CH624381A5 - Process for the preparation of phenoxyalkanecarboxylic esters of hydroxyalkyl salicylates - Google Patents

Description

624 381

2nd

PATENT CLAIMS

1. A process for the preparation of new phenoxyalkane carboxylic acid esters of hydroxyalkyl salicylates of the formula 1

C00 (CH „) -00C 2 n

Ri

FU 1

ur \.

'Eq

(I),

wherein

R2 represents a hydrogen atom, an acetyl radical or a p-chlorophenoxyalkane carboxylic acid radical of the formula

R3 is a hydrogen atom, a straight-chain or branched aliphatic hydrocarbon radical having 1 to 5 carbon atoms or a p-chlorophenoxy radical;

R4 represents a hydrogen atom or a straight-chain or branched aliphatic hydrocarbon radical having 1 to 5 carbon atoms; and n is a number from 2 to 4, characterized in that a) a p-chlorophenoxyalkane carboxylic acid of the formula II

(II)

or a reactive derivative of this acid with an oxyalkyl ester of a salicylic acid of the formula III

C00 (CH2) n0H

15

<. R

rvj.

O-C-COO- (CH „) OK 2 n

R,

20 with a salicylic acid of formula V

(IV)

^ C00H

OR,

(V)

(III);

30 or a reactive derivative of this acid.

2. The method according to claim 1, characterized in that a compound of formula I obtained, wherein R2 represents a hydrogen atom, is acetylated.

3. A process for the preparation of a compound of formula I, wherein R2 is a p-chlorophenoxycarboxylic acid residue of the formula

40

45 means, characterized in that an oxyalkyl ester of a salicylic acid of the formula III, in which R2 is hydrogen, is reacted with a p-chlorophenoxyalkane carboxylic acid of the formula II or a reactive derivative of this acid.

50

or the subject of the invention is a method for the manufacture

b) an oxyalkyl ester of a p-chlorophenoxyalkane carbonate solution of new phenoxyalkane carboxylic acid esters of oxyalkylsalic acid of the formula IV cylates of the formula I.

3rd

624 381

R2 represents a hydrogen atom, an acetyl radical or a p-chlorophenoxyalkane carboxylic acid radical of the formula

R3 is a hydrogen atom, a straight-chain or branched aliphatic hydrocarbon radical having 1 to 5 carbon atoms or a p-chlorophenoxy radical;

R4 represents a hydrogen atom or a straight-chain or branched aliphatic hydrocarbon radical having 1 to 5 carbon atoms; and n is a number from 2 to 4, which is characterized in that a) a p-chlorophenoxyalkane carboxylic acid of the formula II

or a reactive derivative of this acid with an oxyalkyl ester of a salicylic acid of the formula III

COO (CH2) nOH

(III);

or b) an oxyalkyl ester of a p-chlorophenoxyalkane carboxylic acid of the formula IV

/ \

// V O-C-COO- (CH „) OH

(IV)

with a salicylic acid of formula V

COOH

(V)

or a reactive derivative of this acid. If R2 is hydrogen, the compound of the formula I can be acetylated subsequently.

Compounds of the formula I in which R2 is a p-chlorophenoxycarboxylic acid radical are prepared from compounds of the formula III in which R2 is hydrogen by reaction with a p-chlorophenoxyalkane carboxylic acid of the formula II.

Examples of suitable hydrocarbon radicals are alkyl radicals, such as the methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or n-pentyl group, and also branched pentyl groups. Alkyl radicals having 1 to 3 carbon atoms are preferred. The methyl group is particularly preferred.

Suitable reactive acid derivatives of both the salicylic acid and the phenoxyalkane carboxylic acid component are e.g. B. acid chlorides, acid anhydrides or esters.

The esterification of the acids with the oxyalkyl ester is advantageously carried out with the addition of a suitable catalyst, such as hydrogen chloride, sulfuric acid, sulfonyl chloride, p-toluenesulfonic acid or, particularly preferably, with diatomaceous earth in aromatic hydrocarbons at temperatures between 100 and 150 ° C., the Water of reaction io can be removed azeotropically. In the same way, the reaction can also be carried out in halogenated hydrocarbons, such as chloroform or dichloroethane, using sulfuric acid as the dehydrating agent.

The molar ratio between the reactants is preferably 1: 1 to 1: 3. The time to complete the reaction is about 2 to 16 hours.

The preparation of the compound according to the invention is explained in more detail with the aid of the following examples;

20 Example 1

18.2 g (0.1 mol) of salicylic acid mono-glycol ester are dissolved in 200 ml of xylene and, after adding 4.0 g of diatomaceous earth and 18.6 g (0.1 mol) of p-chlorophenoxyacetic acid, heated for 16 hours on a water separator. The xylene solution washed with saturated sodium bicarbo-25 nate solution and with water is i. V. evaporated and crystallized from a little ethanol. 21.6 g (61.4% of theory) of l- (salicyloyl-oxy) -2- (p-chlorophenoxy-acetyl-oxy) -ethane of mp 85-86 ° C. are obtained.

JR (KBr): 3200, 1769, 1670, 1615 / cm. 30 Elemental analysis: C17H15C106 (350.7)

Calc .: C 58.22 H 4.31 Cl 10.11 Found: C 58.35 H 4.38 Cl 10.07

Example 2

35 36.4 g (0.2 mol) of salicylic acid mono-glycol ester are dissolved in 400 ml of xylene and after the addition of 8.0 g of diatomaceous earth and 40.4 g (0.2 mol) of 2- (p-chlorophenoxy) - propionic acid heated for 16 hours on a water separator. The filtered reaction solution is washed with saturated bicarbonate solution and water 40 and i. V. evaporated. The distillation residue is distilled on a thin-film evaporator at 180 ° C. and 4 × 10 ~ 2 torr, 46.0 g (63% of theory) l- (salicyloyloxy) -2- [2- (p-chlorophenoxy) - propionyl-oxy] -ethane can be obtained as a colorless to slightly yellowish oil.

45 JR (film): 3200, 1750, 1675, 1615 / cm.

Elemental analysis: C18H17C106 (364.8)

Calc .: C 59.26 H 4.69 Cl 10.72 Found: C 59.26 H 4.77 Cl 10.16

see example 3

Preparation according to Example 2 using 42.8 g (0.2 mol) of 2- (p-chlorophenoxy) -2-methylpropionic acid.

Distillation on a thin film evaporator at 180 ° C and 4x 10 ~ 2 torr gives 33.0 g (43.3% of theory) of l- (salicyloyl-55 oxy) -2- [2- (p-chlorophenoxy) -2 -methyl-propionyl-oxy] -ethane as a yellowish oil.

JR (film): 3200, 1740, 1625, 1615 / cm.

Elemental analysis: C19H19C106 (378.8)

Calc .: C 60.24 H 5.05 Cl 9.36 60 Found: C 60.40 H 5.11 Cl 9.17

Example 4

31.5 g (0.15 mol) of l- (salicyloyloxy) butan-4-ol is dissolved in 250 ml of xylene and, with the addition of 12.0 g of diatomaceous earth 65, and 63.0 g (0.3 mol) 2- (p-chlorophenoxy) -2-methyl-propionic acid, as described in Example 3, reacted and worked up.

Distillation on a thin film evaporator at 180 ° C

624 381

4th

and 4 x IO "3 Torr gives 28.8 g (47.2% of theory) l- (Salicyloyl-oxy) -4- [2- (p-chlorophenoxy) -2-methyl-propionyl-oxy] - butane as a pale yellow oil.

JR (film): 3190, 1735, 1670, 1615 / cm.

Elemental analysis: C2jH23C106 (406.8)

Calc .: C 61.99 H 5.69 Cl 8.71 Found: C 62.29 H 6.17 Cl 8.62

Example 5

18.2 g (0.1 mol) of salicylic acid mono-glycol ester are dissolved in 200 ml of chloroform and, after the addition of 22.0 g (0.22 mol) of triethylamine, slowly with 45.1 g (0.22 mol) of p- Chlorophenoxyacetyl chloride added. The mixture is heated under reflux for 2 hours. The solution is washed with water, saturated sodium bicarbonate and water. After evaporation, the distillation residue is distilled on a thin-film evaporator at 165 ° C and 2 x 10r2 Torr. The remaining distillation residue is crystallized from a little diisopropyl ether and then from ethanol. 35.1 g (67.5% of theory) of l- [2'-p-chlorophenoxy-acet-oxy) -benzoyl-oxy] -2- (p-chlorophenoxyacetoxy) -ethane, mp 108 ° C. receive.

JR (KBr): 1780, 1765, 1715, 1610 / cm.

Elemental analysis: C25H2oC1208 (519.3)

Calc .: C 57.83 H 3.88 Cl 13.65 Found: C 57.78 H 3.99 Cl 13.52

Example 6

Preparation according to Example 5 using 52.3 g (0.21 mol) of 2- (p-chlorophenoxy) -2-methyl-propionyl chloride.

The distillation residue is distilled on a thin-film evaporator at 180 ° C and 2x ltt ~ 3 Torr. Here, 40.1 g (69.7% of theory) of l- [2 '- (p-chlorophenoxy) isobutyryloxy) benzoyloxy] -2- [2- (p-chlorophenoxy) isobutyryl -oxy] -ethane obtained.

Elemental analysis: C29H28C1208 (575.4)

io Ber .: C 60.54 H 4.91 Cl 12.32

Found: C 60.57 H 5.05 Cl 12.21

Example 7

53.8 g (0.2 mol) of l- [2- (p-chlorophenoxy) propionyl-oxyj-15 propan-3-ol are dissolved in 200 ml of chloroform and after the addition of 22.0 g (0.22 mol ) Triethylamine slowly with 43.6 g (0.22 mol) of acetylsalicylic acid chloride, dissolved in 50 ml of chloroform. The reaction mixture worked up according to Example 5 is distilled on a thin-film evaporator at 190-200 ° C. and 20 0.1 Torr. 43.7 g (51.9% of theory) of l - [(2'-acetoxy) -benzoyl-oxy] -3- [2- (p-chlorophenoxy) -propionyl-oxy] -propane are considered almost get colorless oil.

JR (film): 1755, 1725, 1610 / cm.

Elemental analysis: C21H21C1Ö7 (420.8)

25 calc .: C 59.83 H 5.03 Cl 8.42

Found: C 60.46 H 5.14 Cl 9.24

Examples 8 to 14

The following further compounds were also produced by the process according to the invention:

Example*

No. 2

r3

R4

jr (cm-1)

yield

8th

3rd

h h

ch3

3190, 1740, 1670, 1612

52.9

9

2nd

H

-0-QH4-C1

H

3160, 1770, 1674, 1615

67.8

10th

2nd

0c-c (ch3) 20-c6h4-c1

h h

1760, 1730, 1610

65.7

11

4th

0c-c (ch3) 20-c6h4-c1

ch3

ch3

1765, 1725, 1610

62.8

12

2nd

ch3co ch3

ch3

1760, 1730, 1610

71.2

13

2nd

ch3co h

ch3

1755, 1725, 1608

73.4

14

4th

ch3co ch3

ch3

1755, 1728, 1608

69.1

* With the exception of the compound according to Example 9 (mp 89 ° C.), all the compounds listed are oily liquids which have been distilled on a thin-film evaporator at an oil circulation temperature of 160 to 200 ° C. and a vacuum of IO "2 to 10 ~ 3 Torr.

table

Antilipemic activity on a normal diet and hypercholesterol diet

Example mg / kg

Normal diet

Hypercholesterol diet

cholesterol

%

Triglycerides

%

cholesterol

%

Triglycerides

%

mg%

Reduction mg%

Reduction mg%

Reduction mg%

Lowers

control

96.4

66.7

_

453.4

_

54.2

3rd

100

85.4 *

11.4

67.4

-

469.8

-

47.3 *

12.7

250

87.8

8.9

58.1

12.9

625.9

-

52.1

3.9

6

100

89.7

7.0

73.9

-

527.8

-

35.5 *

34.5

250

80.2 ***

16.8

75.6

-

690.7

-

36.7 *

32.3

12

100

80.3 **

16.7

79.6

-

699.0

-

53.1

2.0

250

76.9 **

20.2

97.1

-

517.0

-

55.1

-

ASS /

100

87.6

9.1

65.8

1.3

483.6

-

51.1

5.7

Clofibrate

1 • 1

250

104.0

-

51.4

29.9

565.8

-

54.3

-

1 . 1

control

95.8

-

69.2

536.6

75.9

_

Ciofibrin -

100

96.9

-

54.8

20.8

572.8

-

69.7

8.2

acid

250

89.4

6.6

50.8 *

26.5

587.8

-

62.7

17.4

control

-

76.9

123.8

-

358.6

-

86.4

-

Clofibrate

250

56.1 ***

27.0

66.5 ***

46.3

347.9

3.0

75.6

12.5

* p <0.05

** p <0.01

*** p <0.001

The compounds produced according to the invention have excellent antilipemic activity with good tolerance.

The therapeutic activity of the compounds according to Examples 3, 6 and 12 was demonstrated in animal experiments on female rats against the known antilipaemica 2- (p-chlorophenoxy) -2-methyl-propionic acid (ciofibric acid), its ethyl ester (clofibrate) and against one mixture of microencapsulated acetylsalicylic acid (ASA) and clofibrate consisting of equal parts by weight.

Here, the compounds or the vehicle (polyethylene glycol 400) were administered over a test period of 14 days by means of a pharyngeal tube. Blood samples were taken 24 hours after the last dose to determine serum cholesterol and serum triglyceride levels:

In a first series, the efficacy was investigated in normoli-pemic rats with a body weight of 60 to 95 g, who received a standardized, pelleted laboratory diet over the entire test period (normal diet). The diet consisted essentially of raw proteins and carbohydrates with a crude fat content of max. 3.9%, enriched with vitamins, minerals and amino acids.

In a second study, the efficacy in hyper-cholesterolemic rats according to the data from Berger et al., Proc. Soc. Exp. Biol. 132, 293 (1969).

The initially normolipemic animals were given the standardized normal diet described above in powdered form, to which 2% cholesterol and 1% cholic acid had been added, in order to achieve artificial hyperlipidemia.

The results of these two series are summarized in the table. The statistical significance p of the results is also given.

The test model used here under normal diet as well as hypercholesterol diet allows a safe demarcation of the activity in comparison with the known antilipaemics ciofibric acid and clofibrate, since it is known that the latter only intervene endogenously in the metabolic process, i.e. only show a good activity under normal diet, while this activity due to exogenous metabolism influences z. B. is completely lost by fat or massive cholesterol intake.

As the test results show, the compounds according to Examples 3, 6 and 12, which are direct descendants of the

624 381

Ciofibric acid or clofibrate can apply, comparable to clofibrate in terms of lowering cholesterol.

However, this does not apply to the lowering of the triglyceride value on a hypercholesterol diet, since in contrast to clofibrate, the compounds according to Examples 3 and 6 in particular bring about a significant reduction.

Taking into account that in the tested compounds according to Examples 3, 6 and 12, the ciofibrinic acid residue represents the active principle with regard to the lipid lowering and that the compounds according to Example 3.54%, according to Example 6.70%, and according to Example 12.49% contain this active principle, this results in comparison with ciofibric acid resp. Clofibrate is a much higher therapeutic index.

The other compounds falling under the formula show a comparable effect.

The acute oral toxicity of the compounds produced according to the invention was determined on mice by the method of C. S. Weil, Biométries 8, 249-263, 1952.

Compound according to Ex. 3: LD50 1492 mg / kg (1276-1744) Compound according to Ex. 6: LDS0 1142 mg / kg (992-1309) Compound according to Ex. 12: LDS0 1116 mg / kg (1013-1228)

For comparison, the oral toxicity of a mixture of equal parts by weight of microencapsulated acetylsalicylic acid and clofibrate in the rat was examined using the Litchfield & Wilcoxon method. The determined 7-day LDS0 was 860 mg / kg (804-920).

The compounds produced according to the invention therefore show a significantly lower toxicity than the starting products.

Medicaments can contain one or more phenoxyalkane carboxylic acid esters of the formula (I) as active ingredient. The application is preferably oral, e.g. B. in the form of tablets or capsules, the usual pharmaceutical carriers and auxiliaries, such as e.g. Contain lactose, starch, talc or magnesium stearate.

Depending on the case, the compounds produced according to the invention are administered in oral or rectal daily doses of 100 to 1000 mg, preferably 250 to 750 mg, in the customary pharmaceutical forms.

5

5

10th

15

20th

25th

30th

35

40

S