WO2003053427A1 - Use of (+)-(1s,2s)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol as anti-emetic agent - Google Patents

Abstract

The invention relates to the use of (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol for preparing an anti-emetic agent and to anti-emetic pharmaceutical compositions that contain, in addition to one or more pharmaceutical adjuvants, (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol as an active agent and optionally an additional pharmaceutically active substance.

Description

 Use of f +) - (1S, 2S -3- (3-dimethylamino-1-ethyl-2-methylpropyQphenol as an anti-emetic

The present invention relates to the use of (+) - (1 S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol for the preparation of an antiemetic and antiemetically active pharmaceutical compositions which, in addition to or several pharmaceutical excipients (+) - (1 S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol as an active ingredient and optionally a further active pharmaceutical ingredient.

Nausea and vomiting occur in connection with numerous diseases or are considered an undesirable side effect in drug therapy, e.g. by opioid analgesics (AL Kovac, Drugs (2000), 59 (2), 213-243), anesthetics (MR Tramer et al., BMJ (1997), 314, 1088-1092) or cytostatics (C. Veyrat-Follet et al ., Drugs (1997), 53 (2), 206-234). They are from the

Those affected subjectively feel extremely uncomfortable and - if they occur as a side effect of drug therapy - not infrequently lead to poor patient compliance, if not to treatment termination by the patient.

For the treatment of nausea and / or emesis, drugs from different groups of active ingredients are used; for example, anticholinergics, dopamine antagonists, antihistamines, 5HT ₃ antagonists and corticoids (C. Veyrat-Follet et al., Drugs (1997), 53 (2), 206-234; AL Kovac, Drugs (2000), 59 (2) , 213-243). The treatment of nausea and vomiting in connection with cancer therapy with cytostatics, in particular with cisplatin, poses particularly great therapeutic problems; here the 5HT ₃ antagonists have established themselves as the therapy standard (MS Aapro, Drugs (1991), 42 (4), 551-568). However, since their effectiveness is often unsatisfactory, there is still a significant need for further antiemetics, in particular for the prophylaxis and therapy of nausea and emesis accompanying cancer treatment with cisplatin (RE Gregory, DS Ettinger, Drugs (1998), 55 (2) , 173-189). The antiemetic effects of fentanyl (NM Barnes et al.,

Neuropharmacology (1991), 30 (10), 1073-1083; T. R. Manullang et al., Anest Anaig. (2000), 90, 1162-1166) has proven to be unsatisfactory overall (G. Mantovani et al., Anticancer Research (1999), 19, 3495-3502).

It is therefore an object of the present invention to provide further antiemetically active drugs.

This object is achieved by using (+) - (1 S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol in the form of its base or in the form of one of its physiologically tolerable salts and / or Solvate for the manufacture of a medicament for the prevention and / or therapy of nausea and / or vomiting.

(+) - (1 S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol (formula (I))

is known from EP 0 693 475 A1 as a strong and centrally acting analgesic, the effect of which can be at least partly explained by its binding to μ-receptors. In this regard, the compound is similar to opioid analgesics such as e.g. Morphine. In connection with the present invention, (+) - (1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol is also referred to as "active ingredient (I)", which does not only refer to the free base, but also relates to one of its physiologically tolerable salts and / or solvates.

Surprisingly, it has now been shown that (+) - (1S, 2S) -3- (3-

In contrast to morphine (and many other opioid analgesics), dimethylamino-1-ethyl-2-methyl-propyl) phenol not only does not have an emetic effect, ie does not cause nausea or vomiting, but also has an antiemetic effect, ie the emetic effect of known emesis Triggers like morphine or emetin (Ipecacuanha extract) cancels out. This antiemetic effect is not only found at relatively high doses, but also over the entire dose range examined, i.e. also when small doses are administered. These results are confirmed by tests on ferrets, a standard model for the detection of emetic and antiemetic active properties (see, for example, C. Veyrat-Follet et al., Drugs (1997), 53 (2), 206-234; CJ Gardner et al., Br. J. Pharmacol. (1995), 116, 3158-3163). When intraperitoneal (ip) administration of an aqueous solution of (+) - (1 S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol (in the form of the hydrochloride) to ferrets, the active ingredient calls In the examined dose range of 0.01 to 10 mg active substance / kg body weight (short: mg / kg) neither gag reflex nor real vomiting emerged. The same finding is obtained with oral (po) application of the active ingredient (l) solution in the entire dose range investigated, from 1.0 to 10.0 mg / kg.

Furthermore, it was found that the active ingredient (I) in ferrets previously known by the known emesis trigger morphine (C. Veyrat-Follet et al., Drugs (1997), 53 (2), 206-234; CJ Gardner et al. , Br. J. Pharmacol. (1995), 116, 3158-3163) in a dose of 0.1 mg / kg iv was administered, inhibited the vomiting of the animals. This finding is demonstrated in a test on the ferret with another emetic, namely emetin, i.e. Ipecacuanha extract (C. Veyrat-Follet et al., Drugs (1997), 53 (2), 206-234; CJ Gardner et al., Br. J. Pharmacol. (1995), 116, 3158-3163), confirmed: Here too, the administration of (+) - (1 S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol inhibits the emesis triggered by the emetine.

Mechanisms of action by which the anti-emetic activity of (+) - (1 S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol is mediated, based on these results, no reliable statement can be made, but only be speculated. This is all the more true than in the literature (see, for example, C. Veyrat-Follet et al., Drugs (1997), 53 (2), 206-234) for the two emetics morphine and Ipecacuanha extract used in the experiments cited above different mechanisms of triggering the emesis are discussed. So the active ingredient shows - unlike morphine, that in high Doses can have an antiemetic effect - only antiemetic effects over the entire dose range, i.e. even in small doses.

For the use according to the invention of (+) - (1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol for the manufacture of a medicament for the prevention and / or therapy of nausea and / or vomiting it is preferred that the medicament comprise a further active ingredient for the prevention and / or therapy of nausea and / or vomiting. A suitable further antiemetic active ingredient is preferably selected from the following active ingredient groups: dopamine antagonists,

Benzodiazepines, corticosteroids, antihistamines, anticholinergics, phenothiazines, butyrophenones, benzamides and especially 5-HT ₃ antagonists. The further antiemetic active ingredient is, in particular, metoclopramide, domperidone, haloperidol, fluphenazine, sulpiride, tiapride, benzoquinamide, diazepam, betamethasone, dexamethasone, prednisolone, cyclizine, hydroxyzine, diphenhydramine, scopolamine, chlorpromazine, promethidolperperol, perphenol Bemesetron and particularly preferably ondansetron, bemesetron, benzapride, zacoprid, dazoprid, p-chlorophenylalanine, granisetron, tropisetron or dolasetron. Most preferred as another antiemetic agent is ondansetron.

For the use according to the invention of (+) - (1 S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol for the manufacture of a medicament for the prevention and / or therapy of nausea and / or vomiting it is further preferred that the medicament additionally contains at least one opioid-like active ingredient. This combination advantageously allows the simultaneous administration of an opioid, especially for the treatment of severe pain, but also, if appropriate, as an anesthetic, and the antiemetic active ingredient (I), which counteracts the emetic properties of the opioid and prevents or suppresses them. Another advantage is that (+) - (1 S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol in turn has analgesic active properties (EP 0 693 475 A1), so that a reduction in the amount of additional opioid without impairment or Loss of analgesic effect is made possible with the help of this combination. This in turn reduces the risk of other undesirable side effects that can be caused by opioids, for example constipation when morphine is administered.

This additional opioid active ingredient is preferably selected from the group comprising morphine, hydromorphone, fentanyl, buprenorphine, tilidine and tramadol.

Another advantage of the present invention is that the active ingredient (I) exhibits its anti-emetic effect even when a cytostatic active ingredient is administered simultaneously, previously or subsequently. In the above-mentioned emesis model, i.v. of 10 mg / kg cisplatin - agent of choice for the chemotherapy of many cancers - to ferrets by administering (+) - (1 S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol (as hydrochloride) suppresses the vomiting usually caused by cisplatin. This makes (+) - (1 S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol suitable for the prophylaxis and therapy of nausea and emesis accompanying cancer treatment with cytostatics (chemotherapy). The active ingredient (I) is used as an antiemetic in addition to at least one cytostatic agent. The cytostatic is preferably carboplatin,

Doxorubicin, cyclophosphamide, taxol or especially cisplatin.

Another object of the present invention are pharmaceutical compositions for the prophylaxis and / or therapy of nausea and / or vomiting, containing (+) - (1 S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) ) phenol in the form of its base or in the form of one of its physiologically acceptable salts and / or solvates and one or more pharmaceutical adjuvants.

These pharmaceutical compositions preferably comprise at least one further active ingredient for the prevention and / or therapy of nausea and / or vomiting. A suitable further antiemetic active ingredient is preferably selected from the following active ingredient groups: dopamine antagonists, benzodiazepines, corticosteroids, antihistamines, anticholinergics, phenothiazines, butyrophenones, benzamides and in particular 5-HT ₃ antagonists. The other anti-emetic

The active substance is in particular metoclopramide, domperidone, haloperidol, fluphenazine, sulpiride, tiapride, benzoquinamide, diazepam, betamethasone, dexamethasone, prednisolone, cyclizine, hydroxyzine, diphenhydramine, scopolamine, chlorpromazine, promethazine, perphenazine, prochlorperazine, particularly preferred, drochloronazine, prochlorperazine around ondansetron, bemesetron, benzapride, zacoprid, dazopride, p-chlorophenylalanine, granisetron, tropisetron or dolasetron. Most preferred as another antiemetic agent is ondansetron.

In a further preferred embodiment of the pharmaceutical compositions according to the invention, in addition to the active ingredient (I), this additionally comprises an opioid. This additional opioid active ingredient is preferably selected from the group comprising morphine, hydromorphone, fentanyl, buprenorphine, tilidine and tramadol.

Pharmaceutically acceptable salts or physiologically acceptable salts in the sense of this invention are such salts of the active ingredient (+) - (1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol, which are used in pharmaceutical applications physiologically - especially when used on mammals and / or humans - are compatible. Such pharmaceutically acceptable salts can be formed, for example, with inorganic or organic acids. Preferably the pharmaceutically acceptable (physiologically tolerable) salts of the active ingredient base (I) with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid or citric acid, aspic acid educated. The salts formed include hydrochlorides, hydrobromides, phosphates, carbonates, hydrogen carbonates, formates, acetates, oxalates, succinates, tartrates, fumarates, citrates and glutaminates. Hydrochloride formation is particularly preferred, which can be brought about, for example, by adding trimethylsilyl chloride (TMSCI) to the active ingredient base (I) dissolved in a suitable organic solvent. The active ingredient (I) and its physiologically acceptable salts can also be present as solvates, in particular hydrates; the hydrates can be obtained, for example, by crystallization from an aqueous solution.

The medicaments and pharmaceutical compositions according to the invention can be in the form of liquid, semi-solid or solid pharmaceutical forms and in the form of e.g. Injection solutions, drops, juices, syrups, sprays, suspensions, granules, tablets, pellets, transdermal therapeutic systems, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions or aerosols are present and administered and contain in addition to active ingredient (I) in the form of its base or in the form of one of its physiologically tolerable salts and / or solvates depending on the galenic form and depending on the

Application route pharmaceutical auxiliaries, such as carrier materials, fillers, solvents, diluents, surface-active substances, dyes, preservatives, disintegrants, lubricants, lubricants, flavors and / or binders. These auxiliaries can be, for example: water, ethanol, 2-propanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, sucrose, dextrose, molasses, starch, modified starch, gelatin, Sorbitol, inositol, mannitol, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, cellulose acetate, shellac, cetyl alcohol, polyvinyl pyrrolidone, paraffins, waxes, natural and synthetic gums, acacia gum, alginates, dextran, saturated and unsaturated fatty acids, stearate, stearate, stearate, stearate, stearate, stearate, , edible oils, sesame oil, coconut oil, peanut oil, soybean oil, lecithin, sodium lactate, polyoxyethylene and propylene fatty acid esters, sorbitan fatty acid esters, sorbic acid, benzoic acid, citric acid, ascorbic acid, tannic acid, sodium chloride, potassium chloride, magnesium chloride, magnesium oxide, calcium chloride, magnesium oxide, calcium chloride

Silicon dioxide, titanium oxide, titanium dioxide, magnesium sulfate, zinc sulfate, calcium sulfate, potash, calcium phosphate, dicalcium phosphate, potassium bromide, potassium iodide, talc, kaolin, pectin, crospovidone, agar and bentonite.

The choice of excipients and the amounts to be used depends on whether the medicament is to be administered orally, subcutaneously, parenterally, intravenously, pulmonally, intraperitoneally, transdermally, intramuscularly, nasally, buccally, rectally or in another suitable manner. The following are suitable for oral application: Preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups, for parenteral, topical and inhalation application solutions, suspensions, easily reconstitutable powders for inhalation and sprays. In suitable percutaneous application preparations, the active ingredient (I) is e.g. in a depot in dissolved form or in a plaster, optionally with the addition of agents which promote skin penetration. Formulations which can be used rectally, transmucosal, parenterally, orally or percutaneously can release (+) - (1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol with a delay.

The pharmaceutical compositions according to the invention which, in addition to (+) - (1 S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol, in The form of its base or in the form of one of its physiologically tolerable salts and / or solvates, a further antiemetic or an additional opioid or an additional cytostatic agent, can be designed in such a way that these combination preparations release the active compounds present at the same time or almost simultaneously, or control the release in such a way that one of the active ingredients, for example the additional opioid or the additional cytostatic agent, is released and the release of the other active ingredient, for example the active ingredient (I), is delayed, ie occurs later, in order to achieve the desired effect of all active ingredients contained in the composition

Let development unfold. (Of course, if this is desirable for the respective application, the composition can also be designed in such a way that the active ingredient (I) is released first and the further or additional active ingredient is only released later.)

The medicaments and pharmaceutical compositions according to the invention are produced with the aid of means, devices, methods and processes which are well known in the art of pharmaceutical formulation, as described, for example, in "Remington ^'s Pharmaceutical Sciences", published by AR Gennaro, 17th Ed., Mack Publishing Company, Easton, Pa. (1985), in particular in Part 8, Chapters 76 to 93.

For example, for a solid formulation, such as a tablet, the active ingredient of the drug, ie (+) - (1 S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol or one of its physiologically acceptable salts and / or solvates, with a pharmaceutical carrier, for example conventional tablet ingredients, such as corn starch, lactose, sucrose, sorbitol, talc, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, such as water, for example, granulated to give a solid Form composition comprising a compound of the invention or a pharmaceutically acceptable Contains salt in a homogeneous distribution. A homogeneous distribution is understood here to mean that the active ingredient is uniformly distributed over the entire composition, so that it can be easily divided into equally effective unit dose forms, such as tablets, pills or capsules. The solid composition is then divided into unit dose forms. The tablets or pills of the medicament according to the invention or of the compositions according to the invention can also be coated or compounded in some other way in order to provide a dosage form with delayed release. Suitable coating agents include polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and / or cellulose acetate.

Another object of the invention relates to a method for the treatment of emesis and / or nausea in a mammal and / or human, which is characterized in that a therapeutically effective amount of the active ingredient (I) in the form of its base or in the form of one of its physiologically tolerable Salts and / or solvates, optionally in combination with a further antiemetic or an additional opioid or an additional cytostatic agent, is administered.

The amount of active ingredient to be administered to the patient varies and depends on the weight, age and history of the patient, as well as on the type of application, the indication and the severity of the disease. Usually 0.1 to 1000 mg, in particular 1 to 100 mg, preferably 2 to 50 mg of the active ingredient (I) are applied. In the case of combined administration with a further antiemetic, the active ingredient (I) is usually used in an amount of 1 to 100 mg, in particular 1 to 50 mg, and the further antiemetic in an amount of 1 to 250 mg, in particular 1 to 50 mg, administered; in the case of combined administration with ondansetron, it is preferred to use the active ingredient (I) in an amount of 2 to 50 mg and ondansetron in an amount of 4 to 35 mg, in particular 8 to 16 mg, to be administered. When combined with an additional opioid, the active ingredient (I) is usually administered in an amount of 1 to 100 mg, in particular 1 to 50 mg, while the amount of the opoid to be administered depends on whether it is strong or not is a less potent opioid. In the case of combined administration with morphine, this is administered in an amount of 10 to 500 mg po, in particular 10 to 300 mg po, or in an amount of 10 to 50 mg iv, in the case of combined administration with tramadol, this is administered in a Amount of 25 to 500 mg, in particular 25 to 300 mg, administered. When administered in combination with a cytostatic agent, the active ingredient (I) is generally administered in an amount of 1 to 500 mg, in particular 1 to 100 mg, while the amount and the choice of the cytostatic agent or the cytostatics are determined individually. The above-mentioned dose amounts can easily be adapted by the expert user to the individual needs and necessities.

Examples

Animal studies

Testing for anti-emetic effects on ferrets

The investigation was carried out in a modification of the method of CJ Gardner et al., Br. J. Pharmacol. (1995), 116, 3158-3163. Female ferrets were used as test animals and had a permanent IV access implanted into the jugular vein a few days beforehand. The feed was withdrawn from the animals 18 h before the start of the experiment, and water remained freely available. 60 minutes after being placed in individual observation cages (without ground litter with access to 35 g of standard feed), the animals received an ip application of the test substances. 20 minutes later the emesis-inducing substance (morphine or Ipecacucuanha extract (emetin)) applied and the animals were observed for the following behavioral parameters for 2 hours after being put back into the observation cages

• Latency up to the first choking period (min) • Number of retching reactions

• Number of crushing break (vomits)

• Average duration of nausea periods (sec)

• side effects

Rhythmic swallowing movements against the closed glottis were rated as retching, and forced vomiting of vomit contents as vomiting recessions (vomits).

5 animals were treated per test group.

To trigger the emesis, Morphin HCI (RBI Batch 2883/6) in a dose of 0.1 mg / kg i.v. or Ipecacuanha fluid extract, DAC 98 (adjusted to 2% emetin) from Synpharm (batch 9906B067) orally administered according to a dose of 2 mg / kg emetin.

The test result is shown as the group mean (x ± sx) of the events in the reacting animals. The percentage of animals with retches and vomits is also calculated.

Results: a) Check for emetic intrinsic effects: see table 1

Table 1

b) Test for antiemetic activity against morphine: see table 2

Table 2

c) Testing for anti-emetic activity against Ipecacuanha extract: See Table 3

Table 3

* Active reactions are only weakly pronounced

Pharmaceutical formulation according to the invention

1 g (+) - (1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol hydrochloride is dissolved in 1 liter of water for injections at room temperature and then isotonic by adding sodium chloride Conditions set.

Claims

Expectations 1. Use of (+) - (1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methylpropyl) phenol in the form of its base or in the form of one of its physiologically tolerable salts and / or solvates for the preparation a medication to prevent and / or treat nausea and / or vomiting. 2. Use according to claim 1, characterized in that the medicament contains at least one further active ingredient for the prevention and / or therapy of nausea and / or vomiting. 3. Use according to claim 1, characterized in that the medicament additionally contains at least one opioid. 4. Use according to claim 3, characterized in that the opioid is selected from the group comprising morphine, hydromorphone, fentanyl, buprenorphine, tilidine and tramadol. 5. Pharmaceutical composition for prophylaxis and / or Therapy for nausea and / or vomiting, containing (+) - (1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol in the form of its base or in the form of one of its physiologically tolerable salts and / or Solvate and one or more pharmaceutical excipients. 6. Pharmaceutical composition according to claim 5, characterized in that it contains at least one further active ingredient for the prevention and / or therapy of nausea and / or vomiting. 7. Pharmaceutical composition according to claim 5, characterized in that it additionally comprises an opioid. 8. Pharmaceutical composition according to claim 7, characterized in that the opioid is selected from the group comprising morphine, hydromorphone, fentanyl, buprenorphine, tilidine and tramadol.