TWI243678B - A pharmaceutical composition for the treatment and/or prophylaxis of conditions characterized by altered bowel function and/or visceral pain in human or non-human mammals - Google Patents

Abstract

A method for the treatment and/or prophylaxis of conditions characterised by altered bowel function and/or visceral pain in humans or non-human mammals, which method comprises the administration of an effective, non-toxic and pharmaceutically acceptable amount of an NK3 receptor antagonist, wherein the condition characterised by altered bowel function and/or visceral pain is selected from certain irritable bowel syndrome conditions, functional abdominal bloating, functional constipation, functional diarrhea, other bowel conditions and functional abdominal pain.

Description

A7 B7 1243678 V. Description of the invention (1) The present invention relates to novel uses, particularly to the use of mammalian skin neurostimulation in a method for the treatment and / or prevention of symptoms characterized by changes in bowel function and / or visceral pain. Peptide B (NKB) belongs to the tachykinin (τκ) peptide family 5 group, which also includes substance P (SP) and neurokinin A (NKA). Pharmacological and molecular biological evidence, three subtypes of TK receptors (νκ ^, NK2, and NK3) exist, and WKB preferentially binds to the NK: 3 receptor, but this is in contrast to other fast-acting states. The ability to identify individual NK receptors is a point of view and is relatively heterogeneous (Maggi et al., 1993, J. Auton. Pharmacol., 13, 23-93). 10 Selective peptidic NK3 receptor antagonists are known (Drapeau, 1990 Regul. Pept., 31, 125-135), and with regard to the discovery of peptidic NK3 receptor activators, it is pointed out that NKB acts via the NK3 receptor Activation plays an important role in the modulation of neural input in the airway, skin, spinal cord, and black-striatum pathway (Myers and Undem, 1993, J. Phisiol "470, 665-679; Counture et al., 15 1993 , Regul. Peptides, 46, 426-429; Mccarson and Krause, 1994, J.

Neurosd ·, 14 (2), 712-720; Arenas et al., 1991, J. Neurosd ·, 11, 2332-8) o Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs% «

Rome diagnostic criteria (see Intestinal Gut, 1999; 45 (Supplementary II) Π43-ΙΙ47) recognize that functional intestinal disorders include the following different groups: irritating bowel syndrome 20, functional bloating, functional constipation, and functional diarrhea. IBS is generally recognized to include discomfort and / or pain, accompanied by conditions such as diarrhea-major thorns, irritable bowel syndrome, constipation-major irritant bowel syndrome, and alternating irritable bowel syndrome (Gut, 1999; 45 (Supplementary II) 1169-1177). In addition, Rome diagnostic standards recognize that functional abdominal pain is different from functional intestinal disorders. This paper size applies Chinese National Standard (CNS) A4 specifications (210x297 public love) A7 B7 1243678 V. Description of the invention (0 'and functional abdominal pain includes functional Symptoms of abdominal pain and non-specific functional abdominal pain. Gastroenterology, I " 9, II6, 丨 丨 II 丨 Reveals the role of Nk3 receptors in rats in response to colorectal swelling through electrophysiology and behavioral studies 5. International Patent Application Gazette Numbers 98/18762 and 00/21931 disclose a 4K NK3 receptor antagonist, which is said to be useful for treating cardiac receptor disorders, including the irritating bowel syndrome (IBS), accompanied by List of other disorders. Certain selective NK3 antagonists are disclosed in International Patent Application Gazette No. 95/32948. These compounds are disclosed as active for the treatment of 10 diseases: lung disease (asthma, chronic obstructive pulmonary disease) -COPD, allergic airway reactions, coughing), skin conditions and pruritus (such as atopic dermatitis and skin sores and plaques), neuroinflammation and CNS disorders (Parkinson's disease, mobile disorders) Anxiety and mental illness); and treatment: convulsive disorders (such as epilepsy), kidney disease, urinary incontinence, eye inflammation, inflammatory pain, eating disorders (food intake suppression system), allergic rhinitis, neurodegenerative disorders (such as Alzheimer's Moore's disease), psoriasis, Huntington's disease, and depression. A specific compound disclosed in W095 / 32948, which is the compound of Example 85, which is (S > N_ (cardiethylbenzylhydroxyi) Phenylbenzylcarboxamide (compound ⑴). 20 It has now surprisingly been shown that compound (I) has activity to treat symptoms characterized by altered bowel function and / or visceral pain. This includes especially work_ ^ Gastrointestinal disorders and functional abdominal pain. Functional intestinal disorders include symptoms of specific irritating symptoms, especially diarrhea-primary irritating bowel syndrome, constipation-primary irritating bowel syndrome, and alternating irritating bowel syndrome. Compounds⑴ Steamed -4- This paper size applies to China National Standard (CNS) A4 (210x297 mm)

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1243678 A7 B7 V. Description of the invention (3) shows that it can be used to treat diarrhea-the main irritating bowel syndrome cluster. Accordingly, the present invention provides a method for treating and / or preventing symptoms characterized by altered bowel function and / or visceral pain in a human or non-human mammal, the method comprising administering an effective, non-toxic and pharmaceutically acceptable Acceptable amount of NK3 receptor antagonist, such as compound (I) or a pharmaceutically acceptable derivative thereof, wherein the symptoms characterized by altered bowel function and / or visceral pain are selected from certain irritating bowel symptoms蔟 symptoms, functional bloating, functional constipation, functional diarrhea, other bowel symptoms, and functional abdominal pain. The present invention suitably provides a method for treating and / or preventing symptoms characterized by altering intestinal function. The present invention suitably provides a method for treating and / or preventing symptoms characterized by visceral pain. Appropriate symptoms characterized by altered bowel function and / or visceral pain are selected from certain irritating bowel syndrome symptoms, functional bloating, functional constipation, 15 functional diarrhea, and functional abdominal pain. Symptoms of specific irritating bowel symptoms include abdominal wetness-major irritating bowel syndrome, constipation-major irritating bowel syndrome, and alternating irritating bowel syndrome. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. Appropriate irritant bowel syndrome is constipation-the main irritable bowel syndrome. Appropriate irritating bowel syndrome is an alternating irritating bowel syndrome. 20 The preferred irritating bowel syndrome is diarrhea. The main irritating bowel syndrome. Functional abdominal pain suitably includes functional abdominal pain syndromes and non-specific functional abdominal pain. The functional abdominal pain system advantageously includes functional abdominal pain syndromes. Suitable NK: 3 antagonists include detailed and general disclosures in international patents

A7 B7 1243678 V. Description of the invention (4) The compound in the application bulletin No. 95/32948, the content of which is incorporated herein by reference, as if the specific content of W095 / 32948 is completely presented in this article. An advantageous NK3 antagonist is a compound of formula (I): 5 w

10 or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:

Ar is optionally substituted phenyl, naphthyl, or C5_7 cycloalkadienyl, or optionally substituted single or fused ring heterocyclic group, which has aromatic characteristics and contains 5 to 12 ring atoms , And contains up to four heteroatoms 15 in this ring or rings, selected from S, Ο, N; printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, R is linear or branched C1 _ 8 alkyl, C3- 7 Sulfuryl, C4-7 Sulfuryl, optionally substituted phenyl or phenyl Ci-6 alkyl, and up to five optionally substituted heteroaromatics containing up to four heteroatoms selected from 0 and N Cyclic, hydroxyalkyl, amino Ci-6 alkyl, Ciw alkylamino alkyl, 20 diCl-6 alkylamino, Cl-6 alkylamino, Cl-6 alkyloxy, A-6 alkyl Carbonyl, carboxyl, A_6 alkoxycarbonyl, Ci_6 alkoxycarbonyl, Cualkyl, aminocarbonyl, alkylaminocarbonyl, diCi_6 alkylaminocarbonyl, alkyl; or when cyclized on Ar, it is a group- (CH2) p-, where p is 2 or 3; -6- This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) A7 B7 1243678 V. Description of the invention (5) 1 ^ and 112 can be the same or not , Independently is hydrogen or (^ _6 linear or branched alkyl group, or together form-(CH2) n-, where η represents 3, 4 or 5; or heart and R together form a group-(CH2) q, Wherein q is 2, 3, 4 or 5; 113 and 114 may be the same or different, and are independently hydrogen, linear or branched alkyl 5 groups, (6-6 alkenyl, aryl, Ci-6 alkoxy, hydroxyl , Prime, nitro, cyano, carboxyl, carboxyamido, sulfoamido, alkoxycarbonyl, trifluoroamido, fluorenyloxy, phthalimide, amine, mono and di -4-6 alkylamino group, -0 (CH2) r-NT2, where r is 2, 3 or 4, and T is hydrogen or Cu alkyl 10, or it forms a group with an adjacent nitrogen

15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs where V and 乂 丨 are independently hydrogen or oxygen, and u is 0, 1 or 2; -0 (CH2) s-0W, where s is 2, 3 or 4, And W is hydrogen or a Cu alkyl group; via an alkyl group, an amino alkyl group, a mono- or di-alkyl amino group, a si-amino group, an alkyl group, an amino group, an mono- Or a di-alkylamine 20-based fluorenylamino group; having up to four R3 substituents present in the fluorene core; or when cyclized on R5 as an aryl group, R4 is a group-(CH2) t-, Where t is 1, 2 or 3; R5 is a branched or linear C1_6 alkyl group, C3-7 alkyl group, C4-7 alkyl group, optionally substituted aryl group, or Replaced single or -7- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 1243678 A7 B7

A fused ring heterocyclic group, which has aromatic properties. The ring is very early, and the number of people is 5 to 12 and contains up to four heteroatoms in the ring or each ring. Since s, 0, n;, X is 0, S, or] ^ Cen. 5 Suitable mammals are humans. In particular, the present invention relates to a method for treating and / or preventing symptoms characterized by altered bowel function and / or visceral pain in humans or non-human mammals. This method includes administering an effective, A non-toxic and pharmaceutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof. 10 The present invention relates appropriately to the treatment and / or prevention of symptoms characterized by altered bowel function, particularly diarrhea-a major irritant bowel syndrome. The present invention is preferably related to the treatment and / or prevention of diarrhea.

The conventional example of Ar is phenyl, which is optionally substituted by a radical, a halogen, a Ci6 alkyloxy group, or a Ci-6 alkyl group. !! An example of a prime is gas and fluorine, an example of Ci 6 alkoxy is 15 and an example of alkoxy is methyl.

Examples of Ar as a heterocyclic group are thienyl and pyridyl.

An example of Ar as C5_7 cycloalkadienyl is cyclohexadienyl. Examples of R are as follows: Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs! C-8 alkyl groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, heptyl 20; phenyl Ci- 6 alkyl groups: thousands of groups; hydroxyCu alkyl groups: -CH2OH, -CH2CH2OH, CH (Me) OH; amino C1- 6 alkyl groups--CH2 NH2; bis (^-6 alkylamino alkyl group:- CH2NMe2; This paper size applies Chinese National Standard (CNS) A4 specification (21 × 297 mm) A7 B7 1243678 V. Description of the invention (7) CV6 alkoxyalkyl: CH2OMe; Alkylcarbonyl: COMe; < ^ _ 6alkane Oxocarbonyl: COOMe;

Cb6 alkoxycarbonyl < ^-6 alkyl: CH2COOMe; 5 < ^ _6 alkylamino carbonyl: CONHMe; di CV6 alkylamino carbonyl: CONMe2, CO (1-tetrahydropyrrolyl); halogen CV6 alkyl: tri Fluoromethyl;-(CH2) p- when cyclized on Ar:

An example of heart and heart as an alkyl group is fluorenyl; an example of & with 11 to form a group-(CH2) q- is spirocyclopentane. 15 R3 and R4 are printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. Examples are methyl, ethyl, n-propyl, n-butyl, methoxy, hydroxyl, amine, chlorine, fluorine, bromine, and acetamidine. Ethoxy, 2- (dimethylamino) ethoxy, 2- (phthalimide) ethoxy, aminoethoxy, 2- (1-tetrahydropyrrolyl) ethoxy Group, phthalimide, dimethylaminopropoxy, dimethylaminoacetamido, acetamido, dimethylaminomethyl and phenyl. 20 Examples of R5 are cyclohexyl, phenyl, optionally substituted as defined above for Ar; R5 as examples of heterocyclic groups are furyl, thienyl, pyrrolyl, thiazolyl, benzofuranyl and Pyridyl. A preferred group of compounds of formula (I) are the following, of which:

Ar is phenyl and is optionally substituted by <^ _ 6 alkyl or halogen; thienyl or -9- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) ~ Employees of Intellectual Property Bureau, Ministry of Economic Affairs Printed by the Consumer Cooperative 1243678 A7 B7 V. Description of the invention (8) C5-7 is a diphenyl group, R is &lt; ^-6 alkyl, alkoxycarbonyl, alkylcarbonyl, hydroxyl q-6 alkyl; 1 ^ and 112 each Hydrogen or (^ _6 alkyl; 5 R3 is hydrogen, hydroxy, i element, Cu alkoxy, Cu alkyl; R4 is hydrogen, Ci_6 alkyl, Ci-6 alkyl, alkoxy, amine, halogen, Aminoalkyloxy, mono- or di-alkylaminoalkoxy, mono- or di-alkylamino, phthalimidoiminoalkoxy, mono- or di-alkylamino 10 R5 is phenyl, thienyl, furyl, pyrrolyl and thiazolyl. Another group of preferred compounds of formula (I) are the following, of which:

Ar is phenyl, 2-chlorophenyl, 2-thienyl or cyclohexadienyl; R is fluorenyl, ethyl, n-propyl, -COOMe, -COMe; 1 and &amp; each is hydrogen or Methyl; 15 R3 is hydrogen, methoxy or hydroxyl; r4 is hydrogen, methyl, ethyl, methoxy, hydroxyl, amine, chlorine, bromine, dimethylaminoethoxy, 2- (o-phenyl) Dimethylamidoimino) ethoxy, aminoethoxy, 2- (1-tetrahydropyrrolyl) ethoxy, dimethylaminopropoxy, dimethylaminoethylamidoamine, acetamidine Amino and dimethylaminomethyl. 20'5 is phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-thiazolyl, and 3-thienyl; and X is oxygen. A preferred group of compounds within the range of formula (I) above is those having formula (la): -10- This paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm)

A7 B7 1243678 V. Description of the invention (9:

R

(la) where: R, R2, R3, and R4 are as defined in formula (I), and Y and Z may be the same or different, and each is Ar as defined in formula (I). 10 A group of particularly preferred compounds of formula (la) are those having formula (lb), in which the orientation of the group R is downward and Η is upward. 15 r3

Z (lb) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs The best compound of formula 为 is compound ⑴. Compounds of formula (I) or derivatives thereof, such as salts or solvates, are in a pharmaceutically acceptable or substantially pure formula. A pharmaceutically acceptable form refers to a purity that is particularly pharmaceutically acceptable, excluding general pharmaceutical additives, such as diluents and carriers, and does not contain substances considered to be toxic at normal dosage levels. Substantially pure type usually contains at least 50% (except general pharmaceutical additives), which is more than -11-This paper size applies Chinese National Standard (CNS) A4 (210x297 mm) 1243678

And still more preferably 95% of the compound of the formula (1) or more preferably 75%, more preferably 90% of its salt or solvate. 2 The preferred pharmaceutically acceptable form is a crystalline form, including in such a composition. In the case of salts and solvates, the additional ion 14, cereal moiety must also be non-toxic. / Above the above 'suitable pharmaceutically acceptable derivatives include musically acceptable salts and / or solvates. 10 styles. Examples of pharmaceutically acceptable salts of substances include acid addition salts with conventional medicinal acids, such as maleic acid, amidine, azamoic acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, lemon Acid, lactic acid, phenyl alcohol, tartaric acid, succinic acid, benzoic acid, ascorbic acid and pinanesulfonic acid. Examples of pharmaceutically acceptable solvates of the compound of formula (I) include hydrates. 0. The compound of formula (I) may have at least one asymmetric center, and thus may exist as a stereoisomer of 15 or more. The therapeutic drug of the present invention is extended to all such forms and mixtures thereof, including racemates. Other NK: 3 antagonists are disclosed in published patent applications W099 / 36424, WOOO / 39114, W095 / 28931, W096 / 05203, EP776893, and printed by W098 / 54191, EP673928, Employee Consumer Cooperative of the Ministry of Economics and Intellectual Property, W094 / 26735 and W097 / l0229. The contents of the patent gazettes referred to in the last 20 articles are incorporated herein, as if the individual gazettes were detailed and individually incorporated herein for reference, as if they were presented here in their entirety. One specific NK3 antagonist is oxidized ([[dichlorobenzyl) (trimethoxybenzyl)) morphofenyl;] ethyl] spiro [benzopyrenethiophene hexahydropyridine]. A specific NK; antagonist is Rll;? 281. A specific NKθ antagonist is -12-

A7 B7 1243678 V. Description of the invention (11) N10A. A specific Nκ3 antagonist, gN5A1. A specific NK; antagonist is SR-142801. One specific resist is SSR-146977. One specific NK: 3 antagonist is Cam-2425. One specific NK3 antagonist is MDL-105212. 5 This service 3 antagonist is made according to known methods for a specific compound of choice, for example a compound of formula (I), and compound (I) is made according to WQ95 / 32948 or WO &quot; / i4i% _ Revealed method made. Its antagonists, such as R113281, N10A, N5A1, SR-142801, SSR-146977, Cam-2425 and MDL-1052 2 are made in an appropriate manner according to published methods, for example at 10 W099 / 36424 , WOOO / 39114, W095 / 28931, W096 / 05203, EP776893, W098 / 54191, EP673928, W094 / 26735 and WO97 / 10229. The compounds of the method of the present invention, such as compound (I), Or mineral acid reaction, and is converted into its pharmaceutically acceptable acid addition salt. 15 The compound of the method of the present invention, such as the compound (I), can be formed from a suitable solvent by crystallization or recrystallization. For example, a hydrate can be formed from an aqueous solution or a solution containing an inorganic solvent containing water via crystallization or recrystallization. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Other NK3 antagonists, such as R113281, N10A, N5A1, SR-142801, 20 SSR-I46977, Cam 2425 and MDL-1052l2, pharmaceutically acceptable derivatives

Objects include, as appropriate, those disclosed in W099 / 36424, WOOO / 39114, W095 / 28931, W096 / 05203, EP776893, W098 / 54191, EP673928, WO 舛 / 26735, and WO97 / 10229. The compound of the method of the present invention, such as compound ⑴, is used as the NK3 receptor coffin. -13- The size of this paper applies to China National Standard (CNS) A4 (210x297 mm) 1243678 A7 B7

It has been shown to be useful in treating some immediate symptoms, especially for the purposes of this article. Relevant tests include the activity of an anti-agent 'in standard trials. The clinically-disclosed symptoms characterized by hyperstimulation of kallikrein receptors are effective treatments including those disclosed herein. ^ In this article, "Symptoms characterized by altered bowel function" include the main irritating bowel syndrome, constipation. The main irritating bowel syndrome, paternal replacement irritant syndrome, Wei Xinglai, constipation The functional system includes diarrhea-the system includes constipation-the system includes alternating thorns including other bowels. In particular, it is characterized by changes in bowel function. 10 Major irritating bowel symptoms. / Specifically, the symptoms characterized by changes in bowel function are mainly Irritation bowel syndrome. Symptoms characterized by altered bowel function. 15 Symptoms characterized by altered bowel function. As used herein, "other bowel symptoms, The department includes presentations-some employees of the Intellectual Property Bureau of the Ministry of Economic Affairs have printed symptoms such as M, emergency, inflation, incomplete Wei and nervousness, especially emergency, inflation, incomplete exhaust and nervousness. The present invention also provides a method for treating or preventing a symptom characterized by changes in bowel function and / or visceral pain in a human or non-human mammal, the method comprising administering an effective, non-toxic and pharmaceutically An acceptable amount of an NK antagonist, such as compound (I) or a pharmaceutically acceptable derivative thereof. The present invention also provides an NK3 antagonist, such as compound ① or a pharmaceutically acceptable derivative thereof.

1243678 Derivatives accepted for use in the treatment and / or symptoms of visceral pain. / Protect to change intestinal function and also provide NK3 antagonists, such as the use of compound 药学 or its pharmaceutically acceptable derivative II in the manufacture of medicaments, which are used for treatment and / or prevention to change intestinal function and / Or visceral pain. Symptoms characterized by altered bowel function and / or visceral pain are appropriately selected from certain irritating bowel signs / cluster symptoms, functional bloating, functional constipation, functional diarrhea, other bowel symptoms, and functional abdominal pain . 10 15 The present invention further provides a pharmaceutical composition comprising a NK3 antagonist, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable Accepted vehicle for the treatment and / or prevention of symptoms characterized by altered bowel function and / or visceral pain, wherein the symptoms characterized by altered bowel function and / or visceral pain are appropriately selected from certain stimuli Symptoms of bowel syndrome, functional bloating, functional constipation, functional diarrhea, other bowel symptoms, and functional abdominal pain. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, such pharmaceuticals and compositions of the present invention can be prepared by mixing the compounds of the present invention and an appropriate carrier. It may conventionally contain diluents, binders, fillers, disintegrating agents, flavoring agents, coloring agents, lubricants or preservatives. These conventional excipients can be used, for example, when preparing known pharmaceutical compositions for treating such conditions. The pharmaceutical composition of the present invention is preferably in a unit dosage form, and in a form suitable for use in the field of medicine or to be treated. For example, 'the preparation may be in the form of a tape, accompanied by written or printed instructions for use as a therapeutic agent for symptoms. 15- This paper size is applicable to China National Standard (CNS) A4 (210x297 mm) [243678

V. Description of the invention (14) In the present, the proper dosage range of the compound is the compound to be used depending on the intended disease. It also depends on, inter alia, the effect of the drug on the absorbable system, and the frequency and route of vomiting. Odd, == or the composition can be formulated to be administered by any means. Qiaodan ^ / \ Dosage form, or in the form of a single-knowledgeable form for human patients. This composition can be advantageously used for oral, rectal, :: diparenteral, intravenous or intramuscular administration. The formulation releases the active ingredient slowly. 15 15 printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs =: present! 1 such as tablets, capsules, sachets, vials 'powder,': reconstitutable powder, or liquid preparations, such as In the form of a solution or suspension 'or suppository. f If, for example, suitable for oral administration, 'may contain conventional excipients,-: =, such as ", acacia, gelatin, anthocyanin, zeaxanthin; fillers such as sugar or polyethylene, such as lactose, sugar, corn : Sodium glycolate or microcrystalline cellulose; or pharmaceutically; such as sodium lauryl sulfate. The solid composition can be obtained by blending, filling, tabletting or blending. The recombination operation can be used to distribute the active material throughout the composition of the material. When the composition is in the form of a tablet, powder, or bond, it can be used in any carrier suitable for formulating a solid pharmaceutical composition, and its examples are stearin, powder, glucose, lactose, gluten, flour And ^ chalk. The tablets can be coated according to the methods known to general medical practice, especially -16-this paper size applies the Chinese National Standard (CNS) A4 specification (21 × X 297 mm) Α7 Β7 printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Manufacturing 1243678 V. Description of the invention (15) Use of enteric-coated and widely-coated. This composition can also be in the form of a edible gelatin, such as gelatin containing the compound, and if necessary, a carrier or other excipient. Compositions for administration in liquid form may be in the form of, for example, emulsions, polysaccharides, or elixirs, or may be in the form of dry products and reconstituted with water 5 or other appropriate vehicle before use. Such liquid compositions may contain conventional additives such as suspending agents such as anthocyanin, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose Λ aluminum stearate gel, hydrogenated edible Fats; emulsifiers, such as phospholipids, calycosin monooleate or gum arabic, aqueous or sticky aqueous vehicles, including edible oils, such as almond 10 oil, fractionated coconut oil, oily esters, such as Esters of glycerol, or propylene glycol or ethanol, glycerol, water, or regular salt solutions; preservatives, such as p-hydroxybenzoic acid methyl ester or propyl vinegar, or acetic acid; and, if necessary, conventional flavoring or coloring agents. The active compounds of the present invention can also be administered by a non-II cavity route. According to Example 5, the medicine composition can be used as a suppository for rectal medicine. It can also be formulated to be injectable, in aqueous or non-aqueous solvents, suspensions or emulsions, in pharmaceutically acceptable liquids, such as bacteria, pyrogen-free water, or parenterally. Acceptable oil or liquid mixture. This liquid may contain bacteriostatic agents, antioxidants or other preservatives, buffers or solutes to render the solution isotonic with blood, thickeners, suspending agents or other pharmaceutically acceptable additives. This form is presented in units &amp; quantities, such as ampoules or disposable injection devices, or in multiple doses, such as a bottle from which an appropriate dose can be taken, or a solid that can be used to prepare an injectable formula Form or concentrate.

A7 B7 1243678 V. Description of the invention (16) The active compound of the present invention can also be administered by inhalation through the nose or oral route. Such administration can be carried out in a spray formulation comprising the compound of the invention and a suitable carrier, optionally suspended in, for example, a hydrocarbon propellant. The preferred spray formulation contains micronized compound particles and uses a surfactant, solvent or dispersant in combination to prevent the suspended particles from settling. The compound particle size is preferably about 2 to 10 m. -... Another mode of administration of the active compounds of the present invention involves transdermal delivery using a skin patch formulation. A preferred formulation comprises the compound of the present invention, dispersed in a pressure sensitive adhesive, which adheres to the skin, so that the compound is allowed to diffuse from the adhesive through the skin for transmission to the patient. To provide a constant rate of percutaneous absorption, pressure-sensitive adhesives known in the art can be used, such as natural rubber or silicone. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs As mentioned above, the effective dose of a compound depends on the specific compound used, the symptoms of the patient, and the frequency and route of administration. Unit doses usually contain 20 to 1000 mg, and preferably 30 to 500 mg, especially 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg. This composition can be administered one or more times a day, such as two, three, or four times a day, and the total daily dose to a 70 kg adult is usually in the range of 100 to 3000 mg. Alternatively, this unit dose contains 2 to 20 mg of the active ingredient, and if necessary, 20 doses are administered multiple times to obtain the aforementioned dose. Dosages and formulations of specific NK3 antagonists include those disclosed in the aforementioned patent applications. The compounds of the method of the present invention are expected to have no unacceptable toxicological effects when administered according to the present invention. -18- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) A7 B7 1243678 V. Description of the invention (17) The activity of the compounds of the present invention as nk3 ligands is marked by its inhibition of radiation The ability of the NK3 ligand [1 2 51] [Me_phe7] · NKB or [3 Senktide to bind to guinea pigs and human Nκ3 receptors was measured (Renzetti et al., 1991, Neuropeptide, 18, 104- 114; Buell et al., 1992, 5 FEBS, 299 (1), 90-95; Chung et al., 1994, Biochem. Biophys. Res. Commun., 198 (3), 967-972). The binding assay used Allows the determination of the concentration of individual compounds required to reduce I: 1 2 51]-[Me-Phe7] _NKB and [3 H] -senceptide to the NK3 receptor by 50% in equilibrium, the required concentration of individual compounds (IC50 ). The combined test provides an average IC5G value of 2.5 individual experiments performed in two or three replicates for each of the 10 compounds tested. The most effective compound of the present invention showed an IC50 value in the range of l-iooonM; specifically, in the guinea pig cortex, by replacing [3H] -senceptide, the compounds of Examples 22, 47, 48, and 85 showed Ki (nM) are 5.6, 8-8, 12.0, and 4 · 8 (η = 3). The activity of the NK3 antagonist of the compound of the present invention 15 was printed by guinea pig ileum caused by the inhibition of senile peptide by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs (Maggi et al., 1990, Br · J · Pharmacol ·, 101,996- 1000) Contraction with isolated rabbit iris sphincter (Hall et al., 1991, Enr. J. Pharmacol "199, 9-14) and Ca ++ movement mediated by human NK3 receptors (Mochizuki et al., 1994, J. Biol. Chem ·, 269, 9651-9658) and measured 20. In vitro functional testing of guinea pigs and rabbits provides an average KB value of 3-8 individual experiments for each tested compound, where Kb is in The concentration of gram peptide in the response curve required to produce a 2-fold shift to the right of individual compounds. Human receptor functional testing allows the determination to reduce the C a + + movement caused by the activator NKB by 50% Requires the concentration of individual compounds-19- This paper size applies the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1243678 V. Description of the invention (18) value. In this test, the compounds of the present invention performed as It ’s like being completely in The general points are given here. The therapeutic potential of the substance in the treatment of the symptoms mentioned above can be evaluated by using the disease model of beer teeth. The attached month is explained by the following experimental data. Non-limiting. The following is a brief description of the drawings referred to below: Figure 1: Shows that the ascending stimulating nerve reflex is inhibited by the compound ①. The 15 compound is shown in the ovalbumin sensitization mode 'compound ① for the intellectual property of the small intestine economy Bureau Consumer Consumption Cooperative Seal System [::: showing compound ⑴ on the colorectal sensitivity and stress test results of rats 20 Compound (I) cannot affect normal gastrointestinal motility. When measured using the phenol red method, the compound ⑴ At oral doses of ls and 刈 mg / kg, gastric emptying of rats will not produce = or statistically significant immortals. The high-dose second-line used in this research towel is similar to intestinal anti-nociceptive injury Active (see below) and: Compound 20- A7 B7 1243678 V. Description of the invention (19) ⑴ Low affinity for NK-3 receptors in rats, compared to human or guinea pig variants of this receptor It has a higher affinity. Comparatively speaking, the reference standard, morphine sulfate, administered orally at 20 mg / kg produced a significant and statistically significant reduction in gastric emptying (see 5 (See Table 1). This effect is expected and confirms the effectiveness of this test system. Table 1: In rats, after compound (I), morphine sulfate, phenol red, and only vehicle administration, the stomach Ratio of emptying effect Oral therapeutic dose (mg / kg)% gastric emptying 1 phenol red only-0.0 2 vehicle-60.6 3 compound (I) 5 55.2 4 compound (I) 15 50.7 5 compound (I) 50 62.4 6 Morphine Sulfate 20 30.8 ** Significance of the difference from the vehicle treatment group: ** p &lt; 0.01 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs at the doses of 10 (5), 15 and 50 mg / kg of compound (I) Oral administration, when measured using the charcoal powder test, did not produce a significant or statistically significant effect on gastrointestinal motility in rats. Therefore, in each compound (I) -treatment group, the distance traveled by the charcoal powder was a similar vehicle treatment group at each test dose. In comparison, morphine sulfate at a 15 mg oral dose of 10 mg / kg produced a significant and statistically significant reduction in gastrointestinal motility compared with the vehicle-treated group (see Table 2). This effect was expected and confirmed the effectiveness of this test system. -21-This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) A7 B7 1243678 V. Description of the invention (20) Table 2: Compound (I) 'morphine sulfuric acid odor when measured by carbon powder The effect of __ agent on gastrointestinal motility in rats is the same as that of paper and media groups. "Quote" (mg / kg) average distance between groups ^ Physically expressed as total intestinal length%% SD Vehicle-53.0 ± 7.6 2 Compound (I) 5 46.9 ± 5 · 3 3 Compound (I) 15 52.1 ± 7.1 4 Compound (I) 50 50.4 ± 8.6 5 Sulfate 10 37.4 ± 12 &gt; SD = = Standard Statistical significance of deviation and difference of vehicle treatment group: ** p &lt; 0.01 ^: variation

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5 Slow EPSP in guinea pig intestinal neurons was inhibited by compound ①. Compound (I) was used to analyze the four types of neurons to determine their effects on the printing of the Ministry of Economic Affairs and Intellectual Property Bureau of the Ministry of Economic Affairs. Slow EPSP is induced by high-frequency (20 Hz) electrical stimulation applied to the internode strands connected to the two ganglia of the ganglia for 1 second. Baseline EPSP was obtained, and once it subsided, compound 10 at a concentration of 0.01 μM was perfused through the formulation. It was continuously perfused and tested at different intervals, PSP. Once this drug has been circulated for at least 30. Min., When compared with the baseline =, in all four types of neurons, the peak amplitude of depolarization decreases by more than 50%. In a neuron, there is 100% blocking, and it is even For stimulation, the inhibitory proliferative possibility (IPSP) is shown. The other two I5 neurons, based on the amplitude of depolarization, show a _% blockage. Two of these neuron lines are filled with biological cells And combined with streptavidin-22- This paper is applicable to Zhongguan ^ (CNS) A4 specification (21Gx297) ---- ----- A7 B7 1243678 V. Description of the invention (21) Acid and Texas Red (TexasRed) reaction, showing dogel type II morphology on fluorescence microscopy. The reflex activity caused by stretching in the guinea pig isolated colon is suppressed by compound (I) Printed by the Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs 5 For reflection studies, make 5-7 cm The colon is suspended in warm, oxidized physiological saline, so an 8 mm metal rod can be inserted into the lumen, and connected to the pulley system through a wire passing through the intestinal wall, which allows the rod to be pulled by different weights at noon. Block, and expand the intestine. Connect the force sensor to the colon wall with a small wire wire 5 mm on either side of the expansion rod. Use 6, 12, 10, or 20 grams of weight to expand the colon wall, causing rhythm. The contraction acts on the dilated mouth and small relaxation on the anal side. The application of weights of 12 and 20 grams causes a similar pattern of movement, and although the small relaxation on the dilated anal side seems to be more clear, the mouth The stimulus response is not different from the effect of 6 grams of weight. Compound (I) is applied at 25 nM for 30 to 45 minutes, which will reduce the expansion effect in a roughly 15-dependent manner, among which these effects are at a higher expansion. The degree is larger (see the figure below). These data indicate that the antagonism of the NA receptor of compound ① will reduce the up and down caused by dilation = radiation. Because of the effect of compound ⑴ on intestinal reflex, Higher expansion The tensile weight is clearer, so the nk3 receptor and therefore the slow 20t component of the deleted activity can be involved to a greater extent in the use of strong and possibly pathological stimuli = reflections. "Day" is 彳 田 料The figure below shows the change in the ± line stimulus reflection. ^ The area measurement under the curve is expressed in grams • seconds. It is caused by the expansion of 6, η, or g. -A7 B7 1243678 V. Description of the invention (22) After loss. In the small intestine of rats, sensitization by Chinese and Indian albumin increases inhibition by compound (I). Summary and conclusion For the first time, it has been confirmed that compound ⑴15 mg / kg oral Nk3 Antagonism by 5-somes inhibits the increase in passage time of small intestine in rats induced by ovalbumin challenge. These data strongly support the involvement of NK: 3 receptors in pathological (rain-physiological) changes in bowel function. Objective: The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed an increase in the small intestine passage of Dabai 10 mice caused by sensitization to ovalbumin immunostimulation. It has been previously used to confirm the 5-HT3 receptor antagonist alothedon ( alosetron) ability to normalize perturbation patterns of intestinal passage (Clayton NM. Sargent R. Butler A. Gale J. Maxwell MP. Hunt AA. Barre tt VJ. Cambridge D. Bountra C. Humphrey PR, novel selective 5-HT3 The pharmacological properties of the receptor antagonist alothedon and its effect on 15 normal and perturbed small intestine passage in fasting rats, Neurogastroenterology &amp; Motility. 11 (3): 207-17, June 1999) . Significance in giving data on alodon, and possible interactions between the gut and these excitations in the NK3 receptor (Gay J, Fioramonti J, Garcia-Villar R, Edmonds-Alt X, Bueno L (1999) Gut, 44, 497-503) In both cases, the effect of compound (I) was studied in this model. Results Compound (1) was orally administered at 15 mg / kg and did not significantly affect the small intestine in normal unsensitized animals (see Figure 2 below). However, in the ovalbumin sensitization mode, it passed and increased after ovalbumin sensitization. -24- This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) A7 B7 1243678 V. Description of the invention (23 ), Which was greatly inhibited due to oral pretreatment with compound ⑴ 15 mg / kg (see Figure 3). Discussion These data are the first time that compound (I) has been used to confirm that the intestinal motility of the NK3 receptor is not involved in the 5 normal type. This receptor can have significant functions in the activity of the vector-disrupted type. Furthermore, these data and the use of this model now enable the significance of these data obtained in vitro (confirmed that the NK3 receptor is involved in the slow EPSP activity of IPAN; confirm that NK3 receptor activation in human isolated colons, The ability to inhibit non-cholinergic nerve activity is correlated with intestinal pathological diseases in vivo. Intestinal nociception is inhibited by compound (I) In conscious rats, compound ⑴50 mg / kg is administered orally. It has significant anti-nociceptive effects during the expansion of the colorectal region at 30, 45 and 60 mm Hg Without affecting the colorectal tension by 15 degrees (see Figure 4 below). Compound ⑴ 30 mg / kg was orally administered in a similar manner, but these effects were statistically significant only at the highest diastolic pressure. The lowest compound ⑴ dose tested (10 mg / kg orally) did not have antinociceptive activity. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. These data show that selective NK-3 receptor antagonism can reduce bowel sensitivity to harmful 20 expansion effects. -25- This paper size applies to China National Standard (CNS) A4 (210x297 mm)

Claims (1)

1243678 Patent Application: Patent Application No. 91110318 ^ ROCPatent Appln. No.91110318 Amended Claims in Chinese-EncLffl (Unsubmitted on July 9, 1993) (Submitted on July) (2004) 10 15 20 1. A pharmaceutical composition for treating and / or preventing symptoms characterized by altered bowel function and / or visceral pain in a human or non-human mammal, which comprises an effective, non-toxic and pharmaceutically An acceptable amount of fluorene-N- (α-ethylamyl) -3-acryl · 2 · phenylphosphonium-4-carboxamide (compound IX) or a pharmaceutically acceptable salt or solvate thereof. 2. The pharmaceutical composition according to item 丨 of the scope of the patent application, wherein the symptoms characterized by altered intestinal function and / or visceral pain are selected from certain irritating bowel syndrome symptoms, functional abdominal distension, functional constipation, Functional diarrhea, other bowel symptoms, and functional abdominal pain. 3. The pharmaceutical composition according to item 1 of the scope of patent application, which is used to treat and / or prevent symptoms characterized by altered bowel function. 4_ The pharmaceutical composition according to item 2 of the scope of the patent application, wherein the irritating bowel cluster symptom is diarrhea-the main irritating bowel cluster. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 public copy) 91201B- 接