DD287263A5 - PROCESS FOR PREPARING 6- (PYRID-4-YL) -1,2,4-TRIAZOLO- [1,5-A] PYRIDINES - Google Patents

Abstract

The invention relates to a process for the preparation of * by reaction of 3-substituted * with ortho esters, esters, Cyancarbonsaeureestern, Saheehalogeniden, Saeureanhydriden, Dicarbonsaeureanhydriden, lactones or phosgene or urea. The compounds are biologically active. Areas of application of the invention are the pharmaceutical and agrochemical industries. {* * * Esters; Orthoester; Cyancarbonsaeureester; halides; anhydrides; dicarboxylic acid; lactones; phosgene; Urea}

Description

Characteristic of the known state of the art

Some 1,2,4-triazolo [1,5-a] pyridines are already known (T.Okamoto, M. Hirobe, Y. Tamai, E. Yabe, Chern. Pharm. Bull. 14,606 [1966]; KT Potts, HR Burton, J.Bhattacharyya, J Org Chem 31, 260 [1966], K.Gewald, A. Schubert, G. Martin, J. f.pra, Chemie 377, 561 [1975]; H. Berner, H. Reinshagen, Monatshefte f. Chemistry 106, 1059 [1975]; T. lkura, S.Suzne DD-PS 2905823 and US-PS 202977; K. Kubo, N.ltoh, I.Sohzu, Y. solomura, H.Honma, JP.PS 7905996C.A. 91, 57007r (1979), Japanese Patent 8163983 [CA. 95, 203904b [19811; R.C. Phadke, D.W. Rangnekar, Syntghesis 1986, 860).

Also described is their preparation starting from 1-amino-2-imino-1,2-dihydro-pyridines or 1,2-diaminopyridinium salts by cyclization with carboxylic acids or carboxylic acid derivatives (T. Okamoto et al., J. Org. Chem , 260 [1966], T.lkura et al., DD-PS 2905823 and US-PS 202977, JP-PS 8163983). 6- (Pyrid-4-yl) -1,2,4-triazolo [1,5-a] pyridino are not yet known.

Object of the invention

It is the object of the invention to produce novel biologically active 1,2,4-triazolo | 1,5-a) pyridines which can be used as intermediates, starting from easily accessible starting materials.

Explanation of the essence of the invention The invention has for its object to develop a method that allows new 1,2,4-triazolo [1,5-a] pyridines

display.

According to the invention, this object is achieved in that 6- (pyrid-4 / l) -1,2,4-triazolo [1,5-a] pyridines of the formula I, in the X = CN or CONH ₂ and R = OH, alkyl or by OH, OC (O) CH ₃ , CN or COOH substituted alkyl prepared

be prepared by compounds of the formula II

(V. Hagen et al., DD 263769), in which X has the abovementioned meaning with an orthoester, ester, cyano-carboxylic acid ester,

SBurehalogenid, DlcarbonsSureanhydrld or lactone or phosgene or urea advantageously in an organic Solvents are reacted. The inventive method allows the e- (pyrid-4-yl) -1,2,4-triazolo [1,5-a] pyrldines of the formula I in a simple manner

produce, with readily available starting materials are used.

The new 6- (pyrid-4-yl) -1,2,4-triazolo- (1,5-a) pyridines and their salts, which are obtained by reaction with physiologically acceptable

inorganic or organic acids can be represented, are biologically active. In particular, positive inotropic and vasodilatory effects were found.

The 6- (pyrid-4-yl) -1,2,4-triazolo [1,5-a-pyridines prepared according to the invention are also valuable intermediates for

the preparation of other biologically active compounds.

By mixing the compounds I or their salts with physiologically acceptable carriers to reach dei ι

corresponding pharmaceutical administration forms.

The invention will be explained below with reference to exemplary embodiments. embodiments example 1

8-cyano-6- (pyrld-4-yl) -1,2,4-trlazolo [1,5-a) pyrldln

1 g (4.73 mmol) of 1-amino-3-cyano-2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine are refluxed with 16 ml of triethyl orthoformate and 5 ml of formic acid for 5 h. It is mixed with activated charcoal, filtered, neutralized, filtered with suction and off

Recrystallized ethanol.

C ₁₂ H ₇ N ₆ (221.2)

Yield: 0.65 g (63.1% of theory); Schmb.: 273-274'C Example 2

8-carbamoyl-6- (pyrld-4-yl) -1,2,4-trlozolo [1,5-a] pyrldln

2 g (8.7 mmol) of 1-amino-3-carbamoyl-2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine are dissolved in 50 ml of glacial acetic acid for 1 h with 30 ml

Triethyl orthoformate boiled at reflux. It is mixed with activated charcoal, filtered, cooled, filtered with suction, in

Dissolved dilute HCl solution, precipitated by alkalization with aqueous NHj solution, abgei peeps and dried.

C ₁₂ H ₉ N ₆ O, (239.2)

Yield: 1.43 g (68.7% of theory); Shear: 300-301 * C Example 3

e-CyaivZ-ovanmethyl-e-lpyrlcM-yn-i ^ -trlrzoloH.B-alpyrldln

2.11 gdOmmol) of i-amino-S-cyano-imino-S-fpyridyl-1-methyl-dihydro-pyridine are refluxed with 4 ml of cyanogenethylmethyl ester in 80 ml of methyl glycol. It is mixed with activated charcoal, filtered, cooled, added water, allowed to stand overnight in the refrigerator and vacuumed.

C _u H _e N _e (260.3)

Yield: 1.8 g (69.2% of theory); Schmb.: 290-297 ⁰ C (Zers.)

Example 4

e-carbamoyl ^ -cyanmethyl B fpyrid ^ ^ -ylM -triazolor.i.S-alpyrldin

0.5 g (2.2 mmol) of 1-amino-3-carbamoyl-2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine are refluxed with 1 ml of ethyl cyanoacetate in 25 ml of butanol for 1 h , It is cooled and recrystallized from much methylene glycol.

C ₁₄ H ₁₀ N ₆ O ₁ (278.3)

Yield: 0.4 g (65.3% of theory); Schmb .:> 310 ⁰ C (Zers.)

Example 5

2- (2-carboxy-ethyl) -8-cyano-6- (pyrld-4-yl) -1,2,4-trlazolo [1,5-a] pyrldln

0.5 g (2.4 mmol) of 1-amino-3-cyano-2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine are treated with 1 g of succinic anhydride in 3 ml of glacial acetic acid for 0.5 h art , Reflux cooked. It is cooled, mixed with water, filtered off and recrystallized from DMF with addition of activated carbon.

C ₁₆ H ₁₁ N ₆ O ₂ (293.3)

Yield: 0.49 g (69.6% of theory); Shear: 248-254 ⁰ C

Example 6

2- (3-Acetoxy-propyl) -8-carbamoyl-e- (pyrld-4-yl) -1,2,4-triazole (1,5-a] pyridine-2,3g (10mmol) 1-amino-3 -carbamoyl-2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine are refluxed with 10 ml of γ-butyrolactone in 10 ml of glacial acetic acid for 3 hours, 1 ml of acetic anhydride is added, for another 0, Cooked 5h, mixed with charcoal, filtered, neutralized, filtered off with suction and recrystallized from EtH -> nol.

C ₁₇ H ₁₇ N ₆ O ₂ (339.4)

Yield: 1.75 g (51.6% of theory); Schmb.: 183-187 "C

Example 7

e-cyano -oxo-e-ipyrld ^ -yl ^ -dlhydro-i ^ -trloazolone.B-al-pyridine hydrate 423md, (2mmol) 1-amino-3-cyano-2-imino-5- (pyrid -4-yl) -1,2-dihydro-pyridine are suspended in 8 ml of dioxane, admixed with 0.4 ml of triethylamine and stirred with addition of 3.5 mmol COCI ₂ in toluene at 0-5 ⁰ C for 15 min. It is allowed to stand for 4 days, mixed with a little water, filtered off, taken up in ethanol with the addition of some 6N NH ₃ solution, neutralized with 6N HCl solution and filtered with suction.

C ₁₂ H ₈ N ₆ O ₂ (235.2)

Yield: 60 mg (11.9% of theory); Shear:> 320 ° C (decomp.)

Testing for biological effect

Example 8

Isolated, spontaneously active guinea pig atrium

For the experiments male guinea pigs with a body mass of 400-50Og were used. The isolated, spontaneously active atrium was examined after 60 minutes of adaptation of the organ preparations in a temperature controlled at 32 ⁰ C carboxylated Tyrodelösung the influence of inotropy and frequency under the action of 6- (pyrid-4-yl) -1,2,4-trlazolo - pyridine [1,5-a]. Thus, a 23% increase was inotropy dor example, upon administration of the compound in Example 6 ν .η oiner concentration of 10 ~ ⁴ mol / l found.

Claims (3)

1. A process for the preparation of 6- (pyrid-4-yl) -1,2,4-triazolo [1,5-a] pyridines of Formal I in the X = CN or CONH ₂ and R = H ₁ OH, alkyl or by OH, CC (O) CH ₃ , CN or COOH substituted alkyl and optionally their pharmaceutically acceptable salts and the corresponding pharmaceutical administration forms, characterized in that Compounds of the formula II in which X has the abovementioned meaning, with an orthoester, ester, Cyancarbonsäureester, acid halide, acid anhydride, dicarboxylic anhydride or lactone or phosgene or urea are reacted and the compounds of formula I optionally converted into their pharmaceutically acceptable salts and / or with appropriate pharmaceutical Carriers are mixed. 2. The method according to claim 1, characterized in that the reaction takes place in an organic solvent. 3. Process according to claims 1 and 2, characterized in that are used as the solvent alcohols, methyl glycol, toluene, DMF, glacial acetic acid or formic acid. Field of application of the invention The invention relates to a process for the preparation of e-tPyrid ^ -yD-i ^^ - triazolo-H.B-ajpyridinen dB 'formula I. in which X is CN or CONH, and R is H, OH, alkyl or by OH, OC (O) CH ₃ , CN or COOH substituted alkyl. The compounds are biologically active. For example, they show positive inotropic and vasodilatory effects. The compounds also provide valuable intermediates for the preparation of other biologically active compounds. The invention is applicable in the pharmaceutical and agrochemical industries.