Patent Application
20080090859
Preferred compounds for use according to the invention are compounds of formula I
in which
Other preferred modulating compounds for use according to the invention are selected from a group consisting of Alvimopan (see for example Am. J. Surg. 2001 Nov;182(5A Suppl):27S-38S), Loperamide (see for example J Pharmacol Exp Ther 1999 Apr;289(1):494-502), Spiradoline (see for example Pol. J. Pharmacol. 1994 Jan-Apr;46(1-2):37-41), Fedotozine (see for example Expert Opin Investig Drugs. 2001 January;10(1):97-110), Pentazocine (see for example Biol Pharm Bull. 1997 November;20(11):1193-8), ICI204448 (see for example Br J Pharmacol. 1992 August;106(4):783-9), U-50488H (see for example Life Sci. 2002 March 1;70(15):1727-40), ADL 10-0101 (see for example Pain 2002 March;96(1-2):13-22), ADL 10-0116 (see for example Pain 2002 March;96(1-2):13-22) and ADL 1-0398 (from Adolor Corp., USA)
In one preferred embodiment of the invention the modulating compounds are selected from a group consisting of Alvimopan, Loperamide, Fedotazine and Asimadoline.
In another preferred embodiment of the invention the modulating compounds are selected from a group consisting IC1204448, U-50488H, ADL 10-0101, ADL 10-0116 and ADL 1-0398.
In a more preferred embodiment of the invention, the modulating compounds are selected from a group consisting of Alvimopan, Loperamide, Asimadoline, ADL 10-0116 and ADL 1-0398.
Especially preferred for use according to the invention is Asimadoline or a salt or solvate thereof.
According to the invention, the term “pharmaceutical for the diagnosis of disorders” comprises pharmaceuticals that are used directly for diagnostic purposes as well as pharmaceuticals that enable or facilitate the application of diagnostic methods, for example by influencing the sensitivity, especially the sensitivity to pressure and pain in the patient. Moreover, the modulating compounds can advantageously applied directly as diagnostic tool, for example for distinguishing the disorders as described herein from other disorders and/or to determine the respective aetiology of the disorder and especially to determine the subtypes of the disorders (for example by the dependency of the disorder from the subtypes of opiate receptors) as described herein, which can be of extraordinary therapeutic value.
The compounds for use according to the invention are additionally advantageous as they preferably do not pass the blood-brain barrier or only to a minor, not relevant extent. This minimizes the risks of unwanted adverse effects.
Furthermore the compounds for use according to invention do not, or only to a minor, not relevant extent, interact with the Central nervous system of the patient they are administered to.
Compounds for use according to the present invention are preferably selected from compounds which cannot pass through the blood-brain barrier on account of their structure and therefore do not exhibit a dependence potential. Also, until now no actions have been found which would restrict the use of the advantageous actions for the claimed indications in any way.
In all indication areas, clinical pictures or symptoms described here, in particular the use of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide and especially the use of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide, hydrochloride (Asimadoline) as modulating compound and thus as a pharmaceutical or as active ingredient in a pharmaceutical has emerged as particularly effective. This particular high efficiency of asimadoline in all indications described herein is preferably maintained in all sorts of preparation forms.
Asimadoline preferably shows a high efficiency or potency in the prophylaxis and/or the treatment of neuropathy and/or the symptoms associated therewith.
More preferably, Asimadoline shows a high efficiency or potency in the prophylaxis and/or the treatment of diabetic neuropathy and/or the symptoms associated therewith.
Accordingly, a preferred subject of the invention relates to the use of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenyl-acetamide and/or the pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, and more preferred the salts and/or solvates thereof, and especially preferred the physiologically acceptable salts and/or solvates thereof, for the manufacture of a pharmaceutical for the diagnosis, prophylaxis and/or treatment of neuropathy, especially diabetic neuropathy.
Accordingly, an especially preferred subject of the invention relates to the use of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide and especially the use of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide, hydrochloride, for the manufacture of a pharmaceutical for the diagnosis, prophylaxis and/or treatment of neuropathy, especially diabetic neuropathy.
A further preferred embodiment of the instant invention relates to the use of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide and especially the use of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide, and/or the pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios, and more preferred the salts and/or solvates thereof, and especially preferred the physiologically acceptable salts and/or solvates thereof, for the manufacture of a pharmaceutical for the diagnosis, prophylaxis and/or treatment of disorders, clinical pictures or indications, selected from the group consisting of post-herpetic neuralgia, chemotherapy induced neuropathy, vulvodynia and lupus erythematosus.
A further especially preferred embodiment of the instant invention relates to the use of of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide and especially the use of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide, hydrochloride, for the manufacture of a pharmaceutical for the diagnosis, prophylaxis and/or treatment of disorders, clinical pictures or indications, selected from the group consisting of post-herpetic neuralgia, chemotherapy induced neuropathy, vulvodynia and lupus erythematosus.
A further especially preferred embodiment of the instant invention relates to the use of of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide and especially the use of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide, hydrochloride, for the manufacture of a pharmaceutical for the diagnosis, prophylaxis and/or treatment of disorders, selected from the group consisting of post-herpetic neuralgia, vulvodynia, lupus erythematosus and chemotherapy induced neuropathy.
An especially preferred embodiment of the instant invention relates to the use of the compound N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide, hydrochloride, for the manufacture of a pharmaceutical for the prophylaxis and/or treatment of neuropathy, especially diabetic neuropathy.
According to the invention, the use of the modulating compounds for the manufacture of a pharmaceutical for the prophylaxis and/or treatment of the disorders, clinical pictures and/or symptoms as described herein is preferred.
Further subject of the instant invention is the use of the modulating compounds as defined herein in the diagnosis, prophylaxis and/or treatment, preferably prophylaxis and/or treatment, of disorders, clinical pictures and/or symptoms as described herein.
Further preferred subject of the invention is the use of the modulating compounds as defined herein in the diagnosis, prophylaxis and/or treatment, preferably prophylaxis and/or treatment of neuropathy, the clinical pictures and symptoms associated therewith, and related disorders as described herein.
According to the invention, the use of the modulating compounds for the manufacture of a pharmaceutical for the treatment the disorders, clinical pictures and/or symptoms as described herein is especially preferred.
The compounds for use according to the present invention and/or their physiologically acceptable salts and/or their physiologically acceptable derivatives can therefore be used for the production of pharmaceutical compositions or preparations by bringing them into the suitable dose form together with at least one excipient or auxiliary and, if desired, with one or more further active compounds. The compositions or preparations thus obtained can be employed as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (e.g. oral or rectal) or parenteral administration and do not react with the compounds for use according to the present invention, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatin, soya lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc or cellulose.
For oral administration, in particular tablets, coated tablets, capsules, syrups, juices or drops are used. Of interest are especially coated tablets and capsules having enteric coatings or capsule shells. For rectal administration, suppositories are used, and for parenteral administration, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants are used.
The compounds for use according to the invention can also be lyophilized and the lyophilisates obtained used, for example, for the production of injection preparations.
The compositions or preparations indicated can be sterilized and/or contain auxiliaries such as preservatives, stabilizers and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colourants and/or flavourings. If desired, they can also contain one or more further active compounds, e.g. one or more vitamins, diuretics, anti-inflammatorial compounds, anti-diabetics, analgetics, anti-phlogistics or compounds other than the compounds for use according to the invention, such as compounds that are not subject of the present invention, that can be used in the diagnosis, prophylaxis and/or treatment of the disorders, clinical pictures and/or symptoms as described herein, for example to improve or enhance the therapeutic effect and/or tolerance of the modulating compounds further.
Further subject of the invention is a pharmaceutical composition, characterized in that it comprises a pharmaceutically effective amount of one or more compounds effective as selective opiate receptor modulators as defined herein (modulating compounds).
Further subject of the invention is a pharmaceutical composition, characterized in that it comprises a pharmaceutically effective amount of two or more compounds effective as selective opiate receptor modulators as defined herein (modulating compounds).
Further subject of the invention is a pharmaceutical composition as described above/below, characterised in that it contains one or more additional compounds, selected from the group consisting of physiologically acceptable excipients, auxiliaries, adjuvants, carriers and pharmaceutically active ingredients other than the modulating compounds according to the invention.
Preferably, the pharmaceutically active ingredients other than the modulating compounds are selected from anti-diabetics and pharmaceutically active ingredients (other than the modulating compounds) useful for the diagnosis, prophylaxis and/or the treatment of neuropathy, the clinical pictures and symptoms associated therewith.
More preferably, the pharmaceutically active ingredients (other than the modulating compounds) useful for the diagnosis, prophylaxis and/or the treatment of neuropathy, the clinical pictures and symptoms associated therewith are selected from pharmaceutically active ingredients for the symptomatic treatment of the disorders, clinical pictures and/or symptoms as described herein, such as alpha-lipoic acid, neurotropic vitamins, especially vitamin B6 and vitamin B12, anticonvulsants, especially Gabapentin, calcium-antagonists, Baclofen, Diclofenac, Metamizol, chinin, local anesthetics, analgetics, especially central acting analgetics, and antidepressants, especially tricyclic antidepressants, and combinations thereof. More preferably, they are selected from alpha-lipoic acid, vitamin B6, vitamin B,12, Gabapentin, Baclofen, Diclofenac, Metamizol, chinin and the combination of Metamizol and chinin, and combinations thereof.
According to the invention, modulating compounds as defined herein are not pharmaceutically active ingredients for the symptomatic treatment of the disorders, clinical pictures and/or symptoms as described herein.
Thus, a preferred embodiment of the instant invention relates to the combination of one or more of the modulating compounds according to the invention and one or more compounds other than the modulating compounds according to the invention that are selected from anti-diabetic drugs or anti-diabetics and combinations thereof.
Accordingly, subject of the present invention is a pharmaceutical composition that comprises a pharmaceutically effective amount of one or more modulating compounds, one or more anti-diabetic drugs or anti-diabetics and combinations thereof, and optionally one or more compounds, selected from the group consisting of physiologically acceptable excipients, auxiliaries, adjuvants, carriers and pharmaceutically active ingredients other than the modulating compounds according to the invention.
Anti-diabetics according to the invention include, but are not limited to, Insulines, such as naturally derived, conventionally derived or gene technology derived Insulines, preferably selected from short-acting Insulines, rapid-acting Insulines, retarded Insulines, long-acting Insulines and combination products comprising Insulines and in all application forms thereof, such as oral, parenteral, per injectionem, nasal and pulmonal; α-Glucosidase-Inhibitors, such as Acarbose, Miglitol and Voglibose; Biguanides, such as Metformin; Sulfonyl ureas, such as Carbutamid, Tolbutamid, Glibornurid, Glibenclamid, Glimepirid, Gliquidon, Glisoxepid, Gliclazid, Glisentid, Glipizid, Glisolamid, Chlorpropamid and Glyburid; Insulin-Sensitizer, especially Thiazolidendione and Glitazone, such as Pioglitazon, Rosiglitazon, Diab II, Isaglitazone, GW-409544, Balaglitazon and rhIGF-1/rhIGFBP-3 complex; Insulinotropin-Antagonists, such as Repaglinide, Glimepiride and Nateglinide; Glucagon-like Peptide 1-Agonists, such as Exenatide, Exenatide LAR and Liraglutide; Calcium channel-Antagonists, such as Mitiglinide; Sodium/glucose cotransporter inhibitors, such as T-1095; Glucagon-Agonists, such as Glucagon; Amylin-Agonists, such as Pramlintid; Monoclonal Antibodies and Derivatives thereof, such as AGT-1 and Daclizumab; Glutamatdecarboxylase Stimulators, such as Diamyd; and TNFα-Antagonists, such as Humicade and Etanercept.
α-Glucosidase-Inhibitors, Biguanides, Sodium/glucose cotransporter inhibitors, Insulinotrope Anti-diabetics, especially Sulfonyl ureas, Insulin-Sensitizer and Insulinotropin-Antagonists, Glucagon-like Peptide 1-Agonists, Calcium channel-Antagonists and Sodium/glucose cotransporter inhibitors are commonly characterised as oral anti-diabetics. Oral anti-diabetics are preferred anti-diabetics in respect to the instant invention.
Suitable anti-diabetics, categories and ways of classification as well as mechanism of action, activity profiles and adverse effects are described in Mutschler, Arzneimittelwirkungen, 8th edition; Mutschler, Forth: Pharmakologie und Toxikologie 2001; Diabetes mellitus—neue Therapien und Strategien—special edition: Forschung und Praxis 2001.
More preferred, anti-diabetics according to the invention are selected from the group consisting of Chlorpropamide, Glibenclamide, Tolbutamide, Metformin, Nateglinide, Repaglinide, Gliclazide, Glipizide, Glimepiride, Pioglitazone and Rosiglitzone.
Further subject of the invention is a Kit consisting of separate packs of
The kit comprises suitable packs or containers, such as boxes, individual bottles, blister packings, bags or ampoules. The kit may, for example, comprise separate ampoules in each of which there is an effective amount of the respective pharmaceutically active ingredient or ingredients, for example in solid form, dissolved form or lyophylized form. Alternatively, the kit may, for example, comprise separate strips of blistered tablets containing the respective pharmaceutically active ingredient or ingredients, or separate boxes containing the respective strips of blistered tablets.
Preferred is a Kit as described above, wherein separate pack (b) comprises one or more anti-diabetics, preferably anti-diabetics as described above, as the one or more compounds other than the modulating compounds. Optionally, separate pack (b) comprises one or more additional compounds, selected from the group consisting of physiologically acceptable excipients, auxiliaries, adjuvants and carriers.
Preferably, in the separate packs (a) and/or (b), the compounds comprised are comprised as pharmaceutical compositions, respectively, wherein the respective pharmaceutical compositions preferably are as described above/below.
If the compound for use according to the invention is a compound with basic properties, it is usually called a base or free base of the compound. It can be advantageous to convert the free base into the associated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and the acid in an inert solvent, such as ethanol, followed by evaporation. The Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, sulfurous acid, dithionic acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as, for example, orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, hexanoic acid, octanoic acid, decanoic acid, hexadecanoic acid, octadecanoic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, benzenesulfonic acid, trimethoxybenzoic acid, adamantanecarboxylic acid, p-toluenesulfonic acid, glycolic acid, embonic acid, chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline, glyoxylic acid, palmitic acid, parachlorophenoxyisobutyric acid, cyclohexanecarboxylic acid, glucose 1-phosphate, naphthalenemono- and -disulfonic acids or laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and/or purify the compounds of the formula I. On the other hand, compounds of the formula I can be converted into the corresponding metal salts, in particular alkali metal salts or alkaline earth metal salts, or into the corresponding ammonium salts, using bases (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate). Suitable salts are furthermore substituted ammonium salts, for example the dimethyl-, diethyl- and diisopropylammonium salts, monoethanol-, diethanol- and diisopropanolammonium salts, cyclohexyl- and dicyclohexylammonium salts, dibenzylethylenediammonium salts, furthermore, for example, salts with arginine or lysine.
Alternatively, compounds for use according to the invention with acidic properties can be converted into the associated base-addition salt using a base, for example by reaction of equivalent amounts of the acidic compound and the base in an inert solvent, such as ethanol, followed by evaporation. Examples for suitable bases are physiologically acceptable amines, hydroxides or carbonates, such as ethanol amine, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate—oder Kaliumhydroxid oder—carbonat), that transfer the compounds for use according to the invention into the respective ammonium salts or metal salts.
On the other hand, if desired, the free bases of the formula I can be liberated from their salts using bases (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate).
Pharmaceutically acceptable derivatives of compounds for use according comprise prodrugs, metabolites and the like. Examples for such prodrugs and/or metabolites comprise compounds for use according to the invention that are modified with groups that are readily degraded/removed, such as alkyl groups, acyl groups and/or biodegradable polymers, and therefore liberate the compound for use according to the invention from the respective derivative. Examples for suitable biopolymers are described in the literature, for example Int. J. Pharm. 115, 61-67 (1995).
As used herein, the term “solvate” preferably refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula I or a salt or physiologically functional derivative thereof and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water. Examples for suitable solvates are the mono- or dihydrates or alcoholates of the modulating compounds.
The invention furthermore relates to a pharmaceutical composition, comprising one or more compounds effective as a selective opiate receptor modulator as defined above, preferably a pharmaceutical composition, comprising one or more compounds effective as a selective opiate receptor modulator as defined above, characterized in that the compound or the compounds are comprised in pharmaceutically active amounts.
Pharmaceutical compositions according to the invention can be obtained or produced according to methods known in the art or analogously to these methods. Usually, the pharmaceutical compositions according to the invention are produced with non-chemical methods, for example by mixing the active ingredients, i. e. one or more modulating compounds (or a salts thereof) and optionally one or more compounds other than the modulating compounds according to the invention (or a salt thereof), and optionally further ingredients, e. g. physiologically acceptable excipients, auxiliaries, adjuvants and carriers, and converting the mixture into the desired dosage form, for example into tablets by molding methods or into solutions by solving the active ingredients in a solvent. In general, the active ingredients are converted into a pharmaceutical composition together with one or more excipient, for example a solid, liquid and/or semiliquid excipient, or one or more auxiliaries and, if desired, in combination with one or more further active ingredients.
These preparations can be used as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc or vaseline. Suitable for oral administration are, in particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal administration are suppositories, suitable for parenteral administration are solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical application are ointments, creams or powders. The novel compounds can also be lyophilized and the resultant lyophilizates used, for example, for the preparation of injection preparations. The preparations indicated may be sterilized and/or comprise assistants, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes, flavours and/or a plurality of further active ingredients, for example one or more vitamins.
For administration as an inhalation spray, it is possible to use sprays in which the active ingredient is either dissolved or suspended in a propellant gas or propellant gas mixture (for example CO2 or chlorofluorocarbons). The active ingredient is advantageously used here in micronized form, in which case one or more additional physiologically acceptable solvents may be present, for example ethanol. Inhalation solutions can be administered with the aid of conventional inhalers.
As a rule, the modulating compounds according to the invention can generally administered in analogy to other known active ingredients or preparations of prior art, e.g. the ones commercially available, for the indications claimed. However, due to the advantageous properties of the modulating compounds according to the invention, an administration at the lower end of the dosages given for the compounds of prior art is often preferred.
Accordingly, the modulating compounds are preferably administered in doses between about 0.001 mg and 200 mg, more preferably between about 0.01 mg and 100 mg, even more preferably between about 0.01 mg and 50 mg and in particular between 0.01 and 30 mg, per dose unit. Preferred examples of suitable administration doses are selected from about 0.1 mg, about 0.5 mg, about 1.0 mg, about 2.0 mg and about 5.0 mg. Said administration doses (dose units) are preferably administered from once a day up to five times a day, more preferably from once a day up to three times a day. Even more preferably, said administration doses (dose units) are administered once a day or twice a day (BID—Bis In Die).
The daily dose is preferably more than or equal to about 0.0001 mg/kg, more preferably more than or equal to about 0.001 mg/kg, even more preferably more than or equal to about 0.005mg/kg, more than or equal to about 0.01 mg/kg or more than or equal to about 0.1 mg/kg of body weight. The daily dose is preferably less than or equal to about 30 mg/kg, more preferably less than or equal to about 20 mg/kg, even more preferably less than or equal to about 15 mg/kg, less than or equal to about 5 mg/kg or less than or equal to about 1 mg/kg of body weight.
Accordingly, the daily dose is preferably between about 0.0001 and 30 mg/kg, more preferred between about 0.001 and 20 mg/kg, even more preferred between about 0.005 and 15 mg/kg, especially preferred between about 0.01 and 10 mg/kg and in particular between about 0.01 and 2.0 mg/kg of body weight, for example a daily dose selected from about 0.0075 mg/kg of body weight, about 0.0125 mg/kg of body weight, about 0.025 mg/kg of body weight, about 0.075 mg/kg of body weight, about 0.15 mg/kg and about 0.25 mg/kg of body weight. In some cases, it is advantageous if the daily dosis is given in one single dosis. In many cases, it is advantageous if the daily dosis is given in two separate portions each comprising the half amount of the given daily dosis.
In general, notes on the dosage of the modulating compounds in mg are based on the pharmaceutical effective compounds itself or, if the compound is administered as salt, for example as hydrochloride, preferably on the weight of the compound as its salt. The dosage given in mg/kg is based on the body weight of the patient in kg to which the compound is administered.
The specific dose for each individual patient depends, however, on various factors, for example on the activity of the specific compound employed, on the age, body weight, general state of health and sex, on the diet, on the time and route of administration, and on the excretion rate, pharmaceutical combination and severity of the particular disorder to which the therapy applies. Oral administration is preferred.
Subject of treatment or administration according to the aspects of the invention is every patient in need of such a treatment or an administration, preferably an animal, especially and nonhuman mammalian, and especially preferred a human being.
Experimental:
A) Insulin deficient diabetes was induced in rats by a single injection of streptozotocin (50 mg/kg, intraperitoneally). After having confirmed the development of diabetes by established hyperglycemia, determined in blood samples taken from the rats, asimadoline was administered subcutaneously at doses of 1 mg/kg, 5 mg/kg and 15 mg/kg. For comparison, gabapentin, the most recent treatment for diabetic neuropathy, at 50 mg/kg was included. To determine mechanical threshold (tactile allodynia) for foot withdrawal, a series of Von Frey filaments (minimum 0.25 g; maximum 15 g) was applied in sequence to the plantar surface of the right hindpaw with a pressure that causes the filament to buckle, starting with a filament of a buckling weight of 2 g. Absence of a response after 5 seconds was regarded a negative response, and the next heavier filament was applied. Lifting of the paw was recorded as a positive response, and the next lightest filament were applied. This sequence was continued until four measurements have been made after an initial change in the behavior or until five consecutive negative (given the score of 15 g) or four positive (score of 0.25 g) scores were obtained. The resulting sequence of positive and negative scores was used to determine the 50% response threshold.
When measured 3 h after administration, asimadoline dose-dependently inhibited and at the highest dose nearly completely abolished tactile allodynia to level of non-diabetic rats, comparable to gabapentin 50 mg/kg.
The data are shown in table 1. That the beneficial effects are indeed due to the opioid mechanism of asimadoline can also be seen in Table 1. The anti-allodynic effect of the highest dose of asimadoline was completely abolished by the intraplantar (i.pl.) injection of the selective kappa antagonist nor-BNl (nor-binaltorphimine).
B) Neuropathic pain was induced by surgical sympathectomy, i.e. the L5 and L6 spinal nerves on one side were tightly ligated in anesthetized rats. After 15 days of recovery, a series of Von Frey filaments (0.4- 15 g) was applied in sequence to the plantar surface of the ligated hind paw to determine the 50% mechanical threshold for foot withdrawal as described before.
When measured 2 h after administration, asimadoline dose-dependently and at the highest dose nearly completely abolished tactile allodynia to the level of non-ligated rats, comparable to gabapentin 100 mg/kg. The data are shown in table 2.
C) Because neuropatic pain is characterized by allodynia for various sensory modalities, also thermal allodynia was investigated in a monkey model where allodynia was induced by the topical application of 0.004 Mol of capsaicin to the surface of the tail. Allodynia was assessed by the latency for withdrawal of the tail following immersion of the tail into water with non-noxious temperatures of either 38° C. or 42° C. (cut-off latency of 20 sec).
When measured 45 min after administration, asimadoline dose-dependently and at the highest dose nearly completely abolished thermal allodynia to the level of non-ligated rats under the 38° C. condition. The data are shown in table 3.
| Number | Date | Country | Kind |
|---|---|---|---|
| 03024781.1 | Oct 2003 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP04/11548 | 10/14/2004 | WO | 00 | 10/3/2006 |
