EP1438047A2 - Compounds for reducing excessive intake of food - Google Patents

Abstract

The invention relates to the use of dopamine receptor agonists for the production of a pharmaceutical for reducing excessive intake of food.

Description

Compounds to reduce excessive food intake

The invention relates to the use of dopamine receptor agonists for the manufacture of a medicament for reducing excessive food intake.

Background of the invention

Excessive food intake usually leads to obesity or obesity, i. an increase of the normal weight exceeding the standard limit. Being overweight is not only a high health risk but also a societal problem. Overweight is a risk factor for a variety of conditions such as high blood pressure, diabetes mellitus, hyperlipidemia, osteoarthritis, gout, and associated vascular disease, especially arteriosclerosis. Furthermore, induced by an overweight mental distress can occur up to depression.

The only effective therapeutic measure is the reduction of calorie intake. This is difficult to achieve in many patients despite knowing the consequences listed above. The object of the invention is to make it easier for the patient to reduce calorie intake and thus to reduce the health risks associated with obesity.

Description of the invention

It can now be surprisingly shown that dopamine receptor agonists selected from the group consisting of Dp, D ₂ , D ₃ and D ₄ receptor agonists, can be used to reduce excessive food intake in therapeutically effective doses useful.

Accordingly, the present invention is directed to the use of dopamine receptor agonists selected from the group consisting of D 1, D ₂ , D ₃ and D ₄ receptor agonists for the manufacture of a medicament for reducing excessive food intake. Dopamine receptor agonists are preferably selected from the group consisting of adrogolides, A-86929, rotigotine, NeurVex, nolomirole, pramipexole, talipexole, CHF 1512, (-) - stapholidine, DAR-201, diacrine / genzyme, bromocriptine, bupropion, LEK - 8829, BAM-1110, AIT-203, NS-2330, Terguride, Aripiprazole, OPC-4392, GMC-1111, PD-148903, Apomorphine HCl, PD-89211, PD-158771, Cabergqline, Sumanirole, PNU-14277E, POL -255 _r Dihydrexidine, GBR-12783, Quinagolide HCI, (R) -Bupropion, S-32504, S-33592, SKF-80723, SKF-83959, fenoldopam, Ropinirole, SKF-82958, SKF-77434, DU 127090, SLV-308, SLV 318, NeuroCRIB, SP-1037C, Spheramine, Gallotrank, Preclamoi, DAB-452, Y-435, BP-897, ProSavin, Etilevodopa, P63, A 68930, A 77636, Alaptide, Alentemol, Cl 1007; PD 143188, BLSI, YES 116a; YES 116, Melevodopa; Levodopa methyl; CHF 1301; NSC 295453; Levomet, MR 708, PD 128483, RD 211, SKF 38393, SKF 81297, U 86170F, U 91356A, WAY 124486 and Z 15040.

In the use according to the invention preferably doρamin-D ₃ -

Receptor agonists, preferably pramipexole or talc ipexol for use. Particularly preferred is the use of o.g. Dopamine receptor agonists for

Production of a drug to reduce excessive food intake in overweight.

Further preferred is the use of o.g. Dopamine receptor agonists for

Preparation of a medicament for the treatment of obesity in type 2 diabetes. Especially preferred is the use of o.g. Dopamine receptor agonists for the manufacture of a medicament for continuous application to

Reduction of excessive food intake

Most preferred is the use of o.g. Dopamine receptor agonists for

Preparation of a medicament for transdermal application for reducing excessive food intake.

Pramipexole and talipexole are particularly preferred because they have a high selectivity to the dopamine D ₃ receptor. It can be shown that this reduces the side effects of a pharmacological influence on food intake. The D ₃ receptor is predominantly localized in those regions of the brain that are associated with emotion. Activation of the D ₃ receptor by a dopamine agonist, preferably by pramipexole and talipexole, more preferably by pramipexole, may aid in lessening mood by overacting an excessive food intake or diseased food intake.

The dopamine D ₃ receptor agonists pramipexole and talipexol which can preferably be used in the context of the present invention may optionally be used in the form of their enantiomers or their racemates, if appropriate in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the hydrates and solvates.

Of paramount importance in the context of the application according to the invention is the dopamine D ₃ receptor agonist pramipexole, optionally in the form of its Enantiomers or its racemate, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of hydrates and solvates.

Reference to any of the aforementioned dopamine D ₃ receptor agonists includes a reference to the optionally existing enantiomers or the racemate of the particular compound. For example, reference to pramipexole includes reference to the (+) enantiomer as well as to the racemate. In the context of the present invention, however, the (-) - enantiomer is of particular importance.

The dopamine D ₃ receptor agonists which may be used according to the invention may optionally be used in the form of their pharmaceutically acceptable acid addition salts and optionally in the form of their hydrates and / or solvates. Pharmaceutically acceptable acid addition salts of the dopamine D ₃ - receptor agonists are understood according to the invention as salts selected from the salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, fumaric, succinic, lactic, citric, tartaric and maleic acids, the Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and acetic acid are particularly preferred. Of particular importance is the salts of hydrochloric acid.

In the case of the pramipexole which can be used particularly preferably according to the invention, it is likewise preferable to use the hydrochlorides, in which regard pramipexol dihydrochloride is of particular importance. In the case of transdermal administration, the base of pramipexole is preferably used. Of the hydrates of pramipexole, pramipexole dihydrochloride monohydrate is particularly preferred.

The dopamine receptor agonists which can be used according to the invention, preferably dopamine D ₃ receptor agonists, preferably pramipexole or talipexol, particularly preferably pramipexole, can optionally be used in combination with further active compounds. Preferred combination partners are compounds selected from the classes of dopamine-Di, D ₂ , D _3, or D ₄ - receptor agonists selected from the group consisting of adrogolides, A-86929, rotigotine, NeurVex, nolomirole, - pramipexole, talipexole, CHF 1512, (-) - Stepholidine, DAR-201, Diacrine / Genzyme, Bromocriptine, Bupropion, LEK-8829, BAM-1110, AIT-203, NS-2330, Terguride, Aripiprazole, OPC-4392, GMC-1111, PD- 148903, Apomorphine HCl, PD-89211, PD-158771, Cabergoline, Sumanirole, PNU-14277E, POL-255, Dihydrexidine, GBR-12783, Quinagolide HCl, (R) -Bupropion, S-32504, S-33592, SKF- 80723, SKF-83959, Fenoldopam, Ropinirole, SKF-82958, SKF-77434, DU 127090, SLV-308, SLV 318, NeuroCRIB, SP-1037C, Spheramine, Gallotrank, Preclamol, DAB-452, YM-435, BP- 897, ProSavin, Etilevodopa, P63, A 68930, A 77636, Alaptide, Alentemol, CI 1007; PD 143188, BLSI, YES 116a; YES 116, Melevodopa; Levodopa methyl; CHF 1301; NSC 295453; Levomet, MR 708, PD 128483, RD 211, SKF 38393, SKF 81297, U 86170F, U 91356A, WAY 124486 and Z 15040, the antidepressants, the anorectics, preferably silver halide, the lipase inhibitor, preferably orlistat, and the sympathomimetics, preferably ephedrine , By synergistic effects in the intended effect, in the case of the use of combinations containing in addition to the dopamine receptor agonists according to the invention one of the above-mentioned further active ingredients, the dosage of the individual components can be reduced.

The effect according to the invention of the dopamine agonists according to the invention is to be explained by the following example of pramipexole. It merely serves to illustrate the invention and is not to be regarded as limiting.

Effect of pramipexole on feed intake in mice

Pramipexole inhibits feed intake in mice when used continuously. Continuous application by means of osmotic pumps led to a permanent, statistically highly significant inhibition of feed intake (Fig. 1). In contrast, a single application on a consecutive day with a comparable dose did not lead to a significant reduction in feed intake (Fig. 1).

Furthermore, a permanent weight reduction was observed in the long-term application, which was statistically highly significant detectable even after completion of pramipexole treatment (Fig.2).

Test procedure One-time application:

Ten mice (strain: C57BL / 6) were deprived of food for 24 h with free access to drinking water. 20 minutes before the end of the fasting period pramipexole (2.5 mg / kg body weight sc) was administered. The control group, also 10 mice, received physiological saline, the solvent used for pramipexole. After that was offered to the ^"animal feed and feed consumption over 4 days in 30 min measured rhythm. Experimental procedure Continuous application:

Ten mice (strain: C57BL / 6) were deprived of food for 24 h with free

Access to drinking water. 20 minutes before the end of the fasting period, the animals were subcutaneously implanted with the alzet® mini-osmotic pump (model 2002) with a release dose of 2.5 mg pramipexole / 24 h s.c. The pumping rate was 0.54 μl / h. In a similar experiment, a group of 10 control animals received the solvent, physiological saline solution, applied with the same pumping rate. The continuous release of the substance or the solvent was measured for 4 days. Feed intake was measured at 2 hour intervals over the first 10 hours, later daily.

The measurement of the weight change for the long-term application took place over a period of 22 days, with pramipexole administration being terminated after 14 days. The weight change was measured daily.

The dosage of the dopamine receptor agonists according to the invention is naturally highly dependent on the strength of the symptoms to be treated, on the one hand, and on the choice of the active ingredient, on the other hand. For example, and without restricting the subject matter of the present invention to it, possible dosages are given at this point in particular for the compound pramipexole which is particularly preferred according to the invention. This can be used in dosages of about 0.05 to 3 mg, preferably of about 0.1 to 1.5 mg, per day. These dosages are based on pramipexole in the form of its free base. Based on the preferably used salt form pramipexole dihydrochloride monohydrate, the above-mentioned dosages correspond to about 0.07 to 4.26 mg, preferably 0.14 to 2.13 mg pramipexole dihydrochloride monohydrate per day.

A possible method of dosing which can only be understood by way of example as an explanatory example is stated below (based on pramipexole in the form of its free base): individual doses in weekly intervals, depending on the action and tolerability. 1st week: 1 tablet containing 0.088 mg pramipexole 3 times daily;

2nd week: 1 tablet containing 3 times daily 0.18 mg pramipexole;

3rd week and following: 3 times daily 1/2 tablet containing 0.7 mg pramipexole. The dopamine D ₃ receptor agonists may be administered orally, transdermally, ^{'intrathecally,} by inhalation, nasally or parenterally in the application of the invention, preferably transdermally or parenterally, more preferably transdermally. Suitable application forms are, for example, tablets, in particular preferably slow-release tablets, capsules, suppositories, solutions, juices, emulsions, dispersible powders, implants or patches, particularly preferably micronal patches. With regard to possible embodiments of a transdermal application form which can be used according to the invention, reference is made at this point, in particular with regard to pramipexole, to the exemplary embodiments according to US Pat. No. 5,112,842, to which reference is hereby expressly made. For example, tablets may be prepared by mixing the active ingredient (s) with known excipients, for example, inert diluents such as calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or Achieving the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate are obtained. The tablets can also consist of several layers.

The following are some examples of pharmaceutical preparations which can be used according to the invention. These are merely illustrative, without limiting the scope of the invention to the same.

Tablet 1:

Ingredients: mg pramipexole dihydrochloride monohydrate 1, 00

Mannitol 121, 50

Cornstarch 79.85

Highly dispersed silica, anhydrous 2.30

Polyvidon K25 2.35 Magnesium stearate 3 * 00

Total 210.00

Tablet 2:

Ingredients: mg pramipexole 0.5 mannitol 122.0 corn starch, dried 61, 8 corn starch 18.0 Highly dispersed silica, anhydrous 2,4

Polyvidon K25 2.3 Magnesium Stearate 3.0 Total 210.0

Tablet 3:

Ingredients: mg pramipexole 0.25

Mannitol 61, 00

Cornstarch 39.90

Highly disperse silica, anhydrous 1, 20

Polyvidon K25 1, 15 Magnesium stearate 1, 5

Total 105,00

Tablet 4:

Ingredients: mg pramipexole 0.125 mannitol 49.455 corn starch dried 25.010 corn starch 7,300

Highly dispersed silica, anhydrous 0.940

Polyvidon K25 0.940 Magnesium Stearate 1, 230 Total 85,000

Solution for injection:

Pramipexole dihydrochloride monohydrate 0.3 mg Sodium chloride 0.8 mg Benzalkonium chloride 0.01 mg

Aqua adjection ad 100 ml

Claims

claims 1) Use of dopamine receptor agonists selected from the group consisting of D, D ₂ , D ₃ and D receptor agonists for the manufacture of a medicament for reducing excessive food intake. 2) Use according to claim 1 of dopamine D ₃ receptor agonists for the manufacture of a medicament for reducing excessive food intake. 3) Use according to claim 1 or 2 for the manufacture of a medicament for reducing excessive food intake in overweight. 4) Use according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment of obesity in type 2 diabetes. 5) Use according to one of claims 1 to 4 for the manufacture of a medicament for continuous application. 6) Use according to one of claims 1 to 5 for the manufacture of a medicament for transdermal application. 7) Use according to any one of claims 2 to 6, characterized in that as dopamine D ₃ receptor agonists pramipexole and / or talipexole optionally in the form of their enantiomers, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of hydrates and solvates , 8) Use according to one of claims 2 to 6, wherein the dopamine D ₃ - receptor agonist pramipexole, optionally in the form of its enantiomers, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of hydrates and solvates. 9) A pharmaceutical composition containing as active ingredient a dopamine D ₃ receptor agonist optionally in the form of its enantiomers, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the hydrates and solvates or their physiologically acceptable salts in combination with one or more active substances selected ^. from the group of dopamine Dp, D ₂ , D ₃ or D ₄ agonists, anorectics, lipase inhibitors and sympathomimetics: 10) A pharmaceutical composition according to claim 9, containing as active ingredient pramipexole optionally in the form of its enantiomers, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of hydrates and solvates or their physiologically acceptable salts in combination with one or more active substances selected from the group of Dopamine di-, D ₂ -, D ₃ - or D ₄ - agonists, anorectics, lipase inhibitors and sympathomimetics. attachment * p <0.05 Significance vs. A: Alzet pump NaCl 0.9% s.c. ** p <0.01 control group *** p <0.001 B: Alzet pump PPX 2.5mg / 24h s.c. test group Fig. 1 4-day long-term application of pramipexole (PPX) compared to a single application on 4 consecutive days 0 1 2 3 4 5 6 7 8 910 11 1213141516 171819 2021 22 days Fig. 2 Body weight reduction during 14-day continuous subcutaneous (s.c) infusion of pramipexole and 7-day follow-up