DD263761A5 - PROCESS FOR PREPARING PYRIDINE DERIVATIVES - Google Patents

Abstract

The invention relates to processes for the preparation of novel pyridine derivatives which can be used as active pharmaceutical ingredients. The invention provides processes for the preparation of novel compounds which have valuable pharmacological properties. The object of the invention is the provision of pharmacologically valuable compounds. According to the invention, the object is achieved by preparing pyridine derivatives of the formula (I) in which the substituents have the meaning given in the description, for example by reacting a compound of the formula (IIa) or a tautomer thereof with a compound of the formula (II b), wherein the substituents have the meaning given in the description, or reacts tautomers, salt and / or acetals thereof. Formulas (I), (II a), (II b)

Description

Field of application of the invention

The invention relates to processes for the preparation of novel pyridine derivatives which possess valuable pharmacological properties and can thus be used as medicaments, such as nootropics, antidepressants and antiparkinson agents.

Characteristic of the known technical solutions

Known technical solutions for the preparation of these new compounds are not yet available.

Object of the invention

The invention provides processes for the preparation of novel compounds which have valuable pharmacological properties.

Explanation of the essence of the invention

The object of the invention is to produce new pharmacologically valuable compounds which can be used as medicaments, such as nootropics, antidepressants and antiparkinson agents. According to the invention the object is achieved in that pyridine derivatives of the formula

5> n

I R,

(I)

their tautomers and their salts are prepared, wherein R, is hydrogen or C | -C ₇ alkyl, one of R ₂ and R ₃ is hydrogen, C ₁ -C ₇ -alkyl, aryl-C, -C ₇ alkyl, Cr-Ce-alkenyl, or Cj-Ce-alkynyl and the other is C | -C ₇ alkyl, aryl-C, -C ₇ alkyl, Ci-Ce ·-alkenyl or C3-C means ₆ alkynyl, R ₄ is hydrogen , C, -C alkyl means ₇ alkyl or aryl-Ci-C ^ and R ₅ is Ci-C ₇ alkyl, halogen, Ct-C ₇ -alkoxy, C ~ C ₇ -alkylthio, _{C) -C7} -Alkansulfinyl , ^ -Cf-alkanesulfonyl, carboxy, Ca-Ce-alkoxycarbonyl, carbamoyl, Ci-w-alkylcarbamoyl, di-Ci ^ -alkylcarbamoyl, cyano or trifluoromethyl, and the index η is 0,1 or 2, containing pharmaceutical preparations a compound of formula I, a tautomer or a salt thereof, and their preparation.

Aryl is primarily carbocyclic aryl, especially phenyl or naphthyl, which is unsubstituted or, e.g. B, by halogen, Ci-C ₇ -alkyl, C ₁ -C ₇ -alkoxy, hydroxy and / or Cj-Ce-alkanoyloxy, may be mono- or polysubstituted, such as two or three times. Naphthyl is, for example, 1- or 2-naphthyl. Preferred aryl-C 1 -C ₄ -alkyl is, for example, phenyl-C 1 -C ₄ -alkyl, in particular benzyl or 2-phenylethyl.

The compounds of formula I and their salts can be in dynamic equilibrium with corresponding tautomeric forms. The 2-oxo-dihydro-pyridines of the formula I can, for. Example, if R _{4 is} hydrogen or if R ₃ and R _{4 are} each hydrogen, as 2-hydroxy-pyridines of the formula

HO

(La)

1 "-NH-C = NR ₂

HO

(Ib)

available. Similarly, when R _{3 is} hydrogen, the compounds of formula I may be in equilibrium with tautomers of the formula

• , - NH-C = NR ₂

(Ic)

stand.

Above and below, the term tautomers of the formula I, as well as corresponding compounds of the formulas la, I b and Ic.

If the index η 2, R _{5 may have the} same or further different meanings. If η is different from O, R 5 is preferably C 1 -C 6 -alkyl, halogen and trifluoromethyl.

Compounds of the formula I can be present as, in particular pharmaceutically acceptable, acid addition salts. These are, for example, with strong inorganic acids such as mineral acids, eg. As sulfuric acid, phosphoric acid or hydrohalic acids, with strong organic carboxylic acids, such as Ci-C ₄ -alkanecarboxylic acids, eg. As acetic acid, such as optionally unsaturated dicarboxylic acids, eg. As oxalic, malonic, maleic or fumaric acid, or as hydroxycarboxylic acids, eg. B.

Tartaric acid or citric acid, or with sulfonic acids, such as C 1 -C ₄ -alkanoic or optionally substituted benzenesulfonic acid,

z. As methane or p-toluenesulfonic acid formed.

Corresponding acid addition salts can be formed with one or both basic centers, correspondingly e.g. B. pyridinium and / or amidinium salts are present.

Also included are unsuitable for pharmaceutical uses salts, since these can be used for example for the isolation or purification of free inventive compounds or their pharmaceutically acceptable salts.

Unless defined otherwise, the general definitions used above and below have the following meanings in the first place.

C, -C ₇ alkyl is z. As methyl, ethyl, propyl, isopropyl, η-butyl, isobutyl, sec-eutyl, tert-butyl and further includes corresponding pentyl, hexyl and heptyl. Bevc is added Ci-C ₄ -alkyl.

Halogen is in particular halogen with atomic numbers up to and including 35, such as fluorine, chlorine and bromine, and iodine.

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Ci-Cy-alkoxy is ζ. For example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutyloxy and tert-butyloxy. Preference is given to C ₁ -C ₄ -alkoxy.

C, -C ₇ -alkylthio is z. For example, methyl, ethyl, propyl, isoprop / I, η-butyl, sec-butyl and tert-butylthio and further includes corresponding pentyl, hexyl and Heptylthioreste. Preference is given to C 1 -C ₄ -alkylthio.

C 1 -C ₇ -alkanesulfinyl or -sulfonyl is in particular C 1 -C ₄ -alkanesulfinyl or -sulfonyl, such as methane, ethane, propane, isopropane, n-butane, sec-butane and tert-butyl Butanesulfinyl or sulfonyl.

In C; rC ₆ alkenyl or alkynyl, the multi-bond is located in higher than in the a-sign. Preference is given to C ₃ -C ₄ -alkenyl or -alkynyl, such as allyl and methallyl or propargyl.

In Cr-Cc-alkoxycarbonyl, alkoxy has the meanings given above.

Alkyl has the abovementioned meanings in C ₁ -C ₇ -alkyl or di-C ₁ -C ₆ -alkylcarbamoyl.

Cr-Ce-alkanoyl is z. As acetyl, propionyl, butyryl, isobutyryl or pivaloyl. Preferably, C 1 -C 5 alkanoyl.

The compounds of the formula I or corresponding tautomeric forms thereof and their pharmaceutically usable acid addition salts have, for. B. valuable pharmacological properties. Thus, a novel activity profile could be determined for the class of compounds according to the invention. The compounds of formula I or corresponding tautomeric forms thereof and their pharmaceutically acceptable salts prove to be catecholamine O-methyltransferase (COMT) inhibitors. These intrinsic shadows can be detected in three in vivo test systems, with COMT inhibition in vivo by the observed reduction of homovanillic acid in the rat C. striatum or by inhibition of 3-methoxytyramine accumulation after monoamine oxidase inhibition in C. striatum each rat from a dose of 0.1 mg / kg after

i. p. Application be verified. It can also be observed in the context of a single cell lead in the anesthetized rat from about 3 mg / kg, an increase in the firing of locus coeruleus cells.

experiment descriptions Determination of homovanillic acid (HVA) in c. striatum of the rat

Striata are prepared from rat brain and stored frozen at -2O ⁰ C until analysis. The striata are homogenized in pairs in 2 ml of the mobile phase needed for the HPLC separation described below. This mobile phase contains 1000 ng vanillic acid per extract as an internal standard. Cell fragments are removed by centrifugation. 50 to 200 μΙ of the supernatant are in a BAS liquid chromatography system (Bioanalytical Systems, W. Lafayette, Ind., USA) is injected, which _ie with a C -MBondapak phase inversion Jule (Waters Ass., Milford, USA), electrochemical with a TL3 Dektektorzelle and an LC4 control system. The detector cell contains cp _w graphite paste and the potential is set to +0.85 V against an Ag / Ag Cl reference electrode. The mobile phase containing 0.1 mol / l citric acid, 0.075 mol / l disodium hydrogen phosphate, 2.5% tetrahydrofuran and 0.05 mol / l sodium octyl sulfate is adjusted to pH = 3 with hydrochloric acid. The column temperature is brought to 28 ° C to 4O ⁰ C and the flow rate to 1 to 1.3 ml / min, uri to achieve optimal separation. Five animals are used per group.

Determination of 3-methoxy-3-methyne depletion after MAO inhibition by Clorgyline Rats administered the test substance 5 minutes prior to injection of 10 mg / kg of Clorgyline (sc) perorally or intraperitoneally are irradiated 30 minutes later with microwave dOkW power, duration 1.7 to 1.8 seconds, Puesv-Hner microwave energy technology, Schwanewede / Bremen, Federal Republic of Germany) killed. After cooling the animals, the striata are dissected out and in a mixture of 2ml 0.1 mol / l citric acid, 0.075 mol / l disodium hydrogen phosphate, 2.5% tetrahydrofuran and 0.05 mmol / l sodium octyl sulfate, with hydrochloric acid to pH = 3 is adjusted and added as an internal standard 10OOng vanillin, homogenized. Zeüfragmente be separated by centrifugation. 50 to 200 μΙ of the supernatant are injected into a BAS Liquid Chromatography System (Bioanalytical Systems, W. Lafayotte, Ind., USA) equipped with a C ₁₈ -pBondapak phase reversal column (Waters Ass., Milford, USA) and a 5100-A Coulometer Detector, Model ESA, with a Detector Cell, Model 5010 (ESA Inc., Bedford, Mass., USA); Potential of detector 2: +0.45 V, detector 1 off). The mobile phase consists of a citrate-phosphate buffer (prepared by mixing 0.1 M citric acid and 0.1 M disodium hydrogen phosphate at pH = 3) to which 10% ethanol and 1.55 mM / l sodium octyl sulfate are added; the pumping speed is 1.3ml / min.

As a result of the COMT inhibition, the metabolic degradation of the i.i catecholamines formed by neurons and subsequently released by nerve stimuli, e.g. As dopamine, inhibited, and there is an increase in concentration of these amines in the synaptic cleft. Thus, for example, the cause of depressive symptoms and Parkinson's disease, z. As the dopamine deficiency, largely eliminated. When using the compounds according to the invention is carried out simultaneously with the COMT inhibition in the neurons an enrichment of the required for the methylation S-adenosyl-methionine. Conventionally, an increase in S-adenosyl-methionine concentration causes an increase in learning ability.

Accordingly, the compounds of formula I or corresponding tautomers thereof and their pharmaceutically acceptable salts z. As pharmaceuticals, such as al .; Nootropics, antidepressants and antiparkinson agents. Another object of the invention is the use of erfindu lysgemäßen compounds for the preparation of medicaments, especially nootropics, antidepressants and anti-Parkinson agents, and for therapeutic and prophylactic treatment. In this case, the commercial preparation of the active substances may be included. More particularly, the invention relates to compounds animal formula I, their tautomers and their salts, wherein R, is hydrogen or C | -C ₇ alkyl, one of R ₂ u'id R ₃ is hydrogen, C ₁ -C ₇ -alkyl or aryl -C, C ₇ alkyl and the other is C ₁ -C ₇ -A ^ yI or aryl-dC ₇ alkyl group and R., is hydrogen or C ₁ -C ₇ -AIkV-I, R ₅ C _t - C ₇ alkyl and the index η is 0 or 1. The invention especially relates to compounds of the formula I, their tautomers and their salts, wherein R ₁ is hydrogen or Ct-C ₇ alkyl, one of R ₂ and R ₃ is hydrogen, C, -C ₇ -Alky> or aryl-d -Cralkyl and the other C ₁ -C ₇ -AlkVl or aryl - ^ - C ^ alkyl and R _{4 is} hydrogen and the index is η (is.

The invention relates in particular to compounds of the formula I, their tautomers and their salts, in which one of the radicals R ₂ and R _{3 is} hydrogen, C 1 -C ₇ -alkyl, phenyl or naphthyl-C 1 -C ₇ -alkyl and the other C , -C ₇ alkyl, phenyl or naphthyl-C ^ alkyl, wherein each phenyl or naphthyl unsubstituted or mono- or polysubstituted by halogen, C] -C ₇ alkyl, C ₁ -C ₇ -alkoxy, hydroxy and / or C ₂ -C ₈ alkanoyloxy is substituted.

-6- 253 761

The invention relates in particular to compounds of the formula I, their tautomers and their salts, in which R, hydrogen or C 1 -C ₄ -alkyl, such as methyl, R ₂ and R _3, on the one hand, independently of one another are C 1 -C ₄ -alkyl, such as Propyl, mean or on the other hand R ₂ C | -C ₄ alkyl, such as methyl, and R _{3 is} phenyl-C | -C ₄ alkyl, such as 2-phenylethyl, and R _{4 is} hydrogen and the index η

The invention relates especially to compounds of ^c Ormel I, their tautomers and their salts, wherein R ₁ is hydrogen or C ₁ -C ₄ alkyl, such as methyl, R ₂ and R ₃ on the one hand independently of one another C | -C ₄ alkyl R _{2 is} C ₁ -C ₄ -alkyl, such as methyl, and R _{3 is} phenylC, C ₄ -alkyl, such as 2-phenylethyl, R _{4 is} C 1 -C ₄ -alkyl , such as methyl, and the index is η oist.

The invention relates in particular to compounds of the formula I, their tautomers and their salts, in which R ₁ and R _{4 are} hydrogen and R ₂ and R ₃ are each independently of the other C ₁ -C ₄ -alkyl, such as propyl, and the index η is 0 ,

The invention relates, in particular, to compounds of the formula I, their tautomers and their salts, in which R, is hydrogen, R _{4 is} C ₁ -C -alkyl, such as methyl, and R ₂ and R ₃ are each independently C ₁ -C ₄ -alkyl , such as propyl, and the index η 0

The egg mainly relates to compounds of formula I, their tautomers and their salts, wherein R _{1 is} methyl, R _{4 is} hydrogen and R ₂ and R _{3 are} independently C ₁ -C ₄ -A ^ yI, such as propyl, and dor index η is 0.

The invention relates in particular to the novel compounds mentioned in the examples and to processes for their preparation.

Likewise provided by the invention are processes for preparing the compounds of the invention. The preparation of compounds of formula I, their tautomers and their salts is carried out in a conventional manner and is z. B. characterized in that one

a) a compound of the formula

•> ^ks) n / Κ

-NH-Xi ( ^{| la} )

or a tautomer thereof with a compound of the formula R ₂

X? .-\ (Mb)

R ₃ '

wherein one of the radicals Χ _Ί and X ₂ for a group of the forms! -CO-Ri and the other hydrogen or a group of the formula -CO-Zi and Z _{1 is} a cleavable radical, or reacts tautomers, salts and / or acetals thereof or b) in a compound of the formula

· NCX (HD

⁰ ^ t

a in -N

or a tautomer and / or salt thereof, wherein X _{3 is} a radical convertible into -N , X ₃ in -N ^

R ₃ T1 ₃

convicted or.

c) for the preparation of compounds of the formula I, a tautomer and salt thereof, in which R _{4 is} hydrogen, in a compound of the formula

CRs) V ⁿ

C SJU

(IV)

xi V "" Λ. ₃

or a salt thereof, wherein X _{4 is} protected hydroxy, the hydroxy protecting group splits off or d) a compound of the formula

he

or a tautomer or salt thereof with a compound of the formula

X? - Nf (Vb)

R ₃

a tautomer or a salt thereof, wherein X _{6 is} the group -N = CRi-NH-X ₅ and X _{7 is} hydrogen or X _{6 is} -NH ₂ and X _{7 is} the group -CRi = NX ₆ and X ₅ is a leaving group, reacted and, if desired, a method according to or otherwise available compound converted into another compound of formula I or a tautomer thereof, a mixture of isomers according to the invention is separated into the components, a process according to available free compound of formula I or Tautomeres thereof converted into a salt and / or a salt obtainable according to the method in the free compound of formula I or a tautomer thereof or in a

transferred another salt. "

The reactions described above and below in the variants are carried out in a manner known per se, for. B.

in the customary manner in the presence of a suitable solvent or diluent or a mixture thereof, wherein, as required, with cooling, at room temperature or with heating, for. B. in a temperature range of about -8O ⁰ C to the boiling temperature of the reaction medium, preferably from about -10 ⁰ C to about + 100 ⁰ C, and, if necessary in a closed vessel, under pressure, in an inert gas atmosphere and / or under anhydrous conditions works.

The above and below listed starting material of the formulas Il a and Il b. III, IV and Va and V b, which was developed for the preparation of the compounds of formula I, their tautomers and their salts, is known in part or can also by known methods, for. B. analogously to the process variants described above, are produced.

Salts of the starting materials of the formulas IIa, IIb, III, IV, Va and Vb are primarily corresponding acid addition salts, since these starting compounds have at least one basic center.

Suitable acids for salt formation are, for example, strong inorganic acids, such as mineral acids, eg. As sulfuric acid, phosphoric acid or hydrohalic acids, strong organic carboxylic acids such as Ci-C ^ Alkancarbonsäuren, z. As glacial acetic acid, such as optionally unsaturated dicarboxylic acids, eg. Oxalic, malonic, maleic or fumaric acid, or hydroxycarboxylic acids,

z. As tartaric acid or citric acid, or sulfonic acids, such as Ci-C-alkane or optionally substituted benzenesulfonic acid,

z. For example, methane or p-toluenesulfonic acid.

The 2-oxo-dihydro-pyridine derivatives of the formulas IIa, III and Va can, for. b. also in the form of corresponding tautomeric 2-hydroxypyridines.

Acetals of compounds of the formulas Ua and Il b in which one of the radicals Xi and X _{2 is} the group of the formula -CO-Ri and the other is hydrogen, are those compounds in which the carbonyl function with a mono- or dihydric aliphatic alcohol, such as C 1 -C ₇ -alkanol or C ₂ -C ₆ -alkanediol, acetalated or ketalized.

Option A):

A cleavable Zi radical means, for example, reactive esterified hydroxy or optionally etherified hydroxy or mercapto. Reactive esterified hydroxy is especially hydroxy esterified with a strong inorganic acid or organic sulfonic acid, for example halogen, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, e.g. For example, fluorosulfonyloxy, optionally, z. B. substituted by halogen, substituted Ci-C ₇ -Alkansulfonyloxy, z. B.

Methane or Trifluormethansulfonyloxy, CV-C ^ cycloalkanesulfonyloxy, z. B. Cyclohexansulfonyioxy, or optionally, for. B.

by C 1 -C ₇ -alkyl or halogen, substituted benzenesulfonyloxy, e.g. For example, p-bromophenyl or p-toluenesulfonyloxy. Etherified hydroxy is z. B. optionally, for. As by phenyl, substituted Ci-C ₇ -AIkOXy, such as methoxy, ethoxy or benzyloxy, while as vgrethertes mercapto ζ. B. C, -C ₇ alkylthio, such as methyl or ethylthio, is suitable. Z | is preferably halogen, such as chlorine, or C 1 -C ₄ -alkoxy, such as methoxy or ethoxy.

The reaction of compounds of the formulas Ha and Mb in which one of the radicals Xi and X _{2 is} a group of the formula -CO-Ri and the other is hydrogen is especially in the presence of a condensing agent such as a dehydrating agent or an anhydride of an inorganic acid , carried out.

As a dehydrating agent, in particular carbodiimides, z. BNN'-di-Ci-Ci-alkyl or N, N'-di-Cs-C ₇ -cycloalkylcarbodiimid, such as N, N'-dicyclohexyl-carbodiimide, advantageously with the addition of N-hydroxysuccinimide or optionally, for. B.

by Hilogen, Ci-C ₇ -alkyl or Ci-C ₇ -alkoxy, substituted N-hydroxy-benzotriazole or N-hydroxy-b-norbornene-2,3-dicarboxamide, furthermore suitable carbonyl compounds, eg. B. Ν, Ν-carbonyldiimidazole, suitable 1,2-oxazolium compounds,

z. For example, 2-ethyl-5-phenyl-1,2-oxazolium-3'-sulfonate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, suitable acylamino compounds, eg. B. 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or suitable Phosphorylcyanainide or azides, eg Diethylphosphorylcyanamid or Diphenylphosphorylazid, further triphenylphosphine disulfide or 1 -C _; C4-alkyl-2-halo-pyridinium halides, for example 1-methyl-2-chloro-pyridinium-iodide, can be used.

Examples of anhydrides of inorganic acids are phosphorus pentoxide, phosphorus oxyhalides, such as phosphorus oxychloride, phosgene or thionyl chloride.

Preference is given to using those compounds of the formulas IIa and IIb in which one of the radicals X and X _{2 is} an acetalated or ketalized group of the formula -CO-Ri and the other is hydrogen.

In the reaction of compounds of the formula IIa and IIb in which one of the radicals Xi and X _{2 is} a group of the formula -CO-Ri and the other is a group of the formula -CO-Zi and Zi is a cleavable radical, are preferred

Used starting materials, wherein Zi means halogen, such as chlorine. The reaction is carried out in particular with heating, for. B. in a temperature range of 5O ⁰ C to the boiling temperature of the reaction medium performed. The starting material of the formulas IIa and IIb is in part known and can be prepared in a manner known per se, for example by N-acylation of amines of the formulas

! '.L _NHz (IIIa) or HN ^ (Mc).

Vartf t'b):

R ₂

An in -NT convertible radical X ₃ means, for example, amino.

Corresponding compounds of formula III may, for example, be alkylated with an alkylating agent underlying R ₂ and R ₃ , such as an alkylating agent derived from R ₂ -OH and R ₃ -OH or a reactive esterified derivative thereof or an appropriate carbonyl compound. Such Alkylierungsreagentien are, for example, corresponding halides, sulfates or sulfonates, for. B. the formula R ₂ -Z ₂ and Rr-Z ₂ , wherein Z ₂ z. B. halogen or sulphonyloxy, such as C ₁ -C ₇ alkane or optionally substituted benzenesulfonyloxy, z. For example, methane or p-toluenesulfonyloxy, means. The alkylation of corresponding compounds of the formula III is carried out in particular in the equivalent of a base. Suitable bases are, for example, alkali metal hydroxides, -hyrides, -amides, -alkanolates, -carbonates, -triphenylmethylidene, -Oi-C ₁ -C ₇ -alkylamides, -amino-C ₁ -C ₇ -alkylamides or -C-Crulkylsilylamides, naphthalenamine, C | -C ₇ alkylamines, basic heterocycles, ammonium hydroxides and carbocyclic amines. Examples which may be mentioned are lithium hydroxide, sodium hydroxide, hydride, amide, ethylate, potassium tert-butoxide, carbonate, lithium triphenylmethylidene, diisopropylamide, potassium 3- (aminopropyl) amide, bis- (trimethylsilyl) amide, dimethylaminonaphthalene, Di- or triethylamine, pyridine, benzyltrimethylammonium hydroxide, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) called. Are used as alkylating agent z. B. carbonyl compounds used, the reaction z. In the presence of a reducing agent, e.g. B. with formic acid and formamide analogous to the Leuckart-Wallach reaction, carried out. X _{3 of} the formula III may also be a leaving group such as reactive esterified hydroxy or optionally etherified hydroxy or mercapto. Reactive esterified hydroxy is especially hydroxy esterified with a strong inorganic acid or organic sulfonic acid, for example halogen, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, e.g. For example, fluorosulfonyloxy, optionally, z. B. by halogen, substiutiertes Ct-C ₇ -Alkansulfonyloxy, z. Methane or trifluoromethanesulfonyloxy, C ₅ -C ₇ cycloalkanesulfonyloxy, e.g. B. cyclohexanesulfonyloxy, or optionally, for. B. by Ci-C ₇ alkyl oaer halogen, substituted benzenesulfonyloxy, z. For example, p-bromophenyl or p-toluenesulfonyloxy. Etherified hydroxy is z. B. optionally, for. As by phenyl, substituted Ci-C ₇ alkoxy, such as methoxy, ethoxy or benzyloxy, while as etherified mercapto ζ. B. Ci-C ₇ alkylthio, such as methyl or ethylthio, is suitable. X ₃ is preferably halogen, such as chlorine, or C ₁ -C ₄ -alkoxy, such as methoxy or ethoxy. Corresponding compounds of the formula III, wherein X _{3 is} a leaving group, are reacted with an amine of the formula

R ₂ HN (Hc) or a salt thereof reacted.

The starting material of formula III, wherein X _{3 is} amino, is z. B. accessible by reacting a compound of formula

! "-NH-CO-Ri (IHa),

c / Y

a tautomer or salt thereof with ammonia.

To starting compounds of the formula III, wherein X _{3 is} a leaving group, it is possible, for. B., by first treating a compound of formula HIa with a halogenating reagent such as phosgene (X ₃ = halogen) and reacting the corresponding resulting compounds of formula III, for example, with a desired alcohol or mercaptan.

Variant c):

Suitable protected hydroxy X4 is, for example, esterified, etherified or acetalated hydroxy, such as acyloxy, silyloxy, optionally substituted alkoxy or tetrahydropyranyloxy. The acyl radical in acyloxy means, for example, optionally, for. B. substituted by halogen, substituted C 1 -C ₅ -alkanoyl or benzoyl, such as acetyl, monochloroacetyl or benzoyl, or optionally substituted by a phenyl radical, substituted C ₂ -C 5 -alkoxycarbonyl, such as ethoxy, tert-butyloxy, benzyloxy, 2-bromobenzyloxy or 4-methoxybenzyloxy-carbonyl. SiIyI in silyloxy is z. B. tri-C, -C ₄ alkyl-silyl, such as trimethylsilyl or tert-butyl-dimethylsilyl. Optionally substituted alkyl according to the corresponding alkoxy is, for example, optionally z. B. by a phenyl radical, substituted Ci-Ci-alkyl, such as tert-butyl, benzyl or 3-bromobenzyl.

The cleavage of the respective hydroxy protecting group takes place in a manner known per se, for example by hydrolysis, acidolysis, reduction, hydrazinolysis or treatment with thiourea.

Thus, for example, Cr-Cs-acetyl, C ₂ -Cs-AlkSnOyI-, benzoyl, ethoxycarbonyl-benzoyloxycarbonyl, Totrahydropyranyl- or silyl radicals by hydrolysis, especially in the presence of an acid or primarily a base, cleaved while

z. B. 2-bromobenzyloxycarbonyl, benzyloxycarbonyl, benzyl, 3-Brcmbenzyl- or tert-butyl radicals by acidolysis, for. B. by treatment with a strong acid such as hydrochloric acid, hydrobromic acid / glacial acetic acid.

Hydrofluoric acid or Trifluoressigsäuie be split off. From benzyloxy hydroxy can also be obtained by reduction, for. Example, by catalytic hydrogenation, advantageously in the presence of a hydrogenation catalyst, or by treatment with sodium in liquid ammonia, are released.

The compounds of formula IV are obtainable, for example, by reaction of compounds of the formula

V ·

X ₁ ,

, -CO-N ^

^S R3

or a salt thereof with a compound of the formula Ri-CO-N ^ (IVb) or an acetal or ketal thereof, wherein analogous

the process variant a) is proceeded.

Varianted):

The leaving group X ₅ is preferably cyano.

The starting material of the formula Vb, wherein X _{7 is} the group -CRi = NX ₅ and X _{5 is} cyano, may, for. B. can be obtained by reacting a compound of formula

ß-z Htf (lic) or a salt thereof with a compound of the formula NC-N = CZ 2 (Vc), wherein Z _{2 is} a leaving group, for. B.

\ ₃ Ri

C | -C ₄ -alkoxy, reacts.

For the preparation of compounds of the formula Va in which X _{e is} -N = CR 1 -NH-X ₅ and X _{5 is} cyano, the starting point is, for example, a compound of the formula III a and the reaction is carried out with a compound of the formula X ₅ N = CR, -NH ₂ (Vd), optionally with heating.

The invention also relates to the novel compounds obtainable by the above process variants.

A compound of the formula I which is obtainable according to the invention or in another way, a tautomer or salt thereof, can be converted in a manner known per se into another compound of the formula I or a tautomeric form thereof.

If one of the radicals R ₂ and R _{3 is} hydrogen, corresponding compounds of the formula I, their tautomers or salts can be N-alkylated in a manner known per se; likewise carbamoyl R _{5 can be} N-alkylated. The (aryl) C ₎ -C ₇ alkylation takes place for. B. with a reactive ester of an (aryl) C | -C ₇ alkyl halide, z. B. bromide or iodide, (aryl) Ci-C ₇ alkyl sulfonate,

z. For example, methanesulfonate or p-toluenesulfonate, or a di-C, -C ₇ alkyl sulfate, z. Example, dimethyl sulfate, preferably under basic conditions, such as in the presence of sodium hydroxide or potassium hydroxide solution, and advantageously a phase transfer catalyst such as tetrabutylammonium bromide or benzyltrimethylammonium chloride, while more basic condensation agents, such as alkali metal amides, hydrides or alcoholates, eg. As sodium amide, sodium hydride or sodium sthanolate, may be required.

Likewise, the compounds of the formula I, their tautomers or salts in which at least one of the radicals R ₂ and R _{3 is} different from hydrogen, can be transamidated by treatment with a corresponding amine.

Compounds of the formula I, tautomers or salts thereof, wherein R _{4 is} hydrogen, can be alkylated with the aid of a suitable alkylating agent to give those compounds of the formula I in which R _{4 is} (aryl) -C _t -C ₇ -alkyl.

Further, one can optionally esterify existing hydroxy groups, for. B. by treating with a C ₂ -C ₇ alkanecarboxylic anhydride or halide in Cz-Ce-alkanoyloxy or convert by reaction with a reactive ester, in particular bromine or hydrochloric acid ester of a dC ₇ alkanol in corresponding etherified hydroxy. Conversely, one can release solvolysis in esterified or etherified hydroxy groups, such as C ₂ -C ₈ -AIkBnOyIoXy or C ₇ alkoxy, d \ e hydroxyl group (s), preferably under acidic conditions. In an analogous manner, it is also possible to hydrolyze acylated hydroxy to hydroxy.

Thio in C, -Cy-alkylthio (Rs) can be z. B. oxidize in the usual way to corresponding sulfinyl or sulfonyl. Suitable oxidizing agents for the oxidation to the sulfoxide stage include, for example, inorganic peracids, such as peracids of mineral acids, e.g. Periodic acid or persulfuric acid, organic peracids, such as corresponding percarboxylic or persulfonic acids, eg. As perameisen-, peracetic, trifluoroperacetic, p-nitroperbenzoic, m-chloroperbenzoic or perbenzoic or p-Toluolpersulfonsäure, or mixtures of hydrogen peroxide and acids, eg. B. mixture of hydrogen peroxide with acetic acid, into consideration. Frequently, the oxidation is carried out in the presence of suitable catalysts, suitable acids as catalysts, such as optionally substituted carboxylic acids, for. As acetic acid or trifluoroacetic acid, or transition metal oxides, such as oxides of elements of the V. or Vl. Subgroup, z. As vanadium, molybdenum or tungsten oxide, are mentioned. The oxidation is advantageously carried out under mild conditions. The oxidation to the sulfone can also be carried out with dinitrogen tetroxide as a catalyst in the presence of oxygen at low temperatures, as well as the direct oxidation of thio to sulfonyl. However, this usually involves the use of the oxidizing agent in excess.

A cyano group (R ₅ ) may, for. B. hydrolytically, preferably under acidic or basic conditions, for. In the presence of an alkali metal hydroxides and, if desired, in the presence of hydrogen peroxide in an aqueous-alcoholic solvent, are converted to the carbamoyl group.

Likewise, the substituent cyano may be prepared, for example, by treatment with a C ₁ -C ₇ alkanol, e.g. 8. in the presence of an acid such as hydrochloric acid, in Cz-Ce-alkoxycarbonyl (R ₅ ) are converted.

In compounds of the formula (I) which have as substituents an esterified or amidated carboxy group (RO), a solcho group can be obtained, for example, by hydrolysis, for example in the presence of an oinosbasic agent, or an acidic agent, such as a mineral acid convert to nine free carboxy group.

Forner can be in compounds of formula (I), which have as substituents a carboxy group (Rj), these z. By treating with an alcohol such as a lower alkanol in the presence of a suitable esterifying agent such as an acidic reagent, e.g. As an inorganic or organic acid or a Lewis acid, 2.6. Zinc chloride, or a water-binding condensing agent, e.g. A carbodiimide, such as N, N'-dicyclohexylcarbodiimide, or by treatment with a diazo reagent, such as a diazo-lower alkane, e.g. As diazomethane, in an esterified carboxy group (R ₅ ) convert. This can also be obtained by reacting compounds of the formula I in which the carboxy group (R ₅ ) in free form or in salt, such as ammonium or metal, z. Alkali metal, such as sodium or potassium salt form, with a reactive ester of a C ₎ -C ₇ alkyl halide, e.g. Methyl or ethyl chloride, bromide or iodide, or an organic sulfonic acid ester such as a corresponding C 1 -C ₇ alkyl ester, e.g. For example, methanesulfonic acid or p-Toluolsulfonsäuremethylester or ethyl ester. Compounds of the formula (I) which have as substituents an esterified carboxy group (R ₆ ) can be obtained by transesterification, for. Example, by treatment with an alcohol, usually a higher than that of the esterified carboxy group in the starting material corresponding alcohol, in the presence of a suitable transesterifying agent, such as a basic agent, for. Example, an alkali metal C, -C ₇ -dlkanoats, -Ci-Cralkanolats or cyanide, such as sodium acetate, methoxide, ethylate, tert-butoxide or cyanide, or a suitable acidic agent, optionally with removal of the resulting alcohol , z. B. by distillation, in other ester compounds of the formula (I). It is also possible to start with corresponding, so-called activated esters of the formula (I) which have as substituents an activated esterified carboxy group (see below) and convert this to another ester by treatment with a C 1 -C ₇ -alkanol.

Compounds of the formula (I) which have as substituents an amidated carboxy group can advantageously also be obtained from the corresponding acid and ester compounds of the formula (I) which have as substituents an optionally esterified carboxy group. So you can z. B. Compounds of formula (I) having a free carboxy group with urea at elevated temperatures, with a formamide, z. Dimethylformamide, in the presence of a suitable condensing agent such as phosphorus pentoxide, at elevated temperatures, or with an amine in the presence of a suitable condensing agent such as a carbodiimide, e.g. B. Ν, Ν'-diethyl-carbodiimide, further a phosphine, such as triphenylphosphine (eg., Together with bis-2-pyridyl disulfide), or a silane, such as trichlorosilane (eg, together with pyridine) implement, and the corresponding amide compounds of the formula (I) which contain as substituents an amidated carboxy group (R ₅ ). They can also be obtained from compounds of the formula I which have as substituents a carboxy group present in salt form (R ₅ ), for. B. by adding a corresponding ammonium salt, for. B. by treatment with a dehydrating agent, such as phosphorus pentoxide, dehydrated, or a corresponding alkali metal, z. For example, sodium salt with an amine, preferably in the presence of a suitable condensing agent, such as phenylphosphonic acid, umsotzt.

In compounds of formula (I) containing as substituents the carboxyl group (R ₅ ), these may also first be converted into a reactive derivative such as an anhydride, including a mixed anhydride such as an acid halide, e.g. Chloride (e.g., by treatment with a thionyl halide, e.g., chloride), or an anhydride with a formic acid ester, e.g. C 1 -C 6 -alkyl esters (e.g., by treating a salt such as an ammonium or alkali metal salt with a halo such as chloroformate such as C 1 -C ₇ alkyl ester) or an activated ester such as a cyanomethyl -, Nitrophenyl-, z. For example, 4-nitro-phenyl, or Polyhalogenphenyl-, z. For example, pentachlorophenyl ester (eg, by treatment with a corresponding hydroxy compound in the presence of a suitable KondensationsmittRls, such as Ν, Ν'-dicyclohexyl-carbodiimide), and then reacting such a reactive derivative with an amine and so to amide compounds of the formula (I. ), which have as substituents an amidated carboxy group. This can be obtained directly or via intermediates; so you can z. For example, an activated ester, such as a 4-nitrophenyl ester, of a compound of formula I having a carboxy group, first reacted with a 1 -unsubstituted imidazole, and the resulting 1-imidazolylcarbonylic compound is reacted with the amine. However, it is also possible to use other non-activated esters, such as C 1 -C ₇ -alkyl esters of compounds of the formula (I) which are suitable as substituents, for example. B. Cj-Ca-alkoxycarbonyl (R ₅ ) have to react with amines. Contained dia compounds of formula (I) C ₃ -C ₆ -AIkCrIyI- or C ^ -Ce-alkynyl groups, these can be converted in a conventional manner into corresponding saturated radicals. Thus, for example, the hydrogenation of multiple bonds by catalytic hydrogenation in the presence of hydrogenation catalysts, wherein z. B. precious metals or their derivatives, for. 8. oxides, are suitable, such as nickel, Raney nickel, palladium, platinum oxide, optionally on support materials, for. B. on carbon or calcium carbonate, can be raised. The hydrogenation may preferably be carried out at pressures between 1 and about 100at.

Salts of compounds of the formula (I) or their tautomers can be prepared in a manner known per se. For example, acid addition salts of compounds of formula (I) or a Ta-acidomer thereof are obtained by treatment with an acid or a suitable ion exchange reagent. Salts can be converted in the usual way in the free compounds, acid addition salts ζ. Β by treatment with a suitable basic agent. Depending on the procedure or reaction conditions, the compounds according to the invention with salt-forming, in particular basic properties, can be obtained in free form or preferably in the form of salts. As a result of the close relationship between the new compound in free form and in the form of their salts, the above salts and the free compound are to be understood as meaningful and expedient if appropriate in advance and subsequently under the free compound or its salts.

The novel compounds, including their salts of salt-forming compounds, may also be obtained in the form of their hydrates or include other solvents used for crystallization.

The new compounds may, depending on the choice of starting materials and procedures, in the form of one of the possible isomers or as mixtures thereof, z. Example, depending on the number of asymmetric carbon atoms, as pure optical isomers, such as antipodes, or as mixtures of isomers, such as racemates, diastereoisomeric mixtures or racemate mixtures.

Resulting Racematgemische can be separated due to the physico-chemical differences of the components in a known manner in the pure isomers or racemates separately, for example by fractional crystallization. Obtained racemates can be further decomposed by known methods into the optical antipodes, for example by recrystallization from an optically active solvent, chromatography on chiral adsorbents, with the aid of suitable microorganisms, by cleavage with specific immobilized enzymes, on the formation of inclusion compounds, ζ. Using chiral crowns, where only one enantiomer is complexed, or by transferring to diastereomeric salts, e.g. B. by reacting a basic end racemate with an optically active acid such as carboxylic acid, ζ. As tartaric or malic acid, or sulfonic acid, eg. B. camphorsulfonic acid, and separation of the thus obtained Diastereomernngemisches, z. For example, because of their different solubility, in the Diasterer ». -oron, from which the desired enantiomer can be freedet by the action of suitable means. It is advantageous to isolate the active enantiomer. The invention also relates to those embodiments of the process according to which one proceeds from a compound obtainable as an intermediate at any stage of the process and performs the missing steps or uses a starting material in the form of a derivative or salt and / or its racemates or antipodes or in particular forms under the reaction conditions.

In the process of the present invention, preference is given to using those starting materials which lead to the compounds described particularly valuable at the outset. Novel starting materials that have been developed specifically for the preparation of the compounds of the invention, their use and processes for their preparation also form an object of the invention, wherein the variables R ₁ , R ₂ , R ₃ , R ₄ and R _{5 are} the preferred Compound groups of formula I or tautomers thereof have specified meanings. In particular, compounds of the formula III, their tautomers and salts in which X _{3 is} amino, are preferred as starting material.

The invention also relates to the use of the compounds of the formula (I) or tautomers thereof or of pharmaceutically acceptable salts of such compounds having salt-forming properties, in particular as pharmaceutical, primarily nootropic, antidepressant and antiparkinson-active, active substances. In this case, they can be used, preferably in the form of pharmaceutically acceptable preparations, in a process for the prophylactic and / or therapeutic treatment of the animal or human body, in particular as nootropics, antidepressants and agents for the treatment of Parkinson's syndrome.

The invention also relates to pharmaceutical preparations containing the compounds of the invention or pharmaceutically acceptable salts thereof as active ingredients, and to processes for their preparation.

The pharmaceutical compositions of the present invention containing the compound of the invention or pharmaceutically acceptable salts thereof are those which are enteral, such as oral, rectal, and parenteral administration to warm-blooded animals, the pharmacologically active ingredient being used alone or in combination with a pharmaceutical applicable carrier material is included. The daily dosage of the drug depends on the age and the individual condition as well as on the mode of administration.

The new pharmaceutical preparations contain e.g. from about 10% to about 80%, preferably from about 20% to about 60%, of the active ingredient. Pharmaceutical preparations according to the invention for enteral or parenteral administration are e.g. As such in dosage unit forms, such as dragees, tablets, capsules or suppositories, further ampoules. These are in a conventional manner, for. B. by conventional mixing, granulation, coating, solution or lyophilization process. So you can pharmaceutical preparations for oral use f'halten by combining the active ingredient with solid.ι carriers, a mixture obtained optionally granulated, and the mixture or granules, if desired or necessary, after addition of suitable excipients to tablets or dragee Cores processed. Suitable carriers are in particular fillers, such as sugars, for. As lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, eg. Tricalcium phosphate or calcium hydrogen phosphate, distant binders such as starch pastes, using e.g. Corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and / or polyvinylpyrrolidone, if desired, disintegrants such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate , Aids are primarily flow. Flow regulators and lubricants, eg. For example, silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragoe cores are provided with suitable, optionally gastric juice-resistant coatings, which u.a. concentrated sugar solutions, which may contain arabic gum, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the manufacture of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose or hydroxypropylmethylcellulose phthalate. The tablets or dragee coatings may contain dyes or pigments, e.g. As for the identification or labeling of different doses of active ingredients, be attached.

Other orally applicable pharmaceutical preparations are gelatine capsules, as well as soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules can be the active ingredient in the form of granules, eg. B. in admixture with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, stabilizers also being added.

As rectally applicable pharmaceutical preparations come z. As suppositories into consideration, which consist of a combination of the active ingredient with a suppository base. As suppository mass z. Natural or synthetic triglycerides, paraffinic hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules containing a combination of the active ingredient with a basic bulking agent may also be used. As basic materials come z. As liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question.

For parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, eg. As a water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions, wherein suitable lipophilic solvent or vehicle, such as fatty oils, ζ. As sesame oil, or synthetic fatty acid esters, ζ. As ethyl oleate or Trifjlyccjride used or aqueous injection suspensions, which viscosity-increasing substances, eg. As sodium carboxymethylcollulose, sorbitol and / or dextran, and optionally also contain stabilizers.

The dosage of the active ingredient depends on the species of warm-blooded animals, the age and the individual condition as well as the mode of administration. Normally, an approximately daily dose of about 150 mg to about 1500 mg, preferably in several equal divided doses, is to be estimated for a warm-blooded animal weighing about 75 kg on oral administration.

embodiments

The following examples illustrate the invention described above; however, they are not intended to limit their scope in any way. Temperatures are given in degrees centigrade.

Example 1:

8.3 g (76 mmol) of 6-amino-2-hydroxypyridine and 20 g (114 mmol) of N, N-di-n-propylformamide dimethylacetal are placed in 70 ml of xylene under argon. While stirring, it is heated to 100 ^° C. for one-half hour. Then allowed to cool, evaporated in a water-jet vacuum and the residue is filtered over ten times the amount Florisil using methylene chloride. The fractions containing the product are evaporated and then crystallized from η-hexane. N- (2-hydroxy-6-pyridyl) -N, N'-di-n-propyl-formamidine or N- (2-pyridone-6-yl) -N ', N'-di-n- propyl-formamidine, mp. 102-104 ⁰ C.

For conversion into the methanesulfonate, the free base is dissolved in methylene chloride and then treated with methanesulfonic acid until a pH of 3 is reached. Ether is then added with stirring, the product crystallizing out spontaneously. The crystals are filtered off with suction, washed well with ether and dried under high vacuum. This gives N- (2-hydroxy-6-pyridyl) -Ν ', Ν'-di-n-propylformamidine methanesulphonate

I IJ _# y

HO ⁷ VV Y '- CH ₁ SO ₃ H

•

or N- (2-pyridone-6-yl) -N ', N'-di-n-propyl-formamidine methanesulfonate

I Il · ·

/ V'vY; , CH3SO3H

from the m. 160-162'C.

Example 2:

In analogy to Example 1, N- (2-hydroxy-6-pyridyl) -N ', N'-dimethyl-formamidine or N- (2-pyridone-6-yl) -N', N'-dimethylformamidine of the m.p. 159-161 ⁰ C are produced; starting from 3.3 g (30 mM) of 6-amino-2-hydroxypyridine and 5.4 g (45 mmol) of Ν, Ν-dimethylformamide dimethyl acetal in 30 ml of xylene.

Deispiel3:

Analogously to Example 1, N- (2-hydroxy-6-pyridyl) -N'-methyl-N'-butyl-formamidine or N- (2-pyridone-6-yl) -N'-methyl-N'- butylformamidine of mp. 85-86 ⁰ C are obtained; starting from 3 g (27 ml) of 6-amino-2-hydroxypyridine and 6.6 g (41 mmol) of N-methyl-N-butyl-formamide dimethyl acetal in 30 ml of toluene.

Example 4:

Analogously to Example 1, N- (2-hydroxy-6-pyridyl) -N'-methyl-N '- (2-phenylethyl) -acetamidine dihydrochloride or N- (2-pyridone-6-yl) -N is obtained '-methyl-N' - (2-phenylethyl) -acetamidine-dili-hydrochloride, m.p. 177-179X; starting from 4 g (24 mmol) of N-1-hydroxy-e-pyridyl-O-acetimidate and 4.9 g (36 mmol) of methyl phenylethylamine in 20 ml of xylene.

The starting material can be prepared as follows:

4,4g (4OmMoI) of 6-amino-2-hydroxypyridine are dissolved in 30m! Orthoessigsäuretrimethylester heated to reflux for 12 hours. Then the reaction mixture is evaporated. The residue is combined with ether while stirring, whereby the product crystallizes out spontaneously. It is filtered off with suction and dried under high vacuum. This gives N- (2-hydroxy-6-pyridyl) -acetimidsäuremethylester, mp 128-129 ⁰ C.

Example 5:

In analogy to Example 4, N- (2-hydroxv-6-pyridyl) -N ', N'-di-n-propyl-acetamidine or N- (2-pyridone-6-yl) -N', N ' -di-n-propylacetamidine of mp. 140-141 ⁰ C are obtained; starting from 2 g (12 mmol) of N- (2-hydroxy-6-pyridyl) -acetimidic acid methyl ester and 1.8 g (18 mmol) of di-n-propylamine in 20 ml of xylene.

Examples:

To a suspension of 1.1g (22.4mMoi) NaH (50% dispersion in mineral oil) in 30ml abs. Tetrahydrofuran is added at room temperature under argon and with stirring a solution of 4.5 g (20.3 mmol) of N- (2-hydroxy-6-pyridyl) -N ', N'-di-n-propylformamidine in 15 ml abs. Dropped tetrahydrofuran. The mixture is stirred at this temperature for a further 15 minutes and then a solution of 1.4 ml (22.4 mmol) in 5 ml of tetrahydrofuran is added. This reaction mixture is stirred for 24 hours at room temperature. It is then diluted with ethyl acetate and washed once with water. The organic phase is separated, dried and evaporated. The crude product thus obtained is then purified chromatographically on silica gel.

The purified product is mixed with half an equivalent of fumaric acid in ether and crystallized by subsequent addition of petroleum ether. This gives N- (1-methyl-2-pyridone-6-yl) -N ', N'-di-n-propylformamidine hemifumarate, mp. 92-94 ⁰ C.

Example 7:

To a solution of 2.7 g (1OmMoI) N- (2-methoxy-6-pyridyl) -N ', N'-di-n-propylformamidinhydrochlorid in methylene chloride at -60 ⁰ C under stirring 1.2 g (1OmMoI) BCI _{3 added} slowly. Then it is stirred for another 30 minutes at this temperature. It is then allowed to warm to 0 ° C and after a further hour carefully mixed with 15 ml of absolute methanol. The reaction mixture is then poured into ice-water and made alkaline with 2N sodium hydroxide solution and extracted twice with methylene chloride. The oganic phases are combined, dried over Na ₂ SO ₄ , filtered through a Florisil layer and then evaporated. The crude product thus obtained is crystallized from ether / petroleum ether. This gives N- (2-hydroxy-6-pyriciyl) -N ', N'-din-propylformamidine or N- (2-pyridone-6-yl) -N', N'-di-n-propylformamidine of the Mp . 102-104 ⁰ C. The starting material N- (2-methoxy-6-pyridyl) -N ', N'-di-n-propyl-formamidine hydrochloride, mp. 148-149 ⁰ C, in analogy to example 1 getting produced; starting from 1.24 g (10 μmol) of 2-amino-6-methoxypyridine and 2.63 g (15 mmol) of Ν, Ν-di-n-propylformamide dimethylacetal in 20 ml of xylene.

Example 8:

In an analogous manner as described in one of Examples 1-7 can be prepared:

N- (1-methyl-2-pyridon-6-yl) -N ', N'-dipropyl-acetamide,

N- (1-benzyl-2-pyridon-6-yl) -N ', N'-dipropyl-formamidine,

N- (2-pyridone-6-yl) -N'-propyl-acetamidinbzw. N- (2-hydroxy-6-pyridyl) -N'-propyl-acetamidine, N- (2-pyridone-6-yl) -N'-ethyl-N'-isopropyl-fomamidine or N- (2-hydroxy 6-pyridyl) -N'-ethyl-N'-isopropylformamide, N- (2-pyridone-6-yl) -N ', N'-dipropyl-propionane. ^! dinbzw. N- (2-hydroxy-6-pyridyl) -N ', N'-dipropyl-propionamidine, N- (1-propyl-2-pyridon-6-yl) -N', N'-dipropyl-fomamidine.

Example 9:

In analogy to Example 6 can be prepared N- (1-propyl-2-pyridone-6-yl) -N ', N'-di-n-propyl-formamidine, a viscous oil with Rf = 0 / .3 (toluene / Ethanol / concentrated aqueous NH ₃ = 90: 20: 1).

It is assumed that 3 g (14 mmol) of N- (2-hydroxy-6-pyridyl) -N ', N'-di-n-propylformamidine or N- (2-pyridone-6-yl) -N', N ' -di-n-propylformamidine, 710 mg (15 mmol) of NaH as a 50% dispersion in mineral oil and 1.5 ml (15 mmol) of n-propyl iodide in 30 ml of absolute tetrahydrofuran. In contrast to Example 6 is allowed to react for 56 hours under reflux.

Example 10:

In an analogous manner as described in Example 6 kano N- (1-methyl-2-pyridone-6-yl) -N ', N'-di-n-propyl-acetamidine can be prepared. It is obtained as a viscous oil, R f = 0.28 (methylene chloride / methanol / conc. Aqueous NH ₃ = 300: 10: 1).

It is assumed that 1 g (4.4 mmol) of N- (2-hydroxy-6-pyridyl) -N ', N'-di-n-propyl-acetamidine or N- (2-pyridone-6-yl) -N' , N'-di-n-propyl-acetamidine, 230mg (4.6moles) NaH (50% dispersion) and 290μΙ (4,6moles) of methyl iodide in 10ml absolute tetrahydrofuran.

Example 11:

In analogy to Example 6, N- (1-benzyl-2-pyridon-6-yl) -N ', N'-di-n-propylformamidine as a viscous oil, R f = 0.35 (hexane / ethyl acetate = 1: 4 ), getting produced. 3 g (14 mmol) of N- (2-hydroxy-6-pyridyl) -N ', N'-di-n-propylformamidine or N- (2-pyridone-6-yl) -N', N'-di-, are obtained. n-propylformamidine, 720mg (15mMo!) NaH (50% dispersion) and 1.8ml (15mMol) benzylbromide in 30ml absolute *, tetrahydrofuran.

Example 12:

To a solution of 9.1 g (58 mmol) of N, N-di-n-propyl-propionamide in 90 ml of absolute chloroform is added dropwise at ⁰ ° C. with stirring and exclusion of moisture 37 ml of a 1.9 molar solution of phosgene in toluene. This mixture is stirred for 5 hours at 0 ° C and then concentrated in vacuo. The residue is taken up in 40 ml of absolute chloroform and added dropwise to a suspension of 6.4 g (58 mmol) of 2-amino-6-hydroxypyridine in 50 ml of absolute chloroform. Subsequently, 20 ml (145 mmol) of triethylamine are added and stirring is continued for 20 hours at room temperature. The reaction mixture is then diluted with dichloromethane and washed twice with Wapser. The organic phase is dried over MgScu and then concentrated in vacuo. The resulting crude product is purified by chromatography on silica gel and then crystallized from ether / petroleum ether. N- (2-pyridone-6-yl) -N ', N'-di-n-propylpropionamidine or N- (2-hydroxy-6-pyridyl) -N', N'-di- npropyl-propionamidine of the mp 112-113 ° C.

Example 13

In analogy to Example 12 can be N- (2-pyridone-6-yl) -N'-ethyl-N'-isopropanol-acetarnidin or N- (2-hydroxy-6-pyridyl) -N'-ethyl-N produce'isopropyl acetamidine, mp. 110-111 ⁰ C; starting from 8.4 g (65 mmol) of N-ethyl-N-isopropyl-acetamide, 40 ml of 1.9 molar solution of phosgene in toluene, 7.2 g (65 mmol) of 2-amino-6-hydroxypyridine and 16.5 mg (163 mmol) of triethylamine ,

The starting material can be prepared as follows:

8.7 g (1 μmol) of N-ethyl-N-isopropylamine are carefully mixed with 50 ml of acetic anhydride and heated under reflux for 1 hour. Then it is concentrated in a water-jet vacuum. The residue is taken up in dichloromethane, washed once each with 2 N hydrochloric acid, 2 N sodium hydroxide solution and water. The organic phase is dried and concentrated. The residual oil is distilled under high vacuum. This gives N-ethyl-N-isopropyl-acetamide of bp. 60-62 ° C / 0.08 mm / kg.

Example 14:

To a stirred solution of 8.3 mL (99 mmol) n-propylamine in 8 mL water is added portionwise at room temperature over 20 minutes, 2.3 g (14 mmol) of N- (2-hydroxy-6-pyridyl) -N'-cyano-formamidine added. The reaction mixture is stirred for 2 hours at room temperature. Then it is extracted three times with chloroform. The combined organic phases

are dried over MgSO ₄ and evaporated. The crude product thus obtained is chromatographed on silica gel with methylene chloride and then crystallized from ether / n-hexane. This gives N- (2-pyridone-6-yl) -N ^l '-propyl-formamidine or N- (2-hydroxy-6-pyridyl) -N'-propyl-formamidine, mp. 178-179 ⁰ C.

 The starting material can be prepared as follows:

11 g (100 mmol) of 2-amino-6-hydroxypyridine and 9.8 g (100 mmol) of ethyl N-cyanoformamidine are stirred in 100 ml of ethanol for 12 hours under reflux. The reaction mixture is then concentrated in vacuo and purified by chromatography on silica gel. The thus purified product is dissolved in chloroform / methanol and crystallized by the addition of ether. This gives N- (2-hydroxy-6-pyMdyl) -N'-cyano-formamidine or N- (2-pyridone-6-yl) -N'-cyano-formamidine, mp. 216-218 ° C.

Example 15:

Analogously to Example 14, N- (2-hydroxy-6-pyridyl) -N ', N'-di-n-propyl-formamidine and N- (2-pyridone-6-yl) -N', respectively, can be prepared. N'-di-n-propyl-formamidine prepared, mp 102-104 ⁰ C. starting from 13.7ml (10OmMoI) di-n-propylamine and 2.3g (14mMol) N- (2-hydroxy-6-pyridyl) -N'-cyano-formamidine in 10ml water.

Example 10:

in analogy to Example 12, N-i2-hyuroxy-6-pyridinyl-N ', N'-u'i-ii-propylformamidine or N- (2-pyridone-O-yl-N ^: , N ^r -di-n-propyl-formaniidin be obtained, mp 102-104 ⁰ C;., starting from 6.5 g (5OmMoI) Ν, Ν-di-n-propylformamide, 35ml 1,9molare solution of phosgene in toluene, 5.5 g (5OmMoI ) 2-Amino-6-hydroxypyridine and 12.7 g (125 mmol) triethylamine.

Example 17:

4.25 g (50 mmol) of N-cyano-acetamide and 6.9 g (50 mmol) of Ν, Ν-dipropylamine hydrochloride are heated in 40 ml of water with stirring for 3 hours at 100 ⁰ C. The cooled reaction mixture is made alkaline with 2 N sodium hydroxide solution, whereupon an oil separates. This is separated and the aqueous phase extracted once more with dichloromethane. The organic phases are purified and concentrated, and the residue is taken up in dioxane and added to a suspension of 4.9 g (44 mmol) of 2-amino-6-hydroxy-pyridine in 20 ml of xylene and heated to reflux for 12 hours The product purified in this way is crystallized from chloroform / ether to give N- (2-hydroxy-6-pyridyl) -N ', N'-di-n-propyl-acetamidine or N- (2 -pyridone-6-yl) -N ', N'-di-n-propyl-acetamide, mp. 140-141 ⁰ C.

Example 18:

3.3 g (20 μmol) N- (2-hydroxy-S-pyridyl) -N ', N'-dimethyl-formamidine or N- (2-pyridone-6-yl) -N', N'-dimethy ' Formamidine and 5.1 g (5OmMoI) of N, N-di-n-propylamine are stirred in 20 ml of xylene for 12 hours under reflux. The reaction mixture is evaporated and then filtered over ten times the amount Florisil using dichloromethane. The product-containing fractions are combined and evaporated. Crystallization from dichloromethane / n-hexane gives N- (2-hydroxy-6-pyridyl) -N ', N'-di-n-propylformamidine and N- (2-pyridone-6-yl) -N', N'-di -n-propylformamidin of mp. 102-104 ⁰ C.

Example 19:

1.8 g (10 μmol) N- (2-pyridone-6-yl) -N'-propylformamidine or N- (2-hydroxy-6-pyridyl) -N'-propylformamidine, 1.9 g (11 mmol) of propyl iodide and 1.5 g (11 mmol) of potassium carbonate are stirred in 30 ml of absolute ethanol at 80 ⁰ C for 24 hours. Then the reaction mixture is filtered and evaporated. The residue is taken up in methylene chloride, washed with water and then dried over Na ₂ SO ₄ and evaporated. The crude product thus obtained is purified by chromatography. Methylene chloride / ether crystal gives N- (2-pyridone-6-yl) -N ', N'-di-n-propyl-formamidine and N- (2-hydroxy-6-pyridyl) -N', respectively. N'-di-n-propyl-formamidine of the mp. 102-104 ⁰ C.

Example 20:

Analogously to Example 14 it is possible to prepare N- (2-hydroxy-6-pyridyl) -formamidine or N- (2-pyridone-6-ylj-formamidine, starting from 1.8 g (10 mM) N- (2- hydroxy-6-pyridyl) -N'-cyano-formamidine and 40 ml of ammonia-saturated ethanol at 6O ⁰ C.

Example 21:

Analogous to one of the examples 1-20 described one can produce:

N- (2-hydroxy-3-methyl-6-pyridyl) -N ', N'-di-n-propyl-formamidine or N- (3-methyl-2-pyridone-6-yl) -N', N'-di-n-propylformamidine, N- (5-trifluoromethyl-2-hydroxy-6-pyridyl) -N ', N'-di-n-propyl-formamidine and N- (5-trifluoromethyl-2-pyridone -6-yl-N ', N'-di-n-propylformamidine,

N- (4-chloro-2-hydroxy-6-pyridyl) -N ', N'-di-n-propyl-formamidine or N- (4-chloro-2-pyridone-6-yl) -N', N'-di-n-propylformamidin.

Example 22:

Tablets containing 50 mg each of the active ingredient, for. N- (2-hydroxy-6-pyridyl) -N ', N'-di-n-propyl-formamidine methanesulfonate and N- (2-pyridone-6-yl) -N', N'-di, for example n-propylformamidine methanesulfonate can be prepared as follows.

Composition (10000 tablets) 500.0 g active substance 500.0 g lactose 352.0 g potato starch 8.0 g gelatin 60.0 g talc 10.0 g magnesium stearate 20.0 g Silica (highly dispersed) q.s. ethanol

The active ingredient is mixed with the lactose and 292 g of potato starch, the mixture is moistened with an alcoholic solution of gelatin and granulated through a sieve. After drying, the remainder of the potato starch, talc, magnesium stearate and fumed silica are mixed and the mixture is compressed into 145.0 mg weight tablets and 50.0 mg active ingredient content, which may optionally be provided with partial scores for finer dosage adjustment ,

Example 23:

Lacquered tablets, containing in each case 100 mg of the active ingredient, for. N- (2-hydroxy-6-pyridyl) -N ', N'-di-n-propyl-formamidine methanesulfonate and N- (2-pyridone-6-yl) -N', N'-di, for example n-propylformamidine methanesulphonate can be prepared as follows:

Composition (for 1000 tablets) 100.00 g active substance 100.00 g lactose 70.00 g corn starch 8.50 g talc 1.50 g Rol ^ ilimetoora * 2.36 g Hydroxypropyl methylcellulose 0.64 g shellac q.s. water q.s. methylene chloride

The active ingredient, the lactose and 40 g of the corn starch are mixed and moistened with granules of paste made from 15 g of corn starch and water (with heating). The granules are dried, the remainder of the corn starch, the talc and the calcium stearate are added and mixed with the granules. The mixture is compressed into tablets (weight: 280 mg) and coated with a solution of the hydroxypropylmethylcellulose and the shellac in methylene chloride; Final weight of the coated tablet: 283mg.

Example 24:

In an analogous manner as described in Examples 22 and 23, tablets or coated tablets containing a compound of the invention, for. B. according to Examples 1-21, are produced.

Claims (14)

1. A process for the preparation of pyridine derivatives of the formula i ¹ J -N = ON their Tautameren and their salts, wherein Ri is hydrogen or Ci-C means ₇ alkyl, one of R ₂ and H ₃ is hydrogen, Ci-C ₇ alkyl, aryl-C) -C ₇ alkyl, C ₃ -C ₆ Alkenyl or QHV-alkynyl and the other C ₁ -Cyalkyl, arylC, C ₇ -alkyl, QrCg-alkenyl or C ₃ -C ₆ -alkynyl, R _{4 is} hydrogen, C ₁ -C ₇ -alkyl or aryl- Ci-C ^ alkyl and R _{5 is} C ₁ -C ₇ -A ^ yl, halogen, Ci-C ₇ -alkoxy, Ci-C ₇ -alkylthio, Ci-CrAlkansulfinyl, Ci-CrAlkansulfonyl, carboxy, C ^ Cs-alkoxycarbonyl , Carbamoyl, C 1 -C ₇ -alkylcarbamoyl, di-C 1 -C 6 -alkylcarbamoyl, cyano or trifluoromethyl, and the index η is Ο, 1 or 2 and, where appropriate, the usual pharmaceutic application forms, characterized in that
a) a compound of the formula <Vn
'LnH-X. ( "Al ^R 4
or a tautomer thereof with a compound of the formula (Hb), wherein one of the radicals X ₁ and X _{2 is} a group of the formula -CO-Ri and the other hydrogen or a group of the formula -CO-Z ₁ and Zi is a cleavable radical, or reacts tautomers, salts and / or acetals thereof or b) in a compound of the formula - , '' - N = JX ₃ (III) y " ² or a tautomer and / or salt thereof, wherein X _{3 is} an in -n convertible radical R ₃ R ₂ X _{3 is converted} to -N or R ₃ c) for the preparation of compounds of formula I, a tautomer and salt thereof, wherein R _{4 is} hydrogen, in a compound of formula Χ <V or a salt thereof, wherein X _{4 is} hydroxy protected, the hydroxy protecting group splits off, or d) a compound of the formula or a tautomer or salt thereof with a compound of the Fei r. .! Tautomers or a salt thereof, wherein Xe is the group -N = CR ₁ -NH-X ₅ and X _{7 is} hydrogen or X _{6 is} -NH ₂ and X _{7 is} the group -CRi = NX ₅ and X _{5 is} a leaving group stands, converts and, if desired, a compound obtainable in accordance with the method or otherwise converts another compound of the formula I or a tautomer thereof, resolves an isomer mixture obtainable according to the process into the components, converts a free compound of the formula I obtainable according to the process or a tautomer thereof into a salt and or a salt which is obtainable according to the process is converted into the free derivative of the formula I or a tautomer thereof or into another salt and, if appropriate, each compound of the general formula I is processed with customary galenic auxiliaries and carriers to give customary pharmaceutical applications. 2. The method according to claim 1, characterized in that compounds of formula I, their tautomers and their salts are prepared, wherein R _{1 is} hydrogen or C ₁ -C ₇ -AIKyI, one of Rpste R ₂ and R _{3 is} hydrogen, C ₁ C ₇ -AllCyI or aryl-d-cralkyl and the other C ₁ -C ₇ -AIRyI or aryl-Cr-cralkyl and R _{4 is} hydrogen or C, -C ₇ -alkyl, R _{5 is} C ₁ -C ₇ - AIRyI means and the index η is 0 or 1. 3. The method according to claim 1, characterized in that compounds of formula I, their tautomers and their salts are prepared, wherein R _{1 is} hydrogen or C ₁ -C ₇ -AlkV ^- I, one of the radicals R ₂ and R _{3 is} hydrogen, C ₁ -C ₇ -AIRyI or aryl-C ₁ -C ₄ -alkyl and in particular C ₁ -C ₇ -alkyl or aryl-C ₁ -C ₄ -alkyl and R _{4 is} hydrogen and the index η is 0. 4. The method according to claim 1,2 or 3, characterized in that compounds of formula I, their tautomers and their salts are prepared, wherein one of the radicals R ₂ and R _{3 is} hydrogen, C ₁ -C ₇ AIRyI, phenyl or naphthyl -CHValkyl and other C ₁ -C ₇ -A ^ yI, phenyl or naphthyl-C ^ C is alkyl, wherein each phenyl or naphthyl unsubstituted or mono- or polysubstituted by halogen, C ₁ -C ₇ -A ^ yI, C ₁ -C ₇ -alkoxy, hydroxy and / or C ₂ -C ₈ -alkanoyloxy is substituted. 5. The method according to claim 1,2 or 3, characterized in that compounds of formula I, their tautomers and their salts are prepared, wherein R _{1 is} hydrogen or C ₁ -C ₄ -AIRyI, such as methyl, R ₂ and R _{3 is,} on the one hand, independently of one another C ₁ -C ₄ -alkyl, such as propyl, or, on the other hand, R _{2 is} C ₁ -C ₄ -alkyl, such as methyl, and R _{3 is} phenylC ₁ -C ₄ -alkyl, such as 2-phenylethyl, and R _{4 is} hydrogen and the index is η O. 6. The method according to claim 1, 2 or 3, characterized in that compounds of formula I, their tautomers and their salts are prepared, wherein R _{1 is} hydrogen or C ₁ -C ₄ -AIRyI, such as methyl, R ₂ and R _{3 is,} on the one hand, independently of one another C ₁ -C ₄ -alkyl, such as propyl, or, on the other hand, R _{2 is} C ₁ -C ₄ -alkyl, such as methyl, and R _{3 is} phenylC ₁ -C -Y-cyyl, such as 2-phenylethyl, R _{4 is} C ₁ -C ₄ -alkyl, such as methyl, and the index is η O. 7. The method according to claim 1,2 or 3, characterized in that compounds of formula I, their tautomers and their salts are prepared, wherein R ₁ and R _{4 are} hydrogen and R ₂ and R _{3 are} independently C ₁ -C ₄ - AIRyI, such as propyl, mean and the index is η O 8. The method according to claim 1,2 or 3, characterized in that compounds of formula I, their tautomers and their salts are prepared, wherein R _{1 is} hydrogen, R _{4 is} C ₁ -C ₄ - Alkyl, such as methyl, and R ₂ and R _{3 are} independently C ₁ -C ₄ alkyl, such as propyl, and the index η 0. 9. The method according to claim 1,2 or 3, characterized in that compounds of formula I, their tautomers and their salts are prepared, wherein R _{1 is} methyl, R _{4 is} hydrogen and R ₂ and R _{3 are} independently C ₁ -C ₄ -alkyl, such as Prcpyl, and the index η is 0. 10. The method according to claim 1,2 or 3, characterized in that N- (2-hydroxy-6-pyridyl) -N ', N'-di-n-propyl-formamidine or N- (2-pyridone-6 -yl) -N ', N'-di-n-propyl-formamidine or a salt thereof. 11. The method according to claim 1,2 or 3, characterized in that N- (2-hydroxy-6-pyridyl) -N ', N'-di-n-propylacetamidin or N- (2-pyridone-6-yl ) -N ', N'-di-n-propylacetamidine or a salt thereof. 12. The method according to claim 1,2 or 3, characterized in that N- (2-hydroxy-6-pyridyl) -Ν ', Ν'-dimethylformamidine or N- (2-pyridone-6-yl) -N' , N'-dimethyl-formamidine, N- (2-hydroxy-6-pyridyl) -N'-methyl-N'-butyl-formamidine; N- (2-pyridone-6-yl) -N'-methyl-N'-butyl-formamidine or N- (2-hydroxy-6-pyridyl) -N'-methyl-N '- (2-phenyl) -acetamidinbzw. N- (2-typridone-6-yl) -N'-methyl-N '- (2-phenyl-ethyl) -acetamidine or a salt thereof. 13. The method according to claim 1,2 or 3, characterized in that N- (1-methyl-2-pyridone-6-yl) -N ', N'-di-n-propylformarnidin, N- (2-hydroxy-6-pyrodiyl) -N ', N'-di-n-propylformamidine or N- (2-pyridone-6-yl) -N', N'-di-n-propylformamidine, N- (1-methyl-2-pyridon-6-yl) -N ', N'-dipropyl-acetamide,
N- (1-benzyl-2-pyridon-6-yl) -N ', N'-dipropyl-acetamide, N- (2-Pyndon-6-yl) -N'-propyl-acetamidine or N- (2-hydroxy-6-pyridyl) -N'-propyl-acetamidine, N- (2-pyridone-6-yl) -N-ethyl-N'-isopropyl-formamidinbzw. N- (2-hydroxy-6-pyridyl) -N'-ethyl-N'-isopropyl-formamidine, N- (2-pyridone-6-yl) -N ', N'-dipropyl-propionamidinbzw. N- (2-hydroxy-6-pyridyl) -N ', N'-dipropionamidin,
N- (1-propyl-2-pyridone-6-yl) -N ', N'-dipropyl-formamidine or a salt thereof. 14. The method according to claim 1, 2 or 3, characterized in that N- (2-pyridone-6-yl) -N'-ethyl-N'-isopropylacetamidine or N- (2-hydroxy-6-pyridyl) - N'-ethyl-N'-isopropyl-acetamidine, N- (2-pyridone-6-yl) -N'-propyl-formamidine and N- (2-hydroxy-6-pyridyl) -N'-propyl-forrnamidine, respectively , N- (2-hydroxy-3-methyl-6-pyridyl) -N ', N'-di-n-propyl-formamidine; N- (3-methyl-2-pyridyl) -Ν ', Ν'-di-n-propyl-formamidine and N- (3-methyl-2-pyridon-6-yl) -N'-N'-di n-propylformamidine, N- (5-trifluoromethyl-2-hydroxy-6-pyridyl) -N ', N'-di-n-propylformamidine and N- (5-trifluoromethyl-2-pyridone-6 -yl) -N ', N'-di-n-propylformamidine, N- (4-chloro-2-hydroxy-6-pyridyl) -N', N'-di-n-propylformamidine and N, respectively - (4-chloro-2-pyridone-6-yl) -N ', N'-di-n-propyl-formamidine or a salt thereof.