5 g (0.05 mol) of 2-phenyl-3- (1- phenyl-3-butyl) -5-hydroxymethyl-oxazolidine 2- [3 '- (1-phenyl-3-butylamino) -2'-hydroxypropyloxy] -S-morpholinyl-S-methyl-pyrazine, and from this with 2.25 g of fumaric acid from methanol / acetone the fumarate, melting point 134-136 °.

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Example 71

In a manner analogous to that described in Example 11, one obtains from

11.1 g (0.05 mol) of 2-chloro-3-phenylthio-pyrazine and 13.2 g (0.06 mol) of 2-phenyl-3-isopropyl-5-hydroxymethyl-oxazolidine, 3-phenyl-thio- 2- (3 ^! -Isopropylamino-2'-hydroxy-propyloxy) -pyrazine, melting point 70-71 °, crystallized from ether-petroleum ether.

The fumarate produced therefrom crystallizes from isopropanol, melting point 167-169 °.

The 2-chloro-3-phenylthio-pyrazine used as starting material can be made as follows:

22 g (0.2 mol) of sodium methylate in 200 ml of ethanol are added in succession to a solution of 10.8 g (0.2 mol) of sodium methylate Mol) thiophenol and 29.8 g (0.2 mol) of 2,3-dichloropyrazine are added dropwise and stir for 1 hour. The reaction mixture is then cooled to 0 °, and the reaction product which has precipitated is filtered off with suction washes with ethanol and water. After drying, 2-chloro-3-phenylthio-pyrazine is obtained, 100-111 °.

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Example 72

In a manner analogous to that described in Example 11, one obtains from

8.2 (0.05 mol) 2,3-dichloro-5-methyl-pyrazine, 11 g (0.05 mol) 2-phenyl-3-isopropyl-5-hydroxymethyl-oxazolidine and 3.4 g of a 50% suspension of sodium hydride in paraffin oil, 2-chloro-3- (3'-isopropylamino-2 '-hydroxy-propyloxy) -5-methyl - Pyrazine, m.p. 109-110 °, crystallized from benzene. The fumarate produced therefrom with fumaric acid crystallizes from methanol-ether, m.p. 164-165 °.

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Example 73

In an analogous manner to that described in Example 3. is obtained from

5.2 g (0.02 mol) of 2-chloro-3- (3'-isopropylamino-2-hydroxy-lpropyloxy) -5-methyl-pyrazine, 3- (3'-Isopropylamino-2-hydroxypropyloxy) -5-methyl-pyrazine, Mp. 78-79 °, crystallized from ether-petroleum ether. The hydrochloride produced from it is crystalline lized from methanol-acetone, melting point 125 °.

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_ -ι Π7 _

²⁴⁰⁶⁹³ °

Example 74

To a suspension of 1.2 g of sodium hydride

11.0 g of 2-phenyl-3-isopropyl-5-hydroxymethyl-oxazolidine are added to 50 ml of dimethoxyethane and stir for 2 hours at room temperature. Then 5.7 g of 2-chloropyrimidine, dissolved in 20 ml of dimethoxyethane was added. The mixture is stirred for a further 2 hours at room temperature and then heated for 17 hours Boil. Then the precipitated inorganic salt is filtered off, the filtrate evaporated in vacuo and the residual 2- [3'-isopropyl-2'-phenyl-oxazolidinyl- (5 ')] methoxypyrimidine isolated as OeI].

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Example 75

8.5 g of 5- (N-hexylcarbamoyl) -2- [3'-isopropyl-2 ^f phenyl-oxazolidinyl- (5 ') - methoxypyrimidine are dissolved in 25 ml of 1-n. Hydrochloric acid added. The mixture is heated to boiling for ten minutes, cooled, the benzaldehyde which has separated out is extracted with ether and 13 ml of 2N are added to the separated water phase. Caustic soda. The oily base which separates out is extracted with ethyl acetate, the extract is washed with water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The evaporation residue is crystallized from petroleum ether. 5- (N-Hexylcarbamoyl, 2- (3'-isopropylamino-2'-hydroxypropoxy) -pyrimidine is obtained as colorless crystals with a melting point of 114-115 °. The hydrogen oxalate, prepared in acetone, melts at 149-150 °.

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Example 76

To a suspension of 0.88 g of sodium hydride in 20 ml 8.2 g of 2-phenyl-3-isopropyl-5-hydroxymethyl-oxazolidine are added to dimethoxyethane and stir for 2 hours at room temperature. 9.0 g of 5- (N-hexylcarbamoyl) -2-chloropyrimidine are then dissolved in 30 ml of dimethoxyethane, added dropwise. The mixture is then stirred for 18 hours at room temperature. After that, the failed Inorganic salt was filtered off, and the filtrate was evaporated in vacuo and the remaining oil contains the 5- (N-hexylcarbamoyl) -2- [3'-isopropyl-2'-phenyl-oxazolidinyl- (5 ')] methoxypyrimidine.

The starting material can be produced as follows:

To a solution of 22.6 g of 2,4 (6) -dichloropyrimidine-5-carboxylic acid chloride in 150 ml of diethyl ether is left at -10 ° with stirring 20.2 g of n-hexylamine are added dropwise over the course of one hour and then the mixture is stirred another hour at 0 °. The precipitate which has separated out is then filtered off. From the filtrate is obtained after distilling off the ether the 5- (N-hexylcarbamoyl) -2,4 (6) -dichloropyrimidine as a colorless oil.

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9.7 g of 5- (N-hexylcarbamoyl) -2,4 (6) -dichloropyrimidine are in 100 ml of 50% ethanol with 20 g of zinc dust heated to boiling for 1 1/2 hours while stirring. Then it is sucked hot, Rinsed with ethanol and the filtrate largely freed from the ethanol by distillation under reduced pressure. That The oil precipitated from the aqueous solution is extracted with ethyl acetate, and the extract is washed with water over sodium sulfate dried and evaporated. The remaining oil is chromatographed on 50 g of Merck silica gel 60 using benzene-ether (1: 1). The fractions containing the product are combined. After the solvent has been distilled off, 5- (N-hexylcarbamoyl) -2-chloro-pyrimidine is obtained as a colorless oil, which gives crystals from petroleum ether with a melting point of 101-102 °.

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Example 77

9.0 g of 2-dimethylamino-5-carbethoxy-4 (6) - [3 ^f -isopropyl ~ 2 ^f -phenyloxazolidinyl- [5 ')] "Methox3 ^T pyriinidine are taken up in 45 ml of 1N hydrochloric acid. The mixture is heated ten minutes to the boil. cools, extracts the benzaldehyde that has separated out with ether and adds 23 ml of 2N sodium hydroxide solution to the separated water phase The oil obtained is dissolved in a little acetone, and a solution of 2.9 g of oxalic acid in acetone is added to give 2-dimethylamino-5-carbethoxy-4 (6) - (3'-isopropylamino-2 ' hydroxypropoxy) pyrimidine oxalate, which is recrystallized from methanol-acetone .

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-Wt-

Example 78

4.8 g of 2-phenyl-3-isopropyl-5-hydroxymethyl-oxazolide are added to a suspension of 0.53 g of sodium hydride in 20 ml of dimethoxyethane and the mixture is stirred for 2 hours at room temperature. Then 5.0 g of 2-dimethylamino-4-chloro-5-carbethoxypyrimidine, dissolved in 30 ml of dimethoxyethane, are added dropwise. The mixture is then stirred for 18 hours at room temperature, at the end for one hour at 80 °. The precipitated salt is then filtered off, the filtrate evaporated in vacuo and the remaining oil contains the 2-dimethylamino-5-carbethoxy-4-f3 ^f -isopropyl-2'-phenyloxazolidinyl- (5 ')] methoxypyrimidine.

The starting material can be obtained as follows:

A suspension of 16 g of 2-dimethylamino-4-hydroxy-5-carbethoxypyrimidine in 100 ml of phosphorus oxychloride is heated to boiling with stirring for half an hour, then filtered hot and the The filtrate was evaporated under reduced pressure. 200 g of ice are added to the oily residue. 200 ml of methylene chloride are added and sets while cooling with ice as long as 30% sodium hydroxide solution until pH 8 is reached. The inorganic salts which have precipitated out are then filtered off and washed with methylene chloride.

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The organic phase is washed with water over sodium sulfate dried and evaporated. 2-Dimethylamino-4-chloro-5-carbethoxypyrimidine is obtained as a yellowish oil that can be reused without cleaning.

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JuI)

Example 80

7.0 g of 5- (2-methoxyethyl) -2- [3 '- »isopropyl-2 ^! -phenyloxazolidinyl- (5 ')] - methoxypyrimidine are in 24 ml 1-n. Hydrochloric acid added. The mixture is heated to the boil for ten minutes, cooled, the benzaldehyde which has separated out is extracted with ether and 12 ml of 2N sodium hydroxide solution are added to the separated aqueous phase. The oily base which separates out is extracted with ethyl acetate, the extract is washed with water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The oil obtained is dissolved in a little isopropanol, a solution of 2.3 g of fumaric acid in 30 ml of isopropanol is added and the solvent is then largely distilled off. The syrup obtained is diluted with acetone, whereupon the 5- (2-methoxyethyl) -2- (3 ^f -isopropylamino-2'-hydroxy-propoxy) -pyrimidine hydrogen fumarate crystallizes. Melting point 103-104 ° after recrystallization from methanol-acetone.

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Example 81

4.1 g of Z-phenyl-S-isopropyl-S-hydroxymethyl-oxazolidine are added to a suspension of 0.48 g of sodium hydride in 10 nil of dimethoxyethane and the mixture is stirred for 2 hours at room temperature. 3.4 g of 5- (2-methoxyethyl) -2-chloropyrimidine, dissolved in 10 ml of dimethoxyethane, are then added. The mixture is stirred for a further 2 hours at room temperature and then heated to boiling for 3 hours. The precipitated inorganic salt is then filtered off, the filtrate is evaporated in vacuo and the remaining oil contains 5- (2-methoxyethyl) -2- [3 '-isopropyl- 2 ¹ -phenyloxazolidinyl) - (5 ')] -methoxypyrimidine.

The starting material can be produced as follows:

6.0 g of 5- (2-methylsulfonyloxyethyl) uracil are added to 100 ml absolute methanol, and the suspension is heated to 120-130 ° in a pressure vessel for one hour. After cooling down the crystals obtained are filtered off with suction to room temperature and washed with methanol. 5- (2-methoxyethyl) uracil is obtained, M.p. 232-234 °.

A suspension of 10.3 g of 5- (2-methoxyethyl) uracil in 50 ml

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Phosphorus oxychloride is heated to boiling for 2 hours. The resulting solution is reduced by distillation under reduced pressure Freed from pressure of excess phosphorus oxychloride and the oil obtained poured onto 200 g of ice. After that the product extracted with ether, the extract with water and sodium bicarbonate solution washed, dried over sodium sulfate and evaporated. The oil obtained is taken up with hot hexane, filtered from undissolved impurities and freed from the solvent by distillation under reduced pressure. You get the 5- (2-methoxyethyl) T2,4 (6) -dichloropyrimidine as colorless OeI that can be reused without cleaning.

8.7 g of 5- (2-methoxyethyl) -2,4 (6) -dichloropyrimidine are in 100 ml of 50% ethanol with 2t) g of zinc dust heated to boiling for 1 1/2 hours while stirring. Then it is sucked hot, Rinsed with ethanol and the filtrate largely freed from the ethanol by distillation under reduced pressure. That The oil precipitated from the aqueous solution is extracted with ethyl acetate, and the extract is washed with water over sodium sulfate dried and evaporated. The remaining oil is chromatographed on 50 g of Merck silica gel 60 using benzene / ethyl acetate (1: 1). The fractions containing the product are combined. After the solvent has been distilled off, this is obtained

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5- (2-methoxyethyl) -2-chloropyrimidine as a colorless oil, which from petroleum ether gives crystals with a melting point of 25-26 °.

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Example 82

4.9 g of 5-methylthiomethyl-2- [3'-isopropyl-2 ^l -phenyloxazolidinyl- (5 ')] - methoxypyrimidine are dissolved in 25 ml of 1-n. Hydrochloric acid added. The mixture is heated to boiling for ten minutes, cooled, the benzaldehyde which has separated out is extracted with ether and 13 ml of 2N are added to the separated water phase. Caustic soda. The oily base which separates out is extracted with ethyl acetate, the extract is washed with water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The oil obtained is dissolved in a little isopropanol and treated with a solution of 0.7 g of fumaric acid in 10 ml of isopropanol, whereupon the 5-methylthiomethyl-2- (3'-isopropylamino - ^ '- hydroxypropoxy) pyrimidine hydrogen fumarate crystallizes. M.p. 142-143 ° after recrystallization from isopropanol.

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Example -83

3.1 g of 2-phenyl-3-isopropyl-5-hydroxymethyloxazolidine are added to a suspension of 0.33 g of sodium hydride in 10 ml of dimethoxyethane and the mixture is stirred for 2 hours at room temperature. Then 2.4 g of 5-methylthiomethyl-2-chloropyrimidine, dissolved in 10 ml of dimethoxyethane, are added. The mixture is stirred for a further 2 hours at room temperature and then heated to boiling for 3 hours .. Then the precipitated inorganic salt is filtered off, the filtrate evaporated in vacuo and the remaining oil contains the 5-methylthiomethyl-2- [3'-isopropyl- 2 ¹ -phenyloxazolidinyl- (5 ')] methoxypyrimidine.

The starting material can be produced as follows:

In a solution of 14 g of 5-hydroxymethyluracil in 80 ml of trifluoroacetic acid methyl mercaptan is passed in over the course of an hour until saturation, the temperature being kept at 25 °. The mixture is then left to stand for 2 hours, the solvent is evaporated off under reduced pressure and the residue is crystallized out Glacial acetic acid. 5-Methylthiomethyluracil is obtained as colorless Crystals of m.p. 239-241 °.

A suspension of 9.4 g of 5-methylthiomethyluracil in 100 ml

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- see -

Phosphorus oxychloride is heated to boiling for 2 hours while stirring, then filtered hot and the filtrate evaporated under reduced pressure. The oily residue is mixed with 200 g of ice, the product extracted with ether, the extract washed with water and sodium bicarbonate solution, dried over sodium sulfate and evaporated. The 5-methylthiomethyl-2,4 (6) - is obtained

dichloropyrimidine as a yellow oil that continues without purification can be used.

6.6 g of 5-methylthiomethyl-2,4 (6) -dichloropyrimidine are added to 60 ml 50% ethanol with 15 g zinc dust with stirring for 1 1/2 hours heated to boiling. Then it is sucked off hot, rinsed with ethanol and the filtrate by distillation under reduced Pressure largely freed from the ethanol. The oil precipitated from the aqueous solution is extracted with ethyl acetate, the Washed extract with water, dried over sodium sulfate and evaporated. The remaining oil is deposited on 50 g of silica gel 60 Merck chromatographed with benzene / ethyl acetate (1: 1). The fractions containing the product are combined. After distilling off the solvent gives 5-methylthiomethyl-2-chloropyrimidine, which yields crystals from petroleum ether with a melting point of 56-57.

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Example 84

20.5 g of 5-ethyl-4 (6) - [3'-isopropyl-2'-phenyl-oxazolidinyl- (5 ')] methoxypyrimidine are in 75 ml 1-n. Hydrochloric acid added. The mixture is heated to the boil for ten minutes, cooled and extracted the separated benzaldehyde with ether and mixed the separated water phase with 38 ml of 2-n. Caustic soda. The oily itself The base which separates out is extracted with ethyl acetate, the extract is washed with water, dried over sodium sulfate and filtered and evaporated under reduced pressure. The OeI obtained delivers 5-ethyl-4 (6) - (3'-isopropylamino-2'-hydroxypropoxy) pyrimidine from cyclohexane as colorless crystals with a melting point of 56 ° -58 °. Its hydrogen fumarate produced in isopropanol melts at 136-137 °.

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Example 85

To a suspension of 1.5 g of sodium hydride in 20 ml of dimethoxyethane are 13.9 g of 2-phenyl-3-isopropyl-5-hydroxymethyl-oχazolidill and stir for 2 hours at room temperature. Then at 0 ° 9.0 g of 5-ethyl-4 (6) chloropyrimidine, dissolved in 50 ml of dimethoxyethane, admitted. The mixture is then stirred for 18 hours at room temperature, then for a further hour at 80 °. After that, the failed The inorganic salt is filtered off, the filtrate is evaporated in vacuo and the remaining oil contains 5-ethyl-4 (6) - [3'-isopropyl-2'-phenyl-oxazolidinyl- (5 ')] methoxypyrimidine.

The starting material can be produced as follows:

A suspension of 52 g of 5-ethyl-4 (6) -hydroxy-2-mercaptopyrimidine 140 g of Raney nickel are added in portions over the course of an hour in 600 ml of water at 70-80 ° while stirring, and then Heated to boiling under reflux for 4 hours. Then the nickel is sucked off hot, rinsed with hot water and that The filtrate was completely evaporated under reduced pressure. The yellow oil that remains crystallizes on cooling; it yields after suction filtration and washing of the suction filter with acetone and ether, the 5-ethyl-4-hydroxypyrimidine. M.p. 95-97 ° (after sintering at 87-88 °).

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To a mixture of 12.5 ml of Ν, Ν-diethylaniline and 50 ml of phosphorus oxychloride 10 g of 5-ethyl-4 (6) -hydroxypyrimidine are added and the mixture is heated to 100-110 ° for 2 hours with stirring. Afterward the excess phosphorus oxychloride is removed by distillation under reduced pressure and the residue to 100 g Poured ice. The product is extracted with ether, the extract is washed with water and sodium bicarbonate solution, Dried over sodium sulfate and evaporated. The leftover After distillation in vacuo, oil gives the 5 ~ ethyl-4-chloropyrimidine, Bp 95-98 ° / 25 Torr, as a colorless oil.

A09834 / 11 30

Example 86

10 g of crude 3- (2,3-epoxy-propoxy) -6-methyl-pyridine-1-oxide are in 200 ml isopropanol with 25 ml isopropylamine under reflux for 6 hours heated to boiling. The reaction mixture is then im Evaporated in vacuo, taken up in 300 ml of ethyl acetate and extracted with 30 ml of saturated potassium bicarbonate solution. The received Oil crystallizes from ether and thus leads to 3- (2-hydroxy-3-isopropylamino-propoxy) -6-methyl-pyridine-1-oxide of m.p. 87-89 °.

The raw material can be produced in the following ways:

a) To a solution of 10 g of crude 3- (2,3-epoxy-propoxy) -6-methylpyridine in 100 ml of dichloromethane, a solution of 12.2 g of m-chloroperbenzoic acid in 100 ml of dichloromethane is stirred in Over the course of about 10 minutes, the temperature of the solution rises to 32 °. The reaction mixture becomes even more Stirred for 30 minutes, then extracted with 40 ml of saturated potassium bicarbonate solution, dried and evaporated in vacuo. The 3- (2,3-epoxy-propoxy) -6-methyl-pyridine-1-oxide obtained in this way is used further raw.

409834 / 113Q

Example 87

A mixture of 0.3 g of 3 - [(3-isopropyl-oxazolidin-2-on-5-yl) methoxy] -6-methyl-pyridine-1-oxide, 30 ml of ethanol, 1.0 g
Sodium hydroxide and 1 ml of water is stirred for 6 hours
heated to reflux. The precipitate is filtered off, the filtrate is evaporated in vacuo and dissolved in ethyl acetate. After drying and evaporation of the solvent, an oil is obtained which crystallizes from ether. After two more
Crystallization from ether melts the 3- (2 ^L hydroxy-3'-isopropylamino-propoxy) -6-methyl-pyridine-1-oxide at 87-89 °.

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Example 88

35 g of 2-phenyl-3-isopropyl-5-hydroxymethyloxazolidine are added to a suspension of 3.8 g of sodium hydride in 40 ml of dimethoxyethane and the mixture is stirred for 2 hours at room temperature. Then 23.5 g of 2-methylmercapto-4- chloropyrimidine, dissolved in 40 ml of dimethoxyethane, was added dropwise. The mixture is then stirred for one hour at room temperature and then for 4 hours under reflux. The precipitated inorganic salt is then filtered off and the filtrate is evaporated in vacuo. The remaining oil contains the 2-methylmercapto-4- [3 ^f -isopropyl-2'-phenyl-oxazolidinyl- (5 ')] -methoxypyrimidine.

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Example 89

5.4 g of 2-methylmercapto-4- [3'-isopropyl-2 ^t -phenyl-oxazolidinyl- (5 ')] - methoxypyrimidine are dissolved in 20 ml of 1-n. Hydrochloric acid added. The mixture is heated to boiling for ten minutes, cooled, the benzaldehyde which has separated out is extracted with ether and 10 ml of 2N are added to the separated water phase. Caustic soda. The oily base which separates out is extracted with ethyl acetate, the extract is washed with water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The oil obtained gives the crystalline, 2-methylmercapto-4 (6) - [3 ¹ -isopropylamino-2 ^1- hydroxy-propoxy] -pyrimidine from tetrachloromethane with a melting point of 82-83.

409834 / 113Q

Example 90

2.57 g of 2-methylmercapto-4 (6) - (3'-isopropylamino-2'-hydroxypropyloxy) -pyrimidine are dissolved in 20 ml of 0.5-n. Dissolved hydrochloric acid, mixed with 10 g of water-moist Raney nickel and then heated to 60 ° for 6 hours with stirring. The occasional dropwise addition of dilute hydrochloric acid is used to ensure that the reaction mixture always has a pH of 5-6. At the end, the nickel sludge is filtered off and washed with water. The filtrates are made alkaline together with dilute potassium hydroxide and. then saturated with potassium carbonate. Extraction with ethyl acetate, drying the extract over sodium sulfate, filtering and evaporating the filtrate under vacuum gives the crude product as a colorless oil. This is combined with 0.9 g of oxalic acid in 5 ml of methanol under heating gelöst.Beim cooling, the 4 (6) - (3'-isopropylamino-2-hydroxypropoxy) pyrimidine hydrogen oxalate, which is obtained by recrystallization from methanol, pure . M.p. 164-165 °.

03 834/1130

Claims (1)

XiT, _. . ... DR. ERXEND DfNNO Patent Claims Patent Attorney 2 8 BREMEN UHLANDSTRASSE. 1. Process for the preparation of new heterocyclic compounds of the general formula I. CH ₃ Het-O-CH -CH (OH) -CH ₀ -FH-CR ₀ - - ^R l wherein Het optionally substituted pyridazinyl, Is pyrimidinyl, pyrazinyl or substituted pyridyl, R is hydrogen or methyl and R is lower alkyl, optionally substituted Phenyl-lower alkyl, carboxy-lower alkyl or functionally converted from carboxy-lower alkyl, their condensation pro products with aldehydes, ketones or carbonic acid, their N-oxides, characterized in that one a) a compound of the formula II ₂₂ -Z ₁ (H) with a compound III 409834/1130 ORIGINAL INSPECTED converts, in which Het., R and R _? have the above meanings and one of the radicals Z ₁ and Z _{0 is} amino and the other is a reactive, esterified hydroxyl group and X is hydroxy, or Z together with X forms an epoxy group when Z is amino, or b) a compound of the formula IV Het - Z (IV), wherein Z is a nucleophilically removable radical and Het has the above meaning with a compound of the formula V CH _ ⁵ HO-CH-CH (OH) -CH-M-C-R (V) ^R l or with the corresponding condensation products with aldehydes, ketones or carbonic acid, in which R-. and R "above Have meanings, implement, or c) in a compound of the formula I, or in a corresponding N-oxide, in which Het, R and R _{p have the} above meanings and which have a removable radical on the nitrogen atom of the amino group and / or on the hydroxyl group, this radical ( e) splits off, or d) a compound corresponding to formula I or a corresponding N-oxide, in which the nitrogen of the propoxy chain is connected to one of its substituents with a double bond, or in which one of the 40 98 34/1130 The tinned carbon atoms have a hydr'o »·. -ppe trag ·., reduced, or e) a compound of the formula OH - Het, in which OH - Het stands for 5-hydroxypyrimidine or for 5-hydroxypyridine, with a compound of the formula Xa ν CH ₀ f ³ Z - CH, - CH - CH ₀ - NH - C - R ₀ (Xa), in which Z stands for a reactive, esterified hydroxyl group, and X denotes the hydroxyl group and R ₁ and R "have the above meanings, or in which X ₁ and Z together form an epoxy group or with the corresponding ring-closed compound of the formula Xb HO. urasetz-t, and if desired, in obtained compounds im Introduces, modifies or splits off substituents within the definition of the end substances, or compounds obtained converted into other end products, and / or obtained isomer mixtures split into the pure isomers, and / or obtained Raeemate split into the optical antipodes, and / or obtained free bases in their salts or obtained Converts salts into the free bases. 409834/1130 2. The method according to claim la), characterized in that that a reactive, esterified hydroxyl group is one with a hydrohalic acid, sulfuric acid or Is sulfonic acid esterified hydroxyl group. 5. Method according to claim Ib), characterized in that that a nucleophilically removable group Z is a halogen atom, a nitro group is a lower alkylsulfonyloxy group, a Lower alkylsulfinyl group, a lower alkoxy group or is an ammonium group. 4-. Method according to claim Ib), characterized in that one works in the presence of a basic condensing agent. 5. The method according to claim 4, characterized in that the basic condensation agents are alkali hydroxides, alkali hydrides or alkali alcoholates. - ^Λ 6. The method according to claim Ic), characterized in that that residues which can be split off are residues which can be split off by solvolysis or reduction. 7- The method according to claim 6, characterized in that 409834/1130 2A06930 residues which can be split off by solvolysis are residues which can be split off by hydrolysis or ammonolysis. 8. The method according to claim J, characterized in that the hydrolysis is carried out in the presence of hydrolyzing agents. 9- The method according to claim 6, characterized in that the reduction is carried out by catalytically excited hydrogen or by metallic reduction. 10. The method according to claim Id), characterized in that that the reduction with a Dileichtmetallhydrid, with a hydride, with an alkali metal cyanoborohydride or by means of catalytically excited hydrogen. 11. The method according to claim Ie), characterized in that that a reactive, esterified hydroxyl group is one with a hydrohalic acid, sulfuric acid or sulfonic acid is esterified hydroxy group. 12. The method according to claim Ie), characterized in that that the compound of the formula OH - Het is used in the form of its metal alcoholate. 409834/1 1 30 2 /> O 6 9 3 13. Method according to one of claims 1-12, characterized in that that one of a compound obtainable as an intermediate at any stage in the process goes out and carries out the missing procedural steps, or terminates the procedure at any stage, or in which a starting material is formed under the reaction conditions, or a reaction component, if appropriate uses in the form of their salts. l4. Method according to one of Claims 1-13. » characterized, that raan compounds of the general formula Ia f ³ 0-CH-GH (OK) -CH-KH-O-R ·· (la) and their condensation products with aldehydes, ketones or carbonic acid and the corresponding N-oxides, where R and R _? have the same meanings as above, R-, hydrogen, halogen, cyano, hydroxy, lower alkyl, Lower alkoxy lower alkyl, amino lower alkyl, lower alkoxy lower alkenyl, Lower alkylamine, di-lower alkylamino, acylamino, acylamino lower alkyl, acylamino lower alkenyl or Is lower alkylsulfonyl and 409834/1130 2 Λ Ο 6 9 3 O R ^ hydrogen, halogen, lower alkyl, hydroxy lower alkyl, Lower alkenyl, optionally substituted phenyl, hydroxy, lower alkoxy, leather alkoxy lower alkyl, amino lower alkyl, Lower alkoxy lower alkoxy, lower alkenyloxy, lower alkylthio, Lower alkylthio lower alkoxy, lower alkylthio lower alkyl, Lower alkylenamino, hydroxynoweralkylenamino, oxaniederalkylenamino, Thianiederalkylenamino, Azaniederalkylenamino, optionally substituted carbamoyl, lower alkylamino, Dinietieralkylamino, optionally substituted phenylthio, acylamino, lower alkylsulfonyl or lower alkoxycarbonyl represents, 15. The method according to any one of claims 1-13, characterized in that that one pyrazines of the formula Iaa 0-CH _o -CH (OH) -CH ₀ -MCR ₀₀ (Iaa) ; ■. λ. and their condensation products with aldehydes, ketones and carbonic acid and their corresponding pyrazine-N-oxides, in which R and R- have the above meaning, R ₂ means lower alkyl with up to 4 carbon atoms, benzyl, halobenzyl, trifluoromethyl- 409834/1130 benzyl, lower alkylbenzyl with up to 7 C-aconiene in the lower "alkyltcil, lower alkoxybenzyl with up to 7 carbon atoms in the lower alkyl part, carboxy-lower alkyl with up to 4 carbon atoms in the lower alkyl part, lower alkoxycarbonyl-lower alkyl with up to 4 carbon atoms each in the Niederalkylteilen, Carbamoylniederalkyl lteilen having up to 4 carbon atoms in the lower alkyl, Ni ^ deralkylaminocarbonylniederalkyl with up to 4 carbon atoms Yn the Niederallc3 ^r, Diniederalkylaniinocarbonylniederalkyl with up to 4 carbon atoms in the Niederalkylteilen, Pyrrb ^ adinocarbonylniederalkyl, Piperazinocarbonylniederalkyl, piperazinocarbonyl lower alkyl, N ¹ - (ß-hydroxyethyl) piperazinocarbonyl lower alkyl, morpholinocarbonyl lower alkyl, thi-omorpholinocarbonyl lower alkyl, 2,6-dimethylthiomorpholinocarbonyl lower alkyl with up to 7 carbon atoms in the lower alkyl part, or cyano-lower alkyl with up to 4 carbon atoms in the lower alkyl part, or cyano-lower alkyl with up to 4 carbon atoms Hydroxy, lower alkyl with up to 7 carbon atoms, lower alkenyl with up to 7 carbon atoms, halogen, Lower alkylamino with up to 7 carbon atoms, di-lower alkylamino with up to 7 carbon atoms in each of the lower alkyl parts, pyrrolidino, piperidino, 4-IIydroxypiperidino, morpholino, thiomorpholino, 2.6 ^J dimethylthiomorpholino, lower alkoxy with up to -7 carbon atoms, Lower alkenyloxy with up to 7 carbon atoms, lower alkoxy-lower alkyl with up to 4 carbon atoms in each of the lower alkyl parts, lower alkoxy-lower alkoxy with up to 4 carbon atoms in each of the lower alkyl parts, lower alkylthio with up to 7 carbon atoms, lower alkylthione-lower alkoxy with up to :. 409834/1130 ORiGiNAL INSPECTED 7 carbon atoms in each of the lower alkyl parts, lower alkanoylamino with up to 7 carbon atoms in the lower alkyl part or Nlederalkoxycarbonylamino with up to 7 carbon atoms in the lower alkyl part. 16. The method according to any one of claims 1-14, characterized in, that compounds of the formula lab ¹¹ . '0-CH ₂ -CH (0H) -CH ₂ -tSH-CR _2b (lab), and their condensation products with aldehydes, ketones or Carbonic acid, where R _n , FU and R have the above meanings, R ₀ , χ j 'ta ■ you means Lower alkyl with up to 4 carbon atoms, benzyl, carbamoylmethyl, lower alkylaniinocarbonylmethyl with up to 7 carbon atoms in the The lower alkyl, methyl Diniederalkylaminocarbony each with up to 7 C atoms in the Niederalkylteilen, Pyrrolidinocarbonylmcthyl, Piperidinocarbony methyl, methyl piperazinocarbonyl, N'-MethylpiperazinocarbonylmethyL, N ¹ -! (Ss-HydroxyäthyX) -piperazlnocarbonylmethyl, Morpholinocarbonylmsthyl, Ihiomorpholinocijrbonylme thy X, Z, 6 -Dimethyl thlomor pholino carbo i "» y XmGi t lriy XC »c3 <33r Cyanomethyl ^ dar-sfcellfc. 409834/1130 17. The method according to any one of claims 1-14, characterized in that that one compounds of the formula Iac O-OiI ₂ -OH (OH) -CH ₂ -KJ-OR ₂₀ (Iac), and their condensation products with aldehydes, ketones or Carbonic acid, where R has the above meaning. Rp means lower alkyl with up to 4 carbon atoms, benzyl, carbamoylmethyl or * cyano- methyl. R denotes hydrogen, halogen, cyano, lower alkyl with up to 7 carbon atoms, lower alkoxy-lower alkyl with up to 7 carbon atoms in each of the lower alkyl parts, lower alkoxy-lower alkenyl with up to 4 carbon atoms in the lower alkyl part and up to 4 carbon atoms in the lower alkenyl part, Niederalkanoylamirio with up to 7 C atoms in the lower alkyl, lower alkoxycarbonylamino having up to 7 C atoms in the lower alkyl ·, Niederalkanoylaniinoniederalkyl having up to 4 carbon atoms in each of the Niederalkylteile, Niederalkoxycarbonylaminoniederalkyl up VM 4 carbon atoms in each of the Niederalkylteile, Niederalkanoylaminoniederalkenyl with up to 4 carbon atoms in the lower alkyl part and up to 4 carbon atoms in the lower alkene part, lower alkoxycarbonylaniinoniedcralkenyl with up to 4 carbon atoms. 409834/1130 in the lower alkyl part vmd up to 4 carbon atoms in the lower alkenyl part, R ,, means hydrogen, hydroxy, lower alkyl with up to 4 carbon atoms, lower alkenyl with 3 or 4 carbon atoms, lower alkylamino with up to 4 carbon atoms, di-lower alkylamino with up to 4 carbon atoms each in the lower alkyl parts, pyrrolidino, Piperidino, 4-hydroxypiperidinp, mprpholino, thiomorpholino, 2,6-dimethylthiomorpholino, piperazino, N'-methylpiperazino, Chlorine, bromine, lower alkoxy with up to 4 carbon atoms, lower alkenyloxy with 3 or 4 carbon atoms in the lower alkenyl part, lower alkoxy-lower alkyl with up to 4 carbon atoms in each of the lower alkyl parts, lower alkoxy-lower alkoxy with up to 4 carbon atoms 'in each of the lower alkyl parts, lower alkylthio with up to to 4 carbon atoms, lower alkylthiortlederalkoxy with up to 4 C atoms in each of the lower alkyl parts, lower alkanoylamino with up to 4 carbon atoms or lower alkoxycarbonylamino with up to 4 carbon atoms in the lower alkyl part. l8. Process according to one of Claims 1-14, characterized in that pyrazines of the formula lad ^N I.
0-CH ₂ -CII (OH) -CTI ₂ ~ NH-CR _2d (lad) where R ^ and R ^ have the above meanings, R "means methyl, R ^ means hydrogen, bromine, chlorine, lower alkyl 409834/1130 with up to 4 carbon atoms, lower alkoxy-lower alkyl with up to each to 4 carbon atoms in the lower alkyl parts, lower alkoxy lower alkenyl with up to 4 carbon atoms in the lower alkyl part and up to 4 carbon atoms in the lower alkenyl part., Lower alkanoylamino with up to 4 carbon atoms in the lower alkyl part, lower alkoxycarbonylamino with up to 4 carbon atoms in the lower alkyl part, lower alkanoylamino lower alkyl each with up to 4 carbon atoms in the lower alkyl parts, lower alkoxycarbonylamino lower alkyl with each up to 4 carbon atoms in the lower alkyl parts. 19. Method according to one of claims 1-14, characterized in that that one pyrazines of the formula Iae OFTEN ₂ -mi-CR _2e ( _Iae) R ₁ la where R is hydrogen or methyl, R ₀ - lower alkyl with la d & 1-4 carbon atoms or phenyl-lower alkyl with up to 4 carbon atoms, in the lower alkyl part, R _{7 is} hydrogen, halogen, lower alkyl with pe 1-4 C atoms, 2- (C-,) - _{lower alkoxyethyl or 2- (C 1-} ,) deralkoxycarbonylaminoethyl and R, hydrogen, halogen, lower alkoxy with 1-4 C atoms, lower alkoxy-lower alkoxy with up to 4 each C atoms in the lower alkyl parts, lower alkenyloxy with up to 4 C atoms, lower alkylthio with up to 4 C atoms, Niedcralkylenamino with 4-6 C atoms in the lower 409834/1130 US " deralkylenamino, hydroxyniedeiralkylenamino with 4-6 carbon atoms in the alkylene chain, oxaniederalkylenamino with 4-5 carbon atoms in the oxaniederalkylenamino, lower alkylamino with up to
4 carbon atoms, di-lower alkylamino with up to 4 carbon atoms each in the ^{lower alkyl parts, phenylthio or N f} -Niederalkylazaniederalkylenamino with 4-6 carbon atoms in the lower alkyl parts and 'in particular R is hydrogen or methyl, R _ge is methyl or Is 2-phenylethyl, R., hydrogen, bromine, methyl, 2- or ^pc
Methoxyäthyl ^ -Methoxycarbonylaminoäthyl and R ₂ , hydrogen, chlorine, methoxy, 2-methoxyethoxy, allyloxy, ethylthio, morpholino, 4-hydroxypiperidino, dimethylamino, isopropylamino, phenylthio or N'-methylpiperazinoist and in particular the compounds mentioned in the examples represents. 20. The method according to any one of claims 1-19, characterized in that in all above.Gruppen the substituent R-zj FW j RZ ^ respectively. R., preferably in the para position to
5-amino-2-hydroxy-propoxy group, but also in
meta position can stand. 21. The method according to any one of claims 1-15, characterized in that compounds of the general
Formula Ib R. CH R "-j- 4-O-CH -CH (OH) -CH -KH-C-R, N 2 2
\\ /
H 409834/1130 - QSSr - nt. and their condensation products with aldehydes, ketones
or carbonic acid and the corresponding N-oxides, in which R ,, R _p , R., and R. have the same meanings as above. 22. The method according to any one of claims 1-13 or 21, characterized in that pyridazines of the formula I, / R _n IT ¹ and their condensation products with aldehydes, ketones ·. or Carbonic acid and its corresponding pyridazine N-oxides, wherein R, R, R ^, and R ^ have the above meanings. 23 · Method according to one of claims 1-13 or 21, characterized characterized in that pyridazines of the formula I, ^R 4a CH, fl ₂ () ₂ N ^R l and their condensation products with aldehydes, ketones or carbonic acid, in which R, R, R _x and R have the above meanings. 2 ^. Method according to one of Claims 1-13 or 21, characterized characterized in that pyridazines of the formula I, 409834/1130 _R Jl ' ^ 0-CH ₂ -CH (OH) -CH ₂ -IIH-OR ₂₀ (I ^), N 1 where R., R _? , R., and R. have the above meanings. 25- The method according to any one of claims 1-13 or 21, characterized characterized in that one pyridazines of the formula I., O-CHp-CH (OH) -CHp -NH-C- ² 2 1 wherein R ₁ , R _2d , R ^ and Ru have the above meanings, produces. 26. The method according to any one of claims 1-13 or 21, characterized in that pyridazines of the formula I. CH ^ 0-CH ₂ -CH (0H) -CH ₂ -mi-CR _2e la be and their condensation products with aldehydes, where R _{1 is} hydrogen or methyl, R _{0 is} hydrogen or xa <~ e Is lower alkyl of up to 4 carbon atoms, R, is hydrogen pe and R 1 is hydrogen, lower alkoxy, halogen, oxane-lower alkylenamino with up to 6 carbon atoms in the lower alkylene part or hydroxy and in particular R is hydrogen, R is methyl, R, Xa c6 pe Is hydrogen and R ₁ ^ is hydrogen, methoxy, chlorine, morpholine) or hydroxyl and especially those in the examples named connections ^ establishes. '409834/1130 27- method according to one of claims 1-13 or 21-26, characterized in that in all of the above groups the substituent R ,, R.,, R. ,, respectively. R, preferably in para- 3 3a 3b 3c Position to the 3-amino-2-hydroxypropoxy group, but can also be in the meta or ortho position. 28. The method according to any one of claims 1-13 *, characterized in that that one compounds of the general formula Ic CH R -l · -jj-O-CH -CH (OH) -CII ₂ -InI-CR ₂ (Ic) and their condensation products with aldehydes, ketones or carbonic acid and the corresponding N-oxides, in which R, R ", R- and R ^ have the same meanings as above have manufactures. 29. The method according to any one of claims 1-13 or 28, characterized characterized in that pyrimidines of the formula I. Cw _r CH (OH) -CiL-HH-CR- ( C. 1 day and their condensation products with aldehydes, ketones or Carbonic acid and its corresponding pyrimidine-N-oxides, in which R, R ^, R and R ,, have the above meanings, produces. •. 409834/1130 30. The method according to any one of claims 1-13 or 28, characterized in that 'pyrimidines of the formula I, and their condensation products with aldehydes, ketones or carbonic acid. 31. The method according to any one of claims 1-13. Or 28, characterized characterized in that pyrimidines of the formula I O C cc ' wherein R_, R ₂ , R, and R ₂ ,, have the above meanings ^ produces. 32. The method according to any one of claims 1-13 or 28, characterized characterized in that pyrimidines of the formula I, "i wherein R., R ₂ d * ^R "= Sb ^{and R} 4b ^{ot) i} Se have meanings _; 33 · Method according to one of claims 1-13 or 28, .due to this characterized in that pyrimidines of the formula I ce 409834/1130 4c 4J 0-CH ₂ -CH (OH) -CH ₂ -NH-CR ₂₆ . U _ce ) » * l and their condensation products with aldehydes, where R is water Yes is substance or methyl, R _{2 is} hydrogen or lower alkyl '· Is up to 4 carbon atoms in the lower alkyl part, R ,,' is hydrogen, cyano, di-lower alkylamino with up to 4 carbon atoms in each of the lower alkyl parts, lower alkoxycarbonylamino-lower alkyl with up to 4 carbon atoms in each of the lower alkyl parts or lower alkyl with up to 6 carbon atoms is ^ and Rk is hydrogen, lower alkanoylamino with up to 4 carbon atoms in the lower alkyl part, lower alkoxy lower alkyl with up to 4 carbon atoms in each of the lower alkyl parts, phenyl, lower alkylthion leather alkyl with up to 4 carbon atoms in each of the lower alkyl parts, lower alkylaminocarbonyl with up to 7 carbon atoms in the lower alkyl part or lower alkoxy carbonyl with up to 5 carbon atoms in the lower alkyl part and in particular R _{n is} hydrogen, R _{0 is} methyl, R, la elQ ^ C Hydrogen, cyano, dimethylamino, 2-methoxycarbonyiaminoethyl, Is methyl or ethyl and R. is hydrogen, acetylamino, 2-methoxyethyl, Phenyl, methylthiomethyl, n-hexylaminoearbonyl or Is ethoxycarbonyl and especially those in the examples called connections. 54. The method according to any one of claims 1-15 or 28-55, characterized marked that in all of the above groups 409834/1130 the substituent R _{1, R 7} ,, R ^., bo between R-, preferably in the para position to the 5-amino-2-hydroxypropoxy group, but can also be in meta or ortho graduation. 35. The method according to any one of claims 1-13, characterized in that that one compounds of the general formula Id ■ fs · ■ 0-CK-CiI (OH) -CH -NH-OR. ( _id ) and their condensation products with aldehydes, ketones, or Carbonic acid and the corresponding N-oxides, in which -R, and R ^ have the above meanings, R ~ halogen, cyano, nitro, lower alkyl, hydroxy lower alkyl, Lower alkenyl, optionally substituted phenyl, hydroxy, lower alkoxy, lower a3-koxy-lower alkyl, Lower alkoxy lower alkenyl, lower alkoxy lower alkoxy, mederalkylthio lower alkoxy, Lower alkenyloxy, lower alkyluhio, lower alkylthio lower alkyl, lower alkylenamino, hydroxy lower alkylenamino, Oxaniederalkylenamino, Thianiederalkylenaminp, Aza-lower alkylenamino, lower alkylamino, di-lower alkylamino, Acylamino, acylamino lower alkyl, acylamino lower alkenyl, Amino-lower alkyl, optionally substituted carbamoyl, optionally substituted carbamoyl-lower alkyl, or lower alkylsulfonyl and η equals 1 ,. Is 2 or 5, where η is 2 or 5 the substituents R, can also be of different types 409834/1130 can, advance. 36. The method according to any one of claims 1-13 or 35 * thereby characterized in that pyridines of the formula I, there CH, R.
1 and their condensation products with aldehydes, ketones and carbonic acid and their corresponding pyridine-N-oxides, where R ₁ , R-, and η are as defined above, R ₀ is Lower alkyl with up to 4 carbon atoms, benzyl, halobenzyl, trifluoromethylbenzyl, lower alkylbenzyl with up to 7 carbon atoms in the lower alkyl part, lower alkoxybenzyl with up to 7 carbon atoms in the lower alkyl part, carboxy-lower alkyl with up to 4 carbon atoms in the lower alkyl part, lower alkoxycarbonyl-lower alkyl with up to 4 carbon atoms each in the lower alkyl parts, carbamoyl-lower alkyl with up to 4 carbon atoms in the lower alkyl part, lower alkylaminocarbonyl lower alkyl with up to 4 carbon atoms each in the lower alkyl parts, di-lower alkylaminocarbdnyl-lower alkyl with up to 4 carbon atoms each in the lower alkyl parts, N ' -Methyl-piperazinocarbonyl ^{-lower alkyl, N 1} - (β-hydroxyethyl) -piperazino-carbonyl-lower-alkyl, morpholinocarbonyl-lower-alkyl, thiomorpholinocarbonyl-lower-alkyl, 2,6-dimethylthiomorpholinocarbonyl-lower-alkyl with up to carbon atoms in the lower-alkyl part or cyano-lower-alkyl with up to U 09834/1130 to 4 carbon atoms in the lower alkyl part. 37 · Method according to one of claims 1-13 or 35j thereby characterized in that compounds of the formula I O-CH ₂ -CH (0H) -CK ₂ -iiH-C ~ R _2b (I) where R _{1 has the} above meaning and η is 1 or 2. Yes * R _3a means Ilalog, cyano, nitro, Niederalky1 with up to 4 C-atoms, lower alkenyl with up to 4 C-atoms, phenyl, halophenyl, Trifluormethy! Phenyl, Niederalky! Phenyl with up to 7 C-atoms in the lower alkyl part, lower alkoxyphenyl with up to 4 carbon atoms in the lower alkyl part, hydroxy lower alkyl with up to 7 carbon atoms in the lower alkyl part, lower alkoxy with up to 7 carbon atoms in the lower alkyl part, hydroxy, lower alkoxy lower alkenyl with up to 4 carbon atoms in the lower alkyl part and up to 4 carbon atoms -Atomen im'Niederalkenylteil, Niederalkoxyniederalkyl with up to 4 C-atoms in the lower alkyl parts, Lower alkoxy-lower alkoxy with up to 4 C-atoms in the lower alkyl parts, Niederalkenyloxy with up to 4 C-atoms in the lower alkenyl part, Niederalkylthione-lower alkoxy with up to 7 C each Atoms, lower alkylthio with up to 7 carbon atoms in the lower alkyl part, lower alkylthio lower alkyl with up to 7 carbon atoms each, lower alkanoy! Amino with up to 7 carbon atoms in the lower alkyl part, lower alkoxycarbonylamino with up to 409834/1130 7 carbon atoms in the lower alkyl part, lower alkylamino with up to 4 carbon atoms each in the lower alkyl parts, lower alkoxycarbonylamino-lower alkyl with up to 4 carbon atoms in the lower alkyl parts, lower alkylamino with up to 7 carbon atoms in the lower alkyl part, di-lower alkylamino each with up to 7 carbon atoms in the lower alkyl parts, pyrrolidino, piperidino, 4-hydroxypiperidino, morpholino, thiomorpholino or 2,6-dimethylthioinorpholino or optionally substituted carbamoyl, R ^, means lower alkyl with up to 4 carbon atoms, benzyl, carbamoylmethyl , Lower alkylaminocarboaylmethyl with up to 7 C-atoms in the lower alkyl part, di-lower alkylaminocarbony! Methyl with up to 7 C-atoms each in the ^{lower alkyl parts, pyrrolidinocarbony! Methyl, piperidinocarbonylmechyl, piperazinocarbonylmethyl, N 1} -methylpiperazinocarbony! Methyl, N ¹ - (ß-hydroxyethyl) -piperazinocarbonylmethyl, morpholinocarbonyltnethyl, thiomorpholinocarbonylmethyl, 2,6-dimethylthiomorpholinocarbony! methyl or cyano- methyl *. 38. The method according to any one of claims 1-15 or 55j thereby characterized in that pyridines of the formula I, (I _d0 ), 409834/1130 where R. and η asked the above meanings, R ^, means chlorine, ι a jo Bromine, cyano, nitro, hydroxy, lower alkyl with up to 4 carbon atoms, Lower alkenyl with 5 or 4 carbon atoms, phenyl, chlorophenyl, breadnphenyl, Trifluoromethylphenyl, Niederalky! Phenyl with up to 4 carbon atoms in the lower alkyl part, -Niederalkoxyphenyl with up to to 4 carbon atoms in the lower alkyl part, hydroxy-lower alkyl with up to 4 carbon atoms, nicderalkoxy with up to 4 carbon atoms, lower alkoxyalkenyl with up to 4 carbon atoms in the lower alkyl part and 3 or 4 carbon atoms in the lower calkenyl part, lower alkoxy-lower alkyl each with up to 4 carbon atoms in each of the lower alkyl parts, lower alkoxy lower alkoxy each with up to 4 carbon atoms in the Lower alkyl parts, lower alkenyloxy with 3 or 4 carbon atoms, lower alkylthio with up to 4 carbon atoms, lower alkanoylamino with up to 4 carbon atoms in the lower alkyl part, lower alkoxycarbonylamino with up to 4 carbon atoms in the lower alkyl part, lower alkanoylamino-lower alkyl each with up to 4 carbon atoms in the lower alkyl parts, lower alkoxycarbonylamino lower alkyl with each up to feu 4 carbon atoms in the lower alkyl parts, lower alkylamino with up to 4 carbon atoms in the lower alkyl part, di-lower alkylamino each with up to 4 carbon atoms in the Niederalkyltei-. len, pyrrolidino, piperidino, 4rHydroxypiperidino, morpholino, Thiomorpholino or 2,6-dimethylthiomorpholino, Carbamoyl, lower alkylaminocarbonyl with 1-4 carbon atoms in Lower alkyl part, di-lower alkylaminocarbonyl with 1-4 each 409834/1130 C atoms in the lower alkyl parts. Lower alkylenaminocarbonyl with 5 carbon atoms in the alkylenamino chain, oxa-, thiao or thiao-lower alkyleneaminocarbonyl with 4 carbon atoms each in the rings or carbamoyl-lower alkyl with up to 4 carbon atoms in the lower alkyl part, R _{2 (j} means lower alkyl with up to 4 carbon atoms η , Benzyl, carbamoylmethyl or cyanomethyl. 39. The method according to any one of claims 1-13 or 35 »thereby characterized in that pyridines of the formula I, r jj-C-CH ₂ -CII (OH) -CH ₂ -Mt-CR _2d wherein R, R, and η have the above meanings, R, denotes Methyl. 4O. Method according to one of claims 1-13 or 55? as characterized in that pyridines of the formula I _de la and their corresponding pyridine-N-oxides and their condensation products with aldehydes, where η is _{1, 2 or 3, R 1} a la Is hydrogen or methyl, R is lower alkyl with up to 4 carbon atoms or phenyl-lower alkyl with up to 5 carbon atoms in the lower alkyl part, IU halogen, nitro, cyano, lower alkyl with up to 4 carbon atoms, lower alkoxy with up to 4 carbon atoms Atoms, 409834/1130 optionally substituted by phenyl, di- (C. u) -lower alkylamino, (C, u) -Lower alkylamino, lower alkoxy-lower alkyl with up to 4 carbon atoms in each of the lower alkyl parts, lower alkanoylamino with up to 5 carbon atoms in the lower alkanoyl part, lower alkenyloxy with up to 4 carbon atoms in the lower alkyl part Lower alkanoylamino-lower alkyl with up to 5 C atoms in the lower alkanoyl part and up to 4 C atoms in the lower alkyl part, hydroxy, hydroxy-lower alkyl with up to 4 C atoms in the lower alkyl part, (C, η) -Lower alkoxycarbonylamino-lower alkyl with up to C atoms in the lower alkyl part, amino-lower alkyl with up to carbon atoms in the lower alkyl part, lower alkylaminocarbonyl with up to 6 carbon atoms in the lower alkyl part, Niederalkylenaminocarbonyl "with up to 5 carbon atoms in the lower alkyl chain or aminocarbonyl lower alkyl with up to 4 carbon atoms in the lower alkyl part and condensation products with aldehydes, preferably condensation products with optionally substituted benzaldehyde and in particular η is _1, 2 or 5, R 1 is hydrogen a J. a or methyl, R _{0 is} methyl or 2-phenylethyl, R, chlorine, nitro, methyl, ethyl, n-propyl, η-butyl, cyano, methoxy, ethoxy, allyloxy, phenyl, methylamino, dimethylamine, 2-aminoethyl, aminomethyl , 2-methoxyethyl, hydroxy, hydroxymethyl, ethylamino, acetylamino, acetylaminomethyl, 2-methoxycarbonylaminoethyl, methoxycarbonylaminomethyl, 2-ethoxycarbonyJ-aminoethyl, n-butyloxycarbonylaminomethyl, 2- [n-butyloxycarbonylaminomethyl, 2- [n-butyloxycarbonylaminomethyl, n-butyloxycarbonylamino] -butyl- , Pyrrolidinocarbonyl or aminocarbonylmethyl and condensation products are those with benzene A09834 / 1130 Aldehydes are especially those mentioned in the 3eiepiele Connections. 41. The method according to any one of claims 1-13 or 35-40, characterized in that the 3-amino-2-hydroxypropoxy radical occupies positions 2, 3 or 4 of the pyridine ring, but preferably position 3 or especially position 2 occupies. 42. The method according to any one of claims 1-13 or 35-40, characterized characterized in that in all of the above groups the substituents R-, for η equal to 2 or 3 are identical or can be different from each other. 43. The method according to any one of claims 1-13 or 23-40, characterized in that in all of the preceding groups one of the substituents R ,, R ^,, R ^ respectively. R preferred in the ortho position or especially in the para position to the 3-amino-2-hydroxy-propoxy radical. 44. The method according to claim 13 *, characterized in that one is an amine of the formula Het-O-CH ₂ -CH (0H) -CH ₂ -NH _2,. where Het has the above meaning, BEZW with an aldehyde. Ketone of the formula O = X ₃ , where X ₃ H is -CH (CH) R ₃ and R _{3 has the} above meanings, reduced to compounds of the formula I in the presence of a reducing agent. 4 09834/1130 45 · Method according to one of claims 1-44. characterized, that one obtained compounds of the formula I with an aldehyde or ketone of the formula X = O, where X is the divalent radical of an aldehyde or ketone or with a reactive derivative thereof to form compounds of the formula Iy Het - 0 - CH ₀ - CH - CH ₀ ι 2 ^x r <v ^R l where Het, R, R _? and X have the above meanings, converts, 46. The method according to claim 45 »characterized in that reactive carbonyl derivatives are acetals, ketals, hemithioketals or thioketals. 47 · Method according to claims 1-44, characterized in that one obtained compounds of formula I with carbonic acid BEZW. with their reactive derivatives to form compounds of Formula I.
ζ Het - 0 - CH ₀ -CH- CH "(Iz), ° ΊΓ ^Ν ~ ι ² "■ · 0. R ₁ in which Het, R and R have the above meanings. 48. The method according to claim 47, characterized in that reactive derivatives of carbonic acid, especially carbonyl halides, Are carbonic acid mono-or-diesters. 409834/1130 49 · Method according to claim 48, thereby; 5ek2nnzeiohnet, that carbonyl halide especially stands for phosgene. 50. The method according to any one of claims 1-44, characterized in that that the compounds of the formula Iy obtained are converted into compounds of the formula I by hydrolysis. 51. The method according to any one of claims 1-44, characterized in that that the compounds of the formula Iz obtained are converted into compounds of the formula I by hydrolysis. 52. The method according to any one of claims 1-44, characterized in that that one in obtained compounds of the formula I with a C-C double bond, this double bond through Hydrogenation converted into a C-C single bond. 53 · Method according to one of claims 1-44, characterized in that that in obtained compounds of the formula I having one or more phenyl nuclei, these are halogenated. 54. The method according to any one of claims 1-44, characterized in that in obtained compounds of the formula I with free carboxy-lower alkyl group R _p , these are esterified. 55. 'The method according to any one of claims 1-44. characterized, that in compounds of the formula I obtained 4 09834/113 at the with esterified carboxy-lower alkyl group R ^, this into the Free carboxy-lower alkyl group FU converted. 56. The method according to any one of claims 1-44, characterized in that that in obtained compounds of the formula I with esterified carboxy-lower alkyl group PL ·, this into the corresponding carbamoyl lower alkyl group converted. 57- The method according to any one of claims 1-44, characterized in that that in compounds of the formula I obtained with a carbamoyl lower alkyl group FL · these are converted into the cyano lower alkyl group convicted. 58. The method according to any one of claims 1-44, characterized in that in obtained compounds of the formula I having a cyano-lower alkyl group R _p , these are converted into the carbamoyl-lower alkyl group or into the carboxy-lower alkyl group. 59 · Process according to one of claims 1-44, characterized in that in the compounds of the formula I obtained in which R., and / or R ₂ is lower alkylamino, the lower alkylamino group (s) is converted into a di-lower alkylamino group R- and / or R ₂ , transferred. 60. The method according to any one of claims 1-44, "characterized in that in the resulting compounds of the formula I, -wherein R-. And / or R ₂ ^ is halogen, · the halogen group (s) with 409834/1130 a corresponding amine by _{lower alkylamino, di-lower alkylamino, lower alkylenamino, hyd t} "oxyn . '· .ederalkyienamino, thianiederalkylenamino, aza-lower alkylenamino or with a corresponding alcohol by lower alkoxy, lower alkenyloxy, lower alkoxy-lower alkoxy, hydroxyl which is replaced with a corresponding mercaptan by lower alkylthio. 61. The method according to any one of claims 1-4-4, characterized in that that in obtained compounds of the formula I which are substituted on the heterocycle by halogen and / or Carry halogen-substituted phenyl groups that catalytically hydrogenate away the halogen atoms. 62. The method according to any one of claims 1-44, characterized in that that in a compound of the formula XXIIIa, or in a corresponding pyrazine-N-oxide f 5 f 0-0H ₂ -CH (OH) -CH ₂ -JiH-OR ₂ (XXIIIa) or of the formula XXIIIb, or in a corresponding pyridazine N-oxide 0-CH-CH (OH) -CH ₀ -NiI-CR ₀ (XXIIIb) ^R l or of the formula XXIIIc, or in a corresponding pyrimidine ~ N-oxide 4 09834/1130 3 ~ Τ 'Η 0-CH ₂ -OH (OH) -OK ₂ -NH-OR ₂ (XXIIIc) V I ■ ^R l the primary amino group by reaction with a compound of formula XXIV Z - lower alkyl (XXIV), where Z is a reactive, esterified hydroxyl group, in a lower alkylamino or. Di-lower alkylamino group convicted. 63. The method according to claim 1, characterized in that one in a compound of the formula XXVa, or in one corresponding pyridirx. -N oxide N 4 N / 4 3. k> •.-Η ^N 0-CH ₀ -CH (OII) -OH ₀ -MCR ₀ (XXVa), wherein R _{1 and R 2 have the} above meanings and X _{3 is} amino or equal to R ₃ and X _{4 is} amino or equal to R ₄ , or of the formula XXVb, or in a corresponding pyridazine-N-oxide CH " ^{/ y} \ 0-CH ₀ -CH (OH) -CH-KH-CR ₀ (XXVb), ^X 3 ~ t * ^{2 2} I ² vX / R _n N 1 409834/1130 wherein R ₁ and R _{9 have the} above meanings and X ^ is amino or equal to R- and X is amino or equal to R, or of the formula XXVc, or in a corresponding pyrimidine-N-oxide X ₃ -J- µ. 0-CH ₂ -CH (0H) -CH-NH-CR _? (XXVc), s * c- ι £ · wherein R-. and R "have the above meanings and X-amino or is Ro and X is amino or R is, or the Formula XXVd or in a corresponding pyridine-N-oxide \ ^d R 1 where η, R and R have the above meanings, the primary (n) Amino group (s) converted into the aylamino group (s). 64. The method according to any one of claims 1-44, characterized in that that in a compound of the formula XXVd f 5 (XXVd), \ _r ^d wherein n, R and R have the above meanings, or in one. corresponding pyridine-N-oxide the primary amino group (s) by reacting with a compound of formula XXVI 409834/1130 Lower alkyl - Z (XXVI), where Z is a reactive, esterified hydroxyl group, in a lower alkylamino or. Din leather alkylamino group convicted. 65 · Method according to one of claims 1-44, characterized in that that in obtained compounds of the formula I which are substituted on the heterocycle by alkylthio, the Alkylthio group (s) hydrogenated away. 66. The method according to any one of claims 1-44, characterized in that that in compounds of the formula I obtained in which R-, and / or R, is lower alkylsulfonyl, the lower alkylsulfonyl group (s) against hydroxy, lower alkoxy, Lower alkoxy-lower alkoxy, lower alkenyloxy, lower alkylthione-lower alkoxy ,. Lower alkylthio, phenylthio, lower alkylamino, Di-lower alkylamino, lower alkylenamino, oxane-lower alkylenamino, aza-lower alkylenamino or thian-lower alkylenamino exchanges. 67 · The method according to any one of claims 1-44, characterized in that that in obtained compounds of the formula I which carry an amino lower alkyl group, this amino lower alkyl group acylated. 6ö. Method according to one of Claims 1-44, characterized in that that in obtained compounds of the formula Id 409834/1130 r. CH -CiI (OH) -CH -KH-C-R. (ld) 2 2 ι 2 "1 wherein R ^ is a nitro group, this nitro group for Amino group reduced. 69. The method according to any one of claims 1-44, characterized in that that in compounds of the formula I obtained in which FL is cyano, the cyano group is converted into the aminomethyl group convicted. 70. The method according to any one of claims 1-44, characterized in that that one converts non-N-oxidized compounds into the corresponding N-oxides. 71. The method according to any one of claims 1-44, characterized in that that one obtained mono or. Di-N-oxides converted into the corresponding non-oxidized compounds. 72. The method according to any one of claims l8, 20, 24, 25, 27., 51, 52, 34, 37, 39, 41-43, 51-59, 61-64 and 71, characterized in that that the in Examples I-30 and 74 called connections. 73 · Method according to one of claims 1-17, 19, 21-23, 26, 28-30, 33, 35, 36, 38, 40, 44-50, 60 and 65-7Ο, characterized in that the in Examples 31-73 and 409834/1130 75 to 90 mentioned connections. 74. 'Method according to one of claims l8, 20, 24, 25, 2.7, 31, 32, '34, 37, 39, 41-43, 51-59, 61-64 and 71, characterized in that one has the new compounds in their clockwise form. 75. The method according to any one of claims 18, 20, 24, 25, 27, 31, 32, 34, 37, 39, 41-43, 51-59, 61-64 and "'71, characterized that the new connections are made in their counter-clockwise form. 76. The method according to any one of claims 18, 20, 24, 25, 27, 31, 32, 34 ,. 37, 39, 41-43, 51-59, 61-64 and 71, characterized in ₇ that the new connections are made in free form. 77. The method according to any one of claims 18, 20, 24, 25, 27, 31 ,. 32, 34, 37, 39, 41-43, 51-59, 61-64 and 71, characterized in that the new compounds are in the form of their Manufactures salts. 78. The method according to any one of claims l8, 20, 24, 25, 27, 31, 32, 34, 37, 39, 41-43, 51-59, 61-64 and 71, characterized in that that the new compounds are prepared in the form of their therapeutically useful salts. 409834/1130 79. The method according to any one of claims 1-17, 19, 21-23, 26, 28-3Ό, 33, 35, 36, 38, 40, 44-50, 60, and 65-70, characterized in that the new connections in their
clockwise form. 80 .. The method according to any one of claims 1-17, 19, 21-23, 26, 28-30, 33, 35, 36, 38, 40, 44-50, 60 and 65-70, characterized in that the new connections in their
manufactures counterclockwise shape. 81. The method according to any one of claims 1-17, 19, 21-23, .26, 28-30, 33, 35, 36, 38, 40, 44-50, 60 and 65-70, characterized in that the new connections in the open
Manufactures form. 82. The method according to any one of claims 1-17, 19, 21-23, 26, 28-30, 33, 35, 36, 38, 40, 44-50, 60 and 65-70, characterized in that that the new compounds are produced in the form of their salts. 83 · Method according to one of claims 1-17, 19, 21-23,
26, 28-30, 33, 35, 36, 38, 40, 44-50, 60 and 65-70, characterized in that the new compounds are prepared in the form of their therapeutically useful salts. 84. Compounds of the general formula I j 5
Het-0-CH ₂ -CH (OH) -CH ₂ -NH-CR ₂ (i), ^R l 409834/1130 where Het is optionally substituted pyridazinyl, pyrimidinyl, pyrazinyl or substituted pyridyl, R is hydrogen or methyl, R _{2 is} lower alkyl, optionally substituted phenyl-lower alkyl, carboxy-lower alkyl or functionally modified carboxy-lower alkyl, their condensation products with aldehydes, ketones or carbonic acid and their N-oxides. 85. Compounds of the general formula Ia f ₃ . . '0-CH-CH (OH) -CH-HH-O-R - (Ia) d the. and their condensation products with aldehydes, ketones or "Carbonic acid and the corresponding N-oxides, in which R ^ and R _{2 have} the same meanings as above, R-z hydrogen, halogen, cyano, hydroxy, lower alkyl, lower alkoxy-lower alkyl, amino-lower alkyl, lower alkoxy-lower alkenyl, lower alkylamine, di-lower alkylamino, Acylamino, acylamino lower alkyl, acylamino lower alkenyl or Is lower alkylsulfonyl and R ₂ , hydrogen, halogen, lower alkyl, hydroxy lower alkyl, lower alkenyl, optionally substituted phenyl, hydroxy, lower alkoxy, lower alkoxy lower alkyl, amino lower alkyl, lower alkoxy lower alkoxy, lower alkenyloxy ,. Niederalkylthio, Niederalkylthioiederalkoxy, Niederalkylthioiederalkyl, Niederalkylenamino, Hydroxyniederaikylenamino, Oxaniederälkylenamino, Thianiederalkylenamino, Äzaniederalkylenamino, given 409834/1130 if substituted carbamoyl, lower alkylamino, di-lower alkyl -ι amino, optionally substituted phenylthio, acylamino, Is lower alkylsulfonyl or lower alkoxycarbonyl. 86. Pyrazines of Formula Iaa 0-CH _o -CH (OH) -CH _o -liH-CH _o (Iaa and their condensation products with aldehydes, ketones or carbonic acid and their corresponding pyrazine-N-oxides, in which R and R have the above meanings, R _2a means lower alkyl with up to 4 carbon atoms, benzyl, halobenzyl, trifluoromethylbenzyl, lower alkylbenzyl with up to 7 ° C Atoms in the Ni-eder-'aUcylteil, Niederalkoxybenzyl with up to 7 C-atoms in the lower alkyl part, Carboxyniederalkyl with up to 4 C-atoms in the lower alkyl part, lower alkoxycarbonyl-lower alkyl with up to 4 C-atoms in the lower alkyl parts, carbamoyl-lower alkyl with up to 4 C atoms in the lower alkyl part, lower alkylaminocarbonyl lower alkyl with up to 4 C atoms each in the lower alkyl parts, di-lower alkylaminocarbonyl lower alkyl with up to 4 C atoms each in the lower alkyl parts, pyrrolidinocarbonyl lower alkyl, piperazinocarbonyl lower alkyl, N'-methylpiperazinocarbonyl lower alkyl, N'-methylpiperazinocarbonyl (hydroxy lower alkyl) -piperazinocarbonyl lower alkyl, morpholinocarbonyl lower alkyl, thiomorpholinocarbonyl lower alkyl, 2,6-dimethylthiomorpholinocarbony lower alkyl with up to 7 carbon atoms in the lower alkyl part or cyano-lower alkyl with up to 4 carbon atoms in the lower alkyl part, 409834/1130 R. means: hydrogen, hydroxy, lower alkyl with up to 4a 7 carbon atoms, lower alkenyl with i> is to 7 carbon atoms, halogen, Lower alkylamino with up to 7 carbon atoms, di-lower alkylamino with up to 7 carbon atoms in each of the lower alkyl parts, pyrrolidino, piperidino, 4-hydroxypiperidino, morpholino, thiomorpholino, 2,6-dimethylthiomorpholino, lower alkoxy with up to 7 carbon atoms, lower alkenyloxy with up to 7 carbon atoms, lower alkoxynifideralkyl with up to 4 carbon atoms each in the lower alkyl parts, Lower alkoxy-lower alkoxy with up to 4 carbon atoms in each of the lower alkyl parts, lower alkylthio with up to 7 carbon atoms, lower alkylthio lower alkoxy with up to 7 carbon atoms in each of the lower alkyl parts, lower alkanoyl- ' amino with up to 7 carbon atoms in the lower alkyl part or lower alkoxy carbonylamino with up to 7 carbon atoms in the lower alkyl part. Compounds of the formula lab (lab), and their condensation products with aldehydes, ketones or carbonic acid, in which R ₁ , TU and R ^ _{a have the} above meanings, R _2b means «aaw». —I Lower alkyl with up to 4 carbon atoms, benzyl ^ carbamoylmethyl, lower alkylaminocarbonylmethyl with up to 7 carbon atoms in the lower alkyl part, di-lower alkylaminocarbony! Methyl with up to 7 carbon atoms each in the lower alkyl parts, pyrrolidinocarbony! Methyl, piperidinocarbonylmethyl, piperazinocarbonyl 4 09834/1130 methyl, N'-methylpiperazinocarbonylmethyl, N ¹ - (β-hydroxyethyl) -piperazinocarbonylmethyl, MorpMolinoearbopylmethyl, Thiomorpholinocarbonylmethyl, 2,6-Dimethylthiomorpholinoearbonylmethyl or Qranome thy 1. 88. Compounds of the formula Iac O-CH ₀ -CH (OH) -CiI-UII-OH ₀ (Iac) c. 2 ι 2C and their condensation products with aldehydes, ketones or Carbonic acid, in which R has the above meaning, FU means lower alkyl with up to 4 carbon atoms, benzyl, carbamoylmethyl or cyanomethyl. R denotes hydrogen, halogen, cyano, lower alkyl with up to 7 carbon atoms, lower alkoxy-lower alkyl with up to 7 carbon atoms in each of the lower alkyl moieties, lower alkoxy-lower alkenyl with up to 4 carbon atoms in the lower alkyl part and up to 4 carbon atoms in the lower alkenyl part, Niederalkanoylamirio with up to 7 carbon atoms in the lower alkyl part, lower alkoxycarbonylamino with up to 7 carbon atoms in the lower alkyl part, lower alkanoylamino-lower alkyl with up to 4 carbon atoms in each of the lower alkyl parts, lower alkoxycarbonylamino lower alkyl with up to 4 carbon atoms in each of the lower alkyl parts, lower alkanoylamino-lower alkenyl with up to 4 carbon atoms in the lower alkyl part and up to 4 carbon atoms in the lower alkenyl part, lower alkoxycarbonylamino-lower alkenyl with up to 4 carbon atoms in the lower alkyl part and up to 4 carbon atoms in the lower alkenyl part, R ,, means hydrogen, hydroxy, lower alkyl with up to 4 carbon atoms, lower alkenyl with 3 or 4 carbon atoms, lower alkylamino with up to 4 carbon atoms, di-lower alkylamino with 409834/1130 - up to 4 carbon atoms each in the Nio'jeralk> ltfciler., Pyrrolidino, Piperidino, 4-hydroxypiperidino, morpholino, thiornorpholino, 2,6-dimethylthiomorpholino, piperazino, N'-methylpiperazino, Chlorine, bromine, lower alkoxy with up to 4 carbon atoms, lower alkenyloxy with 3 or 4 carbon atoms in the lower alkenyl part, lower alkoxy-lower alkyl with up to 4 carbon atoms in each of the lower alkyl parts, lower alkoxy-lower alkoxy with up to 4 carbon atoms in each of the lower alkyl parts, lower alkylthio with up to to 4 carbon atoms, lower alkylthione-lower alkoxy with up to 4 Carbon atoms in each of the lower alkyl parts, lower alkanoylamino with -up to 4 carbon atoms or lower alkoxyearbony-lamino with. up to 4 carbon atoms in the lower alkyl part. 89. Pyrazines of the formula lad (lad) where R, and R ,, have the above meanings, R «1 means methyl, R ₃ ^ means hydrogen, bromine, chlorine, lower alkyl with up to 4 carbon atoms, lower alkoxy lower alkyl with up to 4 carbon atoms in each of the lower alkyl parts, lower alkoxy lower alkenyl with up to 4 carbon atoms in the lower alkyl part and up to 4 carbon atoms in the lower alkenyl part, lower alkanoylamino with up to 4 carbon atoms in the lower alkyl part, lower alkoxycarbonylamino with up to 4 carbon atoms in the lower alkyl part, lower alkanoylamino-lower alkyl with up to 4 carbon atoms each in the lower alkyl parts, lower alkoxycarbonylamino lower alkyl with each 409834/1130 up to 4 carbon atoms in the lower alkyl parts. 90. Pyrazines of Formula Iae 0-CH-OH (OH) -OH -BH-CHEt. (I _a0 ) IL la where R is hydrogen or methyl, R _{2 is} lower alkyl with 1-4 C atoms or phenyl lower alkyl with up to 4 C atoms, in the lower alkyl part, R is hydrogen, halogen, lower alkyl with 1-4 C atoms, 2- ( C _1-4 ) -LoweralkoxyäChyl or 2- (C _1-4 ) -Loweralkoxycarbonylaminoäthyl and R is hydrogen, halogen, lower alkoxy with 1-4 C-atoms, lower alkoxy-lower alkoxy with up to 4 C-atoms in the lower alkyl parts, lower alkenyloxy with up to 4 carbon atoms, lower alkylthio with up to 4 carbon atoms, lower alkylenamino with 4-6 carbon atoms in the lower alkylene chain, hydroxy lower alkylenamino with 4-6 carbon atoms in the alkylene chain, oxaniederalkylenamino with 4-5 carbon atoms in the Oxane lower alkylene chain, lower alkylamino with up to 4 carbon atoms, di-lower alkylamino with up to 4 carbon atoms each in the lower alkyl parts, phenylthio or N'-lower alkylazane lower alkylenamino with 4-6 carbon atoms in the lower alkyl parts and "in particular R _{1 is} hydrogen or methyl is, Rp is methyl or 2-phenylethyl, R., Wasse substance, bromine, methyl, 2- or . ^5c
Methoxyäthyly ^ -Methoxyearbonylaminoäthyl and R ^ is hydrogen, chlorine, methoxy, 2-methoxyethoxy, allyloxy, ethylthio, morpholino, 4-hydroxypiperidino, diniethylamino, isopropylamino, phenylthio or- N'-methylpiperazinoist and .in particular the 409834 / Ί130 compounds mentioned in the examples. 91. pyrazines according to claims 8S * -6ö , wherein in all of the above groups of the uubstituent R _v , R- *, B. ^ or. R is preferably in the para position to the 5-amino-2-hydroxypropoxy group, but can also be in the meta position. 92. Compounds of the general formula Ib ,: f AO-CH -CH (OH) -CH -KH-OR ₂ k I N R ₁ and their condensation products with aldehydes, ketones or carbonic acid and the corresponding N-oxides, in which R, R, R-, and R ^ have the same meanings as have up. 95 pyridazines of the formula I, CH ₅ ^R i and their condensation products with aldehydes, ketones or carbonic acid and their corresponding pyridazine-N-oxides, wherein R _n , R ₀ , R., and R ,. have the above meanings. X ca D Hrd. 94. Pyridazines of the formula I ,, 409834/113 0 4a CH. 0-CH ₉ -CH (OH) -GH-IiH-Cf-R ₀ , ² 2. j 2b ^R T and their condensation products with aldehydes, ketones or carbonic acid, in which R, .R _2b , R ^ and R ^ _{& have the} above meanings. 95 · pyridazines of the formula I. be. 0-CH _o -CH (OH) -CH ₀ -MCR _0n CH. wherein R, R _p , R., and R ^, have the above meanings. 96 · pyridazines of the formula I. bd 4b CH O-CHp-CHC OH) -CHp-I wherein R ₁ , R ^ ,, R ^ ,, and R,., have the above meanings. 1 2d 5b 4b 97. Pyridazines of Formula I. be 4c 0-CH ₂ -CH (OH) - CH ₃ 3- «La ■ 409834/1130 and their condensation products mi r. Aldehydes «where R, is hydrogen or methyl, Rp is hydrogen or lower alkyl with up to 4 carbon atoms, R _{x is} hydrogen _; t and Rk is hydrogen, lower alkoxy, halogen, oxaniederalkylenamino with up to 6 carbon atoms in the lower alkylene part or hydroxy and in particular R _{1 is} hydrogen, R ₀ 'is methyl, R-, la egg © _ _? c Is hydrogen and R. is hydrogen, methoxy, chlorine, morpholine) or hydroxy and most particularly those in the examples named compounds. 98. Pyridazines according to claims 92-97, wherein in all of the above groups the substituent R, R ^ _a * R ^ ₁₃ or. R ^ _{0 is} preferably in the para position to the 3-amino-2-hydroxypropoxy group, but can also be in the meta or ortho position. 99. Compounds of the general formula Ic CH Λ ι ⁵ 'Jj-O-CH-CH (OH) -CII-Mi-CR' (Ic) \ / 2. 2 ι 2 · _N. • ' 1 and their condensation products with aldehydes, ketones or carbonic acid and the corresponding N-oxides, in which R ,, R, R and R ^ have the same meanings as have up. 100 · pyrimidines of the formula I 409834/1130 ^(X ca ^} and their condensation products with aldehydes, ketones or Carbonic acid and its corresponding pyrimidine-N-oxides, in which R, R ", R and R ^ have the above meanings' * 101. Pyrimidines of the formula I CH " 5 and their condensation products with aldehydes, ketones or carbonic acid, in which R- ,, Rov, ' ¹ S ^{and R} ii ^ODi ge meanings. 102. Pyrimidines of the formula I. CC ^R 3a ~ l · -H 0 _{-CH 9} -CH (OH) -CH ₉ -IiB-CR. (I) W y * - <- ■ ι de cc R ^R l wherein R ₁ , R _2q , R and R ^ _{b have the} above meanings. IO5. Pyrimidines of the formula I C U. 4b CH _V f ^O - ^C < ^H 2 ~ ^{CH (0H)} "*" ^CH 2 ~ ^iiH ~ ^CKR 2 (i ^(l cd ^{) N} R ^R l woi-in R, Rod '^ - ^ h ^uac * ^ h ^O ^ ^J ^ S6 have meanings. A09834 / 1130 104. Pyrimidines of the formula I. R -4- ^N I 3cT -H 0-CH ₀ -CH (OH) -CII-NH-OR ₀ (I), W y * - «- ι 2e ce la and their condensation products with aldehydes, where R is water 4.3, is substance or methyl, R is hydrogen or lower alkyl with te up to 4 carbon atoms in the lower alkyl part, R-, hydrogen, cyano, di-lower alkylamino with up to 4 carbon atoms in each of the lower alkyl parts, lower alkoxycarbonylamino-lower alkyl with up to 4 carbon atoms in each of the lower alkyl parts or lower alkyl with up to 6 C- Atoms and R ₂ , hydrogen, lower alkanoylamino with up to 4 carbon atoms in the lower alkyl part, lower alkoxy lower alkyl with up to 4 C7 atoms in each of the lower alkyl parts, phenyl, lower alkylthio lower alkyl with up to 4 carbon atoms in each of the lower alkyl parts, lower alkylaminocarbonyl with up to 7 carbon atoms in the lower alkyl part or lower alkoxycarbonyl with up to 5 carbon atoms in the _{lower alkyl part and in particular R 1 is} hydrogen, R ~ is methyl, R, hydrogen, cyano, dimethylamino, 2-methoxycarbonylaminoethyl, methyl or ethyl and R , Hydrogen, acetylamino, 2-methoxyethyl, phenyl, methylthiomethyl, n-hexylaminocarbonyl or 'ethoxycarbonyl and very particularly the compounds mentioned in the examples. 105 · pyrimidines according to claims 99-104, wherein all of the above groups of the substituent R ₇ ,, R,, R_, respectively. R. ^l 3a ^{5 av} 3b 3c loading 409834/1130 preferably in the para position to the 3-amino-2-hydroxypropoxy group stand, but can also stand in meta or ertho position. 106- compounds of the general formula Id • f, O-CH -CJr (OIi) -CH -KH-O-R 2 2 and their condensation products with aldehydes, ketones, or carbonic acid and the corresponding N-oxides, in which R- and R ~ have the above meanings, Ro halogen, cyano, nitro, lower alkyl, hydroxy lower alkyl, Lower alkenyl, optionally substituted phenyl, hydroxy, lower alkoxy, lower alkoxy-lower alkyl, Lower alkoxy-lower alkenyl, lower alkoxy-lower alkoxy, never-'deralkylthio-lower alkoxy, Lower alkenyloxy, lower alkylthio, lower alkylthio lower alkyl, lower alkylenamino, hydroxy lower alkylenaraino, Oxaniederalkylenamino, thianiederalkylenamino, ΛzaniederaXkylenamino, lower alkylamino, di-lower alkylamino, Acylamino, acylamino lower alkyl, aylamino lower alkenyl ^ Amino-lower alkyl, optionally substituted carbamoyl, optionally substituted carbamoyl-lower alkyl, or lower alkyl sulfonyl and η is 1, 2 or 5, where η is 2 or 5 the substitutes R, can also be different can. A09834 / 113Ö 107. pyridines of the formula I, - i.a. 26 / —0-CH ₂ -CH (OK) -CH ₂ - CH ₃ it 1 and their condensation products with aldehydes ^ .. ketones., and carbonic acid and their corresponding pyridine-N-oxides, where R , R and η have the above meaning, R means J. j idd. Lower alkyl with up to 4 carbon atoms, benzyl, halobenzyl, trifluoromethylbenzyl, lower alkylbenzyl with up to 7 carbon atoms in the lower alkyl part, -Lower alkoxybenzyl with up to 7 carbon atoms in the lower alkyl part, carboxyniedex-alkyl with up to 4 carbon atoms in the lower alkyl part Lower alkoxycarbonyl lower alkyl with up to 4 carbon atoms each in the lower alkyl parts, carbamoyl lower alkyl with up to 4 carbon atoms in the lower alkyl part, lower alkylatninocarbonyl lower alkyl with up to 4 carbon atoms each in the _{lower alkyl parts v} di-lower alkylaminocarbonyl lower alkyl with up to 4 carbon atoms each in the lower alkyl parts , N'-methyl-piperazinocarbonyl ^{-lower alkyl, N 1} - (/ 3-hydroxyethyl) -piperazino-carbonyl-lower alkyl, morpholino- -ι carbonyl-lower alkyl, thiomorpholinocarbonyl-lower alkyl, 2,6-dimethylthiomorpholinocarbonyl lower alkyl with up to C atoms in. Lower alkyl part or cyano-lower alkyl with up to 4 carbon atoms in the lower alkyl part. 409834/1130 108 '. Compounds of the formula I 2406930 (I) ^R l where R- has the above meaning and η is 1 or 2. ^R 3a ^means halogen, cyano, nitro, Niederalky1 with up to 4 carbon atoms, lower alkenyl with up to 4 carbon atoms, phenyl, halophenyl, trifluoromethylphenyl, Niederalky! Phenyl with up to 7 carbon atoms in the lower alkyl part, lower alkoxyphenyl with up to 4 carbon atoms in the lower alkyl part, hydroxy lower alkyl with up to 7 carbon atoms in the lower alkyl part, lower alkoxy with up to 7 carbon atoms in the lower alkyl part, hydroxy, lower alkoxy lower alkenyl with up to 4 carbon atoms in the lower alkyl part and up to 4 carbon atoms in the lower alkenyl part, lower alkoxy-lower alkyl with up to 4 carbon atoms each in the lower alkyl parts, lower alkoxy-lower alkoxy with up to 4 carbon atoms each in the lower alkyl parts, lower alkenyloxy with up to 4 carbon atoms in the lower alkenyl part, lower alkylthione-lower alkoxy with up to 7 carbon atoms each, Lower alkylthio with up to 7 carbon atoms in the lower alkyl part, lower alkylthio-lower alkyl with up to 7 carbon atoms each, lower alkanoylamino with up to 7 carbon atoms in the lower alkyl part, lower alkoxycarbonylamino with up to 7 carbon atoms in the never deralkylpart, Niederallcanoylaminoniederalkyl with up to 4 C-atoms in the lower alkyl parts, Niederalkoxycarbonylamino-lower alkyl with up to 4 C-atoms in the lower alkyl parts, lower alkylamino with up to 7 C-atoms in the lower alkyl part, di-lower alkylamino with up to 7 C-atoms in the lower alkyl parts , Pyrrolidino, Piperidino, 4-IIydroxypiperidino, Marpholino, Thiomorpholino 409834/1130 or 2,6-Dimethy! thiomorpholine or optionally substituted carbamoyl, R _? Means Niederalky1 having up to 4 carbon atoms, benzyl, Carbamoylmetliyl, Niederalkylaminocarbbnylmethyl with up to 7 C atoms in the lower alkyl, Diniederalkylamiriocarbonylmethyl each with up to 7 C atoms in the Niederalkylteilen, Pyrrolidinocarbony methyl, piperidinocarbonylmethyl, Piperazinocarbonylmethyl, N ^1! - Methylpiperazinocarbonylmethyl, N ¹ - (β-hydroxynthyl) -piperazinocarboitylmethyl, morpholinocarbonylmethyl, thiomorpholinocarbonylmethyl, 2,6-dimethylthiomorpholinocarbonyimethyl or cyanomethyl. IO9. Pyridines of the formula L. do Viorin R ₁ and η have the above meanings, R means chlorine, xa pd Bromine, cyano, nitro, hydroxy, lower alkyl with up to 4 carbon atoms, Lower alkenyl with 3 or 4 carbon atoms, phenyl, chlorophenyl, broinphenyl, Trifluoromethylphenyl, Niederalky! Phenyl with up to 4 carbon atoms in the lower alkyl part, Niederalkoxyphenyl with up to to 4 carbon atoms in the lower alkyl part, hydroxy lower alkyl with up to 4 carbon atoms, lower alkoxy with up to 4 carbon atoms, lower 409834/1130 alkoxyalkoxyyl with up to 4 atoms iivi tIicGeralk $ * l ^v in <3 or 4 carbon atoms in the lower alkyl part, lower alkoxy lower alkyl with up to 4 carbon atoms each in each of the lower alkyl parts, lower alkoxy lower alkoxy with up to 4 carbon atoms each in the Lower alkyl parts, lower alkenyloxy with 3 or 4 carbon atoms, lower alkylthio with up to 4 carbon atoms, lower alkanoylamino with up to 4 carbon atoms in the lower alkyl part, lower alkoxycarbonylamino with up to 4 carbon atoms in the lower alkyl part, lower alkanoylamino lower alkyl with up to 4 carbon atoms each Atoms in the lower alkyl parts, lower alkoxycarbonylamino lower alkyl with up to 4 carbon atoms each in the lower alkyl parts, lower alkylamino with up to 4 carbon atoms in the lower alkyl part, di-lower alkylamino with up to 4 carbon atoms each in the lower alkyl part. len, pyrrolidino, piperidino, 4-hydroxypiperidino, morpholino, thiomorpholino or 2,6-dimethylthiomorpholino, carbamoyl, lower alkylaminocarbonyl with 1-4 carbon atoms in the lower alkyl part, di-lower alkylaminocarbonyl with 1-4 carbon atoms each in the lower alkyl parts, lower alkyleneaminocarbonyl with 5 carbon atoms Atoms in the alkyleneamino chain, oxa-, thia- or aza-lower alkyleneaminocrbonyl each with 4 carbon atoms in the rings or carbamo'yln leather alkyl with up to 4 carbon atoms in the lower alkyl part, R _2c means lower alkyl with up to 4 carbon atoms , Benzyl, Carbamoy! Methyl or Cyar.omethyl. HO. Pyridines of formula I ,, dd "· ⁽ Vna 409834/113 0 ORlGiNAL INSPECTED «ST 24Q6930 , R- ,, and η
methyl wherein R, R- ,, and η have the above meanings, R is 1 pO & CCi 111. pyridines of the formula I, e ^(l de ^} 'la and their corresponding pyridine-N-oxides and their condensation products with aldehydes, where η is 1,2 or 5, R _{1 is} hydrogen or methyl, R _? Lower alkyl with up to 4 carbon atoms or phenyl lower alkyl with up to 5 carbon atoms in the lower alkyl part, R -, - halogen, nitro, cyano, lower alkyl .pc with up to 4 carbon atoms, lower alkoxy with up to 4 carbon atoms, optionally substituted phenyl, di- (C, 21) -lower alkylamino, (C ₁ ^) - lower alkylamino, lower alkoxy-lower alkyl with up to 4 carbon atoms in each of the Lower alkyl parts, lower alkanoylamino with up to 5 carbon atoms in the lower alkanoyl part, lower alkenyl oxy with up to 4 carbon atoms in the lower alkyl part. Lower alkanoylamino-lower alkyl with up to 5 carbon atoms in the _{lower alkanoyl part and up to 4 carbon atoms in the lower alkyl part, hydroxy, hydroxy-lower alkyl with up to 4 carbon atoms in the lower alkyl part, (C 1} ν) r-lower alkoxycarbonylamino-lower alkyl with up to 4 carbon atoms in the lower alkyl part, amino-lower alkyl with up to 4 carbon atoms in the lower alkyl part, lower alkylaminocarbonyl with up to A09834 / -1130 to 6 carbon atoms in the lower alkyl part, lower alkylenaminocarbonyl with up to 5 carbon atoms in the lower alkyl chain or arainocarbonyl lower alkyl with up to 4 C-Atoms.rr in the lower alkyl part and condensation products with aldehydes, preferably condensation products with optionally substituted benzaldehyde and in particular η is 1, 2 or 3, R is hydrogen ei JL 3. or methyl, R _{0 is} methyl or 2-phenylethyl, R- is chlorine, nitro, methyl, ethyl, n-propyl, η-butyl, cyano, methoxy, ethoxy, allyloxy, phenyl, methylamino, dimethylamino, 2-aminoethyl, aminomethyl , 2-methoxyethyl, hydroxy, hydroxymethyl, ethylamino, acetylamino, acetylaminomethyl, 2-methoxycarbonylaminoethyl, methoxycarbonylaminomethyl, 2-ethoxyearbonylaminoethyl, n-butyloxycarbonylaminomethyl, 2- [n-butyloxycarbonylaminomethyl, 2- [n-butyloxycarbonylaminomethyl, n-butyloxyarbonylamino] -butylaminyl , or Aminöcarbonylmethyl and condensation products with benzaldehyde and especially the compounds mentioned in the examples. 112. Pyridines according to claims 106-IU, wherein the 5-amino-2-hydroxy-propoxy radical positions 2, 3 or 4 of the pyridine ring occupied, but preferably position 3 or very particularly takes place 2. 113. Pyridines according to claims 106-111, wherein in all above groups, the substituents R, for η equal to 2 or 3 can be identical or different from one another. 40983A / 1130 Il4. Pyridines according to claims ic.o-ill, v; orln in all understandings Groups of one of the subsliuents R ,, R ^,, R_, respectively. R is preferably in the ortho position or especially in the ready Position to the 3-amino-2-hydroxy-propoxy radical. 115. The compounds mentioned in Examples 1-30 and 7 ^. 116. The compounds mentioned in Examples 31-73 and 75-90. 117. The in one of claims 89, 91, 95, 96, 98, 102, 103, 105, 108, 110 and 112-115 named compounds in the form their clockwise optical antipodes. 118. The in one of claims 89, 91, 95, 96, 98, 102, 105, 105, IO8, 110 and 112-115 named compounds in the form • their axially rotating optical antipodes. 119. One of the claims 89, 91, 95, 96, 98, 102, 103, 105, 108, 110 and 112, II5 and II7-II8 compounds mentioned in free form. 120. One of the in one of claims 89, 91, 95, 96, 98, 102, 103, 105, 108, 110 and 112-115 and 117-118 in the form of their salts. ± 2.1. One of the in one of claims 89, 91, 95, 96, 98, 102, 103, 105, 108, 110 and 112-115 and II7-II8 mentioned 409834/1130 bonds in the form of their therapeutically useful salts. 122. Pharmaceutical "preparations containing one of the in one of claims 89, 91, 95, 96, 98, 102-103, 105, 108, 110 and 112-115, 117, II8 and 121 mentioned compounds together with a therapeutically usable carrier material. 123. The one in any one of claims 84-88, 90, 92-94, 97, 99-101. 104, 106, 107, 109, 111 and 116 in the form of their right-handed optical antipodes. 124. The in one of claims 84-88, 90, 92-94, 97, 99-101, 104, 106, 107, 109, 111 and 116 in the form of their left-handed optical antipodes. f 1 125. One of the claims 84-88, 90, 92-94, 97, 99-101, 104, 106, 107, 109, 111, 116, 124 and 125 in free form. 126. One of those mentioned in any one of claims 84-88, 90, 92-94, 97i 99-101, 104, 106, 107, 109, 111, 116, 124 and 125 Compounds in the form of their salts. 127. One of the claims 84-88, 90, 92-94, 97, 99-101, 104, 106, 107, 109 .. Hl, 116, 124 and 125 mentioned Compounds in the form of their therapeutically useful salts. 409834/1130 128. Pharmaceutical preparations anti'ialt-end one of the In one of claims 84-88, 90 / 92-94, 97, 99-101, 104, 106, 107, 109, 111, 116, 124, 125 and 127 compounds together with a therapeutically usable carrier material. 409834/1130