HUP0400966A2 - Use of nk3 receptor antagonists for treatment and/or prophylaxis of conditions characterized by altered bowel function and/or visceral pain - Google Patents

Abstract

(57) The invention relates to a process for the treatment and/or prevention of conditions characterized by altered bowel function and/or visceral pain in humans or non-human mammals, in which process a compound of general formula (I) - in the formula of which Ar is optionally substituted with phenyl, naphthyl or cycloalkadienyl or heterocyclic group; R is an alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, phenylalkyl or heteroaromatic group, hydroxyalkyl, aminoalkyl, alkylaminoalkyldialkylaminoalkyl, acylamino -alkyl-, alkoxy-alkyl-, alkyl-carbonyl-, carboxy-, alkoxy-carbonyl-, alkoxy-carbonyl-alkyl-, carbamoyl-, alkyl-amino-carbonyl-, dialkyl-amino-carbonyl-, halo-alkyl- group, or the -(CH2)p- group cyclized to the Ar group, where p is 2 or 3; R 1 and R 2 are hydrogen, alkyl, or co-(CH 2 )n-, where n is 3, 4 or 5; or R 1 and R together are -(CH 2 ) q -, wherein q is 2, 3, 4 or 5; R3 and R4 are hydrogen atom, alkyl-, alkenyl-, aryl-, alkoxy-, hydroxy group, halogen atom, nitro-, cyano-, carboxy-, carboxamido-, sulfonamido-, alkoxycarbonyl-, trifluoromethyl-, acyloxy- , phthalimido-, amino-, mono- or dialkylamino-, -O(CH2)r-NT2 group, in which r is 2, 3 or 4, and T is a hydrogen atom, an alkyl group or, together with the adjacent nitrogen atom, forms a group in which V and V1 a hydrogen atom or an oxygen atom, and u is 0.1 or 2; -O(CH2)s-OW2, where s is 2, 3 or 4, and W is hydrogen or alkyl; hydroxyalkyl, aminoalkyl, mono- or dialkylaminoalkyl, acylamino, alkylsulfonylamino, aminoacylamino, mono- or dialkylaminoacylamino -group; and there can be up to four R3 substituents on the quinoline nucleus at the same time; or R4 cyclized to the aromatic R5 group is a -(CH2)t- group, in which t1, 2 or 3; R5 is an alkyl, cycloalkyl, cycloalkyl-alkyl group, or an optionally substituted heteroaryl group; A non-toxic and pharmaceutically acceptable amount of X oxygen, sulfur atom or =N-C<N group - or its pharmaceutically acceptable solvate or pharmaceutically acceptable salt is administered. HE

Description

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PUBLICATION COPY

USE OF NK3 RECEPTOR ANTAGONISTS FOR THE TREATMENT AND/OR PREVENTION OF CONDITIONS CHARACTERIZED BY ALTERED BOWEL FUNCTION AND/OR VISCERAL PAIN

The invention relates to a novel use, more particularly to the use of NK3 receptor antagonists in methods for the treatment and/or prevention of conditions characterized by altered bowel function and/or visceral pain.

The mammalian Neurokinin B (NKB) peptide belongs to the Tachykinin (TK) peptide family, which also includes the so-called Substance P (SP) and Neurokinin At (NKA). Based on pharmacological and molecular biological evidence, it has been previously established that the TK receptor has three subtypes (ΝΚχ, ΝΚ2 and NK3), of which NKB binds primarily to the NK3 receptor, although it also recognizes the other two receptors with lower affinity [Maggi et al. _J. Auton. Pharmacol., 13, 23-93 (1993)].

Selective peptide NK3 receptor antagonists are already known [Drapeau, Regül. Pept . , 34, 125-135 (1990)]; results of studies on peptide NK3 receptor agonists suggest that NKB plays a key role in the modulation of neural input to respiratory, skin, spinal cord and nigro-striatal metabolic processes through activation of the NK3 receptor [Myers and Undem, J. Physiol., 470, 665-679 (1993); Counture et al., Regül. Peptides, 46, 426-429 (1993); McCarson and Krause, J. Neurosci., 14 (2) , 712-720 (1994); and Arenas et al., J.

Neurosci., 11, 2332-2338 (1991)].

- 2 According to the Rome diagnostic criteria (see Gut, 45 (Suppl. II), II43-II47 (1999)), functional bowel disorders include the following distinct groups: irritable bowel syndrome (IBS), functional abdominal distension, functional constipation, and functional diarrhea. IBS is generally accepted to include the discomfort and/or pain associated with disorders such as diarrhea-predominant irritable bowel syndrome, constipation-predominant irritable bowel syndrome, and alternating irritable bowel syndrome [Gut, 45 (Suppl. II), II69-II77 (1999)]. Furthermore, the Rome diagnostic criteria state that functional abdominal pain is not the same as functional bowel disorder, and that functional abdominal pain includes functional abdominal pain syndrome and functional abdominal pain not otherwise specified.

Electrophysiological and behavioral studies in rats have shown (Gastroenterology, 116, 1124-1131 (1999)) that NK3 receptors play a role in the response to colorectal distension. International patent applications WO 98/18762 and WO 00/21931 disclose NK3 receptor antagonists which are claimed to be useful in the treatment of disorders involving NK3 receptors, including irritable bowel syndrome (IBS), among other disorders.

International patent application WO 95/32948 discloses certain selective NK3 antagonists. These compounds are described as having activity in the treatment of the following disorders or diseases: respiratory diseases (asthma, chronic obstructive pulmonary diseases (COPD), airway hyperresponsiveness, cough), skin disorders and pruritus (e.g. atopic dermatitis, hives and erythema), neurogenic inflammation and central nervous system disorders (Parkinson's disease, movement disorders, anxiety and psychosis); and can also be used in the treatment of the following disorders or diseases: convulsive disorders (e.g. epilepsy), renal disorders, urinary incontinence, ocular inflammation, inflammatory pain, eating disorders (food intake inhibition), allergic rhinitis, neurodegenerative disorders (e.g. Alzheimer's disease), psoriasis, Huntington's disease and depression.

One specific compound disclosed in International Patent Application WO 95/32948 is (S)-(-)-N-(α-ethylbenzyl)-2-phenyl-3-hydroxy-4-quinolinecarboxamide [Compound (1)] of Example 85.

Surprisingly, we have found that compound (1) shows activity in the treatment of conditions characterized by altered intestinal function and/or visceral pain, specifically in the treatment of functional bowel disorders and functional abdominal pain. Functional bowel disorders include, in particular, irritable bowel syndrome.

conditions, more specifically diarrhea-predominant irritable bowel syndrome, constipation-predominant irritable bowel syndrome and alternating irritable bowel syndrome. Compound (1) has been found to be particularly useful in the treatment of diarrhea-predominant irritable bowel syndrome.

Accordingly, the invention provides a method for treating and/or preventing conditions characterized by altered bowel function and/or visceral pain in humans or non-human mammals, comprising administering an effective, non-toxic and pharmaceutically acceptable amount of an NK3 receptor antagonist, such as compound (1), or a pharmaceutically acceptable derivative thereof, wherein the condition characterized by altered bowel function and/or visceral pain is one of the following conditions: irritable bowel syndrome conditions, functional abdominal bloating, functional constipation, functional diarrhea, other bowel disorders and functional abdominal pain.

Suitably, the method of the invention is for the treatment and/or prevention of conditions characterized by altered intestinal function.

Suitably, the method of the invention is for the treatment and/or prevention of conditions characterized by visceral pain.

Suitably, the conditions characterized by altered bowel function and/or visceral pain are selected from the following: certain irritable bowel syndrome conditions, functional abdominal bloating, functional constipation, functional diarrhea, other bowel diseases and functional abdominal pain.

More specifically, irritable bowel syndrome conditions include, but are not limited to, diarrhea-predominant irritable bowel syndrome, constipation-predominant irritable bowel syndrome, and alternating irritable bowel syndrome.

One suitable irritable bowel syndrome condition is constipation-predominant irritable bowel syndrome.

One suitable irritable bowel syndrome condition is alternating irritable bowel syndrome.

One preferred irritable bowel syndrome condition is diarrhea-predominant irritable bowel syndrome.

Suitably, functional abdominal pain includes functional abdominal pain syndrome and functional abdominal pain not otherwise specified.

Suitable NK3 antagonists include, but are not limited to, the compounds specifically and generally disclosed in International Patent Application WO 95/32948.

Preferred NK3 antagonists are compounds of general formula (I)

(I) — in the formula of which

Ar represents an optionally substituted phenyl, naphthyl or cycloalkadienyl group of 5-7 carbon atoms, or an optionally substituted, monocyclic or fused ring, aromatic heterocyclic group containing 5-12 ring atoms and up to four heteroatoms selected from sulfur, oxygen and nitrogen atoms in the ring or rings;

R is a straight or branched chain alkyl group having 1-8 carbon atoms, a cycloalkyl group having 3-7 carbon atoms, a cycloalkyl-alkyl group having 4-7 carbon atoms, an optionally substituted phenyl or phenyl-(1-6 carbon atoms)-group, an optionally substituted five-membered heteroaromatic group containing up to four heteroatoms selected from oxygen and nitrogen, a hydroxyalkyl group having 1-6 carbon atoms, a aminoalkyl group having 1-6 carbon atoms, an alkylaminoalkyl group having 1-6 carbon atoms, a di(1-6 carbon atoms)-aminoalkyl group, an acylaminoalkyl group having 1-6 carbon atoms,

C1-6 alkoxyalkyl, C1-6 alkylcarbonyl, carboxy, C1-6 alkoxycarbonyl, (C1-6 alkoxy)carbonyl-(C1-6 alkyl), carbamoyl, C1-6 alkylaminocarbonyl, di(C1-6 alkyl)aminocarbonyl, C1-6 haloalkyl, or a group of the general formula -( _CH2 ) _p- cyclized to the Ar group, in which p is 2 or 3;

R1 and R2 are identical or different, independently of each other, hydrogen, straight or branched chain alkyl having 1-6 carbon atoms, or together form a group of the general formula -( _CH2 ) _n- , in which n is 3, 4 or 5; or

R1 and R2 together form a group of the general formula -(CH2)q-, wherein q is 2, 3, 4 or 5;

R3 and R4 are identical or different, independently of each other, hydrogen, straight or branched C1-6 alkyl, C1-6 alkenyl, aryl, C1-6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulfonamido, C1-6 alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, amino, mono- or di(C1-6 alkyl)amino,

a group of the general formula -O(CH ₂ ) _r ~NT2, in which r is 2, 3 or 4, and

T is a hydrogen atom, a C1-C6 alkyl group or, together with the adjacent nitrogen atom, a

forms a group with a general formula in which

V and Vi are independently hydrogen or oxygen, and u is 0, 1 or 2;

a group of the general formula -O(CH ₂ ) _S -OW2, in which s is 2, 3 or 4, and

W represents a hydrogen atom or an alkyl group having 1-6 carbon atoms;

hydroxyalkyl, aminoalkyl, mono- or dialkylaminoalkyl, acylamino, alkylsulfonylamino, aminoacylamino, mono- or dialkylaminoacylamino; and up to four R3 substituents may be present on the quinoline nucleus at the same time; or

R4 cyclizes onto the aromatic group R5 to form a group of the general formula -( _CH2 ) ^t- , where t is 1, 2 or 3;

R5 represents a straight or branched C1-6 alkyl group, a C3-7 cycloalkyl group, a C4-7 cycloalkylalkyl group, or an optionally substituted, monocyclic or fused ring, aromatic heterocyclic group containing 5-12 ring atoms and up to four heteroatoms selected from sulfur, oxygen and nitrogen atoms in the ring or rings;

X represents oxygen, sulfur or a group of the formula =N-C^N - or pharmaceutically acceptable solvates or pharmaceutically acceptable salts thereof.

Suitable mammals are humans.

More particularly, the invention relates to a method for treating and/or preventing conditions characterized by altered bowel function and/or visceral pain in humans or non-human mammals, comprising administering an effective, non-toxic and pharmaceutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.

Suitably, the invention relates to a method of treating and/or preventing conditions characterized by altered bowel function, in particular diarrhea-predominant irritable bowel syndrome.

Preferably, the invention relates to a method for treating and/or preventing diarrhea.

Examples of the Ar group include, but are not limited to, phenyl groups optionally substituted with hydroxyl, halogen, C1-6 alkoxy or C1-6 alkyl. Examples of halogen atoms include chlorine and fluorine, C1-6 alkoxy is methoxy, and C1-6 alkyl is methyl.

Heterocyclic groups included in the meaning of the substituent Ar include, but are not limited to, thienyl and pyridyl groups.

Examples of C5-C7 cycloalkadienyl groups in the meaning of the Ar substituent include, but are not limited to, cyclohexadienyl.

Examples of the R substituent include, but are not limited to:

C1-8 alkyl group: methyl, ethyl, propyl, isopropyl, butyl, heptyl group;

phenyl-(C1-C6 alkyl) group: benzyl group;

C1-6 hydroxyalkyl group: group of formula -CH2OH, -CH2CH2OH, -OH(OHβ)OH;

C1-6 aminoalkyl group: group of _{formula -CH2NH2} ;

di(C1-C6 alkyl)aminoalkyl group: group of formula _-CH2N (CH3) ₂ ;

C1-6 alkoxyalkyl group: group of formula -CH2OCH3;

C1-6 alkylcarbonyl group: group of formula -COCH3;

C1-6 alkoxycarbonyl group: group of formula -COOCH3;

(C1-6 alkoxy)carbonyl-(C1-6 alkyl)-group: group of formula -CH2COOCH3;

C1-6 alkylaminocarbonyl group: group of formula -CONHCH3;

di(C1-C6 alkyl)aminocarbonyl group: -CON(CH3) ₂ , -CO(1-pyrrolidinyl) group;

C1-6 haloalkyl group: trifluoromethyl group;

-(CH ₂ )p- cyclized to the Ar substituent:

group with the formula

An alkyl group having 1-6 carbon atoms in the meaning of the substituents R1 and _R2 is, for example, a methyl group; the group of the general formula -( _CH2 )q- formed by R1 and R together is, for example, spirocyclopentane.

Examples of the meaning of the substituent R3 and R4 include, but are not limited to, methyl, ethyl, propyl, butyl, methoxy, hydroxy, amino, fluorine, bromine, acetoxy, 2-(dimethylamino)ethoxy, 2-(1-phthaloyl)ethoxy, aminoethoxy, 2-(1-pyrrolidinyl)ethoxy, phthaloyl, dimethylaminopropoxy, dimethylaminoacetylamino, acetylamino, dimethylaminomethyl and phenyl.

Examples of the meaning of the substituent R5 include, but are not limited to, the following: cyclohexyl, optionally substituted phenyl as defined above for the meaning of Ar; examples of heterocyclic groups included in the meaning of the substituent R5 include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, benzofuranyl and pyridyl.

A preferred group of compounds of general formula (I) includes those derivatives in which Ar represents a phenyl group optionally substituted with an alkyl group having 1-6 carbon atoms or a halogen atom; a thienyl group or a cycloalkadienyl group having 5-7 carbon atoms;

R is C1-6 alkyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyl, C1-6 hydroxyalkyl;

R1 and R2 each represent a hydrogen atom or a C1-C6 alkyl group;

R3 represents a hydrogen atom, a hydroxyl group, a halogen atom, a C1-6 alkoxy group, a C1-6 alkyl group;

R4 is hydrogen, C1-6 alkyl, C1-6 alkoxy, hydroxy, amino, halogen, aminoalkoxy, mono- or dialkylaminoalkoxy, mono- or dialkylaminoalkyl, phthaloylalkoxy, mono- or dialkylaminoacylamino or acylamino; and

R5 is phenyl, thienyl, furyl, pyrrolyl or thiazolyl.

Another preferred group of compounds of general formula (I) includes those derivatives whose formula

Ar is phenyl, 2-chlorophenyl, 2-thienyl or cyclohexadienyl;

R is methyl, ethyl, propyl, methoxycarbonyl or acetyl;

R1 and R2 each represent a hydrogen atom or a methyl group;

R3 represents a hydrogen atom, a methoxy or a hydroxy group;

R4 represents hydrogen, methyl, ethyl, methoxy, hydroxy, amino, chlorine, bromine, dimethylaminoethoxy, 2-(1-phthaloyl)ethoxy, aminoethoxy, 2-(1-pyrrolidinyl)ethoxy, dimethylaminopropoxy, dimethylaminoacetylamino, acetylamino and dimethylaminomethyl;

R5 is phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-thiazolyl and 3-thienyl; and

X represents an oxygen atom.

A preferred subgroup of the compounds of general formula (I) defined above is the compounds of general formula (Ia),

(la) in which R, R2, R3 and R4 have the same meanings as defined in general formula (I), and Y and Z, which are identical or different, have the same meanings as Ar as defined in general formula (I).

A particularly preferred group of compounds of formula (Ia) are those compounds of formula (Ib) which

(Ib) in which the R group faces downwards and the hydrogen atom faces upwards.

One of the most preferred compounds of formula (I) is compound (1).

The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable form or in substantially pure form. By pharmaceutically acceptable form is meant, inter alia, those compositions in which, in addition to conventional pharmaceutical additives such as diluents and carriers, the active ingredient is present in pharmaceutically acceptable purity, but the composition does not contain any material which is toxic at normal dosage levels.

The substantially pure form contains at least 50%, preferably 75%, more preferably 90%, and even more preferably 95% of the compound of formula (I), or a salt or solvate thereof, without conventional pharmaceutical additives.

One preferred pharmaceutically acceptable form is the crystalline form (including such forms of pharmaceutical compositions). In the case of salts and solvates, the additional ionic and solvent components should also be non-toxic.

As mentioned above, suitable pharmaceutically acceptable derivatives include pharmaceutically acceptable salts and/or solvates.

Examples of pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts formed with conventional pharmaceutical acids. Such pharmaceutically acceptable acids include, but are not limited to, maleic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, citric acid, lactic acid, mandelic acid, tartaric acid, succinic acid, benzoic acid, ascorbic acid, and methanesulfonic acid.

Pharmaceutically acceptable solvates of the compounds of formula (I) include, but are not limited to, hydrates.

The compounds of formula (I) possess at least one asymmetric center, so that the compounds may exist in more than one stereoisomeric form. The invention includes all such forms and mixtures thereof, including racemates.

Additional NK3 antagonists are disclosed in WO 99/36424, WO 00/39144, WO 95/28931, International Patent Application WO 96/05203, European Patent Application No. 776 893, International Patent Application WO 98/54191, European Patent Application No. 673 928, WO 94/26735 and International Patent Application No. WO 97/10229. One particular NK3 antagonist is {[(dichlorophenyl)-(trimethoxybenzoyl)morpholinyl]ethyl}-spiro[benzo(c)thiophenepiperidine]oxide. One particular NK3 antagonist is R113281. One particular NK3 antagonist is N10A. One particular NK3 antagonist is N5A1. One particular NK3 antagonist is SR-142801. One particular NK3 antagonist is SSR-146977. One particular NK3 antagonist is Cam-2425. One particular NK3 antagonist is MDL-105212.

The NK3 antagonist can be prepared by known methods corresponding to the selected compound, for example, compounds of formula (I) and compound (1) can be prepared by methods described in international patent applications WO 95/32948 or WO 99/14196. Other NK3 antagonists, such as R113281, N10A, N5A1, SR-142801, SSR-146977, Cam-2425 and MDL-105212, are known, for example, in international patent applications WO 99/36424, WO 00/39144, WO 95/28931, WO 96/05203, European patent application No. 776 893, WO 98/54191. It is prepared by the methods described in International Patent Application No. 673,928, European Patent Application No. 673,928, International Patent Application No. WO 94/26735 and WO 97/10229.

The compounds used in the process of the invention, for example compound (1), can be converted into their pharmaceutically acceptable acid addition salts by reaction with appropriate organic or mineral acids.

Solutes of the compounds used in the process of the invention, such as compound (1), can be prepared by crystallization or recrystallization from a suitable solvent. For example, hydrates can be prepared by crystallization or recrystallization from aqueous solutions or solutions prepared from organic solvents containing water.

Other NK3 antagonists, such as R113281, N10A, N5A1, SR-142801, SSR-146977, Cam-2425 and MDL-105212, are disclosed, among others, in International Patent Application WO 99/36424, WO 00/39144, WO 95/28931, WO 96/05203, European Patent Application No. 776,893, International Patent Application No. WO 98/54191, European Patent Application No. 673,928, WO 94/26735 and WO 97/10229. pharmaceutically acceptable derivatives disclosed in international patent application published under number

The activity of the compounds used in the method of the invention, such as compound (1), as NK3 receptor antagonists in standard assays indicates that the compounds may have potential therapeutic use in the treatment of certain clinical conditions characterized by overstimulation of tachykinin receptors, particularly those described herein. Relevant assays are described later in the specification.

The term conditions characterized by altered bowel function as used herein refers to, but is not limited to, the following conditions: diarrhea-predominant irritable bowel syndrome, constipation-predominant irritable bowel syndrome, alternating irritable bowel syndrome, functional abdominal bloating, functional constipation, and functional diarrhea.

One specific example of a condition characterized by altered bowel function is diarrhea-predominant irritable bowel syndrome.

A specific example of conditions characterized by altered bowel function is constipation-predominant irritable bowel syndrome.

A specific example of a condition characterized by altered bowel function is intermittent irritable bowel syndrome.

Other intestinal diseases constitute one group of conditions characterized by altered intestinal function.

The term other bowel disorders as used herein includes conditions with the following symptoms: abdominal pain, bowel urge, bloating, incomplete bowel movement and straining, especially bowel urge, bloating, incomplete bowel movement and straining.

The invention also provides a method for treating and/or preventing conditions characterized by altered bowel function and/or visceral pain in humans or non-human mammals, comprising administering an effective, non-toxic and pharmaceutically acceptable amount of an NK3 receptor antagonist, such as compound (1), or a pharmaceutically acceptable derivative thereof.

The invention further provides an NK3 antagonist, such as compound (1), or a pharmaceutically acceptable derivative thereof, for use in the treatment and/or prevention of conditions characterized by altered bowel function and/or visceral pain.

The invention also provides the use of an NK3 antagonist, such as compound (1), or a pharmaceutically acceptable derivative thereof, for the preparation of pharmaceutical compositions for the treatment and/or prevention of conditions characterized by altered bowel function and/or visceral pain. The condition characterized by altered bowel function and/or visceral pain is suitably one of the following conditions: certain irritable bowel syndrome conditions, functional abdominal bloating, functional constipation, functional diarrhea, other bowel disorders and functional abdominal pain.

The invention also provides a pharmaceutical composition for the treatment and/or prevention of conditions characterized by altered bowel function and/or visceral pain, comprising an NK3 antagonist, such as compound (1), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier, wherein the condition characterized by altered bowel function and/or visceral pain is suitably one of the following conditions: certain irritable bowel syndrome conditions, functional abdominal bloating, functional constipation, functional diarrhea, other bowel diseases and functional abdominal pain.

Such a medicament or pharmaceutical composition of the invention may be prepared by mixing a compound of the invention with a suitable carrier. The composition may also contain a diluent, binder, filler, disintegrant, flavoring, coloring, lubricant and/or preservative in the usual manner.

These carriers can be used in the same manner as is done in the preparation of known compositions of active ingredients for the treatment of various diseases.

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Preferably, the pharmaceutical compositions of the invention are in unit dosage form or in a form adapted for human or veterinary use. For example, the compositions may be in the form of a pack with instructions for use attached or printed on the packaging as an agent for the treatment of diseases.

The appropriate dosage range for the compounds of the invention will depend on the particular compound employed and the condition of the patient. In addition, the dosage range will be influenced by, among other things, the absorbability and the frequency and route of administration.

The compounds of the invention can be formulated into compositions suitable for any route of administration. During formulation, the compounds are converted into unit dosage form or into a form which can be administered to a human patient as a single dose. Preferably, the compositions are suitable for oral, rectal, local (topical), parenteral, intravenous or intramuscular administration. The compositions can also be designed so that the release of the active ingredient is slow, i.e. the composition has a prolonged effect over time.

The compositions of the invention may be in the form of, for example, tablets, capsules, wafers, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, such as solutions or suspensions, and suppositories.

For example, compositions suitable for oral administration may contain, among others, the following conventional carriers: binders, such as sugar syrup, acacia, gelatin, dispersible

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bit, tragacanth gum or polyvinylpyrrolidone; fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants such as magnesium stearate; disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; and pharmaceutically acceptable stabilizers such as sodium lauryl sulfate.

Solid compositions may be prepared by conventional mixing, filling, tabletting, etc. processes. In the case of compositions prepared using a large amount of filler, the mixing operations may be repeated in order to evenly distribute the active ingredient. When the composition is in the form of tablets, powders or lozenges, any carrier suitable for the formulation of solid pharmaceutical compositions may be used, for example magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. The tablets may be coated using methods well known in the art of pharmacy; enteric coatings are particularly preferred in this respect. The compositions may also be in the form of swallowable capsules, for example gelatin capsules containing the active ingredient and, if desired, a carrier or other excipients.

Liquid compositions for oral administration may be, for example, emulsions, syrups or elixirs, or may be prepared as dry products from which the composition ready for administration may be reconstituted with water or other suitable vehicle immediately before use. The liquid compositions may contain, among others, the following conventional additives: suspending agents, such as ^sorbitol , sugar syrup, methyl cellulose, gelatin, (hydroxyethyl) cellulose, (carboxymethyl) cellulose, aluminum stearate gel, hydrogenated edible fats; emulsifiers, such as lecithin, sorbitan monooleate or acacia; aqueous or non-aqueous vehicles, including edible oils, such as almond oil, fractionated coconut oil, oily esters, such as glycerol esters, or propylene glycol, ethyl alcohol, glycerin, water or saline; preservatives, such as methyl or propyl 4-hydroxybenzoate or sorbic acid; and, if desired, conventional flavorings and colorings.

The compounds of the invention may be administered by routes other than the oral route. In accordance with standard pharmaceutical practice, the compositions may be prepared, for example, in the form of suppositories suitable for rectal administration. The compositions may also be prepared in injectable forms, for example, as aqueous or nonaqueous solutions, suspensions or emulsions in a pharmaceutically acceptable liquid, such as sterile, pyrogen-free water or a parenterally acceptable oil or liquid mixtures. The liquid may also contain bacteriostatic agents, antioxidants or other preservatives, buffers or solutes to render the solution isotonic with blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Such compositions may be presented either in unit dosage form, such as in ampoules, disposable injection devices, or in multiple dosage forms, such as in a bottle from which the appropriate dose is withdrawn in increments. We can also produce solid forms or concentrates from which we can later produce the injectable form.

The compounds of the invention may also be administered by inhalation, for example by the nasal or oral route. Such administration may be effected by the use of a spray formulation comprising a compound of the invention and a suitable carrier, for example a hydrocarbon propellant, in which the active ingredient is optionally suspended.

Preferred spray formulations comprise micronized particles of the compound in combination with a surfactant, a solvent; a dispersant may also be used to prevent settling of the suspended particles. The particle size of the compound is preferably between about 2 micrometers and about 10 micrometers.

Other routes of administration of the compounds of the invention include transdermal delivery, using a skin patch formulation. One preferred formulation comprises the compound of the invention dispersed in a pressure-sensitive adhesive that adheres to the skin; the active ingredient diffuses from the adhesive through the skin into the patient. Pressure-sensitive adhesives known in the art, such as natural rubber or silicone rubber, can be used to ensure a constant rate of percutaneous absorption.

As mentioned above, the effective dose of the compound depends on the particular compound used, the condition of the patient, and the frequency and route of administration. A unit dose generally contains 20-1000 mg, preferably 30-500 mg, particularly preferably 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg of active ingredient. The composition may be administered one or more times per day, for example two, three or four times per day, and the total daily dose for an adult human weighing 70 kg is between about 100 mg and about 3000 mg. Alternatively, the unit dose may contain 2-20 mg of active ingredient, and such unit doses may be administered several times to achieve the total daily dose as given above.

Specific dosages and formulations of NK3 antagonists include, for example, those disclosed in the patent documents referenced above.

No unacceptable toxic effects are expected when using the compounds of the invention when administered by the method of the invention.

The activity of the compounds of the invention as NK3 ligands is determined by the extent to which they inhibit the binding of radiolabeled NK3 ligands 125 7 3 {[ I]-[Me-Phe]-NKB or [ H]-Senktide] to guinea pig and human NK3 receptors [Renzetti et al., Neuropeptide, 18, 104-114 (1991); Buell et al., FEBS, 229 (1), 90-95 (1992); Chung et al., Biochem. Biophys. Res. Commun., 198 (3), 967-972 (1994)].

The binding assays used allow us to determine the IC50 value of an individual compound, i.e. the concentration of the compound required to reduce the binding of [I]-[Me-Phe]-NKB or [H]-Senktide to the NK3 receptor by 50% at steady state.

In the binding studies, IC ₅₀ values were obtained as the average of 2-5 separate experiments performed in duplicate or triplicate for each tested compound. The most potent compounds of the invention showed IC ₅₀ values between 0.1 nM and 1000 nM. The NK3 antagonist activity of the compounds of the invention was determined based on the extent to which the compounds were able to inhibit senktide-induced contraction of guinea pig ileum [Maggi et al., Br. J. Pharmacol., 101, 996-1000 (1990)] and isolated rabbit iris sphincter muscle [Hall et al., Eur. J. Pharmacol., 19 9, 9-14 (1991)], and calcium ion mobilization mediated by human NK3 receptors [Mochizuki et al., J. Biol. Chem., 269, 96519658 (1994)]. In the in vitro guinea pig and rabbit functional assays, an average K _B value was obtained from 3-8 separate experiments for each compound tested, where K _B represents the concentration of the individual compound required to obtain a two-fold rightward shift in the senktide concentration-response curve. The human receptor functional assay allows the determination of the concentration of the individual compound required to reduce the calcium ion: t—.··. - 2 6 - Μ·::; ν- * mobilization induced by the agonist NKB by 50% (IC ₅ q). In this assay, the compounds of the invention behave as antagonists.

The expected therapeutic efficacy of the compounds of the invention in the treatment of diseases can be estimated using rodent disease models.

The invention is illustrated, without limitation, by the following data.

FIGURES

Below is a brief description of the accompanying figures.

Figure 1 shows the inhibition of the increasing excitation reflex by compound (1).

Figure 2 shows that compound (1) has no significant effect on small intestinal transit in normal, non-sensitized animals.

Figure 3 shows the effect of compound (1) on small intestinal transit in an egg albumin-sensitized model.

Figure 4 shows the effect of compound (1) on colorectal sensitivity and tone in rats.

EXPERIMENTAL RESULTS

COMPOUND (1) DOES NOT AFFECT NORMAL GASTROINTESTINAL MOTILITY

Compound (1) at oral doses of 5, 15 and 50 mg/kg had no significant or statistically significant effect on gastric emptying in rats, as determined by the phenol red method. The high doses used in the study are similar to those doses that have been shown to exert intestinal antinociceptive activity (see below) and are consistent with the low affinity of compound (1) for the rat NK3 receptor, compared to its higher affinity for the human and guinea pig NK3 receptors. In contrast, the reference standard, morphine sulfate, administered orally at a dose of 20 mg/kg, significantly and statistically significantly reduced gastric emptying (see Table 1). This predicted effect demonstrates the applicability of the test system.

Table 1

Gastric emptying rate in rats after administration of compound (1), morphine sulfate, phenol red and vehicle

GROUP ORAL TREATMENT DOSE (mg/kg) GASTRIC EMPTYING (%) 1. phenol red only - 0.0 2. carrier - 60.6 3. (1) compound 5 55.2 4. (1) compound 15 50.7 5. (1) compound 50 62.4 6. morphine sulfate 20 30.8**

significance of difference from vehicle-treated group: **p < 0.01

As determined by the carbon powder test, compound (1) orally administered at doses of 5, 15 and 50 mg/kg had no significant or statistically significant effect on gastrointestinal motility in rats. The distance traveled by carbon powder in the compound (1)-treated group at all doses was similar to that measured in the vehicle-treated group. In contrast, compared to the vehicle-treated group, morphine sulfate at a dose of 10 mg/kg orally significantly and statistically significantly reduced gastrointestinal motility (see Table 2). This predicted effect confirms the applicability of the test system.

Table 2

Effect of compound (1), morphine sulfate and vehicle on gastrointestinal motility as determined by the charcoal powder test

GROUP ORAL TREATMENT DOSE (mg/kg) DISTANCE TRAVELED BY COAL POLLUTANT IN % OF TOTAL INTESTINAL LENGTH ± SD CHANGE RELATIVE TO VEHICLE-TREATED GROUP % 1. carrier - 53.0 ± 7.6 - 2 . (1) compound 5 46.9 ± 5.3 -11, 5 3. (1) compound 15 52.1 ± 7.1 -1.7 4 . (1) compound 50 50.4 ± 8.6 -4.9 5. morphine sulfate 10 37.4 ± 12.4 -29.4

SD = standard deviation significance of difference from vehicle-treated group: ★★p < 0.01

INHIBITION OF SLOW EPSP BY COMPOUND (1) IN GUINEA PIG ENTERIC NEURONS

To determine the effects of compound (1) on slow EPSP (slow excitatory postsynaptic potential), four neurons were analyzed with compound (1). Slow EPSP was elicited by a 1-second high-frequency (20 Hz) electrical stimulation applied to the peripheral internodal strip connecting to the ganglion. A slow EPSP baseline was obtained, and after this had regressed, compound (1) at a concentration of 0.1 μΜ was perfused through the preparation. The perfusion was performed continuously and the slow EPSP was tested at different intervals. After the drug had circulated for at least 30 minutes, the peak amplitude of depolarization in all four neurons decreased by more than 50% compared to baseline. One neuron had 100% blockade, and this neuron showed additional IPSP (inhibitory postsynaptic potential) upon stimulation. The other three neurons showed 60-80% blockade based on the amplitude of depolarization. Two of the neurons showed a type II Dogiel morphology when stained with biocytin and stained with streptavidin and Texas Red under a fluorescent microscope.

INHIBITION OF STRETCH-INDUCED REFLEX ACTIVITY BY COMPOUND (1) IN ISOLATED GUINEA PIG COLON

For reflex studies, a 5-7 cm long colon was suspended in warmed, oxygenated physiological, aqueous sodium chloride solution, and then an 8 mm metal rod was inserted into the cavity. This metal rod was connected to a pulley system by a thread passed through the intestinal wall, which allowed the rod to be pulled with different weights and the intestine to be stretched (stretched). Force transducers were connected to the

to the colon wall. Colonic sub-stretching with 6, 12, or 20 g weights induced rhythmic contractions on the oral side of the stretch and little relaxation on the anal side. Application of 12 and 20 g weights induced similar activity, and although the slight relaxation on the anal side of the stretch was more pronounced, the oral excitatory response was not different from the effects of the 6 g weight. Compound (1) at 250 nM applied for 30-45 min reduced the effects of stretch in a roughly stretch-dependent manner, with greater effects at higher values of stretch (see figure below). These data suggest that compound (1) reduces the stretch-induced ascending and descending reflexes by antagonizing the NK3 receptor. Since the effects of compound (1) on enteric reflexes were more pronounced at higher stretching weights, NK3 receptors — and thus the slow EPSP component of ΙΡΑΝ activity — may play a greater role in reflexes elicited by the application of intense and possibly pathological stimuli.

The data are shown in Figure 1. Figure 1 shows the changes in the ascending excitation reflex, as measured by the areas under the curve, induced by 6, 12, or 20 g of stretch in the absence of compound (1), in the presence of compound (1), and after washout.

INHIBITION OF INCREASED INTESTINAL TRANSIT IN EGG ALBUMIN SENSITIZED LITTLE INTESTINES BY COMPOUND (1) IN RATS Summary and conclusions

We first demonstrated that antagonism of the NK3 receptor with 15 mg/kg p.o. compound (1) inhibits the increase in rat small intestinal transit time induced by egg albumin challenge. These data demonstrate that the NK3 receptor plays a role in pathological (and less physiological) changes in intestinal function.

Goals

Increased rat small intestinal transit induced by sensitization to egg albumin has previously been used to demonstrate that the 5-HT3 receptor antagonist alosetron (alosterone) is suitable for normalizing disturbed intestinal transit [Clayton, N. M., Sargent, R., Butler, A., Gale, J., Maxwell, Μ. P. , Hunt, A. A., Barrett, V. J. , Cambridge, D. , Bounta, C., and Humphrey, P. P., The pharmacological properties of the novel selective 5-HT3 receptor antagonist, alosetron, and its effects on normal and perturbed small intestinal transit in the fasted rat, Meurogastroenterology and Motility, 11 (3), 207-217 (1999)]. Based on the significant data obtained with alosetron and the potential interaction between similar intestinal challenges and the NK3 receptor [Gay, J., Fioramonti, J., Garcia-Viliar, R., Edmonds-Alt, X., Bueno., L., Gut, 44, 497-503 (1999)], we also examined the effects of compound (1) in this model.

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• ··· ·· ·“

Results

In normal, non-sensitized animals, a dose of 15 mg/kg p.o. of compound (1) did not significantly affect small intestinal transit (see Figure 2). However, in the egg albumin-sensitized model, pretreatment with 15 mg/kg p.o. of compound (1) significantly inhibited the increased transit after egg albumin sensitization (see Figure 3). Discussion

The data for compound (1) primarily demonstrate that while the NK3 receptor is not involved in normal intestinal motility, the NK3 receptor plays a significant role in mediating impaired motility. Furthermore, these data and the use of this model also provide the opportunity to correlate the in vitro data (demonstration of the role of NK3 receptors in ΙΡΑΝ slow EPSP activity; demonstration of the ability of NK3 receptor activation to inhibit non-cholinergic excitatory nerve activity in the human isolated colon) with in vivo intestinal pathology.

INHIBITION OF INTESTINAL NOXIENCE BY COMPOUND (1)

In conscious rats, a dose of 50 mg/kg po of compound (1) exerted a significant antinociceptive effect during distension of the colorectal area at 30, 40, and 60 mmHg distension pressures34 : ^: *J·· • · · · · · · · , without affecting colorectal tone. A dose of 30 mg/kg po of compound (1) exerted a similar effect, but the effects were only statistically significant at the highest distension pressure. The lowest dose of compound (1) tested (10 mg/kg, po) had no antinociceptive effect.

These data indicate that selective antagonism of the NK3 receptor may reduce intestinal sensitivity to noxious distension.

Claims (10)

PATENT CLAIMS 1. A method for treating and/or preventing conditions characterized by altered bowel function and/or visceral pain in humans or non-human mammals, characterized by administering an effective, non-toxic and pharmaceutically acceptable amount of an NK3 receptor antagonist, wherein the condition characterized by altered bowel function and/or visceral pain is one of the following conditions: irritable bowel syndrome conditions, functional abdominal bloating, functional constipation, functional diarrhea, other bowel diseases and functional abdominal pain. 2. The method according to claim 1, characterized in that the method is directed to the treatment and/or prevention of conditions characterized by altered intestinal function. 3. The method of claim 1, wherein the irritable bowel syndrome condition is diarrhea-predominant irritable bowel syndrome. 4. A method for treating and/or preventing conditions characterized by altered bowel function and/or visceral pain in humans or non-human mammals, characterized in that a compound of general formula (I) (I) , «·*· ·· ···· <· 3 6 - : • ··* *· — in the formula of which Ar represents an optionally substituted phenyl, naphthyl or cycloalkadienyl group of 5-7 carbon atoms, or an optionally substituted, monocyclic or fused ring, aromatic heterocyclic group containing 5-12 ring atoms and up to four heteroatoms selected from sulfur, oxygen and nitrogen in the ring or rings; R is a straight or branched chain alkyl group having 1-8 carbon atoms, a cycloalkyl group having 3-7 carbon atoms, a cycloalkyl-alkyl group having 4-7 carbon atoms, an optionally substituted phenyl or phenyl-(1-6 carbon atoms)-group, an optionally substituted five-membered heteroaromatic group containing up to four heteroatoms selected from oxygen and nitrogen, a hydroxyalkyl group having 1-6 carbon atoms, a aminoalkyl group having 1-6 carbon atoms, an alkylaminoalkyl group having 1-6 carbon atoms, a di(1-6 carbon atoms)-aminoalkyl group, an acylaminoalkyl group having 1-6 carbon atoms, C1-6 alkoxyalkyl group, C1-6 alkylcarbonyl group, carboxy group, C1-6 alkoxycarbonyl group, (C1-6 alkoxy)carbonyl-(C1-6 alkyl) group, carbamoyl group, C1-6 alkylaminocarbonyl group, di(C1-6 alkyl)aminocarbonyl group, C1-6 haloalkyl group, or a group of the general formula -( _CH2 ) _p- cyclized to the Ar group, in which p is 2 or 3; R1 and R2 are identical or different, independently of each other, hydrogen, straight or branched chain alkyl having 1-6 carbon atoms, or together form a group of the general formula -( _CH2 ) ^n_ , in which n is 3, 4 or 5; or R1 and R together form a group of the general formula -( _CH2 ) _q- , wherein q is 2, 3, 4 or 5; R3 and R4 are identical or different, independently of each other, hydrogen, straight or branched C1-6 alkyl, C1-6 alkenyl, aryl, C1-6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulfonamido, C1-6 alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, amino, mono- or di(C1-6 alkyl)amino, -O( _CH2 ) _r - _NT2 , in which r is 2, 3 or 4, and T is a hydrogen atom, a C1-C6 alkyl group or, together with the adjacent nitrogen atom, a Sun, Sun Ϊ J or ϊ I Π V^(CH^ V^(CH^ forms a group of general formula, in which V and Vi independently represent a hydrogen atom or an oxygen atom, and u is 0, 1 or 2; a group of the general formula -O(CH ₂ )s~OW2, in which s is 2, 3 or 4, and W represents a hydrogen atom or an alkyl group having 1-6 carbon atoms; hydroxyalkyl, aminoalkyl, mono- or dialkylaminoalkyl, acylamino, alkylsulfonylamino, aminoacylamino, mono- or dialkylaminoacylamino; and up to four R3 substituents may be present on the quinoline nucleus at the same time; or R4 cyclizes to the aromatic group _R5 to form a group of the general formula -( _CH2 )t-, where t is 1, 2 or 3; R5 represents a straight or branched C1-6 alkyl group, a C3-7 cycloalkyl group, a C4-7 cycloalkylalkyl group, or an optionally substituted, monocyclic or fused ring, aromatic heterocyclic group containing 5-12 ring atoms and up to four heteroatoms selected from sulfur, oxygen and nitrogen atoms in the ring or rings; X is oxygen, sulfur, or a group of the formula =N-C=N, or a pharmaceutically acceptable solvate or pharmaceutically acceptable salt thereof, in a non-toxic and pharmaceutically acceptable amount. 5. The method according to claim 4, characterized in that the method is directed to the treatment and/or prevention of conditions characterized by altered intestinal function. 6. The method of claim 4, wherein the irritable bowel syndrome condition is diarrhea-predominant irritable bowel syndrome. 7. The process according to claim 4, characterized in that the compound of general formula (I) is (S)-(-)-N-(α-ethylbenzyl)-2-phenyl-3-hydroxy-4-quinolinecarboxamide [compound (1)]. 8. A method for treating and/or preventing conditions characterized by altered bowel function and/or visceral pain in humans or non-human mammals, comprising administering an effective, non-toxic and pharmaceutically acceptable amount of an NK3 receptor antagonist selected from the following: {[(dichlorophenyl)-(trimethoxybenzoyl)morpholinyl]ethyl}-spiro[benzo(c)thiophenepiperidin]oxide, R113281, N10A, N5A1, SR-142801, SSR- -146977, Cam-2425 and MDL-105212, and — where possible — their pharmaceutically acceptable derivatives. 9. The method according to claim 8, characterized in that the method is directed to the treatment and/or prevention of conditions characterized by altered intestinal function. 10. The method of claim 8, wherein the irritable bowel syndrome condition is diarrhea-predominant irritable bowel syndrome. The authorized person: A-b.. C' c/ <71 ΐ <7