DE1768615C3 - Amides of 2-hydroxy-3-methoxy-5-allyl-benzoic acid, process for their preparation and medicaments containing them - Google Patents

Description

where Ri and R _{2 are} identical or different and denote hydrogen or an alkyl radical having 1 to 4 carbon atoms which is optionally substituted by a hydroxyl group, or Ri and R2 together with the nitrogen atom represent a morpholine or piperidine ring.

2. 2-Hydroxy-3-methoxy-5-allyl-N - (/ hydroxyethyl) benzamide.

3. 2-Hydroxy-3-methoxy-5-allyl-N, N-diethylbenzamide.

4. Process for the preparation of amides according to claim 1, characterized in that one is in on known way either

a) an amine of the formula

NH
\

wherein Ri and R2 are those given in claim 1 Have meaning with a functional derivative of the carboxyl group of 2-hydroxy-3-methoxy-5-allyl-benzoic acid condensed, or

b) the ester of an organic carboxylic acid having 1 to 18 carbon atoms in position 2 of the

2-Hydroxy-3-methoxy-5-allyl-benzoic acid by the action of an appropriate esterifying agent forms, the obtained 2-acvloxy-3-methoxy-5-allyl-benzoic acid by action a halogenating agent or a dehydrating agent into a functional derivative transferred, an amine of the above formula to the functional derivative formed can act and the corresponding 2-acyloxy-3-methoxy-5-allyl-benzamide obtained, which is saponified to 2-hydroxy-3-methoxy-5-allyl-benzamide, or

c) a functional derivative of 2-hydroxy-3-methoxy-benzoic acid with an amine of the formula above converted into an amide, then to the 2-hydroxy-3-methoxybenzamide formed allows an allyl halide to act to obtain a 2-allyloxy-3-thoxybenzamide, in which a Claisen rearrangement to 2-Hydroxy-3-methoxy-5-allyl-benzamide is carried out.

5. Medicaments, characterized by a content of amides according to claim 1 as the sole Active ingredient.

The invention relates to arnides of 2-hydroxy-3-methoxy-5-allyl-benzoic acid (Eugentic acid) of the formula

OH

CH ₃ O

CON ₁ (1)

CH ₇ -CH = CH,

where Ri and R2 are identical or different and denote hydrogen or an alkyl radical optionally substituted by a hydroxyl group and having 1 to 4 carbon atoms, or Ri and R ₂ together with the nitrogen atom represent a morpholine or piperidine ring.

The amides of eugetic acid of the foregoing Formula (I) have interesting and peculiar pharmacological properties; they have in particular remarkable choleretic properties, which are clearly superior to those of dehydrocholic acid.

The invention thus also relates to medicaments which are characterized by a content of compounds of the above formula (I) as the sole active ingredient.
Of particular interest among the compounds according to the invention are:

2- hydroxy-3-niethoxy-5-allyl-

N- (j? -Hydroxyethyl) benzamide,

2-hydroxy-3-methoxy-5-allyl-benzoyl-morpholine,

2-Hydroxy-3-methoxy-5-allyl-benzoyl-piperidine,

2-hydroxy-3-methoxy-5-allyl

N- (j3-hydroxypropyl) -benzamide,

2-hydroxy-3-methoxy-5-allyl

N- (n-propyl) benzamide,

2-hydroxy-3-methoxy-5-allyl

N, N-diethyl-benzamide,

2-Hydroxy-3-methoxy-5-allyl-benzamide and

2-hydroxy-3-methoxy-5-allyl

N - («A-dimethyl-j3-hydroxyethyl) benzamide.
The process according to the invention for the preparation of the compounds of the above formula (1) is characterized in that an amine of the formula is used in a manner known per se

NH \

(H)

wherein Ri and R2 have the meaning given above have, with a functional derivative of the carboxyl group of 2-hydroxy-3-methoxy-5-allyl-benzoic acid condensed, (see the attached scheme, route A).

The functional derivative of 2-hydroxy-3-methoxy-5-allyl-benzoic acid used is an acid halide such as chloride or bromide, an acid anhydride mixed anhydride or a lower alkyl ester. One can use the mixed anhydride that is produced by Action of a dialkylcarbodiimide on 2-hydroxy-3-methoxy-5-allyl-benzoic acid is formed.

The condensation temperature of the functional derivative of 2-hydroxy-3-methoxy-5-allyl-benzoic acid depends on the functional derivative and the amine. With ammonia, the reaction is preferably carried out below 50 ° C. With a primary or secondary amine will

at a temperature between 80 ⁰ C and the lückflußtemperatur of ve.-employed amine by going variant of the process according to the invention is characterized rch <.H that the ester is a

table carboxylic acid with 1 to 18 carbon atoms

SSLg 2 der ^ Hydroxy ^ methoxy-S-aUyl-ben-

n ^ aure by the action of a corresponding

υ / esterification agent forms, the obtained 2-aevloxy-3-

Pthnxv-5-allyl-benzoic acid through the action of a u wenierungsageiis or a dehydrating agent η eSSnel'Js derivative transferred to the formed derivative Lktionelle an amine of formula (II) act äJt and the appropriate 2-acyloxy-3-Methox _y -5- alvl-benzamide saponified (cf. the attached scheme, route R in which AC is the residue of an organic _{carboxylic acid with 1 to 18 carbon atoms and X is 1} on a calogen atom, the residue of an acid anhydride or the residue of a mixed anhydride).

The condensation of the functional derivative of the 1 Acvloxy-S-methoxy-S-allyl-benzoic acid with the \ Z \ _n Her formula (11) in an inert ner-complementary and Ä ^ temperature below 5O = C is performed. The functional derivative of 2-acyloxy-3-methoxy-5-allyl-benzoic acid used is preferably a sau- «halide, and the amide is converted in the presence of an acid acceptor.

Another variant of the process according to the invention is characterized in that a functional derivative of 2-hydroxy-3-methoxybenoic acid is mixed with an amine of _| Formula I (II) is converted into an amide, then an allyl halide is allowed to act on the 2-hydroxy-3-methoxvbenzamide formed in order to Allvloxv-3-methoxy-benzamide, in which one carries out a Claisen rearrangement to 2-hydroxy-3-methoxy 5-allyl-benzamide (see the attached scheme path C in which X is a halogen atom, such as chlorine or bromine the remainder of an acid anhydride, the residue of a mixed anhydride or a lower alkoxy ^1ST) the introduction of the allyl group in the 2-hydroxy-3-methoxy-benzamide is by exposure to a Allvlhalogenids in the presence of an alkaline agent SKgtfOhrt the rearrangement of the 2-All _y loxy-3-rneth _oxy Benzamides to ^ ydroxy ^ methoxy ^ allyl-benzamides is carried out by heating at a temperature between 150 and 250 ° C. The following examples explain the invention in more detail.

Example 1 5 «

2-Hydroxy-3-methoxy-5-aHyl-N (j3-hydroxyethyl) benzamide

36 g of ethyl ester of 2-hydroxy-3-methoxy-5-allyl-benzoic acid are mixed (obtained according to from Pearl and Beyer in "]. Amer.Chem.Soc", 71 (1949), 1067 up to 1068, described method) and 6t g ethanolamine, left in contact for 1 hour at room temperature and then brought to 120 ° C. over an hour. Man extracted with chloroform, the organic phases are washed with semi-dilute hydrochloric acid, then with water; the chloroform is evaporated and, after recrystallization from benzene, 2-hydroxy-3-methoxy-5-allyl-N - (/? - hydroxyethyl) benzamide is obtained. (Yield 78.5%).

The product is obtained in the form of colorless crystals which are insoluble in water in dilute sodium hydroxide solution are inviif-h and melt at 95 ° C.

Analysis: C ₁ 1H ₁₇ NO ₄ = 251.27:

Calculated: C 62.12, H 6.82, N 5.57%;
found: C 62.4, H 6.8, N 5.6%.

LR ^ -Spcktrum - Nujol:

OH at 3500 cm- ¹ ,

NH at 3320 cm- ',

C = O at 650 cm ¹ ,

CH = CH ₂ at 905 and 985 cm - '.
UV spectrum - ethanol:

λ max. at 316 and 218 Γημ,

Shoulder at 250 mu,

λ min. at 275 Γημ.

Example 2

2-Hydroxy-3-methoxy-5-allyl-N- (β-hydroxyethyl) benzamide can also be obtained in the following manner
will:

Level a

2-hydroxy-3-methoxy-N- (0-hydroxyethyl) benzamide
14.4 g of 2-hydroxy-3-methoxy-benzoic acid ethyl ester and 30 cm ^{1 of} ethanolamine are mixed, one is heated
Hour at 120 ⁰ C, extracted with chloroform and
washes the organic phases with dilute hydrochloric acid; after evaporation of the solvent
12.8 g of 2-hydroxy-3-methoxy-N- (j3-hydroxyethyl) benzamide are obtained (yield 82%) in the form of colorless crystals which are insoluble in water and soluble in dilute sodium hydroxide solution; M.p. = 97 ° C.
Analysis: C ₁ oH ₁₃ N0 ₄ = 211.21:
Calculated: N 6.64%;
found: N 6.69%.

Level B.

2-Hydroxy-3-methoxy-5-allyl-N - (/} - hydroxyethyl) benzamide

12 g of 2-hydroxy-3-methoxy-N- (β-hydroxyethyl) benzamide, 7.6 g of allyl bromide and 7.87 g of potassium carbonate are mixed in 12 cm ^{3 of} acetone, refluxed for 8 hours, and 50 cm ^{3 of} water are added to and extracted with chloroform; the organic phases are washed with 1N sodium hydroxide solution and distilled in vacuo. The crude allyl ether obtained is gradually heated to 200 ° C; the boiling is maintained for 30 minutes, dilute sodium hydroxide solution is added and the mixture is extracted with chloroform; the alkaline phase is acidified with dilute hydrochloric acid; it is extracted with chloroform. After evaporation of the solvent, the residue taken up in ether crystallizes; 2-hydroxy-3-methoxy-5-allyl-N- (jJ-hydroxyethyl) benzamide (mp = 95 ° C.), which is identical to the product obtained in Example 1, is obtained.

40

Example 3

2-Hydroxy-3-methoxy-5-allyl-N - (β-hydroxypropyl) benzamide

Bringing a mixture of 10.5 g Isopropano amine and 5 g of 2-hydroxy-3-methoxy-5-allyl-benzoesäi re-ethyl ester for one hour at 130 ⁰ C; d solution obtained is extracted with chloroform; The organic phases are washed with half-concentrated hydrochloric acid, then with water and evaporated to dryness; 2-hydroxy-3-methoxy-5-allj N- (β-hydroxypropyl) benzamide is obtained with a yield v (55%.

The product is obtained in the form of colorless crystals which are soluble in dilute sodium hydroxide solution and insoluble in water; M.p. = 86 ° C
Analysis: C ₁₄ H ,, NO ₄ = 265.29:

Calculated: N 5.28%; found: N 536%.

Example 4
2-hydroxy-3-methoxy 5-allyl-benzoyi-morpholine

One brings 25 g of 2-hydroxy-3-πlethoxy-5-allyl-benzoic acid ethyl ester and 61 g of morpholine at reflux for 4 hours; then the excess morpholine is distilled off under reduced pressure, extracted with chloroform and washed the organic phases with dilute Hydrochloric acid, then with water; the chloroform is distilled off and the residue is washed with ether and crystallizes from isopropyl ether; 2-hydroxy-3-methoxy-5-allyi-benzoyl-morpholine is obtained with a yield of 653%

The product is obtained in the form of colorless crystals which are insoluble in water and soluble in dilute sodium hydroxide solution; M.p. = 108 ° C
Analysis: C, ₅ H 19NO ₄ = 277.30:

Calculated: N 5.05%; found: N 5.10%.

Example 5
2-Hydroxy-3-thfiethoxy-5-ayl-benzoyl-piperidine

A mixture of 25 g of ethyl 2-hydroxy-3-methoxy-5-allyl-benzoate is added and 60 g of piperidine at reflux for 3 hours; then the excess piperidine is distilled off under reduced pressure from, extracted with chloroform, the organic phases were washed with dilute hydrochloric acid, then with Water; it is evaporated to dryness and crystallized from isopropyl ether; 2-hydroxy-3-methoxy-5-allyl-benzoyl-piperidine is obtained with a yield of 65..5%.

The product is obtained in the form of colorless crystals; F. = 90 ° C
Analysis: C ₁₆ H ₂₁ NO ₃ = 275.33:

Calculated: N 5.08%;

found: N 5.15%.

Example 6
2-Hydroxy-3-melhoxy-5-allyl-N- (n-propyl) benzamide

Level A.
2-acetoxy-3-methoxy-5-allyl-benzoic acid

35 g of 2-hydroxy-3-methoxy-5-allylbenzoic acid (described by Scheuch in Liebigs Annalen der Chemie, Vol. 125, p. 17) are suspended in 32 cm ^{1 of} acetic anhydride, a few drops of sulfuric acid are added and the mixture is heated to 50 for 15 minutes to 6O ⁰ C; after cooling, 33 cm ^{3 of} water are added, the mixture is left to stand for two hours and extracted with ether; it is evaporated to dryness and crystallized from benzene; 2-acetoxy-3-methoxy-5-allyl-benzoic acid is obtained with a yield of 74.5%.

The product is obtained in the form of colorless crystals; F. = 127 ° C.

Analysis: C,, HuO ₁ = 250.26.
Test with i; isen (III) chloride: negative (absence of level B

2-Acetoxy-3-methoxy-5-allylbenzoic acid chloride

Dissolve 10 g of 2-Aeetoxy-3-methoxy-5-al yl-benzoic acid in 40 cm ^J thionyl chloride and brings to the end of gas evolution to reflux!; the excess thionyl chloride is removed and the mixture is distilled under reduced pressure; an oil which boils at 160 to 161 ° C. at 2 mm Hg and slowly crystallizes: the chloride of 2-acetoxy-3-methoxy-5-allylbenzoic acid is obtained with a yield of 62%; the product melts at 50 ⁰ C.
Analysis: C, ₅ H, jCIO «= 268.57:

Calculated: Cl 13.19%;

found: Cl 13.22%.

Level C
2-acetoxy-3-meihoxy-5-allyl-N- (n-propy]) benzamide

To a solution of 3.6 g of chloride of 2-Accioxy-3-methoxy-5-ai! Yi-benzoic acid and *., 1 g of triethylamine in 25 cm ³ of acetone, is added slowly a solution of 0.86 g of n- Propylamine in 25 cm ^{1 of} acetone, keeping the temperature between +10 ⁰ C and +15 ⁰ C: it is filtered, evaporated to dryness under reduced pressure and crystallized from isopropyl ether: 2-acetoxy-3-methoxy-5- is obtained al! y! -Nn-propylbenzamide with a yield of 61% -

The product is obtained in the form of colorless crystals which are insoluble in dilute sodium hydroxide solution; F. = 90 ° C
Analysis: C ₁₆ H ₂ , NO ₄ = 291.34:

Calculated: N 4.80%;

found: N 4.80%.

Level D
2-Hydroxy-3-methoxy-5-allyl-N- (n-propyl) -benzamide

1 g of 2-acetoxy-3-methoxy-5-allyl-N- (n-propyl-benzamide is dissolved in an excess of 0.9 n-methanolic potassium hydroxide solution, left in contact for 30 minutes and brought to pH by adding dilute hydrochloric acid to 7; after evaporation of the methanol, the residue is taken up in water, hydrochloric acid is added and the mixture is extracted with chloroform; the organic phases are washed with water and distilled to dryness; an amorphous product is obtained which is crystallized from isopropyl ether; one receives O.ül g of 2-hydroxy-3-methoxy-5-allyl-N- (n-propyl) -benzamide (yield 60%) in the form of colorless crystals, which are insoluble in water, soluble in dilute sodium hydroxide solution; F. = 95 ° C
Analysis: C ₁₄ H ₁₉ NO) = 249.29:

Calculated: N 5.61%;

found: N 5.56%.

Example 7
2-Hydroxy-3-methoxy-5-allylN, N-diethylben7amide

Level A.
2-Hydroxy-3-melhoxy-N, N-diethyl-benzamide

Dissolve 16.81 g of Z-hydroxy-Smethoxy-ben / .ocsäure in 400 cm ¹ acetone and added 30.35 g of triethylamine / u.

Then 22 cm ^{1 of} ethyl chloroformate are added. the triethylamine hydrochloride formed is filtered off, 14.63 g of diethylamine are added and the mixture is left to stand for about 12 hours.

The acetone is distilled off and the residue is taken up with a 1 η solution of potassium hydroxide in Ethanol on. After standing for about 12 hours, it is filtered.

The ethanolic solution is acidified with 1N hydrochloric acid and then evaporated under reduced pressure. The residue is taken up in ether, washed with water and the ether is evaporated. After crystallization from isopropyl ether, the product obtained is obtained in the form of colorless crystals; F. = 86 ^C C (yield 43%).
Analysis: C ₁₂ H ₁₇ NOj = 223.26:

Calculated: N 6.27%:

found: N 6.30%.

Level B.
2-Allyloxy-3-methoxy-N, N-diethylbenzamide

A suspension of 9.6 g of 2-hydroxy-3-methoxy-NN-diethylbenzamide, 5.71 g of allyl bromide and 5.93 g of potassium carbonate in 50 cm ^{1 of} acetone is refluxed for 8 hours. The acetone is distilled off in vacuo, the residue is taken up in ether and washed with 1η sodium hydroxide and with water. After evaporating the ether, the remaining oil is distilled. A fraction (8 g) boiling between 137 and 139 ° C. at 0.3 mm is obtained.
Analysis: C ₁₅ H ₂₁ NO ₃ = 263.32:

Calculated: N 5.31%;

found: N 5.30%.

Level C
2-Hydroxy-3-methoxy-5-allyl-N, N-diethy! -Benzamide

8 g of 2-allyloxy-3-methoxy-N, N-diethyl-benzamide are gradually brought to 21O ⁰ C and held for half an hour at this temperature. After cooling, the product is extracted with 1N sodium hydroxide solution. It is acidified with dilute hydrochloric acid and extracted with ether. The oil obtained is distilled under reduced pressure after evaporation of the ether. A fraction boiling between 155 and 165 ° C at 0.4 mm is obtained (yield 25%).
Analysis: CisH ,, NOj = 263.32:

Calculated: N 5.31%;

found: N 5.26%.

Example 8

2-Hydroxy-3-methoxy-5-allyl-N- (ox-dimethyl- / S-hydroxyethyl) -benzamide

30 g 2- ^ dTOXy-S-IHeIhOXy-5-alIyI-benzoe-

ethyl acid ester are gradually added to 74.8 g of 2-amino-2-methyl-1-hydroxypropane. The mixture is ^{brought to 130 °} C. for one hour. After cooling, it is taken up in chloroform, washed with dilute hydrochloric acid, then with water. The chloroform is evaporated under low pressure; crystals are obtained which are recrystallized from isopropyl ether. The product is obtained in the form of colorless crystals; M.p. = 98 ° C (yield 57%). Analysis: CH ₂₁ NO ₄ = 27932:

Calculated: N 5.01%:

found: N 5.03%.

Example 9 2-hydroxy-3-methoxy-5-ally] benzamide

Level a
2-allyloxy-3-methoxy-benzamide

1.71 g of 2-hydroxy-3-methoxy-benzamide are suspended. 1.41 g of potassium carbonate and 1.45 g of allyl bromide in 12 cm ^{3 of} acetone. It is refluxed for 8 hours. The acetone is then evaporated in vacuo, taken up in water and extracted with ether. The ethereal solution is washed with 1N sodium hydroxide solution and with water, then evaporated in vacuo. Colorless crystals with a melting point of 80 ° C. are obtained, which are insoluble in water and dilute sodium hydroxide solution (yield 95.5%).
Analysis: CuHnNO ₁ = 207.21:

Calculated: N 6.76%;

found: N 6.75%.

Level B.
2-Hydroxy-3-methoxy-5-α-lyl-benzamide

1 g of 2-allyloxy-3-methoxy-benzamide is heated at 200 ° C. for 20 minutes. The after cooling and recrystallization colorless crystals obtained from benzene melt at 142 ° C. (yield 30%).

Analysis: CnH, jNOj = 207.21:
Calculated: N 6.76%;
found: N 6.80%.

The 2-hydroxy-3-methoxy-benzamide used as the starting material in this example is as follows manufactured:

a) 2-Benzyloxy-3-methoxy-benzoic acid ethyl ester

14 g of ethyl 2-hydroxy-3-methoxy-benzoate are introduced into a solution of 1.62 g of sodium in 100 cm ^{1 of} absolute alcohol. The sodium phenolate formed is filtered off, dried and dissolved in 310 cm ^{1 of} dimethylformamide. 9.88 g of benzyl chloride are added to the solution obtained. then heated to 120 ^° C. for two hours

After cooling, it is filtered, the solvent is evaporated and the residue is taken up in ether. The ethereal solution is washed with dilute sodium hydroxide solution, then with water and evaporated to dryness. The ethyl 2-benzyloxy-3-methoxybenzoate obtained is obtained in the form of an oil, since at 176 to 180 ° C. it passes over at 0.4 mm (yield 75.5%).

Analysis: C ₁₇ H ₁₈ O ₄ = 286.31.

Molecular weight found: 288.2.

b) 2-benzyloxy-3-methoxy-benzoic acid c

The ethyl 2-benzyloxy-3-methoxybenzoate obtained above is refluxed in alcohol shear potassium hydroxide solution saponified for 30 minutes. After cooling, crystals are obtained 2-Benzyloxy-3-methoxy-benzoic acid, which can be obtained from lso recrystallized propyl ether (yield 62%). The colorless crystals formed melt at 90 "C. Analysis: C ₁ ^ Hi ₄ O ₄ = 258.26. Molecular weight found: 257.5.

709 613/6!

ίο

c) 2-Hen / yloxy-J-meihoxy-ben / amid

7 g of 2-benzyloxy-J-meihoxy-benzoic acid are treated with 3.55 g of thionyl chloride, dissolved in 70 cm ^{1 of} chloroform. The mixture is heated to reflux for two hours and then the solvent is distilled off under reduced pressure. The crude silicon chloride is obtained, which is introduced into 50 cm ^{1 of} concentrated ammonia. The crystals formed are filtered off with suction and recrystallized from ether; colorless crystals with a melting point of 70 ° C. (yield 32%) are isolated.
Analysis: Ci-, Hi ₅ NOj = 257.27:

Calculated: N 5.44%;

found: N 5.57%.

d) 2-hydroxy-3-methoxy-benzamide

2.57 g of 2-benzyloxy-3-methoxy-benzamide, dissolved in 50 cm ^{3 of} absolute alcohol, are hydrogenated in the presence of 0.5 g of palladium on charcoal for a few minutes. After filtration, the alcoholic solution is evaporated and the product obtained is recrystallized from isopropanol. The 2-hydroxy-3-methoxy-benzamide is obtained in the form of colorless crystals; M.p. = 154 ° C (yield 70%).

Analysis: C ₈ HqNO ₃ = 167.16:
Calculated: N 8.37%;
found: N 8.58%.

As indicated above, the products of formula (I) have interesting pharmacological properties. In particular, they have a significant choleretic effect. They can be used for Treatment of dyspeptic disorders due to biliary insufficiency, functional Leger-Gall-Stömngen, Food intolerance, urticaria, itching, migraines and constipation caused by the liver.

The amides of 2-hydroxy-3-methoxy-5-allyl-benzoic acid according to formula (I) are used by the oral, transcutaneous or rectal route. she can be offered in the form of injectable solutions or suspensions, tablets, coated tablets Wafers, capsules, odoriferous powders, granules, emulsions or suppositories.

ίο The appropriate dose is staggered between 300 and 400 mg per day in the adult in an amount of 100 to 200 mg per dose depending on the Route of administration. The pharmaceutical forms such as injectable solutions or suspensions, tablets, Dragees, wafers, capsules, smelling powders, grains, emulsions and suppositories are after usual process.

Test report

The choleretic efficacy is determined by determining changes in the level of the bile divorce was investigated in male rats weighing approx. 250 g.

After anesthesia with urethane, a catheter is inserted into the upper part of the main bile duct.

The investigated products are administered intraduodenally at equal doses of 1/5 and 1/25 of the DL ₅₀ (DL ₅ administered intraperitoneally).

The biliary level is checked every 30 minutes, for the first time half an hour before administration: examined product, measured.

The results obtained are summarized in Tables I and II.

Table I (dose: 1/5 DLso)

Increase in the level of bile after administration of the product

Connection of example no.

dose
mg / kg

From 0 to 30 min.

From 30 to b0 min.

From 60 to 90 min.

3
4th
5
7th
8th
9
Sodium dehydrocholate

230 + 103% + 94% + 68% 226 + 61% + 54% 200 + 54% + 55% + 45% 255 + 31% + 31% + 15% 220 + 119% + 146% + 113% 230 + 29% + 39% 260 + 11% + 40% + 40% 280 + 110% + 60% + 30%

Table II (dose: 1/25 DLso)

Increase in the level of bile after administration of the product

Connection of example no.

dose
mg / kg

From 0 to 30 min.

From 30 to 60 min.

From 60 to 90 min.

1
3
4th
5
7th
8th
Sodium dehydrocholate

46 + 82% + 540/0 + 42% 45 + 14% + 5% 40 + 25% 0 51 + 20% + 20% _ 44 + 110% + 80% +360/0 46 + 14% 0 56 + 35% + 10% 0

Way A:

OH
CH ₁ OI COX

CH- CH -CH,

Reaction scheme

NH

12th

OH
CH ₁ OI CON

R.

Wen B:

OH
CH ₃ OI COOH

CH, -CH = -CH, OAC
CH ₃ OI COOH

CH, -CH = CH,

OAC
CH, OI CON

CH ₂ -CH = CH ₂

OH
CH ₃ O! CON

R.

CH, -CH = CH,

WesiC:

OH
CH ₃ O I COX

OAC
CH ₃ OI COX ₁

CH ₂ -CH = CH ₂

OH CH ₃ OI CON

R.

R,

CH, O

OH /

CON

CH ₂ -CH = CH ₂

CH ₃ O

OCH ₂ -CH = CH ₂

CON V \

Claims (1)

Patent claims: 1. Amides of 2-hydroxy-3-methoxy-5-allyl-benzoic acid the formula CH ₃ O CON CH ₂ -CH = CH ₂