DE2323906A1 - PHARMACEUTICAL PREPARATION AGAINST OBESITY - Google Patents

Description

Brentford, Middlesex, UK

^M Pharmaceutical preparation against obesity ⁿ

Priority: May 11, 1972, Great Britain, No. 22 105/72

The invention relates to pharmaceutical preparations used for treatment of obesity and for the prophylaxis and treatment of diabetes, arteriosclerosis and coronary sclerosis (coronary artery calcification) are valuable.

There are numerous ailments in human and veterinary medicine, associated with extensive deposition of body fat. One type of abnormal fat deposit becomes larger than normal amounts of fat stored in the usual fat deposits, so that obesity or obesity occurs. At a Another type of abnormal fat deposit is the fatty one Material deposited mainly in organs, such as the liver

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ORK & NAL INSPECTSO

or kidney, making these organs considerably enlarged and become noticeably impaired in their puncture. In addition, of course, all fatty substances that are present in the tissues occur more or less strongly in the blood, so that various signs of degeneration, the most important of which is arteriosclerosis and, as a consequence, arteriosclerosis Coronary veins are, at least partially, with the increased Related to serum fat levels.

Carnitine, namely ß-Hydroxy-i -trimethylammonium-butyrobetaine, is the compound known by the general formula Γ;

It has been suggested that it act as a carrier molecule for the transport of intermediate products of fatty acids; The change in and outside of the mitochondria (cell inclusions) is responsible (see, for example, IB Fritz, Adv. Lipid Res. ] _ (1963), p. 285). It is known that the carnitine level in tissue is reduced when the fat metabolism is increased, as is the case, for example, with alloxan diabetes and Choliu-Kangel dex * (see Mehlman et al., Metabolism, £ 0 (1971), S.100-107) It has already been suggested that carnitine increases the rate of fatty acid oxidation in brown adipose tissue ”(cf. Dranota and colleagues, Experientia £ 4 (1968), p. 43). However, it has been found that administration of carnitine alone is not effective in reducing body weight in mammals. In fact, carnitine is in the book by

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Negwer ⁿ Organisch Chemische Arzneimittel und their Synonyma "(1966) listed as an appetite stimulant and a preparation containing carnitine, which is sold by the company" Cheminova Kspanola SI ^W , is used to treat abnormal weight loss.

It has now been found that the administration of carnitine together with a lipolytic factor reduces the Body weight and also a reduction in body fat. This is a surprising finding, especially with regard to the previous use of carnitine.

The term "fat-splitting factor" denotes a substance which either (a) when it reacts with a tissue in vitro, an increase of at least 10 percent of the leisure time caused by fatty acids from this tissue compared to the normal or basic speed of the Release of the same species under the same conditions,

or (b) when administered to mammals, causes an increase of at least 10 percent in the rate of breakdown of triglyciases compared to the normal rate of breakdown in the same mammals.

The subject of the present invention is therefore pharmaceutical Preparations for combating and reducing obesity, which contain a mixture of (a) carnitine or its acid addition salts and (b) at least one fat-splitting Factor as well as at least one pharmacological

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compatible carrier material and / or diluent are.

As is common practice, such preparations are usually written or printed instructions for use accompanied by medical treatment, which in this case is a means of reducing body weight and / or for use in the prophylaxis or treatment of diabetes or arteriosclerosis.

Although one prefers that carnitine and the fat splitting factor If administered in one preparation, a reduction in body weight can also be achieved through separate administration of carnitine and a fat-splitting factor " Therefore, the subject matter of the present invention also includes such pharmaceutical preparations, the carnitine or its Acid addition salt together with at least one pharmacologically acceptable carrier material and / or diluent included with another pharmaceutical preparation a content of at least one fat-splitting factor with at least one pharmacologically acceptable carrier material and / or diluents are present.

Any fat-splitting factors can be in or in connection can be used with the preparations according to the invention. In particular, different classes of compounds are known, which have a lipolytic activity.

Examples of suitable classes of fat-splitting factors are:

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(a) Xanthines and in particular a xanthine of the general type Formulas II or III

(II)

(in)

in which R ₁ and Rp can be identical or different and are hydrogen atoms or alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl or alkylaminoalkyl radicals, Κ · ζ * R / ^ur * £ Rc can be identical or different and denote hydrogen atoms or alkyl radicals or alkoxy or heterocyclic radicals which are optionally substituted by hydroxyl groups or halogen atoms or aryl or heterocyclic radicals.

Numerous examples of such xanthines are from J. A. Beavo and colleagues, in Mol. Pharmacol. £ (1970) pp. 597-603, Typical compounds that can be co-administered with carnitine are

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1,3-dimethyl-xynthin (theophylline); 1, 3-diraethyl-xanthine-ethylene-diamine - (aminophyll); 1,3 ~ DiKieihyl-7-hyaroxyrßethyl-xanthine; 1,3-Diinethyl »7-hydroxypropyl-xanthine; 1,3-dimethyl-7- {2-chloroethyl) xanthine; 1,3-Diiaethyl-7-piperidylmethyl-xanthine; 1, 3 ~ I) i2iethyl-7-morpholynylmethyl-xynthin; 1, 3,7-trimethyl-xanthine; 1, 3 5 7-trimethyl-8- _/ / ~ 2- (5-hydroxy methyl) -tetrahydrofuryl / -xanthine;

1, ^^ - trimothyl-Sjg-dihydro-e-ethyleridioxy-xauthin; 1-methyl-3-n- "butyl-xanthine; 1-methyl-3-isobutyl-xanthine; 1,8-dimethyl-3- (2-isobutenyl) -xanthiT! I; 1,3-diethyl xanthine;

1,3,7-triethyl xanthine; 1-ethyl-3-n-propyl-xanthine; 1-ethyl-3-isobutyl-xanthine; 1-ethyl-3- (2,3-dibromopropyl) -8-methyl-xatjthin; 1-Xthyl _r 3-phenylethyl-χanthine; 1,3-di-n-propyl-xanthine; 1,3-diallyl xanthine;

1-n-pentyl-3-ethyl-xanthine or 3-n-propyl-7-n-butyl-xanthine.

The preferred compounds are theophylline and its ethylenediamine complex, namely aminophylline.

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(b) Phenethylamines and especially compounds of the general Formula IV

⁶ I ⁷

R1

J ⁶

Ar - CH - CH - NH - R ₈ (IV)

in which Ar is a phenyl radical optionally substituted by at least one halogen atom, a trihalomethyl or a hydroxyl group, Rr is a hydrogen atom or a hydroxyl group and R ₇ and R _{R can be} identical or different and are hydrogen atoms or alkyl radicals having 1 to 6 carbon atoms.

Some examples of PhenäthylamineYi, according to reports Have fat-splitting properties are from D.R. Peller and co-workers, in Biochem. Pharmacol. IjJ, (1970) pp. 705-713. and by B. Rudman in J. Lipid Res. 5. (1964) pp.28-37. Special compounds, which together with carnitine in öen Pharmaceutical preparations that can be used are aiaphetamine, p-hydroxy-amphetamine, chlorophenamine and preferred Penfluramin, namely the N-ethyl-Oc-methyl-m- (trifluoromethyl) -i> heny 1 äthy glue in.

(c) 6-amino-uracile, ε.Β.

1-methyl-G-aminouracil;

1,3-dimethyl-6-amiuouracil;

i-methyl-G-aminouracil;

3-methyl-1-isobutyl-6-aminouracil or a 1-alkyl-6-amino-3-ethyluracil;

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(d) adenines such as adenine itself and 8- (1-hydroxy-isopropyl) adenine;

(e) Thyroid derivatives, e.g. thyroidin, triiodothyronine or Thyroxine;

(f) other compounds with known fat-splitting compounds Activity, such as ascorbic acid, <X ~ glycerophosphate, as well as compounds of the general formulas V, VI and VII

NH

/ r ~ \ Il

(f \ U.-CO-NH -C-CN (V)

CKH

NH ₂ (VI)

MeN 7- C V-NH-O-NH ₂ -

The carnitine which can be used according to the invention can be used in the d-, 1- or in the dl form.

In the production of the new preparations according to the invention

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the active ingredients are incorporated into a suitable carrier material, such as a pharmaceutical carrier material, a drink or a food. Any suitable pharmaceutical carrier materials can be used for the production of the preparations according to the invention, such as starch, lactose, glucose, sucrose, rice flour, talc or calcium carbonate, if solid preparations are to be produced. If digestible capsules are to be produced, gelatin, for example, can be used as a carrier material. Examples of liquid pharmaceutical carrier materials are ethanol, glycerine, saline solution or water, together with flavorings and colorings to form a syrup. Also, the carnitine and / or fat-splitting Paktor in a food can, for example, _t in combination with biscuits or in a beverage, for example, meat stock or incorporated as a part into a dietetic food diagram.

The preparations according to the invention bring about a reduction body weight in mammals by means of a specific attack on adipose tissue.

Oral administration is preferred for the preparations according to the invention. Because the carnitine and the fat-splitting factor Can be administered in separate preparations, it is possible to use different doses with little different Amounts of the fat-splitting factor per day in connection with To give a single larger dose of carnitine.

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The ratio of the carnitine to be administered to the fat-splitting one Factor depends on the lipolytic activity of the latter. In general, the weight ratio of Vary 10 s 1 to 1: 5. When using aminophylline the preferred ratio is two parts carnitine to one part aminophylline.

Carnitine can be used in mammals in an amount from 0.5 mg / kg to 200 mg / kg body weight per day and the fat-splitting factor from 1 mg / kg to 100 mg / kg per day can be administered. Preferred dosages are 2 to 20 mg / kg for carnitine and 1 to 10 mg / kg for the fat-splitting factor.

The examples illustrate the invention.

Example 1 Effect of Carnitine Alone.

Eight female mice are subcutaneously ^{injected with monosodium glutamate:} during the first ten days of life, as described as a method for inducing obesity by JW ₀ Olney in "Science" 164 (1969) p. 719. At about 23 weeks of age, the mice are divided into two groups of four mice each. For the next 28 days, one group, the control group, receives a standard diet, while the other group receives the same diet, but with 0.1 percent carnitine. During the experiment, the mice were weighed and then sacrificed. Solvent extraction is used

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the total fat content is determined.

Table I shows the effect of carnitine on growth and the change in fat in obese mice.

Table I.

control treated Body weight at the beginning 48.5 48.7 Weight gain in g / mouse /
28 days - 1.5 - 1.1 Mean fresh fat weight
in g / 100 g mouse 51.5 48.1 percentage change in
Fresh fat / 100 g mouse - - 7.0

Example 2

The experiment of Example 1 is carried out using Carnitine (0.1 percent of diet food) plus aminophylline (0.1 percent of diet food) repeated over 28 days. the Table II shows the effects of this mixture on growth and the change in fat content in obese mice.

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Table II

control treated Body weight at the beginning 56.2 55.2 Weight gain in g / mouse /
28 days - 1.0 - 4.7 Mean fresh fat weight
in g / 100 g mouse 57.6 47.7 percentage change in
Fresh fat / 100 g mouse - -17.2

Example 3

The experiment of Example 1 is on

8 male and 8 female genetically obese mice across repeated for a period of 4 weeks. In this experiment, the mice are fed DL-Carnitiu (0.1 percent of the diet) plus L-thyroxine (subcutaneous injection of 25; ug per mouse) treated. The results are shown in Table III.

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Table III

control woman
lich Carnitine woman
lich Carnitine + woman
lich 67.3 59.5 L-thyroxine 67.8 male
lich + 3.3
± ¹ »° 5 male
lich - 2.7 male
lich - 5.3 middle
At first
weight 61.5 62.3 65.3 middle
Increase /
4 weeks + 2.0
+ 0.63 + 3.0
+ ¹ »53 - 2.3
+ 1.77

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Claims (1)

Patent claims: (j). Pharmaceutical preparations for controlling or reducing. Submission of obesity, characterized by a content of a mixture of (a) Carnitine or its acid addition salts and (b) at least one fat-splitting factor and at least a pharmacologically acceptable carrier material and / or diluent. 2. Pharmaceutical preparations according to claim 1, characterized by a content of xanthine f ettspaltende ⁿ factor. Pharmaceutical preparations according to Claim 2, characterized by a xanthine derivative of the general formula (II) or (III) as a fat-splitting "factor (II) (III) 369847/1158 in which R ₁ and R _{2 can be the} same or different and are hydrogen atoms or alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl or alkylaminoalkyl radicals, RJ, R ^ and R ^ can be the same or different and are hydrogen atoms or alkyl radicals or alkoxy or heterocyclic radicals which are optionally substituted by hydroxyl groups or halogen atoms or aryl or heterocyclic radicals. 4. Pharmaceutical preparations according to claim 3 _} characterized by a content of 1,3-dimethyl-xanthine or its ethylenediamine complex as fettspaltendai factor. 5. Pharmaceutical preparations according to claim 1, characterized by a phenethylamine as a fat-splitting factor. 6. Pharmaceutical preparations according to claim 5, characterized by a phenethylamine of the general formula (IV) as a fat-splitting factor. Ar - CH - CH - NH - Rg (IV) in which Ar is a phenyl radical optionally substituted by at least one halogen atom, a trihalomethyl or a hydroxyl group, Rg is a hydrogen atom or a hydroxyl group and R ₇ and R _{Q can be} identical or different and are hydrogen atoms or alkyl radicals having 1 to 6 carbon atoms. 30984771158 7 · Pharmaceutical preparations according to claim 6, characterized due to a content of penfloramin as fat-splitting Factor. 8. Pharmaceutical preparations according to claim 1, characterized due to a content of 6-ainino-uracil as fat-splitting Pactor. 9 · Pharmaceutical preparations according to claim 1, characterized by a content of adenine, 8- (1-hydroxy-isopropyl) adenine, Thyroxine or a compound of the general formulas (V), (Vl) or (VII) as a fat-splitting factor. 309847 / 11B8