FR2515962A1 - MEDICAMENT PREPARATIONS CONTAINING A TETRAIODOTHYROCARBOXYLIC ACID DERIVATIVE, IN PARTICULAR FOR THE TREATMENT OF HYPERCHOLESTEROLEMIA - Google Patents

Abstract

THE PRESENT INVENTION RELATES TO A NEW MEDICINAL PREPARATION HAVING THERAPEUTIC ACTIVITY IN PARTICULAR AGAINST HYPERCHOLESTEROLEMIA AND HYPERLIPIDEMIA. THIS PREPARATION INCLUDES AS AN ACTIVE PRODUCT AT LEAST ONE COMPOUND OF FORMULA (I): (CF DRAWING IN BOPI) IN WHICH R IS AN ALIPHATIC CARBOXYLIC ACID GROUP, PREFERREDLY AN ACETIC, PROPIONIC OR BUTYRIC ACID, MIXED WITH XANTHIN OR OF BAMETHAN. THERAPEUTIC TREATMENT OF LIPID OVERLOAD AND CELLULITE.

Description

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  The present invention relates to der Duvelles prepared

  medicinal products having a therapeutic activity especially against hypercholesterolemia, hyperlipidemia and certain forms of obesity with fat overload and / or cellulite. Already known for the therapeutic treatment of lipid overloads and cellulite, many products

  among those recently disclosed.

  However, this product has a relatively short shelf life, since it is eliminated from human blood in about 5 hours, which leads to the need for

  administer it to the patient repeatedly,> 4 to 5 times a day.

  This is a major disadvantage, especially for the patient, in view of the generally long duration of such treatments.

  (from 3 to 12 months) Research has therefore been undertaken to

  to find products with therapeutic therapeutic activity

  but with a significantly longer service life.

  researches have resulted in a clear delay effect

  important that the acids respectively 3,5,3 ', 5' -te-

  traiodothyroacetic and 3,5,3 ', 5'-tetraiodothyropropionic and the like, and their mineral or organic salts In fact, the elimination of these products from human blood requires a duration

  approximately 15 to 18 hours, which reduces the number of

  daily administrations to 1 or 2 maximum.

  Accordingly, the object of this invention is to

  a new drug preparation with therapeutic activity

  particularly against hypercholesterolemia, hyperlipidemia and obesity, comprising as active product at least one compound represented by the general formula (I),

I I

HO / 3 O \ 32 \ R 1

  Wherein R is an aliphatic carboxylic acid group, or a pharmaceutically acceptable salt thereof, alone

  or mixed with other active products and / or with excipients

  tainers. 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

  chosen, the active product of formula (I), preferably

  3,5,3 ', 5'-tetraiodothyroacetic acid or its K salt

  or Na, is therefore used alone or in combination with other

  they are 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 divanillidene-cyclohe-

  hexanone (DVCH), cyclobutyrol, sorbitol, triamcinolone,

  amfepramone, meprobamate, acetazolamide, alpha-

  chymotripsin, bromelaines, lipase, vitamin A, etc.

  For administration by injection, the

  active ingredient of formula (I) is preferably used with hyalurea

  ronidase and / or mucopolysaccharidases, alphachymotrypsin, etc.

  For voierectal administration, the product

  tif of formula (I) is preferably used with mucopoly-

saccharidases.

  Finally, with a view to transcutaneous application, the

  active compound of formula (I) is preferably used with a compound

  activator of adenylate cyclase such as a catecholamine com-

  adrenaline or norepinephrine, 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

  Firstly, that of 3,5,3 ', 5'-tetraiodothyroacetic acid is weak. It was measured on the one hand on mice 5 days later.

  a single intraperitoneal administration of the compound

  50% diluted solution in propanediol, and secondly in rats 5 days after a single intravenous administration of the same solution as for mice, either

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  have 1-single administration of the active compound in suspension

  in a carboxymethylcellulose gel Table I shows the range of

  their LD 50 in pg per kilogram of live weight.

TABLE I

  animal administration LD 50 D 50 (Fg / kg) mouse v intraperitoneal 350 rat v intravenous 300 rat per bone 825

  The toxicity of 3,5,3 ', 5'-tetraiodothro-

  The study was further investigated by observations in dogs 4 months after oral administration of the active product diluted in lactose at doses of 150 μg in the form of capsules per kg per day. These observations were as follows: no evidence abnormal; the consumption of food at a slower moment resumed the pace of untreated witnesses; normal respiratory and cardiac rhythms; no disturbance of

  the electrocardiogram, which maintains its sinusoidal base

  normal dal; no detectable biological changes after

  topsy, mild thyroid gland was observed, whereas liver, kidneys and spleen were normal, as well as heart weight on histological examination of thyroid, liver, and bone marrow, as well as 'to the analysis of the blood formula, nothing

was observed of particular.

  The ability of 3,5,3 ', 5'-tetraiodothyroacetic acid to percutaneous penetration was measured in rats to which a cream containing 0.2% of compound, some of which

  radioactive tracer has been applied; it could then be

  a rapid passage through the blood, the appearance of radioactivity

  in the blood being observed less than 10 minutes after the application

cation.

  The therapeutic effect of an acid-based treatment 3, -

  , 3 ', 5'-tetraiodothyroacetic on cholesterolemia installed a

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  was then studied in chickens as follows: 50 chickens were subjected to an atherogenic diet, a diet designed to create a high concentration of cholesterol in the blood, for 30 days, which led to increase the average total amount of cholesterol cholesterol (average over 50 chickens) from 125 mg per ml of blood (normal amount) to 340 mg / 100 ml (cholesterolemia

  30 chickens were given 500 μg of the product

  tif above per kg per day, the other 29 chickens (1 chicken

  having died as a result of the atherogenic diet) being used together

  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 shown in Table II below.

TABLE II

  Duration of treatment 36 days 57 days Total cholesterol (in mg / 100 ml) control chicken 340 315 330 chickens treated 340 145 145

  It can be seen from the table above that the therapeutic action

  against the hypercholesterolemia of 3,5,3 ', 5'-tetraiodo

  thyroacetic is effective since the amount of cholesterol in

  the blood returned after 36 days of treatment to a close

  than normal, given that the atherogenic diet is now

tenuous.

  The clinical effect of some medicinal preparations

  in accordance with the invention has been studied in particular as regards

  therapeutic activity against hypercholesterolemia, hyperli-

  epidemic and obesity The conditions of administration and the results

  The results obtained are described in Examples 1 to 5 below:

Example 1

  Only 3,5,3 ', 5'-tetraiodothyroacetic acid was administered 3 times a day at 350 pg each time to 3 men (subjects 1 to 3) and 4 women (subjects 4 to 7). ages 35 to 52 The results obtained are combined in the

III.

TABLE III

Example 2

  A gelatin preparation containing 350 μg of 3,5,3 ', 5' tetraiodothyroacetic acid, 25 mg of amfepramone and meprobamate mg was administered at a rate of two capsules per day to four male patients aged 45 to 55 years old

  The results obtained are shown in Table IV.

  Subject i 2 3 4 5 6 7 Duration of treatment (weeks) 3 3 4 3 4 5 3 Cholesterol Before 3.40 3.50 3.90 4.15 4.2 3.20 3.80 (mg / ml) After 2.20 2, 20 2.60 3.20 3.10 2.50 2.40 Total Lipids Before 7.0 8.0 6 8.2 9.2 8 (mg / ml) After 6.0 6.0 5.4 7.9 7.5 8.0 6.5 Weight of subject (kg) Before 71 97 84 65 62 70 48 After 68 92 79 60 59 64 47 Size of subject (m) 1.62 1.75 1 , 76 1.54 1.60 1.53 1.55 Decrease in size size (cm) 3 5 5 7 3 7 2 hips 4 6 5 5 4 7 3 thighs 2 2 3 4 2 3 i 5.

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TABLE IV

Example 3

  A cream containing 100 mg of 3,5,3 ', 5'-tetrahydrate

  iodothyroacetic acid, 15,000 TRU of mucopolysaccharidases and an exci-

  (for example 12 g of cetomacrogol, 5 g of hexyl

  lauric acid ester, 0.05 g of methyl p-oxybutyrate and 0.05 g of propyl poxybutyrate, the remainder being water) qsq 100 g, was applied locally to five women suffering from obesity with The results are summarized in Table V. Topic 1 2 3 4 Duration of treatment (weeks) 3 3 8 8 Cholesterol Before 3.10 4.50 4.05 3.20 (mg / ml) After 2.60 2 , 50 3.10 2.50 Total lipids Before 7.5 9.0 9.5 7.8 (mg / ml) After 6.5 7.5 8.2 6.0 Weight of subject (kg) Before 72 87 81 99 After 68 81 77 90 Subject size (m) 1.70 1.75 1.65 1.80

Decrease in

  surations (cm) size 4 6 5 8 hips 3 5 4 6 thighs 2 2 3 2 6.

TABLE V

  NB amel = appearance of the skin tr am = appearance of the skin little am = appearance of the skin B = good improved very improved little improved

  By good tolerance, we mean that the women to whom

  the cream above was applied did not show any effects

secondary detectable.

Example 4

  3,5,3 ', 5'-tetraiodothyroacetic acid was

  plicated as a 0.2% solution in propane diol

  read, by ionization (electrode, 15 m A), at a rate of 20 minutes twice a week and alternating application of the cream

described in Example 3.

  Subject 1 2 3 4 5 Duration of treatment 4 6 6 6 6 (weeks) Cutaneous flexibility Before no means zero none null After good enough b good enough b good Phenomenon little orange Before yes yes yes yes yes

  After am am tr am tr am little am tr am.

Decrease in

  Size (cm) Size 4 6 3 5 4 Hips 3 4 3 6 4 Thighs 2 3 2 4 2 Tolerance B B B B B 7.

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  It was observed a clear decrease of adipose bulges, a clear decrease of the subcutaneous infiltrations of cellulitic type and thus an improvement of the measurements;

  the tolerance to treatment has been excellent.

Example 5

  Two subjects were treated for 8 weeks with

  a preparation containing 0.350 mg of 3,5,3 ', 5'-tetraiodo

  tyroacetic acid and 0.5 mg of triamcinolone, and showed a decrease in

  weight and a simultaneous reduction in obesity.

  as well as an improvement in biological parameters.

Example 6

  A gel preparation containing 0.5 mg

  of 3,5,3 ', 5'-tetraiodothyroacetic acid, 200 mg of divan

  lidene cyclohexanone and 25000 U I of axerophtol acetate (vi

  A) was administered at a rate of 3 capsules per day to four male patients. The treatment was carried out for 2 to 3 weeks and repeated 2 to 3 times, with a week's

  Therapeutic rest between each treatment The results obtained

  -nus are shown in Table VI.

TABLE VI

  Subject I 2 3 4 Duration of treatment 2 x 2 2 x 3 3 x 2 2 x 3 (weeks) Total cholesterol Before 3.10 3.05 2.80 3.60 (mg / ml) After 2.40 2.50 2.10 2.70 Total lipids Before 6.9 6.1 6, o 7.05 (mg / ml) After 6 5.9 5.4 5.6 I 1 results from the preceding examples that, irrespective of the modes implementation and administration, the

  medicinal preparations which are the subject of this invention.

  are valuable therapeutic agents for the treatment of

  hypercholesterolemia, hyperlipidemia, lipo-

  localized dystrophies, certain forms of obesity with

  weight and / or subcutaneous infiltration of

  lulitique. By way of examples to illustrate the invention, mention may also be made of the following compositions A to D for which

  the dosing ranges given correspond to the daily dosage.

globle nalière.

  For daily administration of the total daily dosage tetraiodothyroacetic acid

and / or tetraiodothyro-

  propionic and / or clofibrate and / or cyclobutyrol and / or DVCH and / or sorbitol and / or triamcinolone and / or amfepramone and / or meprobamate and / or acetazolamide and / or alphachymotrypsin and / or bromelain (extracted

of pineapple sativus and A.

  comosus) and / or lipase 1 to 3 mg 1 to 3 mg 1 to 1.5 g 0.3 to 0.8 g 0.6 to 1 g 3 to 5 g 0.05 to 2 mg to 100 mg 0.05 at 0.2g to 300mg -50 to 50,000 UA Hb 000 to 300,000 units

10,000 to 30,000 Business Units

  lipolytic 9. B For administration by injection tetraiodothyroacetic acid

and / or tetraiodothyropro-

  pionic and / or hyaluronidase and / or mucopolysaccharidases and / or alphachymotrypsin 0.5 to 1.5 mg 0.5 to 1.5 mg

5,000 to 20,000 TRU

10,000 to 20,000 TRU

  50,000 U C Hb C For rectal administration of tetraiodothyroacetic acid

and / or tetraiodothyropro-

  pionic and / or mucopolysaccharidases 0.5 to 1.5 mg 0.5 to 1.5 mg

10,000 to 15,000

  D For transcutaneous administration a) Cream, gel, ointment, liniment doses in percent 0.1 to 0.2 tetraiodothyroacetic acid

and / or tetraiodothyropro-

pionic 0.1 to 0.2

  and / or adrenaline, norepinephrine, bamethan, neosynephrine, saline

  butamol, xanthine and derivatives thereof.

  and / or hyaluronidase 5,000 to 20,000 TRU and / or mucopolysaccharidases 10,000 to 15,000 TRU and / or acetazolamine 3 to 10% b) solutions for tetaiodothyroacetic acid ionization 0.05 to 0.2

and / or tetraiodothyro-

  propionic acid 0.05 to 0.2 and / or mucopolysaccharidases 10 000 to 15 000 TRU In addition, it is also possible to provide

  spreading agents presented in the galenic form of microbial

  beads, in order to better utilize the own delay effect of the compounds

active compounds of formula (I).

  10. 11 l. 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 3,5,3 ', 5'-tetraiodothyroacetic acid.

  3,5,3 ', 5'-triiodothyroacetic acid, as well as similar iodophenolated products, can be prepared, for example, by the following successive reactions: a) formation of the compound of formula NO 2

CH O CHO

  NO. 2 by reaction of chlorodinitrobenzaldehyde and p-methoxyphenol in the presence of CH 3 -H or a reducing agent such as bisulphite; B) replacement of the two nitro groups by two -NH 2 groups by reduction (Ni Raney) in an alcoholic medium; then diazotization of the uninsulated diamine and reaction of Sandmeyer in the presence of a

  iodine-iodide solution in a sulfuric acid medium, in order to replace

  place the two -NH 2 groups with two iodo groups; c) forming the corresponding acid by treatment with P C 15 and obtaining the chlorinated derivative, and then treating it

  by KCN and conversion to nitrile, and hydrolysis by HI.

presence of red phosphorus -

  d) iodination with 12 in an ammoniacal medium to provide the tetra derivative

  desired after recrystallization in absolute alcohol,

  having a melting point of 241 C and having the characteristics

  spectral characteristics: infra-red spectrometry (K Br tablet) -1) OH 3460 cm 1 C = O 1708 cm 1 J C-0-C 1147 cm 1 JC-OC 11> 47 cm 12. UV spectrometry maximum absorption at 300 nm + 1.5 (c 1% = 59.0) 1 i cm nuclear magnetic resonance (solvent: (CD 3) 2 CO; S in ppm; internal reference TMS) s proton allure integration (protons) 8.3-9 5 OH, low COOH 2 exchangeable with D 7.88 H 2 and H 6 singlet 2 7.15 H 2 and H 'singlet 2

2 6

3.68 CH 2 singlet '2

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Claims (5)

  1 drug preparation having a therapeutic activity especially against hypercholesterolemia, hyperlipidemia and obesity, characterized in that   that it includes as active product at least one   posed represented by the general formula (I), I I H R (I) I I /   wherein R is an aliphatic carboxylic acid residue   or a pharmaceutically acceptable salt thereof in admixture with xanthine or béthan.   2 Drug preparation according to the claim   1, characterized in that the compound of formula (I)   is 3,5,3 ', 5'-tetraiodothyroacetic acid.   Pharmaceutical preparation according to claim 1, characterized in that the compound of formula (I)   is 3,5,3 ', 5'-tetraiodothyropropionic acid.   4 Drug preparation according to the claim   1, characterized in that said salt is a salt of an alkali metal, an alkaline earth metal salt or an organic salt.   Drug preparation according to one of   Claims 1 to 4 for percutaneous application   born, characterized by the fact that it includes one or   several penetrating agents chosen from the alpha- 14 -   chymotrypsin, bromelaines, lipases, mucopo lysaccharides and hyaluronidase.   6 Drug preparation according to one of   Claims 1 to 4 for oral administration,   characterized by the fact that it includes mischief mate.