AU2007207867B2

AU2007207867B2 - Kappa-opiate agonists for the treatment of bladder diseases

Info

Publication number: AU2007207867B2
Application number: AU2007207867A
Authority: AU
Inventors: Gerd Bartoszyk; Jutta Jacob; Christoph Seyfried; Frank Weber
Original assignee: Tioga Pharmaceuticals Inc
Current assignee: Tioga Pharmaceuticals Inc
Priority date: 2001-04-05
Filing date: 2007-08-16
Publication date: 2009-09-24
Anticipated expiration: 2022-03-13
Also published as: AU2007207867A1

Description

Australian Patents Act 1990 - Regulation 3.2 ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Kappa-opiate agonists for the treatment of bladder diseases The following statement is a full description of this invention, including the best method of performing it known to me: P/00/0 I I Kappa-opiate agonists for the treatment of bladder diseases The invention relates to the use of the medicament N-methyl-N-[(1 S)-1 phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide or one 5 of its pharmacologically acceptable salts for the preparation of medicament formulations for the treatment of bladder diseases, in particular irritable bladder, and the pains associated therewith. The medicament active ingredient N-methyl-N-[(1 S)-1 -phenyl-2-((3S)-3 hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide (asimadolin) 0 N/ N CH 3 HO 10 pharmacologically acceptable salts thereof and a process for the prepara tion are described in US 5,532,266 (Example 1). The medicament active ingredient N-methyl-N-[(1 S)-1 -phenyl-2-((3S)-3 hydroxypyrrolidin-1 -yl)ethyl]-2,2-diphenylacetamide, in particular the hydro 15 chloride thereof, has an analgesic, anti-inflammatory, antiasthmatic, diu retic, anticonvulsive, neuroprotective and antitussive action and, as a kappa-opiate agonist, is particularly suitable for the treatment of hyper algesia caused by inflammation, for the treatment of cerebral oedema, in undersupply states (hypoxia), pain states, and for ameliorating secondary 20 damage from ischaemia. The use of N-methyl-N-[(1 S)-1 -phenyl-2-((3S)-3-hydroxypyrrolidin-1 -yl) ethyl]-2,2-diphenylacetamide or pharmacologically acceptable salts thereof for the preparation of a medicament for the treatment of inflammatory intestinal diseases and the disease symptoms associated therewith, for the -2 treatment of severe pain, in particular of pain hypersensitivity occurring in back complaints, burn injuries, sunburn and rheumatic diseases, and for the treatment of postoperative pain and the ileus which frequently occurs after abdominal operations, are disclosed in EP 0 752 246. 5 N-Methyl-N-[(1 S)-1 -phenyl-2-((3S)-3-hydroxypyrrolidin-1 -yl)ethyl]-2,2 diphenylacetamide or one of its pharmacologically acceptable salts is like wise suitable for the treatment of functional gastrointestinal diseases asso ciated with pain and/or increased or reduced peristalsis, in particular of irritable bowel syndrome or for the treatment of non-ulcerative dyspepsia, 10 obstipation, in particular opiode-induced obstipation, of arthritis, migraine, psoriasis or other itching skin diseases, dysmenorrhoea and fibromyalgia. The object of the invention was to provide a pharmaceutically active com pound which can be employed and is active in the treatment and/or prophy laxis of bladder diseases, in particular irritable bladder, also known as 15 cytalgia, cystalgia, neuralgia vesicae or bladder neurosis, and which simul taneously ameliorate the pains associated with this disease and heal the disease. The term irritable bladder is a chronic state of irritation of the lower urinary tract which occurs in particular in women. Symptoms are dysuria, impera 20 tive desire to urinate, pollakiuria, suprapubic and diffuse pain on sitting. There is frequently a pronounced discrepancy between subjective com plaints and the objective findings. The most frequent causes are diseases of the psychovegetative or endocrine system. Irritable bladder should be distinguished from other syndromes, such as urinary tract infections and 25 changes in the lower urinary tract, diseases of adjacent pelvic organs or central nervous system or spinal cord diseases (for example multiple scle rosis). Surprisingly, it has been found that the medicament active ingredient N-methyl-N-[(1 S)-1 -phenyl-2-((3S)-3-hydroxypyrrolidin-1 -yl)ethyl]-2,2- P \WPDOCS\MDTSpecs2f)271171 doc-10/7/2(X9 -3 diphenylacetamide or one of its pharmacologically acceptable salts, in particular the hydrochloride, is surprisingly active for the treatment of bladder diseases, in particular irritable bladder, in spite of the known diuretic action of asimadolin. In a first aspect, the present invention provides a method of treating a 5 bladder disease, comprising administering N-methyl-N-[(1 S)-1 -phenyl-2-((3S)-3 hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide or one of its physiologically acceptable salts in a dosage between about 0.1 mg and 50 mg per dosage unit. In a second aspect, the present invention provides use of N-methyl-N-[(1S) 1-phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide or one of 10 its pharmacologically acceptable salts in the manufacture of a medicament for treatment of bladder diseases and/or irritable bladder, wherein the medicament is a dosage unit comprising between about 0.1 mg and 50 mg of N-methyl-N-[(1S)-1 phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide. Disclosed herein is the use of the medicament N-methyl-N-[(1S)-1-phenyl 15 2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide or one of its pharmacologically acceptable salts for the preparation of medicament formulations for the treatment of bladder diseases. Also disclosed herein is the use of the medicament N-methyl-N-[(1S)-1 phenyl-2-((3S)-3-hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide or one of its 20 pharmacologically acceptable salts for the preparation of medicament formulations for the treatment of irritable bladder. N-Methyl-N-[(1 S)-1 -phenyl-2-((3S)-3-hydroxypyrrolidin-1 -yl)ethyl]-2,2 diphenylacetamide or one of its pharmacologically acceptable salts can therefore be used for the preparation of pharmaceutical preparations for the treatment of 25 bladder diseases, in particular irritable bladder, by converting it into a suitable dosage form together with at least one excipient or adjuvant and, if desired, with one or more further active ingredients.

P.WPDOCS\DT\Specs\2027t171 doc.-I)7/2009 - 3a Further disclosed herein is a pharmaceutical preparation characterised by a content of N-methyl-N-[(1 S)-1 -phenyl-2-((3S)-3-hydroxy-pyrrolidin-1 -yl)ethyl]-2,2 diphenylacetamide or one of its pharmacologically acceptable salts for the treatment of bladder diseases. 5 Still further disclosed herein is a pharmaceutical preparation characterised by a content of N-methyl-N-[(1 S)-1 -phenyl-2-((3S)-3-hydroxypyrrolidin-1 -yl)ethyl]-2,2 diphenylacetamide or one of its pharmacologically acceptable salts for the treatment of irritable bladder.

-4 The preparations obtained in this way can be employed as medicaments in human or veterinary medicine. Suitable excipient substances are organic or inorganic substances which are suitable for enteral (for example oral or rectal) or parenteral administration and which do not react with the novel 5 compounds, for example water, vegetable oils, benzyl alcohols, polyethyl ene glycols, glycerol triacetate and other fatty acid glycerides, gelatine, soya lecithin, carbohydrates, such as lactose or starch, magnesium stearate, talc or cellulose. Suitable for oral administration are, in particular, tablets, coated tablets, 10 capsules, syrups, juices or drops. Of particular interest are lacquer-coated tablets and capsules having gastric-juice-resistant coatings or capsule shells. Suitable for rectal administration are suppositories, and suitable for parenteral administration are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants. 15 The active ingredients claimed in accordance with the invention may also be lyophilised and the resultant lyophilisates used, for example, for the pre paration of injection preparations. The stated preparations may be sterilised and/or comprise adjuvants, such as preservatives, stabilisers and/or wetting agents, emulsifiers, salts for 20 modifying the osmotic pressure, buffer substances, colorants and/or fla vours. If desired, they may also comprise one or more further active ingre dients, for example one or more vitamins. N-Methyl-N-[(1 S)-1 -phenyl-2-((3S)-3-hydroxypyrrolidin-1 -yl)ethyl]-2,2 diphenylacetamide or one of its pharmacologically acceptable salts is gen 25 erally administered analogously to other known preparations which are commercially available for the claimed indication, preferably in doses of between about 0.1 mg and 50 mg, in particular between 5 and 30 mg, per dosage unit. The daily dose is preferably between about 0.02 and 20 mg/kg, in particular 0.1 and 10 mg/kg of body weight.

-5 However, the specific dose for each individual patient depends on a very wide variety of factors, for example on the efficacy of the specific com pound employed, on the age, body weight, general state of health, sex, on the diet, on the time and method of administration, on the excretion rate, 5 medicament combination and severity of the particular disease to which the therapy applies. Oral administration is preferred. Animal models are described below which confirm the efficacy of asimado lin for the treatment of bladder diseases, in particular irritable bladder. A model for measuring the effect on urine excretion is described in 10 Lipschitz et al., J. Pharmacol. Exp. Ther. 1943; 79: 97-110. The substance to be investigated is given to rats who had previously been denied food overnight while being given free access to water. Increased urine excretion is provoked by simultaneous intraperitoneal injection of 100 ml/kg of physiological saline solution. Immediately after administration of the sub 15 stance, the bladder was emptied by gentle massage of the abdomen above the bladder. The rats are subsequently kept in metabolism cages in which the urine is collected over a period of 6 hours. N-Methyl-N-[(1 S)-1 -phenyl 2-((3S)-3-hydroxypyrrolidin-1 -yl)ethyl]-2,2-diphenylacetamide increases urine excretion as a function of dose, with twice the amount of urine being 20 excreted at a dose of 100 mg/kg. The effect on urine excretion in normal rats is tested analogously (i.e. with out induction of increased urine excretion, see above). N-Methyl-N-[(1 S)-1 phenyl-2-((3S)-3-hydroxypyrrolidin-1 -yl)ethyl]-2,2-diphenylacetamide increases urine excretion as a function of dose, with 5.5 times the amount 25 of urine being excreted at only 30 mg/kg po. The classical animal model for irritable bladder is described in Ghoniem et al., Neurourol. Urodyn. 1995; 14: 657-65. In female apes, irritable bladder P \WPDOCS\MDTSpcs\2027I171 dc- I0A7/2009 -6 is induced by direct infusion of acetone into the bladder. The animals are kept in metabolism cages designed for continuous monitoring of miction (urination) of the animals. The frequency, emptying volumes and flow rate of the urine are measured continuously via urine flow meters. Comparison 5 of urea absorption before and after acetone infusion shows that urea absorption is drastically increased after acetone infusion and only reaches the base value before acetone infusion again after four weeks. Further more, considerable changes in bladder physiology are observed in the first week after acetone infusion: the bladder performance, measured in ml/cm, 10 drops by almost 95%. The emptying behaviour also changes considerably, with the frequency of emptying increasing greatly with the picture of fre quent dribbling and at the same time with an emptying volume reduced by about 70%. Systematic observation of the behaviour of the animals over four weeks shows reduced frequency of general and in particular social 15 activities as the behaviour repertoire, while stereotypical, self-directed behaviour patterns, such as self-grooming, scratching and fondling, increase considerably. These changes in behaviour observed in apes are consistent with the clinical picture of considerable discomfort and pain. N Methyl-N-[(1 S)-1 -phenyl-2-((3S)-3-hydroxypyrrolidin-1 -yl)ethyl]-2,2 20 diphenylacetamide in doses of 3, 10 and 30 mg/kg normalises bladder function in a dose-dependent manner. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated 25 integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior 30 publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims

1. A method of treating a bladder disease, comprising administering N methyl-N-[(1 S)-1 -phenyl-2-((3S)-3-hydroxypyrrolidin-1 -yl)ethyl]-2,2 diphenylacetamide or one of its physiologically acceptable salts in a dosage 5 between about 0.1 mg and 50 mg per dosage unit.

2. The method of claim 1, wherein the dosage is between 5 mg and 30 mg per dosage unit.

3. The method of claim 1 or claim 2, wherein the bladder disease is irritable bladder. 10

4. The method of any of the preceding claims, wherein N-methyl-N [(1 S)-1 -phenyl-2-((3S)-3-hydroxypyrrolidin-1 -yl)ethyl]-2,2-diphenylacetamide or one of its physiologically acceptable salts in a dosage is given in a daily dosage between about 0.02 mg/kg and 20 mg/kg of body weight.

5. The method of any of the preceding claims, wherein N-methyl-N 15 [(1 S)-1 -phenyl-2-((3S)-3-hydroxypyrrolidin-1 -yl)ethyl]-2,2-diphenylacetamide or one of its physiologically acceptable salts in a dosage is given in a daily dosage between about 0.1 mg/kg and 10 mg/kg of body weight.

6. The method of any of the preceding claims, comprising administering N-methyl-N-[(1 S)-1 -phenyl-2-((3S)-3-hydroxypyrrolidin-1 -yl)ethyl]-2,2 20 diphenylacetamide hydrochloride.

7. The method of claim 6, wherein the administration normalizes bladder function.

8. The method of claim 6, wherein the administration ameliorates one or more symptoms of irritable bladder selected from the group consisting of 25 dysuria, imperative desire to urinate, pollakiuria, and suprapubic and diffuse pain upon sitting.

9. Use of N-methyl-N-[(1 S)-1 -phenyl-2-((3S)-3-hydroxypyrrolidin-1 - P.\WPDOCS\MDTSpecs2O0271171 doc. 10I7/209 -8 yl)ethyl]-2,2-diphenylacetamide or one of its pharmacologically acceptable salts in the manufacture of a medicament for treatment of bladder diseases and/or irritable bladder, wherein the medicament is a dosage unit comprising between about 0.1 mg and 50 mg of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1 5 yl)ethyl]-2,2-diphenylacetamide.

10. The use of claim 9, wherein the dosage unit comprises between about 5 mg and 30 mg of N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidin-1 yl)ethyl]-2,2-diphenylacetamide.

11. The use of claim 9, wherein the N-methyl-N-[(1 S)-1-phenyl-2-((3S)-3 10 hydroxypyrrolidin-1-yl)ethyl]-2,2-diphenylacetamide is present as a hydrochloride.