DD287260A5 - PROCESS FOR PREPARING 6-SUBSTITUTED 2-AMINO-3-CYAN-5- (PYRID-4-YL) -PYRIDINES - Google Patents

Abstract

The invention relates to a process for the preparation of * and their pharmaceutically acceptable salts by reaction of * with hydrazine, alkylamines, hydroxyalkylamines; aminoalkylamines; morpholine; piperazine; substituted piperazines; Pyridine or sodium alcoholates and alkanols, alkanethiols, alkanediols and phenols in the presence of suitable bases. Areas of application of the invention are the pharmaceutical and the agrochemical industry {6-substituted 2 * 2 * salts; hydrazine; alkylamine; hydroxyalkylamine; aminoalkylamine; morpholine; piperazine; pyridine; sodium alcoholate; alkanols; alkanethiols; alkanediols; phenols}

Description

Field of application of the invention The invention relates to a process for the preparation of 6-substituted 2-amino-3-cyano-5- (pyrid-4-yl) -pyridines of the formula I.

in which X is amino, hyrirazino, alkylamino, hydroxyalkylamino, morpholino, aminoalkylamino, piperazines, substituted

Piperazine », N-pyridinium chloride, alkoxy, alkylthio, hydroxyalkoxy, phenoxy or hydroxy. The compounds are biological aWv. For example, they show positive inotropic and partially vasodiiatatory effects

with only a slight or negative influence on the heart rate. The links also provide valuable

Intermediates for the production of further biologically active compounds. The invention is applicable in the pharmaceutical and agrochemical industry. Characteristic of the known state of the art

2-amino-3-cyano-5- (pyrid-4-yl) -pyridine is described in the literature (Hagen et al., DD-PS 263 758, V. Hagen et al., Pharmacy 44, 20 [1989]). , Also known are 2-amine | i-6-chloro-3-cyano-5- (pyfid-4-yl) -pyridine and 6-alkyl-2-amino-3-cyano-5- (pyrid-4-yl) yl) pyridines.

Also described are 6-unsubstituted and 6-methylsubstituiörte 2-alkylamino-3-cyano-5- (pyrid-4-yl) -pyridine (G.y. Lesher et

al. US Pat. No. 4,362,734) as well as corresponding 2-oxaalkylamino or 2-aminoalkylamino derivatives (V.Hagen et al., EP-PS 0200024) and their cardiotonic activity.

Object of the invention

It is the object of the invention to prepare new biologically active and intermediate 6-substituted-2-amino-3-cyano-5- (pyrid-4-yd-pyridines.

Explanation of the essence of the invention The invention has for its object to provide a process for the preparation of previously unknown 6-position substituted 2-amino

To develop 3-cyano-5- (pyrid-4-yl) pyridines.

According to the invention, this object is achieved in that 2-amino-6-chloro-3-cyano-5- (pyriJ4-yl) pyridine or its hydrochloride

in suitable organic solvents with hydrazine, alkylamines, hydroxyalkylamines, aminoalkylamines, morpholine,

Piperazine, substituted piperazines, pyridine or sodium or with alkanols, alkanethiols alkanediols or Phenols in the presence of suitable bases, e.g. As NaOH or KOH, and optionally in the reaction with Pyridine and alcoholates formed by Zincke cleavage or hydrolysis in 3-cyano-2,6-diamino-5- (pyrid-4-yl) -

pyridine and 2-amino-3-cyano-6-hydroxy-5- (pyrid-4-yl) -pyridine. The latter compound is in the solid state as 2-amino-3-cyano-5- (pyrid-4-yl) -1,6-dihydro-pyrid-6-one.

As a solvent in the reaction of 2-amino-6-chloro-3-cyano-5- (pyrid-4-yl) -pyridine with the listed amines, alcohols, Thio alcohols or phenols may, for example, alcohols, methyl glycol, acetonitrile, dimethylformamide, mixtures of these Solvent and the respective amino or hydroxy compounds themselves are used. The 6-substituted 2-amino-3-cyano-5- (pyrid-4-yl) -pyridines and their salts, some of which occur directly in the reactions

or z. From the free bases by reaction with physiologically acceptable inorganic or organic acids, are biologically active.

In particular, pronounced positive inotropic and partially vasodilatory effects were found in comparatively

small or partial small or negative influence on the heart rate.

By mixing with appropriate carriers, one arrives at pharmaceutical administration forms. The 6-substituted 2-amino-3-cyano-5- (pyrid-4-yl) -pyridines prepared according to the invention are also valuable Intermediates for the preparation of other biologically active compounds. The invention will be explained in more detail below with reference to exemplary embodiments. Ausführungsbelspiele example 1

2-Amlno-3-cyano-s-hydrazlno-5- (pyrld-4-yl) -pyrldln

2.3 g of dmolol) 2-amino-6-chloro-3-cyano-5- (pyrid-4-yl) -pyridine are refluxed with 8 ml of about 50% hydrazine hydrate in 60 ml of ethanol for 2 h. It is cooled, mixed with water, filtered off with suction and washed with water, ethanol and ether.

C _n H ₁₀ N ₁ , (226,2)

Yield: 1.45 g (64.1% of theory). Shear: 220-225 ⁰ C (Zers.) Example 2

2-Amino-3-cyano-6-ethylamlno-5- (pyrid-4-yl) pyridine

2.3 g of dmolol) 2-amino-6-chloro-3-cyano-5- (pyrid-4-yl) -pyridine are more intensively mixed with 8 ml of ethylamine in 20 ml of DMF

Reflux slowly heated to 8O ⁰ C. It is stirred for 1 h at 8O ⁰ C, mixed with water, filtered with suction, water

washed, recrystallized from ethanol and dried at 11O ⁰ C.

C ₁₃ H ₁₃ N ₆ (239.3)

Yield: 1.7 g (71.0% of theory). Schmb.:205-206°C Example 3

2-Amlno-3-cyano-6- (2-hydroxy-ethylamlno) -5- (pyrld-4-yl) -pyrld! N

4,6 g (20 mmol) of 2-amino-6-chloro-3-cyano-5- (pyrid-4-yl) -pyridine are refluxed in 20 ml of ethanolamine for 0.5 h.

It is mixed with water, filtered off and recrystallized from ethanol.

C ₁₁ H ₁₁ N ₆ O ₁ (265.3)

Yield: 4.6 g (90.2% of theory). Schm .: 194-196'C Example 4

2-Amlno-3-cyano-6- (2-hydroxy-propylamlno) -5- (pyrld-4-yl) -pyrldln

Analogously to Example 3 from 2.3 g (10mir oil) 2-Am! No-6-chloro-3-cyano-5 (pyr! D-4-yl) -pyridine and 10 ml of 3-amino-propan-1-ol.

C ₁₄ H ₁ JN ₄ O, (269.3)

Yield: 1.4 g (52.0% of theory). MP: 202-204 "C Example 5

2-amino-3-cyano-6-morpholino-5- (pyrid-4-yl) pyridine

2.67 g of dmolol) 2-amino-6-chloro-3-cyano-5- (pyrid-4-yl) -pyridine hydrochloride are refluxed with 8 ml of morpholine for 10 min. It is mixed with water, filtered off, dried, taken up in CHCl ₂ , admixed with activated charcoal, filtered, concentrated and filtered with suction.

C ₁₆ H ₁₆ N ₆ O ₁ (281.3)

Yield: 2.1 g (74.7% of theory). Schmb: 257-259'C Example 6

2-Amino-3-cyano-6- (3-dimethylamino-propylamino) -5- (pyrld-4-yl) -pyridine-2,3,3-domo mmol) 2-amino-6-chloro-3-cyano-5-pyridine 4-yl) -pyrldin are mixed with 2.6ml i-Amlno-3-dlethylamino-propane in 30ml

Methyl glycol refluxed for 1.6 h. It is cooled, with 1N aqueous NaOH verseW, filtered off with suction and from ethanol

recrystallized.

Ci ₁ H ₂₄ N ₈ (324.4)

Yield: 2.58 g (79.5% of theory). Schmb.: 178-179 ⁰ C

Belsplei 72-Amino-3-cyano-6- (4-dlphanylmethyl-plperazlno) -5- (pyrld-4-yl) -pyrldine2,3g dOmmol) 2-Amino-6-chloro-3-cyano-5- (pyrid 4-yl) -pyridine are refluxed with 5 g of 4-diphenylmethylpiperazine in 50 ml of methyl glycol 3h. Ee is cooled, treated with water and 1N aqueous NaOH, filtered off with suction, dried, dissolved in Tcluong, treated with activated charcoal, filtered, precipitated by addition of hexane and ether, filtered off with suction and recrystallized from ethanol.

C ₂₈ H ₂₆ N ₆ (446.6)

Yield: 2.6 g (58.2% theory). Shear: 144-147 ⁰ C Example S Nth-Amlno-S-cyano-S-lpyrld ^ yo-pyrldin ^ -ylJ-pyrldlnlumchlorld monohydrate

4,6 g (20 mmol) of 2-amino-6-chloro-3-cyano-5- (pyrid-4-yl) -pyridine are refluxed with 60 ml of pyridine for 7 h. It is about

Allowed to stand overnight, filtered off, dried and from 96%. Recrystallized ethanol with addition of activated carbon, wherein the Precipitation is completed by the addition of ether.

Ct (H ₁₂ NeCl ₁ · H ₂ O (327.8)

Yield: 2.75 g (42.0% of theory). Schmb .:> 200 ° C Zers. Example 9

3-Cyano-2,6-dlamino-5- (pyrld-4-yl) -pyrldln327.8 mg (1 mmol) of the pyridinium chloride described in Example 8 are dissolved in 6 ml of DMF with heating and mixed with 3 ml of 72% pure. Hydrazlnhydrat cooked for 0.5 h at reflux. It is mixed with activated carbon, filtered, left to stand, with a little ethanol,

Ether and pentane are added and filtered off with suction.

C ₁₁ H ₉ N ₅ (211.2)

Yield: 110 mg (52.1% of theory). Shear: 305-310 ° C (decomp.) Example 10

2-Amino-3-cyano-G-methoxy-5- (pyrld-4-yl) -pyridine-5,33g (20 mmol) 2-amino-6-chloro-3-cyano-5- (pyrid-4-yl) -pyridine hydrochloride are refluxed for 2 h with a Na-methylate solution prepared from 1 g Na and 100 ml methanol. It is concentrated, mixed with water, filtered with suction, and recrystallized from methanol with the addition of activated carbon.

C ₁₂ H ₁₀ N ₄ O ₁ (226.2)

Yield: 4.18 g (92.4% of theory). Mp: 22O-2O3 ° C Example 11

2-Amino-3-cyano-5- (pyrl-4-yl) -1, e-dlhydro-pyrld-e-on hydrochloride monohydrate 2.26g (10mmol) 3-amino-3-cyano-6-methoxy-5- (Pyrid-4-yl) -pyridln be 15 min. With 25ml conc. HCI boiled at reflux. It is cooled, mixed with ethanol, filtered off with suction and recrystallized from ethanol / water with the addition of a little 1N HCl.

C ₁₁ H ₉ N ₄ OtCl ₁ -H ₂ O (266.7)

Yield: 1.9 g (71.2% of theory). Schmb .:> 300 ⁰ C Zers. Example 12

2-Amino-3-cyano-5- (pyrld-4-yl) -1,2-dihydro-pyrld-6-one 266.7 mg (1 mmol) of the hydrochloride described in Example 12 are dissolved in hot water and added by addition of 1N

NHj solution to pH 8 precipitated. It is filtered off, washed with water and dried at 11O ⁰ C. Yield: 240 mg (90.0% of theory). Schmb .:> 300 ° CZers. Example 13

2-Amino-3-cyano-6-ethylthlo-5 (pyrld-4yl) pyridine 1.15 g (5 mmol) of 2-amino-6-chloro-3-cyano-5- (pyrid-4-yl) -pyridine are added 0.6ml (8.2mmol) of thioethanol and 0.31g (5.5mmol)

KOH in 50 ml of acetonitrile under inert gas for 2 h at room temperature gerühit. It is on its own, mixed with water, aspirated and

recrystallized from ethanol / water.

C ₁₁ H ₁₂ N ₄ S ₁ (256.3)

Yield: 988 mg (77.1% of Thoorio). M .: 189-190 ⁰ C Tasting on biological effects

Bet game 14

Isolated, spontaneously active guinea pig atrium

For the experiments male guinea pigs with a body mass of 400-50Og were used. In the isolated, spontaneously active atrial ending adaptation time of organ preparations were performed after a 60 min. In tempered at 32 ⁰ C carbogendurchperlter Tyrode the investigation of the influence of inotropy and frequency under the influence of 5-substituted 2-amino-3-cyano-5- (pyrid- 4-yl) -pyridine. The compounds showed considerable and dose-dependent positive inotropic effects, partly absent bzv /. even negative frequency influence. Thus, 33% were immersed, for example, upon administration of the compounds of Example 6 and 10 in concentration of 1 × 10 ^-4 mol / l and observed 53% strength increases in inotropy, wherein the compound of Beispiol 6, a simultaneous lowering of the heart rate by 18% revealed.

Example 15

Anesthetized cat I. ν

The examinations were performed on cats of both sexes (body weight 3-4kg) in pentobarbital anesthesia (38mg / kg ip) with closed thorax and spontaneous breathing. Blood pressure was measured by a femoral catheter using a pressure transducer. The measurement of left ventricular pressure (LVP) was also performed with a pressure transducer. From the LVP signal, a differential measuring insert dp / dt _mlJt . determined.

The heart rate was calculated by measuring the period of time from LVP-maximum to I.VP-maximum. The I. v. Application of the substance solutions takes place as a bolus via the V. femoralis. The absolute and percentage changes under substance influence compared to the initial situation were evaluated. The 6-substituted 2-amino-3-cyano-5- (pyrid-4-yl) -pyridines showed on this model a considerable and dose-dependent increase in the contractility of the heart (dp / dt _m , J and in some cases additional reductions in blood pressure, (For example, an increase of the contractility parameter dp / dt _{m was} found to be 58% at the dose of 5 x 10 -5 under the compound of Example 10. Heart rate and blood pressure remained unaffected at this maximum dose of inotropic increase.

Example 16

2-Amlno-3-cyano-s-ethoxy- (pyrld-4-yl) -pyrldln

2.3 g (10 mmol) of 2-amino-6-chloro-3-cyano-5- (pyrid-4-yl) -pyridine are incubated for 2 h with a Na-ethylate solution Ir prepared from 0.23 g of Na and 6 ml of ethanol. 50 ml of acetonitrile at 9O ⁰ C stirred. It is mixed with a little ethanol and water and filtered with suction.

C ₁₃ H ₁₂ N ₄ O ₁ (240.3)

Yield: 1.9 g (79.1% of theory). Schmb.:209-212°C

Example 17

2-Amlno-3-cyano-6-plperazlno-5- (pyrld-4-yl) -pyrldin

2.3g (lOmmol) of 2-Amlno-6-chloro-3-cyano-5- (pyrid-4-yl) pyridine is stirred with 2.8 g of piperazine in 10ml DMF for 1.5 h at 8O ⁰ C. It is mixed with a little Waster, filtered, concentrated to dryness, recrystallized from ethanol, extracted with CHCl ₃ , precipitated with Hoxan and filtered off (|

C ₁₆ H ₁₆ N ₆ (280.3)

Yield: 0.89 g (31.8% of theory). Schmb .: 230-238 ⁰ C (Zers.)

Claims (4)

1. A process for the preparation of 6-substituted-2-amino-3-cyano-5- (pyrid-4-yl) -pyridines of the formula I in which X is amino, hydrazino, alkylamino, hydroxyalkylamino, morpholino, aminoalkylamino, piperazino-substituted piperazino, N-pyridinium chloride, alkoxy, alkylthio, hydroxyalkoxy, phenoxy or hydroxy and, if appropriate, their salts and the corresponding pharmaceutical administration form, characterized in that Amino-6-chloro-3-cyano-5- (pyrid-4-yl) pyridine or its hydrochloride with hydrazine, alkylamines, hydroxyalkylamines, aminoalkylamines, morpholine, piperazine, substituted piperazines pyridine or sodium alcoholates or with alkanols, alkanethiols , Alkandiols or phenols is reacted in the presence of bases and optionally the compounds of formula I or their pharmaceutically acceptable salts are mixed with pharmaceutical excipients. 2. The method according to claim 1, characterized in that are preferably used as bases NaOH or KOH. 3. Process according to claims 1 and 2, characterized in that the reaction is carried out in the presence of an organic solvent. 4. Process according to claims 1 to 3, characterized in that are used as the organic solvent alcohols, methyl glycol, acetonitrile, dimethylformamide, mixtures of these solvents and the respective amino or hydroxy compounds themselves.