DE2255112A1 - PYRIDINE-2-YL-METHYLESTER DERIVATIVES WITH SPASMOLYTIC EFFECT, PROCESS FOR THEIR PRODUCTION AND MEDICINAL COMPOSITIONS CONTAINING THESE COMPOUNDS - Google Patents

Description

8 MUNICH 86, DEN

PO Box 860 820

MÖHLSTRASSE 22, CALL NUMBER 98 39 21/22

Case 71.40475

Pierre Fabre SA, Paris / France 48 _y Ruede Bassanq

Pyridin-2-yl methyl ester derivatives with spasmolytic Effect, process for their preparation and pharmaceutical compositions containing these compounds

The invention relates to pyridin-2-yl methyl ester derivatives with spasmolytic effects occurring in oral, rectal and parenteral Ways of Administering Antispasmodic Medicinal compositions can be incorporated.

The new pyridin-2-yl methyl ester derivatives according to the invention correspond to the following general formula

Ar .R

R. ^X C-0-CH

Ir / \

wherein

R is a hydrogen atom, a straight-chain or branched one low molecular weight alkyl group, a halogen atom, a Phe ~. nyl group ,. a benzyl group, a cyclohexyl group, an alkenyl group or an alkynyl group,

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R ^{1 is} a hydrogen atom, a hydroxyl group, a halogen atom, an alkoxy group, an alkyl group or a

Acyl group,
*

Ar is a phenyl group, a thienyl group, a benzyl group, a different aromatic group or an alkyl group,

Fi "is a low molecular weight alkyl group or a hydrogen atom and

X is a halogen atom, a methyl sulfate group or a picryl radical (C ₆ H ₂ N ₃ O ₇ ")

mean.

The alkoxy groups R 'O-alkyl groups _f O-alkeny groups, O-alkynyl groups, O-CHp-cyclopropyl groups, O-CH ^ -CH ^ -N-dialkyl groups or groups of the following

R H

Formulas 0-CH ₂ -Ar, 0-N, 0-N = CR, 0-N ^,

^ R R

wherein Ar and R have the meanings given above.

Treated for the preparation of these 2-oxymethylpyridine derivatives an amino alcohol with an organic acid or a derivative of this acid.

The following are those in the process according to the invention applied conditions and the resulting derivatives explained in more detail.

Procedure A

Action of an acid chloride on 2-oxymethylpyridine

₊ Ar - C - C - Cl

30982U / 1025

, ι

wherein R and R ^{1 have} the meanings given above, with the exception of: the. Hydroxyl group.

t
• First, 1 mol of the acid is treated with excess thionyl chloride in the cold, whereupon the reaction is terminated by refluxing for one hour. The excess thionyl chloride is then distilled off in vacuo. The acid chloride obtained in this way is used in crude form or, if the boiling point of this product does not exceed 200 ° C. at a pressure of 1 mm Hg, in distilled form / used.

The acid chloride obtained becomes anhydrous with 10 volumes Ether, whereupon this solution is added dropwise to a solution of the stoichiometric amount of 2-oxyinethylpyridine in Ether is given.

The hydrochloride of the corresponding ester precipitates during the elution and can be obtained by filtration. If in In certain cases, additional cleaning is required, this is done by recrystallization from absolute ethanol.

Benzene can also be used as a reaction solvent instead of ether or a chlorinated solvent (methylene chloride, carbon tetrachloride etc.), but it is used to Precipitation of the hydrochloride obtained as the end product is required is to add ethyl ether or petroleum ether.

The following are without limitation of the invention is to be given, derivatives according to the invention:

1. g-chloro-g-pheny! Acetic acid-pyridin-2-yl-ester-hydrochloride (formula I: R = Cl, R ¹ = H, R "= H, Ar = phenyl and X = Cl)

This derivative is obtained with a yield of 85%. Molecular formula: ^c i4 ^H i3 ^C1

F = 114 ° C

Molecular weight: 298

. 30 98-20 / 102 5

You get this connection in the form of white crystals, which are insoluble in water and soluble in alcohol "eu 20%.

~ 1 IR spectrum: y _CH (aromatic) at 3030 cm

v> _{c = 0} (ester) at 1760 cm " ¹

Thin-layer chromatography:

Carrier layer: silicon dioxide (Merck) Solvent: ethyl acetate / petroleum ether (50/50) Development: UV light, R _f value: 0.78

2. oc-Phenyl-g-ä thy! Acetic acid e-pyridin-2-yl-est er

(Formula X: R = C ₃ H ₅ , R ¹ = H, R "= H, Ar - phenyl, X = Cl)

This derivative is obtained with a yield of 80%. Molecular formula: C ₁₀ H ^

Molecular weight: 291.8
F = 123 ° C

This compound is obtained in the form of white crystals which are insoluble in water and soluble in ethanol.

IR spectrum: V _CH (aromatic) at 3030 cm " ¹

^v c = o ^{at 1745 0} ^ "" ¹

Thin layer chromatography:

Carrier material: silicon dioxide (Merck) Solvent: ethyl acetate / petroleum ether (50/50) Development: UV light, R _f value: 0.80

.... 309820/1025

3. Diphenylessiqäur-pyridin-2-yl-methylester-hydrochloride (Formula I: R »Phenyl, R '= H, R" = H, Ar' = Phenyl, X = Cl)

ν. I.

This derivative is obtained with a yield of 75%. Molecular formula: C _O , JL · _{D ClN0 o}

Molecular weight: 340
P * 137 ° C

This compound is obtained in the form of white crystals that are insoluble in water and in alcohol and dimethylformamide are soluble.

1 IR spectrum: v _CH (aromatic) at 3030 cm

V> _c _ ₀ at 1-740 ent " ¹ .

Thin layer chromatography:

Carrier layer: silicon dioxide (Merck) solvent: ethyl acetate / petroleum ether (50 / S0) development? UV light, R _f value; 0.43

4. a-Phenyl-u ^ cyclohexyl acetic acid e ^ pyridin-'2 ^ yl ^ -methy lest er . hydrochiorid

(Formula I: R = C ^ H ₁₁ , R '= H, R "= H, Ar = phenyl, X = Cl)

This derivative is obtained with a yield of 77%. Molecular formula: ₂₀₂₄
Molecular weight: 346
F = ⁰

This compound is obtained in the form of white crystals which are soluble in water (2 %).

IR spectrum: ν (aromatic) at 3028 cm ~ CH _.

^v c = o ^at - ^{1 735 cm}

30ÜÜ2U /! 0 2 p

Thin-Layer Chromatography:

Carrier layer: silicon dioxide (Merck) 'Solvent: ethyl acetate / petroleum ether (5o / 5O) Development: UV light or iodine vapors, R _f value: 0.88

O-Acetylm andelsäu repyri di n-2-yi-methylest er-h ydrochlo r id (Formula I: R = 0-CO-CH _3, R '= H, R "= H, Ar - phenyl, X = Cl)

This derivative is obtained with a yield of 70%.

Sum formula: C ₁ , 11 .., - NO.Cl

Ib Ib 4

Molecular weight: 321.7
F = 108 ⁰ C

These compounds are obtained in the form of white crystals, which are soluble in water (1.7%).

Thin-layer chromatography:

Carrier layer: silicon dioxide (Merck) solvent: ethyl acetate / petroleum ether (5o / 5O) development: UV light, R _f value: 0.78

0- (3 ', 4', 5'- trimeth oxybenzoyl) mandol säurepyridi n-2-ylmethylester-hydrochloride _y

OCH ₃

(Formula I: R = O-CO- / '^ V_ OCH ₃ , R ¹ = H, R "= H, Ar = phenyl,

^^ X X = Cl)

OCH ₃

This derivative is obtained with a yield of 60%. Molecular formula: C ₁ -H ^ _{4 NClO 7}

Molecular weight: 474
F = 134 ° C

The compound is obtained in the form of fine white crystals which are insoluble in water and soluble in water. are.

.... 30 9 8 ^ 'j / Iü2b

IR spectrum: V _{c = 0} at 1700 and 1770 cm " ¹ .

Thin layer chromatography: _s

Carrier layer: silicon dioxide (Merck) Solvent: ethyl acetate / petroleum ether (50/50) Development: UV light or iodine vapors, R _f value: 0.69

7 · 0-Acetylbenzylic acid pyridin-2-yl-methyl ester

(Formula I: R = CH ₁ -, R ¹ = 0-C-CH. ,, R "= H, Ar = phenyl,

ο χ = ei)

This derivative is obtained with a yield of 70%. Molecular formula: C _?? H "ClNO ₄

Molecular weight: 398
F = 140 ° C

The compound is obtained in the form of beige-colored crystals, which are insoluble in water and soluble in ethanol, propylene glycol, methylpyrrolidone and dimethylformamide.

IR spectrum:>' _{c = 0} at 1760 and 1730 cm

Thin-layer chromatography:

Carrier layer: silicon dioxide (Merck) solvent: ethyl acetate / petroleum ether (5θ / 5Ο) development: UV light, R _f value: 0.76

8. Thienylqlyoxylsäurepyridin-2-yl-methylester-hydrochloride (formula I: RR ¹ = 0, R "= H, Ar = thienyl, X = Cl) Molecular _{formula: C ^" H ^ o ClN0 3} S
Molecular weight: 283.7
F = 132 ° C

The compound is obtained in the form of chestnut-colored crystals which are soluble in water and insoluble in ethanol. . "

3OuIUO / 1 025

ΙΙϊ spectrum:) .; (Ester) at 1750 cm " ¹

v " _o (ketone) at 1660 cm""'

Thin ε chi cii t ch r oma togr aph ie: Carrier layer: silicon dioxide (Merck) Solvent: ethyl acetate Folded winding: UV light, R _f -V / ert: 0.73

Methyl ethy lca pronic acid pyridine-2 ~ y3 - methyl ester hydrochloride

(Formula I: R = CH ₃ , R ¹ = C ₂ H ₅ , Ar = CH ₃ -CH ₂ -CH ₂ -CH ₂ -,

R "= H, X = Cl)

Gradient formula: C ₁ JH ₉₉ Molecular weight: 285.7

The compound is obtained in the form of shiny pearlescent gray crystals that are very soluble in water, alcohol, dimethylformamide and ethylene glycol.

F = 114 ° C

Thin layer chromatography: carrier layer: silicon dioxide (Merck) solvent: ethyl acetate / petroleum ether (50/50) development: UV light and iodine, R _f value 0.74

10. Dibenzylessiqsäurepyridin-2-yl-methyl ester hydrochloride

(Formula I: Ar = CH ₀ C ^ H ₁ -, R '= H, R = C _C H _C CH_, R "= H, X = Cl)

2 ο b ⁷ * ο b

Molecular formula: C ₂₂ H ₂₂ ClNO ₂ Molecular weight: 368
F = 122 ° C

The compound is obtained in the form of white crystals which are insoluble in water and soluble in ethanol.

Thin layer chromatography: carrier layer: silicon dioxide (Merck) Solvent: ethyl acetate / petroleum ether (35/65) Development: UV light, R, -Wcrt: 0.70

·. .3 09820/1025

Starting from these derivatives, it is possible to make compounds to produce the different on the nitrogenous' group Have substituents by replacing the hydrochloride with another quaternizing agent {Iodine methylate, methyl sulfate, picrate etc.)

11. g-Ph enyl-g-ä thy! Essi g säurepyridi n-2-yl-- me thy 1 ester- jpd methylate

(Formula I: R = H, R = C ₃ H ₅ , R "= CH ₃ , Ar = phenyl, X = J)

One dissolves (X-phenyl-a-ethyl-acetic acid pyridin-2-yl-meth.ylester (Hydrochloride) in sodium hydroxide solution, extracted with ether and then treated with a stoichiometric amount of JCH. ,,. after which the solvents in vacuo distilled off.

Molecular formula: C ^ Hp-JMOpJ
Molecular weight: 397

The compound is obtained in the form of an orange-yellow oil which is insoluble in water and soluble in ethanol and acetone is.

29
Refractive index: n _n = 1.5 740

12. α, α-Dimethylpropionic acid pyridin-2-yl-methyl ester-iodomethylate

(Formula I: R = R '= Ar = CH ₃ , R "= CH ₃ , X = J)

The iodine methylate is obtained by treating the in acetone dissolved base with methyl iodide. The recrystallization takes place from an ethanol / ether mixture. F = 145 ° C

Molecular formula: C ""H> _{D JN0 or similar}

Molecular weight: 335.2

The compound is obtained in the form of chocolate-colored crystals, which are soluble in water, alcohol, ethylene glycol

3 0 9 8 2 0/1025

and in dimethyl formamide, methyl pyrrolidone and methylene ' ch1οrid are very good.

IJ ii η; ι sch I chtch x: ■> ν. ι α t ο graph ie:

T r ä C) c rs chi cht: S i 1 ici ι j πι d. L ο χ γ d (M e r ck F 254) Solvent: Ethylacetate / Pctrolether (50/50) Development: UV light, R _r value: 0.70

Procedure ^ B_

£ iil £ i £ .i: ir, _Jii.D ^: LE ^ iiIi2 a .SaUrG ₁ auf 2-OxyrnethylpyrJdIn ₁ Jn _n Gegenvpn ^^ ZlA

In anhydrous toluene, for example in the presence of 0.1 mol of p-toluene sulfonic acid, 0.5 mol of mandelic acid reacts with 0.5 mol of 2-oxyiriethylpyrxdine. About 1500 ecm of toluene is used per 150 g of the reactants. The reaction, which lasts several hours, is carried out under reflux in toluene, which is continuously dehydrated with the aid of a Dean-Stark device. The oil obtained is treated with 400 ecm of water, whereupon the solution is saturated with potassium carbonate. It is then filtered off, decanted, and the organic phase is dried over calcium chloride and concentrated. The residue is treated with a solution of hydrochloric acid in ethanol and the hydrochloride is precipitated by adding ether. The yield varies between 70 and 65 %.

13 Mandelic acid pyridiη -2-y1-methyl ester hydrochloride

(Formula I: R = H, R '= OM, R "= H _f Ar - Phenyl, X = Cl) Suramen formula: C..FJ., ClNO ^
Mo1eku i arg ewi ent: 297.7
F = 122 ° C

The compound is obtained in the form of light yellow crystals which are soluble> in water and slightly soluble in dimethylformamide and ^alcohol: i /. ^; .-. i «

IR spectrum: v> _0H at 3450 cm ^{"1, V>} _C _ _Q at 1620 cn" ¹ .. 309820/1025

_r r

Thin layer chromatography:

Carrier layer: Si 3 i ciumdioxyd (Mercli ··) solution: ethyl acetate / petroleum ether (5o / 5O) development: UV light, R, .- value: 0.50

Procedure C

Beη 7. i1 ϊ.'άur eρyridin ~ 2-yl -met hyl ester.

This procedure is a modification of procedure A, Zur This alcohol acid was used to produce the esters of an alcoholic acid converted into the α-chlorinated acid chloride according to the reaction given below:

C - COOH H - PCl ₅

Benzilic acid. Product A.

To 370 g of finely powdered phosphorus pentachloride is added gradually 200 g of benzilic acid. By dissolving in the phosphorus oxychloride (POCl ^) formed, the reaction mixture becomes pasty and then liquid. *

The mixture is kept at room temperature for 2 hours and the reaction is then terminated by heating to 100 ^° C. for two hours.

The phosphorus oxychloride is distilled off in vacuo »the remaining oily residue is treated with 250 ecm of ice-cold water, whereupon the acid chloride (product A) crystallizes out, which is extracted with petroleum ether. The organic layer is dried over sodium sulfate, filtered off, concentrated, and by cooling, 189 g of the crystalline product A. F = 52 ° C, yield 81%.

The condensation reaction with 2-oxymethylpyridine takes place according to the following scheme:

3 0 9 B V. U / ι U 1 b

BAD ORlGlNAU

Product B

1 mol of pyridine is added to 1 mol of 2-oxymethylpyridine dissolved in benzene, whereupon 1.1 mol of acid chloride, dissolved in benzene, is added dropwise. The addition takes place within a few hours, after which the mixture is heated to reflux for 2 hours and the pyridine hydrochloride is filtered off. After evaporation of the solvent, the remaining oil is treated with a solution of hydrochloric acid in ethanol. Then ether is added, whereupon the hydrochloride of product B crystallizes out. It is filtered and dried in the oven at 50 ^° C. The product obtained has the following properties:

α, g-Dipheny1-g-chloroacetic acid pyridine-2-vl-methγ1 ester

(Formula I: Ar - C ₆ H ₅ , R - CgH ₅ , R ¹ · Cl, R "» H, X - ClJ

Molecular formula: Cp ₀ H ^ CIpNOg

Molecular weight: 374.3 '.

F * 131 ° C

The compound is insoluble in water, very sparingly soluble in ethanol, in propylene glycol (5%) and dimethylformamide (20%) soluble.

Thin layer chromatography:

Carrier layer: silicon dioxide (Merck) Solvent: ethyl acetate / petroleum ether (35/65) Development: UV light, R _f value: 0.70,

With the help of this connection one can by the action of Prepare sodium alcoholate or ether directly by the action of primary alcohols according to the following scheme: "

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R _A OH

in which the substituent R has the following meanings: H, C "H [-j CH ^ j-CH-CH", CH = C-CH ₀ , C ^ H ^ ·

In this way, 200 g of α, α-diphenyl-a-chloroacetic acid pyridin-2-yl methyl ester, which are suspended in 500 ecm of the corresponding alcohol, 10 hours at 85 ° C heated. When complete solution has occurred, the excess alcohol is removed by distillation in vacuo removed. The 'oily residue is extracted with ethanol and precipitated with ether, the yield being practically quantitative. ·

For example, the products obtained according to this process are given:

15. o ^ a-Diphenvl-a-ethoxyessiqsäurepyridin ^ -yl-methyl ester hydrochloride

(Formula I: R = C.-H, -, R '= OC ₀ H ₁ -, R "= H, Ar = C _C H- _Ct X = Cl)

Whether ⁷ . (i D ' ⁷ DD /

This derivative was prepared according to Method A or C.

Molecular formula: C ₂₂ H ₂₂
Molecular weight: 329

F = 118 ° C

3 0 9 8 2 0/1 025

The compound is obtained in the form of white crystals, which are soluble in water and ethanol.

Thin layer chromatography:

Carrier layer: silicon dioxide (Merck) ■ Solvent ·: Ethyl acetate / petroleum ether (20/80) Development: UV light, R _f value: 0.45

16. Picrate of the a _r a -Dipheny l ~ a-propoxye s sic acid pyridyl-2-ylmethyl ester

(Formula I: R «C, H _C. R '= OC ₀ H. ,, R" = H, Ar »0, H ₁ -, X«

65 '37' ^r 65 *

C ₆ H ₂ N ₃ O ₇ )

This derivative can be prepared according to method A or C.

Summ en form el: C _oo H „ _r N _{/ 1} 0- ^.
Molecular weight: 590.5
F = 132 ° C

The compound is obtained in the form of yellow crystals which are sparingly soluble in water and insoluble in ethanol.

Thin layer chromatography:

* Carrier material: silicon dioxide (Merck) Solvent: ethyl acetate / petroleum ether (20/80) Development: UV light, R _f value: 0.37

17. O-propylbenzenic acid pyridin-2-yl-methyl ester hydrochloride

(Formula I: R = C ₅ II ₅ , R · - OCH ₂ -CH ₂ -CH ₃ , Ar = ^C ₆ ^H ₅ 1 ^R "= ^H »

X = Cl)

This derivative can be prepared according to method A or C, will.

Molecular formula: Cp-Hp ₄
Molecular weight: 398
F = 114 ° C

3098/0 /, 025

The compound is obtained in the form of white crystals, which are insoluble in water, in ethanol (7%) and in dimethyl formamide, (15% ■) soluble '.

IR spectrum V v> _{c =} l ₀ at 1750 at " ¹

Salt band at 2300 to 2500 cm " ¹

Thin layer chromatography I '■ "= - ■ - carrier layer; silicon dioxide (Merck). Solvent: ethyl acetate / petroleum ether (4O / 6O) Development: UV light, R _f value: 0.83

18. O-Allvlbenzilsäurepvridin-2-Yl-methylester-hydrochloride

(Formula I: R = ^G ₆ ^H ₅ > ^Rt = OCH ₂ -CH = CH ₂ , Ar = CgH ₅ , R "= H,

X ^ = Cl)

This derivative can be prepared according to method A or C. will.

Molecular formula: C ₂₃ H _{22 ClNO 3}
Molecular weight: 396
'F = 127 ° C

The compound is obtained in the form of white crystals, which are insoluble in water and in ethanol, propylene glycol and dimethylformamide are soluble.

Thin layer chromatography:

Carrier material: silicon dioxide (Merck) Solvent: ethyl acetate / petroleum ether (2o / 8O) Development: UV light, R _f value: 0.39

19. O-propargylbenzilic acid pyridin-2-yl-methyl ester hydrochloride

(Formula I: R = CgH ₅ , R ¹ = OCH ₂ -C = CH, Ar = .- (TgH ₅₁ R "= H ₁

'X = Cl)

This derivative can be prepared according to method A or C. will.

Sum formula: C_ ~ H_ _O C1NO_

Molecular weight: 394,

3 0 ϋ ϋ ^ - f J ■ / 1 0- 2 b

F - 119 ° C

The compound is obtained in the form of yellow-faced crystalline, which is insoluble in water and : ίη alcohol and propylene glycol are soluble.

Thin layer chromatography:

Carrier layer: silicon dioxide (Merck) Solvent: ethyl acetate / petroleum ether (3ö / 7O) Development: UV light, R _f value: 0.44

20. Benzilic acid pyridin-2-yl ~ methyl ester ^ r ^ yfi

(Formula I: R »CgH ₅₁ R ·« OH, R "« H, Ar. «Phenyl, X · = Cl)

This derivative is obtained by treating product B with water under reflux. The derivative is obtained with a yield of 90 %,

Molecular formula: C ₂₀ H _{18 ClNO 3}
Molecular weight: 355.8
F - 157 ° C

The compound is obtained in the form of light gray crystals, which are insoluble in water, in heat and in ethanol Are soluble in dimethylformamide and methylpyrrolidone.

IR spectrum: v » _CH at 3180 cm

V _c _ ₀ at 1745 cnT ¹
v> _c _ _c at 1615 cm

Thin layer chromatography:

Carrier layer: silicon dioxide (Merck) Solvent: ethyl acetate / petroleum ether (50/50) Development: UV light, R _f value 0.83

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For further explanation, the protective doses are given below, for example, with which 100% of the guinea pig ileus is used inhibits contractions induced with barium chloride (Prevention) or reduced (healing effect.). The results obtained are as mg / 25 ml of Ringer's solution specified. '

Prevention cure

Mandelic acid pyridin-2-yl methyl ester hydrochloride

Acetylmandelic acid pyridin-2-yl methyl ester hydrochloride

Qt-chloro-a-phenyl acetic acid epyridin-2-ylmethyl ester hydrochloride

a-Phenyl-a-ethyl acetic acid pyridin-2-ylmethyl ester hydrochloride -

Diphenylacetic acid pyridin-2-y1-methyl ester hydrochloride

Benzilic acid pyridin-2-yl-methyl ester hydrochloride

Acetylbenzic acid pyridin-2-y1-methyl ester hydrochloride

3 ', 4 ·, 5'-trimethoxybenzoylmandelic acid pyridin-2-yl-methyl ester hydrochloride

Papaverine (comparison compound)

900 1060 1000 1260 700 530 800 550 400 290 250 294 210 155 700 225 710 294

After studying the chronic toxicity, certain Derivatives clinically investigated on voluntary patients, ■ those at Suffered painful states that see different spasmodis Were of origin. The results achieved so far are promising, being a good success percentage with no harmful side effects like dry mouth ', nausea, allergic Reactions etc. was achieved.

The following are the formulations of pharmaceutical Preparations indicated that were used in the clinical trials.

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Dragees (see 1.f.)

Diphenylacetic acid pyridin-2-yl-methyl ester-

hydrochloride, 100 rag

Noramidopyrine methanesulfonate> 500 mg

Binder ad 1 tablet

Suppositories (s.l.f.)

Acetylbenzilsäurepyridin-2-yl-methylester-

hydrochloride 100 mg

Binder ad 1 suppository of 2 g weight

Suppositories (s.l.f.)

Acetylbenzilsäurepyridin-2-yl-methylester-

hydrochloride * 100 mg

Noramidopyrine methanesulfonate 500 mg

Codeine Phosphate 2O mg

Binder ad 1 suppository

Although the examples given represent simple formulations with the derivatives according to the invention, it goes without saying however, it goes without saying that the pharmaceutical compositions also have other products in addition to the products according to the invention May contain active ingredients.

Pharmacological studies

The toxicological studies of the products according to the invention showed that, with the exception of certain compounds, the toxicity of these derivatives is low. The following are therefore some examples of toxicity values are given:

30 9 8VO / 1 U 2 b

DL _ro an der'Maus for oral administration:

Mandelic acid pyridin-2-yl-methyiester hydrochloride 1330 mg / kg

Ace tylraand el acid epyridin-2-yl-ine thy read

hydrochloride 1700 mg / kg

a-chloro-a-phenylacetic acid pyridin-2-yl-methyl ester hydrochloride 1780 rag / kg

a-Phenyl-a-ethyl acetic acid pyridin ~ 2-yl methyl ester hydrochloride 2200 mg / kg

Diph enyl acetic acid epyridin-2 ~ yl-in ethyl es ter * -

hydrochloride 3000 mg / kg

Benzilic acid pyridin-2-yl methyl ester hydrochloride 5000 mg / kg a, a-Diphenyl ~ a ~ propoxyacetic acid pyridin-2-ylmethyl ester picrate -. '5000 mg / kg

3 ·, 4 ', 5'-trimethoxybenzoylinandelic acid pyridin-2-yl-methyl ester hydrochloride 5000 mg / kg

With the exception of certain derivatives that have a benzyl substituent have, none of the derivatives investigated showed any effect on the central nervous system.

The hemodynamic constants (heart rate, arterial pressure, etc.) were only slightly changed after oral, rectal and parenteral administration of the investigated products. A peripheral vasodilatory effect has been noted in a certain number of the derivatives, but the main interest for these derivatives is based on their antispasmodic (preventive and curative) effects on contracting agents such as histamine, acetylcholine, barium chloride and '■ 5-hydroxytryptamine, which are in vitro (on isolated organs) and in vivo (according to the "method, von Konzett). All these derivatives show an action that is more comparable to that of papaverine than that of atropine or that of synthetic antichollnergic compounds. Furthermore, the derivatives according to the invention have a moderate antitussive effect in certain cases (35% of the effect of codeine, which was used as a comparison compound).

30 9 8 2 0/1025

Claims (3)

Claims ) Pyridin-2-yl methyl ester derivatives of the general formula R · N: - O - CH _? - ⁰ R "X wherein -R is a hydrogen atom, a straight-chain or branched one low molecular weight alkyl group, a halogen atom, a phenyl group, a benzyl group, a cyclohexyl group, an alkenyl group or an alkynyl group, R ^{1 is} a hydrogen atom, a hydroxy group, a halogen atom, an alkoxy group, an alkyl group, an acyl group / ^R group or a group of the formulas 0-NC, ON * CR or ^X R / ^H
O-Ny, where R has the meaning given above, ^N H Ar is a phenyl group, a thienyl group, a benzyl group or an alkyl group, R "is a low molecular weight alkyl group or a hydrogen atom and X is a halogen atom, a methyl sulfate group or a picryl radical (C ₀ H ₂ N ₃ O ₇ ") _λ mean. 2.) a-chloro-a-phenylacetic acid pyridin-2-yl-methyl ester-hydro- chloride. 3.) a-Phenyl-a-ethyl acetic acid pyridin-2-yl-methyl ester-hydro- chloride. 309820/1025 4.) α-Phenyl-α-cyclohexyl acetic acid pyridin-2-yl methyl ester hydrochloride. '' »
5.) Mandelic acid pyridin-2-yl methyl ester hydrochloride. 6.) O-Acetylraandelic acid pyridin-2-yl-methyl ester hydrochloride. 7.) 0- (3 ', 4', 5 '-trimethoxybenzoyl) -nandelic acid pyridin-2-ylmethyl ester hydrochloride. " 8.) O-acetylmandelic acid pyridin-2-yl-methyl ester hydrochloride. 9.) a, ot-Diphenyl-a-ethoxyacetic acid pyridin-2-yl methyl ester hydrochloride. 10.) α, α-Dimethyl-α-propoxyacetic Murepyridin-2-yl-methyl ester. 11.) Thienylglyoxylic acid pyridin-2-yl-methyl ester hydrochloride. 12.) a-Phenyl-a-äthy1essigsäurepyridin-2-yl-methylester-jpdmethylat. 13.) a-Methyl-a-ethylcaproic acid pyridin-2-yl-raethylest§r-hydrochloride. 14.) a, a-Dimethylpropionic acid pyridine-2-ryl-methyl ester iodomethylate. . 15.) O-propylbenzilic acid pyridin-2-yl-methyl ester hydrochloride. 16,) O-Allylbenzilsäurepyridin-2-yl-methylester-hydrochloride .. 17.) O-propargylbenzilsoyridin-2-yl-methyl-ester-hydro-. chloride. 18.) Dibenzilessigsäurepyridin - ^ - yl-niethylester-hydrochloride. 30 9 82 nights / 102 5 ' 19.) α, α-Diphenyl-α-chloroacetic acid pyridine - ^ -. Yl-methyl ester. 20.) Process for the preparation of the compounds according to the claims 1 to 19, characterized in that 2-0xymethylpyridine with an organic acid or a 'corresponding Acid chloride in a solvent .reaetzt. 21.) Method according to claim 20, characterized in that the solvent used is ether, toluene, ethylene chloride or Benzene exhausts / ends. 22.) Pharmaceutical compositions, characterized in that they are a compound according to the claims as active ingredient 1 to 19 included. 23.) Pharmaceutical compositions according to claim 22, characterized characterized in that they can be administered by the oral, rectal or parenteral routes. 24.) Pharmaceutical compositions according to claims 22 and 23, characterized in that they additionally have further Contain active ingredients. 3 0 9 8 / i) I IU 2 b