DE1915023C3 - (2,4-Dlmethoxyphenyl) -3-crotonic acid containing light agent for biliary and liver diseases - Google Patents

Description

H ₁ CO

CH,
C = CH-CO ₂ H

OCH.,

contains.

The invention relates to a new remedy for biliary and liver diseases. This; The active ingredient is (2,4-dimethoxyphenyl) -3-crotonic acid with the gross formula C ₁₂ H ^ U ₄ . and the structural formula

umttcwandcli. In one / one you think z. B. before how explained below:

[. a) 4-methyl-7-hydroxycoumarin

Starting from 220 g of resorcinol and 260 g of ethyi -. «M-ccfil in 2 liters of conical sulfuric acid So one obtains in 71% yield about 251 S-Melhyl-T-hydroxycumariny the one Schmcl / -

, o point of 185 C.

b) Methylated derivative of compound a)

M-Hi tears 200 si of 4-methyl-7-hydroxycoumarin

with "Ί 50 2 methyl sulfate in 2.5 liters of an aqueous

solution of 18 c NaOH react; then you sit down

Add hydrochloric acid until the pH is 2 and separate

the low sleeper. The yield of methylated cm

Product whose melting point be. 157 C. i55g = 72%.

c) (2,4-dimethoxyphynyl) -3-crolonic acid

The product b) is dissolved in methanol, with soda; inline alkaline siem eight and methylsulfate mcthy-S Mhi c rhälf the acid by precipitation with SAI / - - hri oH 1 Man 120 uses a 4-methyl acid: dc P ^ _{g% McthyIsu} if _at and 300 g of 7-methoxy ^^ ^ _{Ausbcutc ; m} ^

Soda η. ^ ^ _{Schmel / I49 point c}

^Μ1 ™ | _M etaHsa! / E of (2,4-dimethoxyphenyl) -3-crotonic acid can be produced by the following process

^25th

CH,
C-CK-CO ₂ H

Λ Χ

H ₃ CO OCH.,

or pharmacologically acceptable salts of this acid, especially metal salts, such as. B. the lithium, Sodium, potassium and magnesium salts, or salts of organic bases, such as. B. the salts of amino acids of the Krebs cycle.

via (2,4-dimelhoxypheny!) -3-crotonic acid has been reported variously in the literature: Beilstein's Handbook of Organic Chemistry 4. Up! (1927), Vol. 10, p. 440: Chemisches Zcntralblatt Md. 110 (1939 1), p. 3142; Chemisches Zentralblatt Vol. Ill (1940 II). P. 1873; Chemical Abstracts Vol. 58 (1963-1). Sp.! Ο,! 6O; Chszr.iea! Abstraf vol. 65 (1966 II), Sp. 15, 265-266.

It has now been found that this connection has extremely valuable pharmacological properties that make this compound a suitable remedies ges: er, (inlk-n- and liver diseases do.

The compound has a melting point of 149 C. B. according to the one given below Procedures are presented:

One starts with methylumbeiliferone or 4-methyl-7-hydroxycoumarin out. which is first methylated to 4-methyl-7-methoxycumann. This latter Connection is then made by opening the coumarin ring into the (2,4-dimethoxyphenyl) -3-crotonsaiire ^ arTbercitet an aqueous solution of the carbonate «Of the metal in question (Mg. Li. Na or K] 1 and sets in the cold a very concentrated, alcoholic Dissolve the acid with vigorous stirring, whereupon The mixture is heated to 70 ° C. for 30 minutes. The mixture is then evaporated under reduced pressure Pressure at ambient temperature and recover the crystalline residue.

LH's magnesium salt of (2,4-dimethoxyphenyH-3-crotonic acid has, for example, the gross formula C \ ₄ H _2h O _K Mg. The following structural formula:

CH ₁ O

CH,

C - ,, CU COO -

OCH.,

Mg

II For IO si (2.4-Dimethoxyphcnyi) -3-croumic acid dissolved in ethyl alcohol 2.41 g of magnesium carbonate are added in aqueous solution: 12 g are obtained Magnesium-2,4-dimelhoxyphenyl-3-ciOlonul. of-

sen "melting point with decomposition is 135 ° C

and that is sparingly soluble in water. You can also use an amino acid like that

Arginine, citrulline or ornithine a salt.

the ¹ 4 - Dimethoxyph'-nyl - 3 - crotonic acid form. 65 For example, the 2,4-dimelhoxyphenyl

3-crotonate of citrulline «, as follows:

III Ad 4.37 ■ _ ■ 2.4-Dimcthoxyphenyl-3-crotonic acid c 5.20 g of I-Ci-

lriillin in aqueous solution and receives 9 g of the Dimethoxyphenylcrotonnls des C'ilrullins. its melting point with decomposition at 190 C:

NH,

H ₃ CO OCH,

Naehstchend the results of pharmacological tests are reported, which Dimclhoxyphenylcrolonsäure (in the form of their magnesium salt. Unless otherwise stated) was cast them ι nlcr- i ^r>.

Chronic toxicity

This determination was carried out on the rat for 3 months: the daily oral administration of 50 mg kg of the compound to male and female rats caused no visible effects Damage. In particular: I found no differences when determining the weight of the test and comparison animals, and the hemological values were unchanged.

pharmacology
1. Gall stimulating effect

a) In dogs, 50 mg produce kg. administered duodenally, a slight and temporary increase in bile production.

100 mg kg. Administered duoüenally, cause a significant and lasting effect. th increase (2.9 times normal production in the first hour and 2.3 times in the second hour). Observed at the same time an increase in the value of the dry bile extract (twice as much in the first and 1st times in the / wide hour).

b) In rats, 25 mg / kg, administered duodenally, cause a slight increase in bile production (1.4 times in the first and 1.1 times in the next hour) 50 mg kg make a difference and sufficiently constant increase (2.1 times in the first and 1.2 times in the while Lesson). 100 mg kg. Administered by the same route, have a significant and lasting effect Increase in production (2.2 times in the first and 1.5 times in the / long hour).

50

2. Spasmolytic effect (of I.ithiumsal / esi

Studies on smooth tissue; isolated 7wnlFFiniuTil; irm na Knninrhi'ns:

The spasms were induced by acetylcholine in a con / entralion of 10 ^ft g ml. The Dl ·! ,,, of the product is 3.75 - IO ⁴ g ml.

Ciallenhlasc of the guinea pig:

The spasms were induced by pilocarpine in a con / entralion of IO '' gml. The Dl ·! ,,, of the product is 3.75 ■ IO ⁴ g ml.

Investigations on the Oddish muscle in dogs:

The spasms induced by pilocarpine at a concentration of 100 micrograms per kg will be by injecting the lithium sulfate (intravenous) inhibited at a dose of 150 my kg. the The same dose opens the Pilocarpine contracted Oddian muscle.

CH-CO ₂ H. H ₂ NC-NH- (CH ₂ J ₃ -CH

COOH

The 2,4 - dimethoxyphenyl - 3 - crotonic acid and its salts can also be used to treat excessive Gaien production in the biliary outlet, GaI lenstau hepatitis, certain forms of cholelithiasis, digestive migraines, or allergic reactions cause hepatic insufficiency without exhausting all possibilities of their application are.

The compound can be used with an excipient for oral administration, in particular in the form of coated tablets or capsules with a dose of 25 to 10 t) mg of active substance. The middle daily dose is 50 to 200 milligrams.

Examples of preparations, soft (2,4-Dimethoxyphenyi » ϊ-crotonic acid as an effective agent contain:

1. Granules

(2,4-dimethoxyphenyl) -

3-f rotonic acid (magnesium salt) .. Ig

Citric acid 2.5 g

Sodium citrai 3.5 g

Flavors (alcoholic

Orange extract [sangria]) 3 g

Refined sugar 69 g

Alginic Acid. "'. Ig

Granulated sugar 20 g

New coccin 0.025 g

100,025 g

2. Capsules

(2,4-dimethoxyphenyl) -

3-crotonic acid (magnesium salt) .. 25 g

Amidone 21.5 g

Colloidal silica 0.5 g

Magnesium stearate 3 g

Lactose 50 g

100 g

3. tablets
(2,4-dimethylphenyl) -

I acio.se 34.54 g

Corn amidone 16.44 g

Alginic acid 2.20 g

Polyvinylpyrrolidone 1.00 g

Sugar refinade 5.25 a

Colloidal silica 1.75 g

(calcium carbonate 4.72 g

Glycerine Palmitostearic Acid ... 0.50g

Pure talc 0.05 g

I (K) .OO µ

The following results from Comparative Experiment L-n show the superiority of the remedy

compared to known commercial product cycles. the for the the same purpose as the above-described Mitlei can be offered. Winding as comparison products hcranuczoticn:

"- H ₃ CO

(1) HO-CH ₂ -CH ₂ -O ^ oVcH CH COOH (Hydro \ y-2) -alhoxy-4-methoxy-3-cinnamic acid

ίο

CH,

2. Choleretic effects

Λ) In the rat: test method according to:

Boucard and Λ he la. Ann. pharm. rrane .. ⁷ I 78 S- 551 559: Girnux. 13 ο nc aid and Bcaulalon. Soc. Pharm. Montpellier. 1955. IS (1) p155; Grandgeorge. D u ρ erra γ and P ä chcc ο. Therapy, 1973. 28, p. 1013 102 *.

The daily dose was generally about the DL ₅₀ value (IP) in the mouse. In comparison, the amounts of D 207 used are '· "and',"'of the DL, "- Wcncs in the mouse.

Cicroton acid

-COOH

^ -COOH

product

Effectiveness-

Kiicdi / icnt

, H 211

OCH ₃

a - phenyl - orlhomethoxy - rr.agnesiumcinnamal

(2,4-Dimethylphenyl) -3-crotonic acid is referred to below as D 207.

1. Determination of the DL _5n value

2.2

2.1

1.09

2.22

2.07

connection

D 207

Hand.

Prep. (3)

Hand.

Prep. (L)

Hand.

Prap. (2)

product

D 207

YOU,
IP

DL «"
IP

POPO
Mouse Rallc Mouse Rough

(mg / kg) (mg; kg) (mg / kg) (m.u'kg) 1.5

1.2

1.13

2.05

1.90

1.88

1300
1000

3000 3000

2000
2000

2900 D 207

100 mg kg

D 207

50 mg kg

Hand. Prep. (D 200 mg / kg

Hand. Prep. (2) KM) mg / kg

Hand. Preparation (2) 150 mg / kg

Hand. Preparation (2) 2.26,300 mg / kg

The "efficiency factor" is the ratio the (increased) hourly bile secretion after administration of the product for normal secretion.

B) in the dog; Test method according to:

The t rc. Arch, dc physio! .. 1890. 2, Scnc

The dose used entrusts' _{4 of} the DL _5t) -Wcrtc.s (IP) in the case of the mouse door the v _C rgIe: chssubsUinzen and ¹ Z _{13 of} the DL ₅₀ value for D 207.

0.96

1.55 1.36 1.32

Number of years

35 40 40

40 40 40

partunu

Hand. Prep. (3)

Hand. PrepHl
Hand. Prep. 12)

dose
(mg / kg)

100
100
100
100

100

100

100

100

150

150

85

75

20 (1
100

100
300

Effective kits-Kocffizicnl

IH 2H 3H

Number of animals

evaluation

4.00

5.20

2.08

2.31

2.50

2.90

4.60

2.97

2.74
1.02
0.98
1.31

3.11
1.05

1.42
1.40

2.50 5. (M) 2.33 1.93 1.10 3.30 3.75 2.41

1.50
2.80
2.29
1.43
0.32
1.40
Ζ.ΐ j
1.35

1.28

4.48
1.42

1.80
2.00

4H

0.87 1.64 2.37 1.12 0.36

1.28

4.26 1.78

1.82 1. «?

\ I t

7 ^? 8th

II. Spasmolylic effect

This effect was determined in vivo on dogs. It was examined whether the products are able to to prevent the spasms caused by pilocarpine chlorohydrate in the Oddic muscle.

The product comparison period after addition. Pilocarpine bladder count after treatment

Dose Bubble number Bubble number

5 '10' 15 'I' 5 '10' 15 '5' iff 15 '

D 207 12 13 Il 0 0.3 0 1 25 (9 14

100 mg / kg

^! Hand. Prep. (I) 21 20 22 5 1 0 I 10 30 34

200 mg / kg

Claims (1)

Claim: Oral Applicable cure Gallcn- and liver diseases, dad Ureh ϊ ^ ^η is characterized in that it as an effective component U, 4-dimethoxyphenyl) -3-Crotonsäurc the btruK-turformei