CH630803A5 - Medicinal preparations, for the treatment of hypercholesterolaemia in particular - Google Patents

Description

The present invention relates to new medicinal preparations having a therapeutic activity in particular against hypercholesterolemia, hyperlipidemia and certain forms of obesity with excess fat deposits and / or cellulite.

Many active products are already known for the therapeutic treatment of lipid overloads and cellulite, among which, among those recently disclosed, 3,5,5'-triiodothyroacetic acid can be noted. However, this product has a relatively short lifespan, since it is eliminated from human blood in about 5 h, which leads to the need to administer it to the patient repeatedly, 4 to 5 times a day. This is a major drawback, especially for the patient, given the generally long duration of such treatments (from 3 to 12 months). Research has therefore been undertaken in an attempt to find products having a similar therapeutic activity, but having a significantly longer lifespan. This research has led to the demonstration of a significant inherent retardation effect presented by the acids 3,5,3 ', 5'-tetra-iodothyroacetic and

3,5,3 ', 5'-tetra-iodothyropropioïvique and similar, as well as their mineral or organic salts. Indeed, the elimination of these products from human blood requires a duration of approximately 15 to 18 h, which makes it possible to reduce the number of daily administrations to 1 or 2 at most.

Consequently, the subject of this invention consists of a new medicinal preparation having a therapeutic activity in particular against hypercholesterolemia, hyperlipidemia and obesity, comprising as active product at least one compound represented by the general formula (I),

I I (I)

110

I

0

I

wherein R is an aliphatic carboxylic acid group, or a pharmaceutically acceptable salt thereof, alone or in admixture with other active products and / or with excipients.

The mixture R of the compound of formula (I) is preferably an acetic, propionic or butyric acid residue.

Depending on the therapeutic treatment required and the route of administration chosen, the active product of formula (I), preferably 3,5,3 ', 5'-tetra-iodothyroacetic acid or its K or Na salt, is therefore used alone or in mixture with other products, themselves inactive or therapeutically active.

For oral administration, the active product of formula (I) is preferably used with Clofibrate and / or a choleretic cholagogue, such as divanillidenecyclohexanone (DVCH), cyclobutyrol, sorbitol, triamcinolone, amfepramone, meprobamate, acetazolamide, IV chymotripsm, bromelains, lipase, vitamin A, etc.

For administration by injection, the active product of formula (I) is preferably used with hyaluronidase and / or mucopolysaccharidases, α-chymotrypsin, etc.

For rectal administration, the active product of formula (I) is preferably used with mucopolysaccharidases.

Finally, with a view to transcutaneous application, the active product of formula (I) is preferably used with an adenylatecyclase activating compound such as a catecholamine such as adrenaline or noradrenaline, bamethan, neosynephrine, salbutamol, etc., and / or with xanthine or its derivatives, hyaluronidase, mucopolysaccharidases, acetazolamide, etc.

The toxicity of the compounds of formula (I), more particularly that of 3,5,3 ', 5'-tetra-iodothyroacetic acid, is low. It was measured, on the one hand, in mice 5 d after a single intraperitoneal administration of the above compound in 50% dilute solution in propanediol and, on the other hand, in rats 5 d either after a single intravenous administration of the same solution as for mice, ie after a single administration per os of the active compound suspended in a carboxymethyl cellulose gel. Table I indicates the DLS0 value in (ig / kg of live weight.

Table I

Animal

Administration dl50 O-g / kg)

Mouse intraperitoneal route

350

Intravenous rat

300

Rat per os

825

The toxicity of 3,5,3 ', 5'-tetra-iodothyroacetic acid was further studied by observations made on dogs 4 months after

5

10

15

20

25

30

35

40

45

50

55

60

65

3

630 803

oral administration of the active product diluted in lactose at doses of 150 u.g in the form of capsules per kilo and per day. These observations were as follows: no abnormal manifestations; food consumption, which slowed down for a while, resumed that of untreated controls; normal respiratory and heart rhythms; no disturbance of the electrocardiogram, which retains its normal sinusoidal basic movement; no detectable biological changes. After autopsy, a slight pallor of the thyroid was observed, while the liver, kidneys and spleen were normal, as well as the weight of the heart. On histological examination of the thyroid, liver, bone marrow, as well as analysis of the blood formula, nothing was observed in particular.

The ability of 3,5,3 ', 5'-tetra-iodothyroacetic acid to percutaneous penetration was measured on rats to which a cream containing 0.2% of compound, of which a part in radioactive form is as a tracer , has been applied; a rapid passage through the blood could then be observed, the appearance of radioactivity in the blood being observed less than 10 min after application.

The therapeutic effect of a treatment based on 3,5,3 ', 5'-tetra-iodothyroacetic acid on installed cholesterolemia was then studied in chickens as follows: 50 chickens were subjected to a atherogenic diet, a diet intended to create a high concentration of cholesterol in the blood, for 30 d, which led to an increase in the total average amount of cholesterol (average over 50 chickens) from 125 mg / 100 ml of blood (amount 25 normal) at 340 mg / 100 ml (installed cholesterolemia). Then,

30 chickens received per os 500 jxg of the above active product per kilo and per day, the other 19 chickens (1 chicken having died following the atherogenic diet) being used as a control. The atherogenic diet is maintained both for the 19 control chickens and for the duration of the treatment of the 30 treated chickens; the results obtained are presented in table II.

It appears from the table that the therapeutic action against hypercholesterolemia of 3,5,3 ', 5'-tetra-iodothyroacetic acid is effective, since the amount of cholesterol in the blood has returned, after 36 d of treatment, at an almost normal level, taking into account that the atherogenic regime is maintained.

The clinical effect of some medicinal preparations according to the invention has been studied, in particular with regard to the therapeutic activity against hypercholesterolemia, hyperlipidemia and obesity. The administration conditions and the results obtained are described in Examples 1 to 5 below.

Example 1:

3,5,3 ', 5'-tetra-iodothyroacetic acid alone was administered 3 times a day at a rate of 350 ug per time to 3 men (subjects 1 to 3) and to 4 women (subjects 4 to 7 ) between 35 and 52 years of age. The results obtained are collated in Table III.

Table III

Topic

1

2

3

4

5

6

7

Duration of treatment (weeks)

3

3

4

3

4

5

3

Cholesterol (mg / ml)

Before

3.40

3.50

3.90

4.15

4.2

3.20

3.80

After

2.20

2.20

2.60

3.20

3.10

2.50

2.40

Total fat (mg / ml)

Before

7.0

8.0

6

8.2

9

10.2

8

1 after

6.0

6.0

5.4

7.9

7.5

8.0

6.5

\ Before

71

97

84

65

62

70

48

Subject weight (kg)

1 after

68

92

79

60

59

64

47

Subject size (m)

1.62

1.75

1.76

1.54

1.60

1.53

1.55

Decrease in measurements (cm)

cut

3

5

5

7

3

7

2

hips

4

6

5

5

4

7

3

thighs

2

2

3

4

2

• 3

1

Topic

1

Duration of treatment (weeks) Cholesterol (mg / ml)

Total fat (mg / ml)

Subject weight (kg)

Subject size (m)

Decrease in measurements (cm) waist hips thighs

Before After Before After Before After

3

3.10

2.60

7.5

6.5

72

68

1.70

4

3 2

3

4.50

2.50

9.0

7.5

87

81

1.75

6 5 2

4.05

3.10

9.5

8.2

81

77

1.65

5 4 3

3.20 2.50 7.8

6.0v

99 V

90

1.80

Table II

Duration of treatment

-

36 d

57 d

Total cholesterol (mg / 100 ml)

Control chickens

340

315

330

Treated chickens

340

145

145

Table IV

630 803

4

Example 2:

A preparation in the form of capsules containing 350 yg of 3,5,3 ', 5'-tetra-iodothyroacetic acid, 25 mg of amfepramone and 100 mg of meprobamate was administered at the rate of two capsules per day to 4 patients with male aged 45 to 55. The results obtained are shown in Table IV.

(See previous page)

Example 3:

A cream containing 100 mg of 3,5,3 \ 5'-tetra-iodothyroacetic acid, 15,000 TRU of mucopolysaccharidases and an excipient (for example comprising 12 g of ketomacrogol, 5 g of lauric acid hexylester, 0.05 g of methyl p-oxybutyrate and 0.05 g of propyl p-oxybutyr-ate, the rest being water (100 g), was applied locally to 5 women suffering from obesity with cellulite. The results obtained are collated in Table V.

Table V

Topic

1

2

3

4

5

Duration of treatment (weeks) Skin flexibility f Before 1 After

4

no good

6

medium enough b.

6

no good

6

none enough b.

6

no good

Orange peel phenomenon

Decrease in measurements (cm) waist hips thighs Tolerance

J Before 1 After yes improved.

4 3 2 B

yes tr. am.

6 4 3 B

yes tr. am.

3 3 2 B

yes little am.

5

6 4 B

yes tr. am.

4 4 2 B

amel. = improved appearance of the skin tr. am. = appearance of the skin very improved little am. = poorly improved appearance of the skin B = good; by good tolerance is meant that the women to whom the above cream was applied did not have any detectable side effects.

Example 4:

3,5,3 ', 5'-tetra-iodothyroacetic acid was applied in the form of a 0.2% solution in dilute propanediol, by ionization (electrode -; 15 m A), at a rate 20 min twice a week and alternately applying the cream described in Example 3.

There has been a marked reduction in adipose bulges, a marked reduction in subcutaneous infiltration of the cellulite type and, thereby, an improvement in body measurements; tolerance to treatment has been shown to be excellent.

Example 5:

Two subjects were treated for 8 weeks with a preparation containing 0.350 mg of 3,5,3 ', 5'-tetra-iodothyroacetic acid and 0.5 mg of triamcinolone, and showed a significant decrease in weight and a simultaneous reduction in obesity, as well as an improvement in biological parameters.

35 Example 6:

A preparation in the form of capsules containing 0.5 mg of 3,5,3 'acid, 5'-tetra-iodothyroacetic acid, 200 mg of divanillidenecyclohexanone and 25,000 IU of acerophtol acetate (vitamin A) was administered at the rate of 3 capsules per day to 4 patients of the male sex 40. The treatment was carried out for 2 to 3 weeks and repeated 2 or 3 times, with a week of therapeutic rest between each treatment. The results obtained are presented in Table VI.

Table VI

Topic

1

2

3

4

Duration of treatment (weeks)

2x2

2x3

3x2

2x3

Total cholesterol (mg / ml)

f Before

3.10

3.05

2.80

3.60

1 after

2.40

2.50

2.10

2.70

Total fat (mg / ml)

f Before

6.9

6.1

6.0

7.05

1 after

6

5.9

5.4

5.6

It follows from the preceding examples that, whatever the embodiments and administration adopted, the drug preparations which are the subject of the present invention constitute therapeutic agents of value for the treatment of hypercholesterolemia, hyperlipidemia , localized lipodystrophies, certain forms of obesity with overweight and / or subcutaneous infiltration of cellulite type.

By way of examples to illustrate the invention, mention may also be made of the following compositions A to D for which the ranges of dosages given correspond to the overall daily dosage.

A. For oral administration Overall daily dosage

60 tetra-iodothyroacetic acid 1 to 3 mg and / or tetra-iodothyroacid acid

propionic 1 to 3 mg and / or Clofibrate there 1.5 g and / or cyclobutyrol 0.3 to 0.8 g

65 and / or DVCH 0.6 to 1 g and / or sorbitol 3 to 5 g and / or triamcinolone 0.05 to 2 mg and / or amfepramone 50 to 100 mg

5

630 803

and / or meprobamate and / or acetazolamide and / or a-chymotrypsin and / or bromelain (extracted from Pineapple sativus and A. comosus)

and / or lipase

0.05 to 0.2 g 50 to 300 mg 50 to 50,000 U.C. Hb

100,000 to 300,000 units 10,000 to 30,000 units of lipolytic activity

B. For administration by injection tetra-iodothyroacetic acid 0.5 to 1.5 mg and / or tetra-iodothyroacid acid

propionic and / or hyaluronidase and / or mucopolysaccharidases and / or a-chymotrypsin

0.5 to 1.5 mg 5000 to 20,000 TRU 10,000 to 20,000 TRU 50,000 U.C. Hb

C. For rectal administration tetra-iodothyroacetic acid 0.5 to 1.5 mg and / or tetra-iodothyroacid acid

propionic 0.5 to 1.5 mg and / or mucopolysaccharidases 10,000 to 15,000

D. For transcutaneous administration a) cream, gel, ointment,

liniment doses in percentage tetra-iodothyroacetic acid 0.1 to 0.2 and / or tetra-iodothyroacid acid

propionic 0.1 to 0.2

and / or adrenaline, noradrenaline, bamethan, neosynephrine, salbutamol, xanthine and derivatives thereof and / or hyaluronidase and / or mucopolysaccharidases and / or acetazolamine b) solutions for ionization tetra-iodothyroacetic acid and / or tetra-iodothyro- acid

propionic and / or mucopolysaccharidases

5000 to 20,000 TRU 10,000 to 15,000 TRU 3 to 10%

0.05 to 0.2 0.05 to 0.2

10,000 to 15,000 TRU

35

3,5,3 ', 5'-triiodothyroacetic acid, as well as similar iodophenol products, can be prepared, for example, by the following successive reactions:

a) Formation of the compound of formula

CHU

by reaction of chlorodinitrobenzaldehyde and p-methoxyphenol in the presence of CH3 - H2 or of a reducing agent such as bisulfite.

b) Replacement of the two nitro groups by two groups

—NH2 by reduction (Ni Raney) in alcoholic medium; then diazota-tion of the non-isolated diamine and Sandmeyer reaction in the presence of an iodo-iodide solution in sulfuric acid medium, in order to replace the two —NH2 groups with two iodo groups.

c) Formation of the corresponding acid by treatment using PCI 5 and obtaining the chlorinated derivative, then treatment of the latter with KCN and transformation into nitrile, and hydrolysis by HI in the presence of red phosphorus.

d) Iodization with I2 in an ammoniacal medium to provide the desired tetra-iodized derivative, after recrystallization from absolute alcohol, having a melting point of 241 ° C. and having the following spectral characteristics:

- infrared spectrometry (KBr pellet)

v OH 3460 cm "1

v C = O 1708 cm "1 v C — O — C 1147 cm" 1

- UV spectrometry

maximum absorption at 300 nm ± 1.5

sî% = 59.0 1 cm nuclear magnetic resonance

(solvent: (CD3) 2CO; s in ppm; internal reference TMS)

In addition, one can also provide preparations with spread diffusion presented in the galenic form of microbeads, in order to better use the inherent retarding effect of the active compounds of formula (I). 45

Finally, the preparation of the active compounds of formula (I), used in the medicinal preparations according to the invention, will now be described with reference to the following example concerning the preparation of the acid 3,5,3 ', 5'- tetra-iodothyroacetic.

S

Protons

Pace

Integration (protons)

8.3-9.5

oh, cooh bass

2 exchangeable with D20

7.88

h2 and h6

singlet

2

7.15

h'2 and h'6

singlet

2

3.68

ch2

singlet

2

R

Claims (9)

630 803 1. Drug preparation having a therapeutic activity in particular against hypercholesterolemia, hyperlipidemia and obesity, characterized in that it comprises as active product at least one compound represented by the general formula (I), wherein R is an aliphatic carboxylic acid residue, or a pharmaceutically acceptable salt thereof, alone or as a mixture with other active products and / or with excipients. 2. Drug preparation according to claim 1, characterized in that the compound of formula (I) is 3,5,3 ', 5'-tetra-iodothyroacetic acid. 2 3. Drug preparation according to claim 1, characterized in that the compound of formula (I) is 3,5,5 ', 5'-tetra-iodothyropropionic acid. 4. Drug preparation according to claim 1, characterized in that said salt is an alkali metal salt, an alkaline earth metal salt or an organic salt. 5. Drug preparation according to one of claims 1 to 3, characterized in that said other active products comprise one or more compounds chosen from choleretic cholagogues, cyclobutyrol, sorbitol, triamcinolone, amfepramone, mepro-bamate , acetazolamide, lVchymotripsine, bromelains, lipases and vitamin A. 6. Drug preparation according to one of claims 1 to 3, characterized in that said other active products comprise one or more compounds chosen from mucopolysaccharidases, hyaluronidase and lVchymotripsine. 7. Drug preparation according to one of claims 1 to 3, characterized in that said other active products comprise one or more compounds chosen from catecholamines, bame-than, neosynephrine, salbutamol, xanthine or its derivatives, the hyaluronidase, mucopolysaccharidases and acetazolamide. 8. Drug preparation according to claim 7, characterized in that it comprises at least one compound of formula (I) and a catecholamine. 9. Drug preparation according to claim 8, characterized in that the catecholamine is adrenaline or noradrenaline.