FR2630736A1 - UNDECYLATED ESTER OF P-CHLOROPHENOXYISOBUTYRIC ACID AND MEDICAMENT CONTAINING IT FOR THE TREATMENT OF HYPERLIPIDEMIA - Google Patents

Abstract

The subject of the invention is the undecyl ester of p-chlorophenoxyisobutyric acid of formula: (CF DRAWING IN BOPI) This compound constitutes the active principle of a medicament for the treatment of hyperlipidemia. The medicament according to the invention finds its application in medicine for the treatment of hyperlipidemia, including atherosclerosis and various vascular pathologies.

Description

The present invention relates to organic chemistry

  that and, more particularly, a new product, the ester

  undecylic acid of p-chlorophenoxyisobutyric acid and a

  the container, for the treatment of hyperlipid-

mie.

  The ethyl ester of p-chloro acid is known

  rophenoxyisobutyric acid of formula: COH3 0Cl <J1 - C- COOC H CH

  which is the active ingredient of clofibrate (Miscleron) (GB-A-

860-303).

  Notwithstanding its important action hypolipopro-

  As a result, this drug is sufficiently toxic to limit its application. Its LD50 is 1.0 g per kg body weight of the animal. He produces different

  unwanted side effects on the liver and kidneys.

  As a consequence of the short chain of hydro-

  of the esterifying acid, the ethyl ester of

  p-chlorophenoxyisobutyric acid is easily saponified

  by the enzymes of the digestive system and some of the product is removed from the body without providing the required action. For this reason, it is necessary, in order to obtain a therapeutic effect, to administer it in the body at high doses (300 mg per kg of

body weight).

  The compound according to the invention, and the medicament

  the container are original and are not described

in the litterature.

  The problem posed in the present invention is to develop a new compound having a

  high hypolipoproteinemic activity, which is the main

  active ingredient of a medicament for the treatment of

  perlipidemia, the toxicity of which is low and which

  present no side effects.

  This problem is solved by the new compound

  according to the invention namely the und & cylic ester of the

  p-chlorophenoxyisobutyric acid of formula:

'CH3

C1i -0 -C - CoocIII23 CH3

  This compound has hypolipoprotein activity

téinémiante.

  The drug for the treatment of hyperli-

  epidemic, comprising an active ingredient and a pharmaceutical excipient, contains according to the invention, as a

  active ingredient, the undecyl ester of p-chloro

phenoxyisobutyric.

  The medicament according to the invention can be used

  in different forms. It will preferably be used

in the form of tablets.

  According to the invention, the drug in the form of tablets preferably comprises the active principle, at a rate of 0.05 g per tablet and, as an excipient,

starch or sugar powder.

  In order to improve its resorption, the

  - Dicament according to the invention comprises in addition, as an excipient, menthol, at a rate of 0.001 to 0.003 g per tablet.

  The medicament according to the invention is practically

  not toxic. Its acute toxicity is 15 times more

  weaker than that of the drug known as' clofi-

  brate. It has no side effects. In addition

  their, the dose of drug according to the invention giving a treatment effect similar to that obtained by the dose

  Conventional clofibrate is 3 times less strong.

  The new compound according to the invention, the undecyl ester of pchlorophenoxyisobutyric acid, is a colorless dense liquid, boiling at the temperature of

  215-230 ° C, at 5-10 mm Hg x (6.66-13.33 x 102 Pa).

  His elementary analysis corresponds to calculation.

  The compound according to the invention is obtained by

  heating of undecyl alcohol with p-chloro

  phenoxyisobutyric acid or a p-chlorophenic acid halide

  noxyisobutyric acid in a solution of pyridine, with, in

  following, isolation of the desired product by the methods con-

naked.

  The compound according to the invention has a

  hypolipoproteinemiant activity and is the active ingredient

  drug for the treatment of hyperlipidemia.

  The above-mentioned activity of the compound according to

  vention and the drug prepared from it has been studied in animal experiments and in

  therapeutic test conditions.

  The specific activity of the compound according to the invention

  has been studied in two animal species (rabbits and

  rats) using different models of hyperlipoprotein-

mie.

  In order to determine the hypolipoprotein

  As a best agent for the compound according to the invention, its action has been analyzed at different doses on the degree of modifications caused by an animal feed.

containing cholesterol.

  The experiments involved Chinchilla rabbits of both sexes with an initial weight of 2.0 to 2.5 kg, which received daily for 90 days, with the food of cholesterol at a rate of 250 mg per day.

  kg of body weight. It was determined in the serum

  guin, taken from the marginal vein of the ear, before the experiment and at the end of 90 days after the start of cholesterol feeding, using the method

  cholesterol, lecithin, lipid

  totals and beta-lipoproteins. Cholesterol feeding was discontinued and the animals were separated.

  in five groups: the animals in the first group received

  the following 30 days an ordinary food ration

  nary; animals from groups 2, 3 and 4 received during

  following 30 days by oral ingestion, the compound se-

  the invention at the dose of 33, 66 or 134 mg / kg of body weight; while the animals of the 5th group received

  Orally known drug, clofibrate.

  At the 15th and 30th days, it was determined in all animals

  sore in the blood plasma metabolic parameters

  lipid. The results of the experiments are shown in

1 and 2 below.

  The analysis of the studied parameters of metabolism

  me lipid in the blood plasma of rabbits shows that

  both drugs reduce the degree of increase in

  lactol, total lipids, beta-lipoproteins and

  lecithin. The hypolipoproteinemic action of the compound

  according to the invention is more pronounced (although

  in smaller doses) than that of the known product clofibrate. Protective action of the compound according to the invention and clofibrate in rats with hyperlipidemia caused by administration of Triton WR-1339 (intraperitoneal injection at 300 mg / kg) was also studied. The study method was as follows. We have

  administered orally to rats the drug (clo-

  fibrate or compound according to the invention) for 10 days,

  after which a (single) intraperitoneal injection was

  Tonal Triton WR-1339. The animals were caught in

  experience 4 hours later. Control animals do not receive

  only the Triton. The results of this experiment are given in Tables 3 and 4 below. As can be seen in Table 3, Triton injection causes

  hyperlipoproteinemia, which manifests itself in an important

  increase in plasma levels of all

  meters studied. Pre-animal administration

  of the compound according to the invention provides a protective action.

  trice. Clofibrate acts in the same way but is less active than the compound according to the invention used in

smaller doses.

  The hypolipidaemic activity of the compound according to the invention and of the clofibrate was studied on the model of hyperlipidemia caused by intraperitoneal injection of Tween-80 at a rate of 2.0 mg per kg of body weight of the animals. After 12 hours after injection, Tween-80 contributes 1.5 to 2.5 fold increase

  total lipids, cholesterol, beta-lipo-

  proteins and triglycerides. At the dose of 66 mg per kg of body weight, in oral administration, the compound according to the invention reduces in two days the level of total lipids and cholesterol and shows a tendency to reduce beta-lipoproteins and triglycerides. At a dose of 164 mg / kg (introduction twice in

  stomach in 2 days), the compound according to the invention

  a clearer effect and reduces all

  lipid parameters. Clofibrate (250 mg / kg)

  It also has a lipid-lowering action, but compared to the highest dose of the compound according to the invention the clofibrate provides a less pronounced action on the

  development of hyperlipoproteinemia.

  The results of these investigations appear

in Table 4.

Table 1

Comparative study of the action of

  compound according to the invention, and

  clofibrate on the parameters of lipid metabolism in rabbits, which are not adequately treated with cnolesterol Lipids, mg% Lot of animals Cholesterol of animals, or after 90 days 30 days after calving after treatment. arrat tively by du du

choies- choies- choles-

terol térol

2 3 4 5 6

1First lot 87+ 992+ 505+ 207+

2.2 50.1 15 24.1

P <0.05 <0.05 <0.05

Second lot 79+ 949+ 397+ 187+

3.4 82.9 23.2 12.0

P <0.05 <0.05 <0.05

Third lot 85 929+ 426+ 164+

4.8 5.9 38.8 11.1

P <0.05 <0.05 <0.05

4 Fourth batch 76+ 909+ 311+ 158+

, 3 42.5 92.0 15.9

P <0.05 <0.05 <0.05

Fifth lot 87+ 921+ 501+ 166+

4.2 57.7 35.2 * 9.2

P <0.05 <0.05 <0.05

  P - in relation to the initial level Table i (continued) Lip i of s, mg% Lecithin Total lipids after 90 days 30 days after 90 days following after days of

  Calf treat- stop stop calf treat-

  by -Uu - from the initiation

  tial cholescholes- choles- tial choles-

térol térol térol térol

1 7 8 9 10 11 12

1 148+ 429+ 321+ 205+ 291+ 995+

7.3 21.2 19.2 20.4 15.7 34.3

<0.05 <0.05 <0.05 <0.05

2 166+ 326+ 277 190+ 279+ 1343 +

11.3 27.0 24.0 18.0 13.2 108.7

<0.05 <0.05> 0.05 <0.05

3 i61 + 39zL + 256_ + 191 + 245 924+

13.6 23.8 11.1 8.3 19.4 76.0

<0.05 <0.05> 0.05 <0.05

4 176+ 402+ 244+ 186+ 285+ 1185+

11.3 22.9 24.2 15.3 21.9 134.6

<0.05 <0.05> 0.05 <0.05

179+ 412+ 266+ 221+ 244_ 926+

12.1 18.0 29.0 23.08 18.75 89.6

<0.05 <0.05> 0.05 <0.05

  Table i (continued) L i p i d e s, mg% Total lipids Beta-lipoprotein days 30 days after 90 days 30 days after after-days after after stopping calf stoppage treatment-stop stopping de-inition by d

  choles- choies- tial choies- c oes- coules-

térol térol térol térol térol

1 13 14 15 16 17 18

1,614+ 442 89x1003 + 823 + 407 +

57.4 20 4.8 42.1 42.1 46

<0.05 <0.05 <0.05 <0.05 <0.05

2 5853 354+ 93+ 950 508+ 284 ±

83.1 42.9 7.4 58.3.71.2 55.6

<0.05> 0.05 <0.05 <0.05 <0.05

3,566+ 293 91+ 1026+ 551+ 242+

, 8 17.2 7.5 48.7 10.4 24.4

<0.05> 0.05 <0.05 <0.05 <0.05

4 3594+ 295+ 99+ 979+ 465+ 230+

48.3 18.7 7.5 157.1 67.4. 33.7

<0.05> 0.05 <0.05 <0.05 <0.05

489 + 292+ 93 .1004+ 573 232+

, 0 24.0 11.2 132.1 123.1 55.8

<0.05. > 0.05 <0.05 <0.05 <0.05

Table 2

  Comparative study of the action of the compound

  according to the invention and clofibrate

  the parameters of lipid metabolism in rabbits, previously treated with cholesterol reduction of N N Action

  cholesterol lecithin lipids beta-li-

rol c totals poppy

nes

1 2 3 4 5 6

  1 Clofibrate 82% 46% 68% 77% 250 mg per kg

weight

  porel. 2 Compound following 80% 42% 74% 70%

before the

  vention, 33 mg / kg 3 Compound 82% 52% 68% 76%

before the

  vention, 66 mg / kg 4 Compound following 83% 54% 76% 77%

before the

vention, 164 mg / kg

2630736

Table 3

  Comparative study of protective action

  of the compound according to the invention and of

  the development of hyperlipoprotein

  nemie in rats caused by Triton WR 1339

  NONO Conditions of the experiment Number Lipids to-

animal rate, mg%

1 2 3 4

  1 intact animals II 398 + 18 2 Triton (300 mg / kg intraperitoneal injection only 0.05) 3 Compound according to the invention (164 mg / kg po P1 0, 05 days, then Triton once) 4 Clofibrate (250 mg / kg per 10 317+ 45 bw 10 days and Triton P1, s5 on one occasion) P2? 0.05 P1 - relative to Triton P2 - compared to the following compound the invention Table 3 (continued)

beta-lipopro-

   N N Cholesterol, mg% Lecithin, m teins, mg%

1 5 6 7

i 84 + 7.3 157 + 9.4 67 7.1

2,396 + 24,520 + 41,982 + 19

P <0.05 P <0.05 P <0.05

3 118 + 20 201 + 20.3 88 + 11.4

  Pl <09.05 P1 << 0.05P O <0.05 4 154 + 19 354_42- 122i10,3

P1 <0905 <00P1 <0.05 P <0.05

P2 <0905 P2 <0.05 P2 <0.05

  Pl - with respect to the Triton -P2- compared to the compound following the invantion

12 2630736

Table 4

  Comparative study of the protective action of the compound according to the invention and of clofibrate on the development of hyperlipoproteinemia in rats, caused by Tween-80 Number Lipids, mg% N NO Conditions of the lipid experiment total evils

1 2 3 4

  1 intact rats 6 299 + 17.6 2 Tween-80 2.0 mg / kg route 10 528 + 42.4 intraperitoneal P <0.05 3 Compound according to the invention 8 244 + 31.5 tion 66 mg / kg during Pl <005 of 2 days 4 Compound according to the invention 10 311+ 28.4 164 mg / kg during P1 <0.05 2 days Clofibrate 250 mg / kg at 6 344+ 42 courses of 2 days P1 <0.05

P2 <0.05

  P1 - with respect to Tween-80 P2 - compared to the compound according to the invention 164 mg per kg of body weight TABLE 4 (continued) NONO ipides, mg% cholesterol beta-lipoprotein troglycides 5 6 7 i 50 + 14, 8 88.4 + 11.0 2504.7

2 118 + 12.8 -165 + 26 70 + 8.5

P <0.05 P <0.05 P <.05

  3 61.8 + 5.5 i44I11.2 61 + 9, .5 Pl <00Pl, 05 P1> 0.05

4 63.7 + 9.0 126 + 12.0 51.0 + 6.1

P1 0.05 P1 <P <0.05

85 + 11 116 + 12.0 91 + 18.2

Pi <0.05 P <0.05 P <.05

P2> 005 P2 05 P2> 005

P2 P> 0, O505

  P1 - with respect to the Tween-80 P2 - compared to the compound according to the invention 164 mg per kg of body weight The above-mentioned investigations show that the compound according to the invention is provided with a

  important lipid-lowering and hypocholesterol-

  Miante. Its specific activity is greater than that of clofibrate. Acute and chronic toxicity of

compound according to the invention.

  The acute toxicity of the compound according to the invention

  has been studied in two species of animals:

  white rats weighing 16 to 20 g and rats of one

  weight of 200 to 240 g under conditions of ad-

  enteral and parenteral administration. Acute toxicity of the compound according to the invention in tablet form has been studied in white mice and rats in

  enteral administration conditions. In the

  white roses, a suspension of

  according to the invention in the stomach by means of a syringe.

  The observation of the animals lasted 12 days.

  The results of these experiments show that in oral administration the LD50 of the compound according to the invention is equal to 13.5 g / kg, which is to say that this compound

is practically not toxic.

Another batch of mice received the compound according to the invention by intraperitoneal injection. In these animals, it proved impossible to establish the LD50, which testifies

  also that the product is not toxic.

  In experiments involving rats and also using oral routes of administration and

  intraperitoneal, identical results have been obtained.

  forcing the fact of the non-toxicity of the product. The results

  These experiments are presented in Table 5.

TABLE 5

  Species LD50 (g / kg)) (D L 50 (g / k g)) 5 (Animal Drug Conclusion) intraperperate

( per os.

  (ritoneal () () (Mouse Medicament> 40.0x 13.5 Medicament) (according to the invention> 25.0> 25.0 nontoxic (vention)

(_)

  x) It is not possible to administer one more

  large amount of the drug according to the invention.

  Toxicity investigations

  chronic drug of the invention have been realized

  in rats, guinea pigs and rabbits with

  observation periods of 6 months.

  Each series of experiments involved 7 to 12 laboratory animals. The medicine according to the invention

  has been administered orally at conventional doses

  therapeutically (164 mg / kg) and toxic (820 mg / kg).

  The parameters studied were determined

the deadline of 1, 3 and 6 months.

  The results of the chronic toxicity study

  that the drug according to the invention are as follows. There is no difference in the increase in body weight of the animals in the control group and those receiving the

  drug according to the invention for 6 months.

  These experiments show that at the doses used

  the medicament according to the invention has no significant action

  the number of red blood cells, white blood cells, eosinophils, basophils, neutrophils, lymphocytes and monocytes, as well as hemoglobin levels and

  sedimentation rate of red blood cells.

  Moreover, the medicament according to the invention does not modify the quantity of respiratory movements,

  as well as the level of blood pressure in

pine.

  Teratogenic properties have been studied and

  bryotoxic agents of the medicament according to the invention in ex-

  in rats using the known method.

  A microscopic study of 204 rat embryos (of which 112 were used as controls) was performed by examining the condition

  viscera and skeletal development.

  These investigations demonstrate that the drug

  according to the invention has no teratogenic action and

  bryotoxique. Microanatomical examination of embryos

  not, indeed, detected disturbances in the development

  skeleton and viscera. Therefore, the

  preparation according to the invention does not have any

  ratogenic and does not act on the intrauterine evolution of rats. It can therefore be concluded from the studies

  experiments that have been carried out, that the action of the

  dicament according to the invention during gestation has

16 - 2630736

  not in rats and mice teratogenic effect and

  bryotoxique. The investigations carried out for the study of

  mutagenic properties of the medicament according to the invention testifies

  that it does not induce mutation in somatic cells of both adult animals and fetuses, the latter being more sensitive to

the agent studied.

  Studies on carcinogenic activity show that the drug according to the invention used at doses of 33 mg / kg and 165 mg / kg has no toxic effect on the body of animals, and does not show any signs of carcinogenic activity following its daily administration

for a year.

  The influence of the drug according to the invention on the immune system has been studied. The results of these investigations show that this drug does not exhibit immunomodulatory action on immunity

  cellular than humoral. The study of irritative action

  of the medicament according to the invention has

  neither at the therapeutic dose nor at the toxic dose, it causes significant changes in the histamine level in the peripheral blood of rats and

  rabbits. It can therefore be concluded that the drug se-

  the invention has no irritating properties

local and allergic.

  A pharmacokinetic study was conducted

  than the drug according to the invention.

  The experiments focused on white rats

  without lineage of a weight of 200 to 240 g. The drug se-

  The invention was administered by means of a special needle in the animal stomach at a dose of 164 mg / kg and the concentration of the drug in the blood plasma was determined spectrophotometrically. The results

  of these experiments are shown in Table 6.

TABLE 6

  Plasma levels in the rats of the

  according to the invention following intragastric administration at a dose of 164 mg / kg (Time passed after administration of the drug in the invention, blood plasma, g / 1) hours () (at (1 5 242 x 10-4 (2 5 418 x 10 (35381 x 10 4 (45 380 x 10

(6 5 -299 x 10-

  (12 5 465 x 104 24 5) (24 5 415 x 10 4 (48 5 124 x 10 4 () It is apparent from these data that already after one hour after administration of the medicament according to the invention, the plasma concentration reaches 242 x 10-4 g per liter, and at the end of two hours -4 418 x 10 g per liter, after which the plasma concentration falls, then after 12 hours goes up to -4

  465 x 104 g per liter. Next, the plasma concentration

  tick of the drug gradually decreases.

  Ongoing clinical trials of the drug according to the invention show that its use in patients suffering from hyperlipidemia brings a reduction

  cholesterol levels, lipids to-

  levels and phospholipids, by comparing these parameters

normal numbers.

  Thanks to its very low toxicity, the undesired ester

  cyclic p-chlorophenoxyisobutyric acid did not

  harmful action on the body and the physiological functions

of the patient.

  The treatment is carried out in several courses.

  For a month, the patient takes 2 to 3 tablets of 0.05 g

  every day and then, after a break of one month,

  fart this cure. After an interruption of 6 to 12 months,

repeat again the cure.

  The drug according to the invention is used

  in different pharmaceutical forms, such as

  gelatin capsules, dragees, aerosols. The drug according to the invention is preferably used in the form of

  0.05 g tablets in sublingual application.

  The medicament according to the invention does not have any

  indications for its use and does not present any

secondary fetuses.

  The invention will be further illustrated with the help of

  non-limitative examples following the preparation of the new

  compound, the undecyl ester of p-chlorophenic acid

noxyisobutyrique.

EXAMPLE 1

  It is maintained at a temperature of 160-175 ° C,

  for 10 hours, a mixture of 100 g of p-chlorophenic acid

  noxyisobutyric acid (melting point 118-119 ° C) and 200 g of undecyl alcohol with extraction by distillation of the water which evolved. After the end of the warming, the reaction mixture is allowed to cool to room temperature, diluted with 1 liter of benzene and washed.

  benzene solution with 1 1 of a 2% solution of

  sodium carbonate and water. Benzene is distilled at atmospheric pressure, then the remains are distilled

  solvent on a bath at the temperature of 100 C under

  from about 100 mm Hg (1.33 x 104 Pa). The residue is then distilled under vacuum at 5-15 mm Hg (6.66 at 20 x 102 Pa) and

collect the fraction 210-230 C.

  We obtain 115-125 g (67-73% of the theory)

  undecylic acid ester of p-chlorophenoxyisobutyric acid

  with a boiling point of 210-230 ° C at -15 mm Hg (6.66 at 20 x 102 Pa) Percentage found: C = 9.73;

  Percentage calculated for C21H3303Cl: Cl = 9.63.

EXAMPLE 2

  A solution of 46.7 g of undecyl alcohol in 150 ml of pyridine dried on caustic and distilled potash is cooled to -9 to -100 ° C with constant mixing. While continuing

  mix, 58 g of chlorine are added to the chilled solution.

  p-chlorophenoxyisobutyric acid at one speed

  such as the temperature inside the reaction mass

  can not rise above -8 C. Then,

  at the same temperature, we continue to mix the mas-

  The mixture is then reacted for 3 hours, after which the mixture is diluted with 500 ml of benzene and the solution is washed with ml of a 10% solution of hydrochloric acid, 150 ml of a 5% solution of caustic soda and the water. The solution is filtered through anhydrous sodium sulphate. Subsequently, the solvent is removed completely and the residue is distilled under vacuum at 5-15 mm Hg (6.66 to 20 x 102 Pa), and

  RECEIVE the fraction distilling at 210-230 ° C.

  70 g (70% of theory) of ester are collected

  undecylic acid of p-chlorophenoxyisobutyric acid at

  boiling point of 210-230 ° C at 5-15 mm Hg (6.60 to

x 102 Pa).

Percentage found: Cl = 9.69;

  Percentage calculated for C21H3303Cl: Cl = 9.63.

Claims (5)

  1. p-chlorophenoxyisodium acid undecylic ester   butyric acid of formula: ## STR2 ## - I CH3   2. Drug for the treatment of hyperli-   epidemic, comprising an active ingredient and a pharmaceutically   maceutical, characterized in that it contains, as a   active ingredient, the undecyl ester of p-chloro   phenoxyisobutyric acid according to claim 1.   3. Medicament according to claim 2 in the form of tablets, characterized in that it contains the   active principle at a rate of 0.05 g per tablet.   4. Drug according to any of the claims   2 and 3, characterized in that it contains, at   pharmaceutical excipient, starch or sugar in powder.   5. Drug according to any of the claims   3 and 4, characterized in that, as an excipient, it additionally contains menthol at a rate of 0.01 to 0.003 g. per tablet.