KR20040016865A - Novel Use - Google Patents

Abstract

Humans selected from certain irritable bowel syndrome symptoms, functional abdominal distension, functional constipation, functional diarrhea, other intestinal symptoms and functional abdominal pain, including administering an effective, non-toxic, pharmaceutically acceptable amount of NK ₃ receptor antagonist Or a method of treating and / or preventing a condition characterized by altered bowel function and / or visceral pain in a non-human mammal.

Description

New Use {Novel Use}

Mammalian peptide neurokinin B (NKB) belongs to the tachykinin (TK) peptide class, which also belongs to the P substance (SP) and neurokinin A (NKA). Pharmacological and molecular biological evidence suggests that NKB has been found despite the presence of three subtypes of TK receptors (NK ₁ , NK ₂ and NK ₃ ) and the relatively irregular ability of NKB and other tachykinins to recognize each NK receptor. It was demonstrated that it binds mainly to the NK ₃ receptor (Maggi et al., 1993, J. Auton. Pharmacol., 13, 23-93).

Selected peptide NK ₃ receptor antagonists are known (Drapeau's 1990 Regul. Pept., 31, 125-135), and the discovery of peptide NK ₃ receptor agonists suggests that NKB is a NK ₃ receptor. Suggests an important role in the regulation of neural influx in the airway, skin, spinal cord and cortical striatum (Myers and Undem, 1993, J. Phisiol., 470, 665-). 679; Contour et al. (1993, Regul. Peptides, 46, 426-429); McCarson and Krause [1994, J. Neurosci., 14 (2), 712-720; Arenas et al. (1991, J. Neurosci., 11, 2332-8).

The Rome diagnostic criteria (see Gut, 1999; 45 (Suppl. II) II43-II47) indicate that functional bowel disorders are divided into the following groups: irritable bowel syndrome (IBS), functional abdominal distension, and functional It is recognized to include constipation and functional diarrhea. IBS is generally known to include discomfort and / or pain with disorders such as diarrhea major irritable bowel syndrome, constipation major irritable bowel syndrome and shift symptom irritable bowel syndrome (Gut, 1999; 45 (Suppl) II) See II69-II77). Roman diagnostic criteria also indicate that functional abdominal pain is distinct from functional bowel disorders and functional abdominal pain includes functional abdominal pain syndrome and nonspecific functional abdominal pain.

Gastroenterology 1999, 116, 1124-1131 discloses the role of NK ₃ receptors in response to colon rectal dilatation in rats by electrophysiological and behavioral studies. International Patent Application Publication Nos. 98/18762 and 00/21931 describe certain NK ₃ receptor antagonists mentioned among the other disorders listed as useful in treating NK ₃ receptor related disorders, including irritable bowel syndrome (IBS). It starts.

Certain selected NK ₃ antagonists are disclosed in WO 95/32948. These compounds include: pulmonary artery disorders (asthma, chronic pulmonary artery obstruction-COPD-, airway hyperactivity, cough), skin disorders and itching (eg, atopic dermatitis and skin swelling and redness), neurological inflammation and CNS disorders ( In the treatment of Parkinson's disease, motor disorders, anxiety and psychosis, and also convulsive disorders (e.g. epilepsy), kidney disorders, incontinence, eye inflammation, inflammatory pain, eating disorders (food intake disorders), allergic rhinitis, neurodegeneration It is disclosed to be active in the treatment of disorders (eg Alzheimer's disease), psoriasis, Huntington's disease and depression.

One particular compound disclosed in WO95 / 32948 is (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide (compound I)

The present invention relates to novel uses, in particular for use in methods of treating and / or preventing symptoms characterized by altered bowel function and / or visceral pain.

The following is a brief description of the drawings.

1 shows inhibition of synergistic excitation reflection by compound I.

2 shows that in the passage of the small intestine of normal non-sensitized animals, compound I has no significant effect.

3 shows the effect on small intestinal passage in the egg white-albumin sensitization model of Compound I.

4 shows the effect of compound I on the intestinal sensitivity and tension of mice.

It has now been surprisingly found that Compound I is active in the treatment of symptoms characterized by altered intestinal function and / or visceral pain. This includes especially functional bowel disorders and functional abdominal pain. Functional bowel disorders include certain irritable bowel syndrome symptoms, in particular diarrhea major symptoms irritable bowel syndrome, constipation major symptoms irritable bowel syndrome and alternating symptoms irritable bowel syndrome. Compound I was found to be particularly useful for treating diarrhea major symptomatic irritable bowel syndrome.

The present invention thus provides for the modification of intestinal function in human or non-human mammals comprising the administration of an effective, non-toxic, pharmaceutically acceptable amount of an NK ₃ receptor antagonist such as Compound I or a pharmaceutically acceptable derivative thereof (Or) providing a method for treating and / or preventing symptoms characterized by visceral pain, wherein the bowel dysfunction and / or symptoms characterized by visceral pain include certain irritable bowel syndrome symptoms, functional abdominal distension, and functional Constipation, functional diarrhea, other bowel symptoms and functional abdominal pain.

The present invention suitably provides methods for the treatment and / or prevention of symptoms characterized by altered bowel function.

The present invention suitably provides a method for the treatment and / or prevention of symptoms characterized by visceral pain.

Suitable symptoms characterized by altered bowel function and / or visceral pain are selected from specific irritable bowel syndrome symptoms, functional abdominal distension, functional constipation, functional diarrhea and functional abdominal pain.

Specific irritable bowel syndrome symptoms include diarrhea major symptoms irritable bowel syndrome, constipation major symptoms irritable bowel syndrome and shift symptoms irritable bowel syndrome.

Suitable irritable bowel syndrome symptoms are constipation major symptom irritable bowel syndrome.

Suitable irritable bowel syndrome symptoms are shift symptomatic irritable bowel syndrome.

Preferred irritable bowel syndrome symptoms are diarrhea major symptom irritable bowel syndrome.

Functional abdominal pain suitably includes functional abdominal pain syndrome and non-specific functional abdominal pain. Advantageously, functional abdominal pain includes functional abdominal pain syndrome.

Suitable NK ₃ antagonists include those compounds specifically disclosed in International Application Publication No. 95/32948, which is incorporated by reference and specific content is described in detail herein.

Advantageous NK ₃ antagonists are a compound of formula (I) or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof.

Where

Ar is an optionally substituted phenyl, naphthyl or C _5-7 cycloalkdienyl group, or aromatic character, having from 5 to 12 ring atoms and up to 4 hetero atoms selected from S, O, N in each ring An optionally substituted single or fused heterocyclic group containing an atom;

R is up to 4 hetero atoms selected from straight or branched C _1-8 alkyl, C _3-7 cycloalkyl, C _4-7 cycloalkylalkyl, optionally substituted phenyl or phenylC _1-6 alkyl, O and N Optionally substituted 5-membered heteroaromatic ring, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoalkyl, diC _1-6 alkylaminoalkyl, C _1-6 acylamino Alkyl, C _1-6 alkoxyalkyl, C _1-6 alkylcarbonyl, carboxy, C _1-6 alkoxycarbonyl, C _1-6 alkoxycarbonylC _1-6 alkyl, aminocarbonyl, C _1-6 alkylamino carbonyl, di-C _1-6 alkylamino-carbonyl, or a halogeno-C _1-6 alkyl; Or, when cyclized to Ar, is a-(CH ₂ ) _p -group where p is 2 or 3, and

R ₁ and R ₂ may be the same or different and are independently hydrogen or a C _1-6 straight or branched alkyl group, or together a — (CH ₂ ) _n — group where n represents 3, 4 or 5 To form; Or R ₁ together with R form a — (CH ₂ ) _q —group where q is 2, 3, 4 or 5;

R ₃ and R ₄ may be the same or different and are independently hydrogen, C _1-6 straight or branched chain alkyl, C _1-6 alkenyl, aryl, C _1-6 alkoxy, hydroxy, halogen, nitro, cya Furnace, carboxy, carboxamido, sulfonamido, C _1-6 alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, amino, mono- and di-C _1-6 alkylamino, -O (CH ₂ ) _r -NT ₂ , where r is 2, 3 or 4 and T is hydrogen or C _1-6 alkyl or a group with adjacent nitrogen atoms

(Wherein V and V ₁ are independently hydrogen or oxygen and u is 0, 1 or 2); -O (CH ₂ ) _s -OW wherein s is 2, 3 or 4 and W is hydrogen or C _1-6 alkyl; Hydroxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, acylamino, alkylsulfonylamino, aminoacylamino, mono- or di-alkylaminoacylamino; Up to 4 R ₃ substituents are present in the quinoline nucleus;

Or R ₄ is a — (CH ₂ ) _t — group where t is 1, 2 or 3 when cyclized to R ₅ as aryl;

R ⁵ has branched or straight chain C _1-6 alkyl, C _3-7 cycloalkyl, C _4-7 cycloalkylalkyl, optionally substituted aryl, or aromatic character, contains 5 to 12 ring atoms, and each ring or each An optionally substituted single or fused ring heterocyclic group comprising up to 4 hetero atoms selected from S, O, N in the ring of;

X is O, S or N-C≡N.

Suitable mammals are humans.

In particular, the present invention relates to changes in intestinal function and / or visceral pain in human or non-human mammals, comprising administering an effective, nontoxic, pharmaceutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof It relates to a method for the treatment and / or prevention of symptoms characterized by.

The present invention suitably relates to the treatment and / or prevention of symptoms characterized by altered bowel function, in particular diarrhea main symptoms irritable bowel syndrome.

The present invention preferably relates to the treatment and / or prevention of diarrhea.

Examples of Ar are phenyl optionally substituted by hydroxy, halogen, C _1-6 alkoxy or C _1-6 alkyl. Examples of halogen are chlorine and fluorine, examples of C _1-6 alkoxy are methoxy and examples of C _1-6 alkyl are methyl.

Examples of Ar as heterocyclic groups are thienyl and pyridyl.

An example of Ar as a C _5-7 cycloalkdienyl group is cyclohexadienyl.

An example of R is:

C _1-8 alkyl: methyl, ethyl, n-propyl, iso-propyl, n-butyl, heptyl;

PhenylC _1-6 alkyl: benzyl;

HydroxyC _1-6 alkyl: -CH ₂ OH, -CH ₂ CH ₂ OH, CH (Me) OH;

AminoC _1-6 alkyl: -CH ₂ NH ₂ ;

DiC _1-6 alkylaminoalkyl: —CH ₂ NMe ₂ ;

C _1-6 alkoxyalkyl: CH ₂ OMe;

C _1-6 alkylcarbonyl: COMe;

C _1-6 alkoxycarbonyl: COOMe;

C _1-6 alkoxycarbonylC _1-6 alkyl: CH ₂ COOMe;

C _1-6 alkylaminocarbonyl: CONHMe;

DiC _1-6 alkylaminocarbonyl: CONMe ₂ , CO (1-pyrrolidinyl);

HalogenC _1-6 alkyl: trifluoromethyl;

Ar

-(CH ₂ ) _p -when cyclized upward.

Examples of R ₁ and R ₂ as C _1-6 alkyl are methyl; An example of R ₁ forming a group — (CH ₂ ) _q — with R is spircyclopentane.

Examples of R ₃ and R ₄ are methyl, ethyl, n-propyl, n-butyl, methoxy, hydroxy, amino, chlorine, fluorine, bromine, acetyloxy, 2- (dimethylamino) ethoxy, 2- (phthal Imido) ethoxy, aminoethoxy, 2- (1-pyrrolidinyl) ethoxy, phthalimido, dimethylaminopropoxy, dimethylaminoacetylamino, acetylamino, dimethylaminomethyl and phenyl.

An example of R ₅ is cyclohexyl, phenyl optionally substituted as defined for Ar above; Examples of R ₅ as heterocyclic groups are furyl, thienyl, pyryl, thiazolyl, benzofuryl and pyridyl.

Preferred groups of compounds of formula I are

Ar is phenyl optionally substituted by C _1-6 alkyl or halogen; Thienyl or C _5-7 cycloalkdienyl group;

R is C _1-6 alkyl, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonyl, hydroxyC _1-6 alkyl;

R ₁ and R ₂ are each hydrogen or C _1-6 alkyl;

R ₃ is hydrogen, hydroxy, halogen, C _1-6 alkoxy, C _1-6 alkyl;

R ₄ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, amino, halogen, aminoalkoxy, mono- or di-alkylaminoalkoxy, mono- or di-alkylaminoalkyl, phthalimidoalkoxy, mono Or di-alkylaminoacylamino and acylamino;

R ₅ are compounds which are phenyl, thienyl, furyl, pyryl and thiazolyl.

A more preferred group of compounds of formula I are

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

R is methyl, ethyl, n-propyl, -COOMe, -COMe;

R ₁ and R ₂ are each hydrogen or methyl;

R ₃ is hydrogen, methoxy or hydroxy;

R ₄ is hydrogen, methyl, ethyl, methoxy, hydroxy, amino, chlorine, bromine, dimethylaminoethoxy, 2- (phthalimido) ethoxy, aminoethoxy, 2- (1-pyrrolidinyl) Oxy, dimethylaminopropoxy, dimethylaminoacetylamino, acetylamino and dimethylaminomethyl;

R ₅ is phenyl, 2-thienyl, 2-furyl, 2-pyryl, 2-thiazolyl and 3-thienyl;

X are compounds that are oxygen

Preferred subgroups of compounds within the scope of formula (I) are those of formula (la).

Where

R, R ₁ , R ₃ and R ₄ are as defined in formula (I), and Y and Z, which may be the same or different, are each Ar as defined in formula (I).

A particularly preferred group of compounds of formula (Ia) are the compounds of formula (Ib) wherein R is oriented downward and H is upwardly oriented.

The most preferred compound of formula (I) is compound (I).

Compounds of formula (I) or derivatives thereof such as salts or solvates are in pharmaceutically acceptable or substantially pure form. Pharmaceutically acceptable form means those of pharmaceutically acceptable purity that exclude conventional pharmaceutical additives, especially diluents and carriers, and do not contain substances considered toxic at normal dosages.

Substantially pure forms are generally at least 50% (excluding conventional pharmaceutical additives), preferably at 75%, more preferably at 90%, particularly even at 95% of the compounds of formula (I) or salts or solvates thereof Will include.

Pharmaceutically acceptable preferred forms are crystalline forms and include crystalline forms in pharmaceutical compositions. In the case of salts and solvates additional ionic and solvent moieties should also be nontoxic.

Suitable pharmaceutically acceptable derivatives as described above include pharmaceutically acceptable salts and / or solvates.

Examples of pharmaceutically acceptable salts of compounds of formula I include conventional pharmaceutical acids such as maleic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, citric acid, lactic acid, mandelic acid, tartaric acid, succinic acid, Acid addition salts with benzoic acid, ascorbic acid and methanesulfonic acid.

Examples of pharmaceutically acceptable solvates of compounds of formula (I) include hydrates.

Compounds of formula (I) may have one or more asymmetric centers and exist in one or more stereoisomeric forms. The treatment of the present invention extends to these forms and mixtures thereof comprising racemates.

Other NK ₃ antagonists are disclosed in published patent applications WO99 / 36424, WO00 / 39114, WO95 / 28931, WO96 / 05203, EP776893, WO98 / 54191, EP673928, WO94 /. 26735 and WO97 / 10229. The contents of these patent publications are included as if each publication were incorporated herein by reference. The particular NK ₃ antagonist is ([[(dichlorophenyl) (trimethoxybenzoyl) morpholinyl] ethyl] spiro [benzo (c) thiophenepiperidine] oxide. The particular NK ₃ antagonist is R113281. The NK ₃ antagonist is N10A The special NK ₃ antagonist is N5A1 The special NK ₃ antagonist is SR-142801 The special NK ₃ antagonist is SSR-146977 The special NK ₃ antagonist is Cam-2425. A particular NK ₃ antagonist is MDL-105212.

NK ₃ antagonists are prepared according to known methods for the particular compound selected, for example compounds of formula I and compound I are prepared according to the methods disclosed in WO95 / 32948 or WO99 / 14196. Other NK ₃ antagonists such as R113281, N10A, N5A1, SR-142801, SSR-146977, Cam-2425 and MDL-105212 are described, for example, in WO99 / 36424, WO00 / 39114, WO95 / 28931 , WO96 / 05203, EP776893, WO98 / 54191, EP673928, WO94 / 26735 and WO97 / 10229, as appropriate.

Compounds of the process of the invention, such as compound I, can be converted into their pharmaceutically acceptable acid addition salts by reaction with a suitable organic or inorganic acid.

Solvates of the compounds of the process of the invention, such as compound I, can be formed by crystallization or recrystallization from a suitable solvent. For example, hydrates can be formed by crystallization or recrystallization from solutions in aqueous solutions or in organic solvents including water.

Pharmaceutically acceptable derivatives of other NK ₃ antagonists, such as R113281, N10A, N5A1, SR-142801, SSR-146977, Cam-2425, and MDL-105212, are described in WO99 / 36424, WO00 / 39114, as appropriate. , WO95 / 28931, WO96 / 05203, EP776893, WO98 / 54191, EP673928, WO94 / 26735 and WO97 / 10229.

The activity of the compounds of the methods of the present invention, such as compound I, as NK ₃ receptor antagonists has been analyzed in standard trials and found to be potent in the treatment of certain clinical symptoms, in particular the symptoms disclosed herein, characterized by over-promoting of tachykinin receptors. It is shown to have utility.

As used herein, "symptoms characterized by changes in intestinal function" include diarrhea major symptoms irritable bowel syndrome, constipation major symptoms irritable bowel syndrome, shift symptomatic irritable bowel syndrome, functional abdominal distension, functional constipation and functional diarrhea.

Symptoms characterized by altered bowel function include diarrhea major symptomatic irritable bowel syndrome.

Symptoms characterized by altered bowel function include, in particular, constipation major symptom irritable bowel syndrome.

Symptoms characterized by altered bowel function include, in particular, shift symptoms irritable bowel syndrome.

Symptoms characterized by altered bowel function include, among others, other bowel symptoms.

As used herein, “other intestinal symptoms” includes symptoms that exhibit signs such as abdominal pain, urinary insufficiency, bloating, incomplete bowel movements and abdominal pressure, in particular urinary insufficiency, bloating, incomplete bowel movements and abdominal pressure.

The present invention relates to changes in intestinal function and / or in human or non-human mammals comprising administering an effective amount of a nontoxic, pharmaceutically acceptable amount of a NK ₃ antagonist such as Compound I or a pharmaceutically acceptable derivative thereof Also provided are methods of treating and / or preventing symptoms characterized by visceral pain.

The invention also provides NK ₃ antagonists such as Compound I or a pharmaceutically acceptable derivative thereof for use in the treatment and / or prevention of symptoms characterized by altered intestinal function and / or visceral pain.

Also provided is the use of an NK ₃ antagonist such as Compound I or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the treatment and / or prophylaxis of symptoms characterized by altered intestinal function and / or visceral pain. . The symptoms characterized by altered bowel function and / or visceral pain are appropriately selected from certain irritable bowel syndrome symptoms, functional abdominal distension, functional constipation, functional diarrhea, other intestinal symptoms and functional abdominal pain.

The invention also provides an NK ₃ antagonist, such as a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical thereof, for the treatment and / or prevention of symptoms characterized by altered intestinal function and / or visceral pain. A pharmaceutical composition comprising an acceptable solvate, and a pharmaceutically acceptable carrier thereof, wherein the symptoms characterized by altered intestinal function and / or visceral pain are characterized by specific irritable bowel syndrome symptoms, functional abdominal distension , Functional constipation, functional diarrhea, other bowel symptoms and functional abdominal pain.

The drugs and compositions of the present invention can be prepared by mixing the compound of the present invention with a suitable carrier. It may include diluents, binders, fillers, disintegrants, perfumes, colorants, lubricants or preservatives in a conventional manner.

These conventional excipients can be used, for example, as in the preparation of known pharmaceutical compositions for treating symptoms.

Preferably, the pharmaceutical composition of the present invention is in unit dosage form and in a form suitable for use in the medical or veterinary field. For example, the preparation may be in the form of a pack with handwritten or printed medications for treating symptoms.

Suitable dosages of the compounds of the present invention depend on the compound used and the condition of the patient. It will also depend on the relationship between titer and absorbency and on the number and route of administration.

The compounds or compositions of the present invention may be formulated by any route, preferably in unit dosage form or in forms that can be administered by a human patient in a single dose. Advantageously the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. The formulations may be made to release the active ingredient slowly.

The composition may be, for example, in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstituted powders or liquid formulations, such as solutions or suspensions, or suppositories.

Compositions, such as those suitable for oral administration, include conventional excipients such as binders such as syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; Fillers such as lactose, sugar, corn-starch, calcium phosphate, sorbitol or glycine; Tableting lubricants such as magnesium stearate; Disintegrants such as starch, polyvinyl-pyrrolidone, sodium starch glycolate or microcrystalline cellulose; Or pharmaceutically acceptable curing agents such as sodium lauryl sulfate.

Solid compositions can be obtained by conventional methods such as mixing, filling and tableting. Repeated mixing operations can be used to disperse the active agent throughout the composition using a large amount of filler. Any suitable carrier can be used in formulating the solid pharmaceutical composition when the composition is in the form of a tablet, powder or lozenge, for example magnesium stearate, starch, glucose, lactose, sucrose, rice powder and chalk. Tablets may be coated according to methods known in the conventional pharmaceutical art, in particular with enteric skin. The composition may also be in the form of a capsule that can be digested, for example gelatin comprising the compound, if desired, together with a carrier or other excipient.

Compositions for oral administration in liquid form may be, for example, in the form of emulsions, syrups or elixirs, or may be dry products which are reconstituted prior to use with water or other suitable excipients. Suitable liquid compositions include conventional additives such as suspending agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gels, hydrogenated edible fats; Emulsifiers such as lecithin, sorbitan monooleate, or acacia; Cooking oils such as almond oil, fractionated coconut oil, oily esters such as glycerin, or propylene glycol, or esters of ethyl alcohol, aqueous or non-aqueous excipients including glycerin, water or conventional saline; Preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid; And conventional flavoring or coloring agents, if desired.

The active compounds of the invention can also be administered by the parenteral route. According to routine pharmaceutical methods, the compositions may be formulated as suppositories for rectal administration. They may also be formulated in the form of injectables of aqueous or non-aqueous solutions, suspensions or emulsions in pharmaceutically acceptable liquids, such as sterile pyrogen-free water or parenterally acceptable oils or liquid mixtures. Liquids may include bactericides, antioxidants, or other preservatives, buffers or solutes, thickeners, suspensions or other pharmaceutically acceptable additives to make the solution isotonic with blood. Such forms may be in unit dosage form, such as ampoules or disposable syringes or multi-dose forms, such as solid forms or concentrates, from which a bottle or injectable preparation may be obtained which may come in suitable dosages.

The active compounds of the invention can also be administered by intranasal or oral route by inhalation. Such administration may optionally be carried out by a spray formulation comprising a compound of the invention and a suitable carrier, for example suspended in a hydrocarbon propellant.

Preferred spray formulations comprise fine compound particles with surfactants, solvents or dispersants which prevent the settling of suspended particles. Preferably, the compound particle size is about 2 to 10 microns.

Another method of administering the active agent of the invention includes transdermal delivery using a skin-patch formulation. Preferred formulations include a compound of the invention dispersed in a pressure sensitive adhesive that adheres to the skin such that the compound is delivered from the adhesive through the skin to the patient. For a constant rate of transdermal absorption, pressure sensitive adhesives known in the art such as natural rubber or silicone can be used.

As mentioned above, the effective dosage of the compound depends on the particular compound used, the condition of the patient and the frequency and route of administration. The unit dosage will generally be 20 to 1000 mg, and will preferably comprise 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg. The composition may be administered one or more times per day, for example two, three or four times daily, and the total daily dose for a 70 kg adult will typically be between 100 and 300 mg. Or the unit dose will comprise from 2 to 20 mg of active ingredient and may be administered several times for the preceding daily dose if desired.

Dosage forms and formulations of particular NK ₃ antagonists include those mentioned in the patent application.

Unacceptable toxicological effects are not expected when the compounds of the methods of the invention are administered in accordance with the invention.

Activity of compounds of this invention as NK ₃ ligands are radiolabeled NK ₃ ^{ligands, [125 I] - [Me} -Phe 7] -NKB or ^[3 H] -Senktide inhibiting that is coupled to a guinea pig and human NK ₃ receptors Measured by its activity (Renzetti et al., 1991, Neuropeptide, 18, 104-114; Buelle et al., 1992, FEBS, 299 (1) 90-95); Chung, et al., 1994, Biochem. Biophys. Res. Commun., 198 (3), 967-972). Binding assays to determine the concentration of individual compounds (IC50) needed to reduce the specific binding of [ ¹²⁵ I]-[Me-Phe ⁷ ] -NKB and [ ³ H] -Senktide to the NK ₃ receptor at equilibrium conditions by 50% This was used. Binding assays provide mean IC ₅₀ values of 2-5 individual experiments performed in duplicate or triplicate for each compound tested. The most potent compounds of the invention exhibit IC ₅₀ values in the range of 1-1000 nM; Especially in guinea pig cortical membranes displaced with [ ³ H] -Senktide, the compounds of Examples 22, 47, 48 and 85 show K _is (nM) of 5.6, 8.8, 12.0 and 4.8 (n = 3), respectively. NK ₃ -antagonist activity of the compounds of the present invention is characterized by guinea pig ileum (Maggi et al., 1990, Br. J. Pharmacol., 101, 996-1000) and iris sphincter isolated from rabbit (Hall). (1991, Eur. J. Pharmacol., 199, 9-14) and Senktide-induced contraction and human NK ₃ receptor mediated Ca ⁺⁺ mobilization (Mochizuki et al., 1994, J. Biol) Chem., 269, 9651-9658). In vitro functional analysis of guinea pigs and rabbits provides the average K _B value of 3-8 individual experiments for each compound tested, where K _B is required to shift the concentration response curve of senktide to the right by 2 times Concentration of the individual compounds. The concentration of individual compounds (IC ₅₀ value) required to reduce the Ca ⁺⁺ recruitment induced by the agonist NKB by 50% is determined by human receptor function analysis. In this assay, the compounds of the present invention act as antagonists.

For the avoidance of doubt, all documents, including but not limited to the patents and patent applications mentioned in this specification, are incorporated by reference.

The therapeutic titers of the compounds of the present invention in treating the above symptoms can be analyzed using rodent disease models.

The present invention is illustrated by the following experimental data, but is not limited thereto.

Experiment result

No Effect of Compound I on Normal Gastrointestinal Motility

Compound I had no significant or statistically significant effect on rat gastric emptying at oral doses of 5, 15 and 50 mg / kg, as measured using the phenol red method. The high dose used in this study is similar to the dose exhibiting intestinal nociceptive activity (see below) and compared to the higher affinity of the NK-3 receptor of Compound I for human- or guinea pig variants, the rat NK- Low affinity for three receptors was consistent. In contrast, morphine sulfate orally administered at 20 mg / kg as a control standard resulted in a significant and statistically significant decrease in gastric emptying (see Table 1). This effect was foreseen and demonstrated the validity of the test system.

Rat gastric fasting rate after administration of Compound I, morphine sulfate, phenol red and excipient alone group Oral treatment Dose (mg / kg) Stomach emptying (%) 123456 Phenolic Red Sole Excipient Compound I Compound I Compound I Morphine Sulfate --5155020 0.060.655.250.762.430.8 ^** Significance of difference from excipient treatment group: p ^** <0.01

Compound I, administered orally at doses of 5, 15, 50 mg / kg, as measured using the activated carbon feeding test, also had no significant or statistically significant effect on gastrointestinal motility in rats. Therefore, the distance traveled by activated charcoal feed in each compound I-treated group was similar to the excipient treated group at each test dose. In contrast, an oral dose of 10 mg / kg morphine sulfate resulted in a significant and statistically significant decrease in gastrointestinal motility compared to the excipient treatment group (see Table 2). This effect was foreseen and demonstrated the validity of the test system.

Effect of Compound I, Morphine Sulfate and Excipients on Rat Gastrointestinal Motility, Measured by Activated Carbon Mill Test group Oral treatment Dose (mg / kg) Total digestive tract length + mean distance traveled by activated carbon as SD (%) % Difference with excipient treated animals 1 2 3 4 5 Excipient Compound I Compound I Compound I Morphine Sulfate -5155010 53.0 + 7.646.9 + 5.352.1 + 7.150.4 + 8.637.4 + 12.4 --11.5-1.7-4.9-29.4 SD = significance of difference from standard deviation excipient treatment group: p ^** p <0.01

Slow EPSP Inhibition by Compound I in Guinea Pig Intestinal Neurons

Four neurons were analyzed with Compound I to determine the effect of Compound I on Slow EPSP. Slow EPSP was induced by high-frequency (20 Hz) electrical stimulation applied to the surrounding node strands for 1 second. Once reference slow EPSP was obtained and then settled, 0.1 μM concentration of Compound I was injected through the formulation. Continuous infusions and slow EPSPs were tested at various intervals. In all four neurons, each time the drug was cycled once for at least 30 minutes, there was a decrease in peak amplitude of polarization loss greater than 50% compared to baseline. It was 100% blocked in one neuron and exhibited the post-synaptic potential difference (IPSP) upon stimulation. The other three neurons showed 60-80% blocking based on the amplitude of the polarization loss. Two neurons were filled with biocithin and reacted with streptavidin and Texas Red, which shows Dogiel type II morphology in fluorescence microscopy.

Inhibition of Renal Induced Reflex Activity by Compound I in Colon Isolated from Guinea Pigs

For reflex studies, a 5-7 cm long colon is suspended in warm, oxygenated physiological saline, an 8 mm metal bar is inserted into the river and threaded through the intestinal wall to extend the intestine by pulling the bar to different weights. To the pulley system. A force transducer was attached from the 5 mm end of the extension bar with a small wire hook to the colon wall. Using a weight of 6, 12 or 20 g to dilate the colon wall caused regular contractions on the mouth side and some relaxation on the anus side for dilation. Addition of 12 and 20 g weights resulted in a similar pattern of activity, with a slight relaxation on the anal side to dilation more obvious, but the mouth-excited response was not different from the effect at 6 g weight. Compound I 250 nM applied for 30-45 minutes reduced the effects of expansion in an approximately expansion dependent manner, with greater impact at higher degrees of expansion (see attached figure). These data suggested that NK ₃ receptor antagonism by Compound I reduces the up and down reflexes caused by expansion. Since the effect on the intestinal response of Compound I was more evident at heavier extended weights, the slow EPSP component of the NK ₃ receptor and IPAN activity was potent and probably more strongly related to reflexes caused using pathological stimuli. will be.

The data is shown in FIG. 1, showing the change in 6, 12 or 20 g extended induced upward excitation reflection (seconds), measured in the area under the curve (g.sec) in the absence and presence of compound I and after washing.

Inhibition of Intestinal Passage Increase by Compound (I) in Egg White-Albumin-sensitized Mice

Summary and conclusion

NK ₃ receptor antagonism by Compound I 15 mg / kg po was first demonstrated to inhibit the increase in rat small intestinal transit time caused by egg white-albumin administration. These data strongly demonstrate that NK ₃ receptors are involved in pathological (non-physiological) changes in intestinal function.

purpose

Increasing rat small intestinal transit induced by sensitization to egg white-albumin immunity has previously been used to demonstrate activity that normalizes the chaotic pattern of intestinal transit of the 5-HT ₃ receptor antagonist allosetron (Clay Clayton NM. Sargent R. Butler A. Gale J. Maxwell MP. Hunt AA. Barrett VJ. Cambridge D. Bounty C. Humphrey PP. The Pharmacological properties of the novel selective 5-HT3 receptor antagonist, alosetron , and its effects on normal and pertubed small intestinal transit in the fasted rat. Neurogastroenterology & Motility. 11 (3): 207-17, 1999 Jun.]). Given the significance of the data for allosterone and the potential interaction between the above administration in the digestive tract and the NK ₃ receptor (Gay J, Fioramonti J, Garcia-Villa The effect of Garcia-Villar R, Edmonds-Alt X, Bueno L (1999) (Gut, 44,497-503), and Compound I was studied with this model.

result

Compound I 15 mg / kg po had little effect on small intestinal passage in normal, non-sensitized animals (see Appendix 2). However, in the egg white-albumin sensitization model, the increased passage seen after egg white-albumin sensitization was significantly inhibited by pretreatment with compound I15 mg / kg po (see FIG. 3).

Argument

These data demonstrate for the first time that the receptor can play a significant role in modulating the chaotic pattern of motility, as opposed to the involvement of the NK ₃ receptor in normal patterns of small intestine motility. In addition, these data and the implications of these data obtained in vitro by using this model (proven relevance of NK ₃ receptors in IPAN slow EPSP activity; inhibiting excitatory neuronal activity of noncholine agonists in colons isolated from humans) Proven activity of the NK ₃ receptor) and in vivo intestinal pathology.

Inhibition of Enteric Tolerance by Compound I

In conscious rats, compound I50 mg / kg, po had a significant nociceptive inhibitory effect without affecting colon-rectal tension during expansion of the colon-rectal area at dilation pressures of 30, 45 and 60 mmHg. . Compound I 30 mg / kg, po acted similarly, but the effect was statistically significant only at the peak expansion pressure. The lowest dose of Compound I tested (10 mg / kg, po) did not have an adverse effect of inhibition.

These data indicate that selective NK-3 receptor antagonism may reduce intestinal sensitivity to deleterious expansion.

Claims (10)

Humans selected from certain irritable bowel syndrome symptoms, functional abdominal distension, functional constipation, functional diarrhea, other intestinal symptoms and functional abdominal pain, including administering an effective, non-toxic, pharmaceutically acceptable amount of NK ₃ receptor antagonist Or a method of treating and / or preventing a condition characterized by altered bowel function and / or visceral pain in a non-human mammal. The method of claim 1 for the treatment and / or prevention of symptoms characterized by changes in intestinal function. The method of claim 1, wherein the irritable bowel syndrome symptom is diarrhea major symptom irritable bowel syndrome. Intestinal function changes in human or non-human mammals comprising administering an effective, non-toxic, pharmaceutically acceptable amount of a compound of Formula (I) or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof And / or a method for treating and / or preventing symptoms characterized by visceral pain. <Formula I> Where Ar is an optionally substituted phenyl, naphthyl or C _5-7 cycloalkdienyl group, or aromatic character, having from 5 to 12 ring atoms and up to 4 hetero atoms selected from S, O, N in each ring An optionally substituted single or fused heterocyclic group containing an atom; R is up to 4 hetero atoms selected from straight or branched C _1-8 alkyl, C _3-7 cycloalkyl, C _4-7 cycloalkylalkyl, optionally substituted phenyl or phenylC _1-6 alkyl, O and N Optionally substituted 5-membered heteroaromatic ring, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, C _1-6 alkylaminoalkyl, diC _1-6 alkylaminoalkyl, C _1-6 acylamino Alkyl, C _1-6 alkoxyalkyl, C _1-6 alkylcarbonyl, carboxy, C _1-6 alkoxycarbonyl, C _1-6 alkoxycarbonylC _1-6 alkyl, aminocarbonyl, C _1-6 alkylamino carbonyl, di-C _1-6 alkylamino-carbonyl, or a halogeno-C _1-6 alkyl; Or, when cyclized to Ar, is a-(CH ₂ ) _p -group where p is 2 or 3, and R ₁ and R ₂ may be the same or different and are independently hydrogen or a C _1-6 straight or branched alkyl group, or together a — (CH ₂ ) _n — group where n represents 3, 4 or 5 To form; Or R ₁ together with R form a — (CH ₂ ) _q —group where q is 2, 3, 4 or 5; R ₃ and R ₄ may be the same or different and are independently hydrogen, C _1-6 straight or branched chain alkyl, C _1-6 alkenyl, aryl, C _1-6 alkoxy, hydroxy, halogen, nitro, cya Furnace, carboxy, carboxamido, sulfonamido, C _1-6 alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, amino, mono- and di-C _1-6 alkylamino, -O (CH ₂ ) _r -NT ₂ , where r is 2, 3 or 4 and T is hydrogen or C _1-6 alkyl or a group with adjacent nitrogen atoms (Wherein V and V ₁ are independently hydrogen or oxygen and u is 0, 1 or 2); -O (CH ₂ ) _s -OW wherein s is 2, 3 or 4 and W is hydrogen or C _1-6 alkyl; Hydroxyalkyl, aminoalkyl, mono- or di-alkylaminoalkyl, acylamino, alkylsulfonylamino, aminoacylamino, mono- or di-alkylaminoacylamino; Up to 4 R ₃ substituents are present in the quinoline nucleus; Or R ₄ is a — (CH ₂ ) _t — group where t is 1, 2 or 3 when cyclized to R ₅ as aryl; R ⁵ has branched or straight chain C _1-6 alkyl, C _3-7 cycloalkyl, C _4-7 cycloalkylalkyl, optionally substituted aryl, or aromatic character, contains 5 to 12 ring atoms, and each ring or each An optionally substituted single or fused ring heterocyclic group comprising up to 4 hetero atoms selected from S, O, N in the ring of; X is O, S or N-C≡N. The method of claim 4, wherein the treatment and / or prevention of symptoms is characterized by changes in intestinal function. The method of claim 4, wherein the irritable bowel syndrome symptom is diarrhea major symptom irritable bowel syndrome. The method of claim 4, wherein the compound of formula I is (S) -N- (α-ethylbenzyl) -3-hydroxy-2-phenylquinoline-4-carboxamide (Compound I). An effective, nontoxic, pharmaceutically acceptable amount of ([[(dichlorophenyl) (trimethoxybenzoyl) morpholinyl] ethyl] spiro [benzo (c) thiophenepiperidine) oxide, R113281, N10A, N5A1 , SR-142801, SSR-146977, Cam-2425 and MDL-105212 or, if appropriate, intestinal of human or non-human mammal, comprising administering an NK ₃ antagonist selected from the group consisting of pharmaceutically acceptable derivatives thereof. A method of treating and / or preventing a condition characterized by a change in function and / or visceral pain. The method of claim 8, wherein the condition is characterized by a change in intestinal function. The method of claim 8, wherein the irritable bowel syndrome symptom is diarrhea major symptom irritable bowel syndrome.