JPH08512038A - Uses of phenethanolamine derivatives for the treatment of gastrointestinal disorders - Google Patents

Abstract

(57) [Summary] Compound of the following formula (I): (In the above formula, R ⁰ is a hydrogen atom, methyl or hydroxymethyl, R ¹ is a substituted alkyl, R ² and R ³ are each hydrogen, halogen, hydroxy, alkoxy, carboxy, alkoxycarbonyl, alkyl, nitro, haloalkyl. Group or substituted alkyl, X is oxygen or sulfur, and Ar is optionally substituted phenyl or naphthyl) and its pharmaceutically acceptable salts for use in the treatment of gastrointestinal disorders.

Description

Detailed Description of the Invention          Uses of phenethanolamine derivatives for the treatment of gastrointestinal disorders   The present invention relates to novel medical uses of certain phenethanolamine derivatives and their inclusion. To a pharmaceutical composition having. In particular, the present invention relates to atypical β-adrenoceptor (β- This also acts as an agonist in (also known as the 3-adrenoceptor) It relates to the use of such compounds. Such receptors are described, for example, by J.R.S.Arch et al. ., Nature, 309,163-165 (1984); C. Wilson et al., Eur.J.Pharmacol., 100,309-3 19 (1984); L.J.Emorine et al., Science, 245,1118-1121 (1989); A. Bianchett i et al., Br. J. Pharmacol., 100, 831-839 (1990).   The atypical .BETA.-adrenoceptor is an adrenergic and noradrenergic hormone. Belong to the adrenoceptor family that mediates the physiological actions of. Adrenocceptor α₁‐ 、 α₂-, Β₁-, Β₂-And β₃-(Atypical) subtypes are their pharmacological properties And can be specified based on physiological effects. These receptors (β₃Since Chemical agents that stimulate or block (external) are widely used in clinical medicine. More recently In order to reduce side effects that are partly due to interactions with other receptors, Emphasis was placed on specific receptor selectivity.   Atypical .BETA.-adrenoceptor is known to be present in adipose tissue and gastrointestinal tract ing. Compounds that act as agonists at atypical β-adrenoceptors are standard Identified using trials (see, eg, C. Wilson et al., Supra).   A particular class of phenetanolamine compounds is disclosed in European Patent Specification No. 0 543 6. 62-A, in which the compound of the following general formula (I) and its drug Describes academically acceptable salts. [In the above formula   R⁰Is a hydrogen atom, a methyl group or a hydroxymethyl group,   R¹Is the substitution C_1-12An alkyl group, which is substituted with at least one of the following substituents A It is)   R²And R³Is a hydrogen atom, halogen atom, hydroxyl group, C_1-5Arco Xy, carboxy, C_2-7Alkoxycarbonyl group, C_1-5Alkyl group, nit B group, halo C_1-4Alkyl group or substituted C_1-12Alkyl groups (at least 1 Substituted with one of the following substituents A),   X is an oxygen atom or a sulfur atom,   Ar is a group of the following formula (C) or (D): (In the above formula:   R^FourIs a hydrogen atom, a halogen atom, a hydroxy group, a hydroxymethyl group, C_1-5A Lucoxy group, C_1-5Alkyl group, aliphatic carboxylic acid C_1-6Acyloxy group, nitro Group, cyano group, aralkyloxy group (aralkyl part is as follows), Aryloxy groups (where the aryl part is as follows), aryl groups Or halo C_1-4Is an alkyl group,   R^FiveIs a hydrogen atom, a halogen atom, a hydroxy group, C_1-5Alkoxy group, C_1-5 An alkyl group or a nitro group,   R⁶Is a hydrogen atom, a halogen atom, a hydroxy group, C_1-5Alkoxy group or C_{1- Five} Is an alkyl group),   The above aralkyl part is C_1-3Alkyl group (The group is 1 or 2 as follows. Substituted with the aryl group of),   The aryl group is unsubstituted or substituted with at least one of the following substituents B Carbocyclic C_6-10An aryl group,   The substituent A is a carboxy group, C_2-7Alkoxycarbonyl group, aryloxy Cycarbonyl group (aryl part is as above), aralkyloxycal Bonyl group (aralkyl part is as described above), C_1-6Alkyl carbamoy Group, dialkylcarbamoyl group (each alkyl moiety having 1 to 4 carbon atoms ), Carbamoyl group, hydroxycarbamoyl group, hydroxy group, 1-6 Carboxylic acid acyloxy groups having carbon atoms and 2,4-dioxothiazolidi Selected from the group n-5-yl,   The substituent B is a halogen atom, C_1-4Alkyl group, C_1-3Alkoxy group, nitro Group, halo C_1-4Selected from an alkyl group and a hydroxy group]   These compounds are associated with diabetes, obesity, hyperlipidemia, hyperglycemia, complications of diabetes, obesity It is said to be useful in the treatment or prevention of related hypertension and osteoporosis.   In general, atypical β-adrenoceptor agonists are febrile antiobesity agents and antidiabetic agents. It has been found to be particularly useful as a disease agent. Atypical β-adrenoceptor agonist Compounds with activity include animal growth promoters, platelet aggregation inhibitors, positive muscle inotropic agents and And as an anti-atherosclerotic agent, it is useful for treating hyperglycemia and It is also described to be useful in therapy.   The compounds of general formula (I) that act as agonists at atypical β-adrenoceptors are Gastrointestinal disorders, especially peptic ulcer, esophagitis, gastritis and duodenitis (caused by H. pylori Intestinal ulcer (including inflammatory bowel disease, especially ulcerative colitis, ileitis, clones) Diseases and proctitis), and gastrointestinal ulcers, especially non-steroidal anti-inflammatory drugs (NS) AID) or treatment of inflammatory gastrointestinal disorders including those caused by corticosteroids It was found to be useful for medical treatment.   A preferred subclass of compounds of general formula (I) for use according to the invention are compounds of formula (I Compounds defined in I): And physiologically acceptable salts and solvates thereof, R in the above formula¹¹And R¹²One of them represents a hydrogen atom, R¹¹And R¹²Other out of One is group -CH₂CO₂Represents H, R¹⁴Is a chlorine, fluorine or bromine atom or methyl Or a trifluoromethyl group.   It will be clear that the above compounds of formulas (I) and (II) are optically active. The use of both the individual isolated isomers and mixtures thereof, including the racemates, Is considered to belong within the range of. Particularly preferred formula (I) for use according to the invention The compounds of and (II) are -CH (OH)-groups and -CH (CH₃) -Unbased This is the case where the asymmetric carbon atom has the (R) configuration.   Another preferred group of compounds of formula (II) is R¹¹Is based on -CH₂CO₂Represents H This is the case.   Particularly preferred compounds of general formula (I) for use according to the invention are: (R, R)-[4- [2- [2- (3-chlorophenyl) -2-hydroxyethyl] Lumino] propoxy] phenyl] acetic acid Alternatively, it is a physiologically acceptable salt or solvate thereof.   Suitable physiologically acceptable salts of the compounds of general formula (I) are hydrochloride, hydrobromide Acid salt, sulfate, phosphate, benzoate, naphthoate, hydroxynaphthoate , P-toluenesulfonate, methanesulfonate, sulfamate, Asco Rubate, tartrate, citrate, oxalate, maleate, salicylate , Fumarate, succinate, lactate, glutarate, glutaconate, acetate or Or acid addition salts derived from inorganic and organic acids, such as tricarballylate is there. The compound may form a salt with a suitable base. For example of such salt Is an alkali metal (eg sodium or potassium), alkaline earth metal (eg (Eg calcium or magnesium), ammonium and substituted ammonium There is.   For pharmaceutical use, the above salts are physiologically acceptable, but other salts are also possible, for example It may be useful in the preparation of compounds of general formula (I) and their physiologically acceptable salts. Would be clear.   The present invention relates to peptic ulcer, esophagitis, gastritis, duodenitis, intestinal ulcer and gastrointestinal ulcer. Of human or non-human mammals with or susceptible to inflammatory gastrointestinal disorders such as There is provided a method of treatment, which comprises the compound of general formula (I) or its physiological Comprising administering to said mammal an effective amount of an acceptable salt or solvate. The one.   In a preferred aspect of the present invention, the symptoms are ulcerative colitis, ileitis, Crohn's disease or Is a human or non-human subject with intestinal ulcer, which is an inflammatory bowel disease such as proctitis There is provided a method of treating a mammal, which comprises a compound of general formula (I) or An effective amount of its physiologically acceptable salt or solvate may be administered to the mammal. And including and.   In a particularly preferred aspect of the invention, the symptoms result from a non-steroidal anti-inflammatory drug A method for treating a human or non-human mammal suffering from gastrointestinal ulcer is provided. , The method comprises the compound of general formula (I) or a physiologically acceptable salt or solvent thereof. It comprises administering to the mammal an effective amount of a Japanese product.   References in this specification to treatment not only relate to the relief of symptoms, but also to prophylactic treatment. Reach   In another aspect, the present invention relates to peptic ulcer, esophagitis, gastritis, duodenitis, intestinal ulcer. And for the treatment of inflammatory gastrointestinal disorders such as gastrointestinal ulcers, especially for human medicine , A compound of the general formula (I) or a physiologically acceptable salt or solvate thereof A therapeutic agent comprising an effective amount is provided.   In another preferred aspect of the invention, the symptoms are ulcerative colitis, ileitis, Crohn's disease. Or for the treatment of the symptoms of intestinal ulcer, which is an inflammatory bowel disease such as proctitis, the general formula (I ) Or a physiologically acceptable salt or solvate thereof. A therapeutic agent is provided.   In another particularly preferred aspect of the invention, the condition is due to a non-steroidal anti-inflammatory drug. For the treatment of gastrointestinal ulcer symptoms There is provided a therapeutic agent comprising an effective amount of a salt or solvate included.   In yet another aspect, the invention provides peptic ulcer, gastritis, duodenitis, intestinal ulcer and For the manufacture of a medicament for the treatment of inflammatory gastrointestinal disorders such as gastrointestinal ulcer, of the general formula (I) The use of a compound or a physiologically acceptable salt or solvate thereof is provided.   In yet another preferred aspect of the invention, the symptoms are ulcerative colitis, ileitis, claws. Manufacture of a drug for treating the symptoms of intestinal ulcer, which is an inflammatory bowel disease such as Alzheimer's disease or proctitis Relating to the compound of general formula (I) or a physiologically acceptable salt or solvent thereof Uses of Japanese food are provided.   In yet another particularly preferred aspect of the invention, the symptoms are non-steroidal anti-inflammatory agents. A compound of general formula (I) for the manufacture of a medicament for the treatment of gastrointestinal ulcer symptoms. Or, the use of its physiologically acceptable salt or solvate is provided.   Compounds of general formula (I) or physiologically acceptable salts or solvates thereof Used to treat the symptoms of gastrointestinal ulcer caused by steroidal anti-inflammatory drug (NSAID) If this is the case, it is preferred to co-administer the compound of general formula (I) with the NSAID. The truth is clear. The active ingredients may be used in the form of separate pharmaceutical formulations, or It may be used in a combination formulation. In such a combination formulation, of course, the active ingredients are It must be stable and compatible with each other in the particular formulation being made.   At least one compound of general formula (I) or a physiologically acceptable salt thereof, or Is a solvate and at least one non-steroidal anti-inflammatory drug and at least one physiological agent. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient is a novel composition. Are considered physical and form another aspect of the invention.   Similar combination prescriptions are also useful in treating gastrointestinal ulcer symptoms caused by corticosteroids. It will be clear that you can use it.   Compounds of general formula (I) and their physiologically acceptable salts and solvates While formulated for administration in any otherwise preferred manner, the invention is within the scope of Is at least one compound of general formula (I) or its physiology adapted for veterinary use Also included are pharmaceutical compositions comprising a pharmaceutically acceptable salt or solvate. this Such compositions are preferably combined with one or more physiologically acceptable carriers or excipients. Provided for use in a better way. The carrier or excipient is another component of the formulation. Must be “acceptable” in the sense of being compatible with and not harmful to its recipients.   For this reason, compounds for use according to the invention may be oral, oral, parenteral, rectal or Is formulated for transdermal administration or by inhalation or insufflation (from mouth or nose) It may take any form suitable for administration.   For oral administration, the pharmaceutical composition may include a binder (eg, pregelatinized maize starch). , Polyvinylpyrrolidone or hydroxypropylmethylcellulose), filler -(Eg lactose, microcrystalline cellulose or calcium hydrogen phosphate), smooth Swamp Agents (eg magnesium stearate, talc or silica), disintegrants (eg. For example, potato starch or sodium starch glycolate) or wetting agents (eg Conventional means with pharmaceutically acceptable excipients such as sodium lauryl sulphate). It can take the form of, for example, a tablet or capsule. Tablets It may be coated by methods well known in the art. Liquid formulations for oral administration are eg In the form of liquids, syrups or suspensions, or they are It may be provided as a dry formulation prepared in any other suitable vehicle. Liquid like this Body preparations are suspensions (eg sorbitol syrup, cellulose derivatives or hydrogen). Supplementary edible fats), emulsifiers (eg lecithin or gum arabic), non-aqueous vehicles Kuru (eg almond oil, oily esters, ethyl alcohol or edibles) Oils) and preservatives (eg methyl or propyl p-hydroxybenzoate, Manufactured by conventional means with a pharmaceutically acceptable additive such as sodium sorbate). Be done. The formulation may optionally contain buffer salts, flavoring agents, coloring agents and sweetening agents. .   Formulations for oral administration should be suitably formulated to give controlled release of the active compound. Good.   For buccal administration, the compositions take the form of tablets or lozenges formulated in conventional manner. .   The compounds for use according to the invention may be injected, eg by bolus injection or continuous infusion. May be formulated for parenteral administration according to. Injectable formulations may be, for example, ampoules or Served as a unit dosage form in a multi-dose container, a preservative is added. The composition is oily Or in the form of a suspension, solution or emulsion in an aqueous vehicle. Alternatively, it may contain formulation agents such as suspending, stabilizing and / or dispersing agents. on the other hand, The active ingredient is prepared in a suitable vehicle, eg sterile pyrogen-free water, before use It may be in a powder form.   Compounds for use according to the invention may be, for example, cocoa butter or other glycerides. Transrectal compositions such as suppositories or retention enemas, containing such conventional suppository bases May be prescribed to.   In addition to the formulations described previously, the compounds may be formulated as a depot preparation. Such a long term The active formulation may be implanted (eg subcutaneously, transdermally or intramuscularly) or by intramuscular injection. Be administered. Thus, for example, compounds intended for use according to the invention are Limers or hydrophobic substances (eg as an emulsion in an acceptable oil). Or with an ion exchange resin or as a sparingly soluble derivative, eg sparingly soluble salt To be done.   Suggested compounds for use according to the invention for human (body weight about 70 kg) administration The dose provided is the active ingredient per unit dose, expressed as the weight of the free base. It is 0.1 mg to 1 g, preferably 1 to 100 mg. The unit dose is, for example, 1 day ~ 4 times administered. The dose depends on the route of administration. Patient age and weight and treatment Routine changes in dosage may be necessary depending on the severity of the condition being treated. It will be obvious that no. The exact dose and route of administration will ultimately be determined by the attending physician. Or at the discretion of the veterinarian.   The compounds of general formula (I) for use according to the invention are derived from phenethanolamines. It is manufactured by several methods well known in the art for manufacturing the body. Appropriate The method is described, for example, in European Patent Specification 0 543 662-A.   The following non-limiting examples illustrate the synthesis of compounds of general formula (I) for use according to the invention. Is shown.   The temperature is ° C. Thin layer chromatography (T.l.c.) is unless otherwise noted SiO₂"Drying" is done in magnesium sulfate except where noted otherwise. With respect to drying.Intermediate 1 Methanesulfonic acid (R)-(2-benzyloxycarbonylamino) propyl ester Steal   (R) -1- (2-Hydride in dichloromethane (200 ml) maintained at -10 ° Of roxy-1-methylethyl) carbamic acid benzyl ester (14.95 g) Triethylamine (7.9 g) was added to the stirring solution, and then methanesulfonyl chloride was added. Lide (8.93 g) was added dropwise while maintaining the reaction temperature at -10 °. This reaction liquid Stir at temperature for 1.5 h, then concentrate under reduced pressure. Partition the residue between water and ethyl acetate Then, the aqueous phase was further extracted with ethyl acetate. Combine the organic extracts with N hydrochloric acid and carbonic acid. Wash successively with aqueous sodium hydrogen and saturated brine, dry, evaporate and The title compound (18.81 g) was obtained as a colorless solid and was used without purification. n.m.r. (CDCl₃): Δ 1.27 (d, 3H), 2.99 (s, 3H), 4. 07 (m, 1H), 4.16 (m, 1H), 4.27 (m, 1H), 4.86 ( brs, 1H), 5.11 (s, 2H), 7.3-7.4 (m, 5H)Intermediate 2 (R) -2- [4-[(2-benzyloxycarbonylamino) propoxy] phenyl [Ethenyl] acetamide   Dry sodium hydride (60% dispersion in oil, 2.86 g) under nitrogen atmosphere , N-Dimethylformamide (150 ml) in 4-hydroxyphenylacetamide Was carefully added to a stirred solution of dode (10.4 g). The mixture is stirred for 3 hours, then Intermediate 1 (18.77 g) solution was added and the mixture was heated at 60 ° for 3.5 hours and then allowed to ring. It was left for 72 hours at ambient temperature. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. I arranged it. The organic phase was separated, washed with water, dried and evaporated. Part of this residue (10 g) was chromatographed on silica with 10% methanol in chloroform. It was eluted. Concentration of the appropriate fractions gave the title compound (2 as a cream solid). ． 71 g, containing impurities) was obtained. n.m.r. (DMSO-d₆): Δ1.14 (d, 3H), 3.32 (s, 2H), 3.48 (m, 1H), 3.75-3.95 (m, 2H), 5.01 (s, 2H ) , 6.80-6.88 (m, 2H), 7.12-7.18 (m, 2H), 7.2 8-7.45 (m, 5H)Intermediate 3 (R) -2- [4- (2-amino-1-propoxy) phenyl] acetamide   Intermediate 2 (2.7 g) in methanol (230 ml), 10% palladium on charcoal (28 0 mg) and a suspension of dry ammonium formate (1.67 g) with stirring and nitrogen atmosphere. It was heated under reflux under air for 4 hours. The catalyst was filtered off and the filtrate was concentrated. The residue Subjected to silica chromatography, chloroform: methanol: 0.880 water. Elution with ammonium oxide (60: 10: 1). By evaporation of the appropriate fraction, Title compound as colorless solid (contaminated with 4-hydroxyphenylacetamide (1.51 g) was obtained. n.m.r. (DMSO-d₆+ D₂O): δ1.05 (d, 3H), 3.12 (m, 1H), 3.28 (s, 1H), 3.66-3.74 (m, 2H), 6.86 ( d, 2H), 7.15 (d, 2H)Intermediate 4 (R, R) -2- [4- [2- [2- (3-chlorophenyl) -2-hydroxy Ethylamino] propoxy] phenyl] acetamide   Intermediate 3 (1.4 g) and trimethylsilyl in dimethylsulfoxide (5 ml) A solution of luacetamide (0.95 g) was stirred under a nitrogen atmosphere for 2 hours and then ( R) -3-Chlorophenyloxirane (1.03 g) was added and the solution was added at 70 ° to 6 Maintained for days. Pour the solution into a mixture of 2N hydrochloric acid and ethyl acetate and separate the phases The aqueous phase was washed with ethyl acetate. Basify the aqueous phase and extract with ethyl acetate. It was The combined organic extracts are dried and evaporated and the residue is chromatographed on silica. And eluted with 10% methanol in chloroform. Concentration of appropriate fractions This gave the title compound (0.645 mg) as a colorless solid. m.p.122 -125 ° [Α^D] -16.1 ° (c0.4 MeOH) Actual measured value: C62.8; H6.5; N7.85% C₁₉H_{twenty three}ClN₂O₃Calculated value: C62.9; H6.4; N7.85%Example 1 (R, R)-[4- [2- [2- (3-chlorophenyl) -2-hydroxyethyl] Lumino] propoxy] phenyl] acetic acid   Intermediate 4 (490 mg) in 2N hydrochloric acid (14 ml) was heated under reflux for 70 minutes. Mixed The combined solution was cooled and evaporated. Dissolve the residue in water, filter the solution and freeze-dry the filtrate To give a cream solid (504 mg). Amberlit a solution of this solid in water Chromatograph on eXAD-2, eluting with aqueous ethanol. Appropriate The various fractions were combined, concentrated and lyophilized to give the title compound (1 47 mg) was obtained. Actual measured value: C60.1; H6.0; N3.95% C₁₉H_{twenty two}ClNO_Four・ H₂Calculated O: C59.8; H6.3; N3.7% n.m.r. (DMSO-d₆): Δ 1.10 (d, 3H), 2.81 (m, 2H), 3.12 (m, 1H), 3.50 (s, 2H), 3.85 (m, 2H), 4.6 9 (m, 1H), 6.87 (d, 2H), 7.16 (d, 2H), 7.27-7 ． 44 (m, 4H)   Atypical β-adrenoceptor agonist is mediated by atypical β-adrenoceptor A compound which exhibits a pharmacological response (in vitro or in vivo). This activity Resists blockade by standard .BETA.-adrenoceptor blockers, such as propranolol Response to lipolysis by rat adipocytes at submicromolar concentrations It has been measured as the ability to promote.   Another useful tool for identifying atypical β-adrenoceptor agonists is the Measurement of agonist activity in atypical .BETA.-adrenoceptor of the isolated lower esophagus of the rat . A suitable assay is described below as Method 1. Typically this asset In b, the compound of general formula (I) for use according to the invention is isoprenaline To have an equimolar molar ratio (EPMR) of 30 or less.   The rat esophageal assay is Ford et al., Br. J. Pharmacol., 105 (suppl.), 235P, 1992. The method is described below as Method 1. ItMethod 1   The lower esophagus is isolated from male AH / A rats (100-150 g). Attached The serosal muscle is removed from the esophagus, leaving the mucosal muscle plate. Then the tissue β₂-Antagonist ICI 118,551 (10^-6M), β₁-The antagonist atenolol (10^-FiveM) , Phosphodiesterase inhibitor isobutylmethylxanthine (IBMX, 3x1 0^-6M) and the prostaglandin synthesis inhibitor indomethacin (3 x 10^-6M) The tissue was suspended under a static tension of 0.5 g in a Kreb's solution containing   The tissue was then sub-maximally enriched with carbachol (10^-6M) shrinks to stabilize tension When the target increase is reached, a cumulative concentration-effect curve for isoprenaline is generated. new After washing with fresh Kreb's solution, the tissue was carbachol (10^-6Re-contract with M) and test A cumulative concentration effect curve for the agonist is generated.   Relative potency (EPMR) of each test agonist compared to isoprenaline as follows: Do: EC in the above₅₀Is an agonist that produces 50% of the maximum possible response for that agonist Is the molar concentration of.   Using the nonselective .BETA.-adrenoceptor agonist isoprenaline as a reference agonist When a compound is selective for the atypical β-adrenoceptor, it is preferably β₁- Or β₂-At least 30 to 30 times less adrenoceptor than isoprenaline Is effective, and more preferably β₁-Or β₂-Adrenaceptor isoprena It should be 300 to 1000 times less effective than phosphorus.   Atypical .BETA.-adrenoceptor agonist shown to be useful in the treatment of power-induced enema disorders The experimental model provided is described below as Method 2. Operation is H. Satoh et al., G based on the case described in astroenterology, 81, 719-725 (1981), where The effect of compounds on indomethacin-induced gastric sinus injury in refeeding rats was studied. Have been. Indomethacin is known as a non-steroidal anti-inflammatory drug (NSAID) Is an example of a class of compounds, the use of which is often associated with gastrointestinal ulcers.Method 2   Food (without water) was kept for 24 hours in female random-reared rats (70 to 120 g). After that, the rat is re-fed Rat and Mouse No. 1 Maintenance Diet. food One hour after being exposed to the test compound, the test compound or solvent (0.5% w / v in water) was added to the rat. Methylcellulose) is administered orally. After 30 minutes, indomethacin (60 mg / kg , 1% w / v NaHCO in salt water₃)) As a single subcutaneous injection in the back of the neck It The rats were then fed food but withhold water and the animals were cervical 6 hours after administration. Kill painlessly by partial dislocation. Control animals had one subcutaneous dose of appropriate vehicle Received   The stomach of the rat was removed (with a small amount of duodenum attached) and along a large curve By opening and washing the contents with 0.9% w / v sodium chloride solution (brine) Remove. Pin open stomach (top mucosal surface) to polystyrene mat, Examine the area of damage by placing a grid (consisting of 1 mm square) in the sinus area. Sinus loss The wound presents as a different black or dark brown ulcer. Then the entire area of the sinus injury is It is expressed as a percentage of the total surface area of the part.   The protective effect of test compounds on indomethacin-induced sinus injury was calculated using the formula Calculated as a percentage. result   One intravenous (i.v.) dose or oral (p.o.) 30 minutes before indomethacin Dosed as (R, R)-[4- [2- [2- (3-chlorophenyl)] Gastroprotection of 2-hydroxyethylamino] propoxy] phenyl] acetic acid (Example 1) The effect is shown by the following data: Tablets for oral administration   Tablets are manufactured by a conventional method such as direct compression or wet granulation.   The tablets should be appropriated using standard techniques, such as hydroxypropylmethylcellulose. It may be film-coated with a film-forming substance. On the other hand, the tablets may be sugar-coated.Direct compression tablets                                             mg / tablet (I) Active ingredient 4.688       Calcium hydrogen phosphate BP^*             83.06       Croscarmellose sodium NF 1.8       Magnesium stearate 0.45       Compressed weight 90.0 ^* A grade suitable for direct compression   Pass the active ingredient through a 60 mesh sieve, calcium hydrogen phosphate, croscarmello Blend with Sodium and Magnesium Stearate. Obtained Mick The tablets are compressed into tablets using a Manesty F3 tablet press equipped with a 5.5 mm flat beveled edge punch. It                                             mg / tablet (Ii) Active ingredient 0.31       Anhydrous lactose USNF 131.99       Pregelatinized starch USNF 7.0       Magnesium stearate BP 0.7       Compressed weight 140.0   Pass the active ingredient through a 60-mesh sieve, lactose, pregelatinized starch and Blend with magnesium stearate. The resulting mix is 7.5 mm standard concave Compress into tablets using a Manesty F3 tablet press equipped with punches.syrup   It may be sucrose-containing or non-sucrose-containing. A.Sucrose syrup            mg / 5ml dose     Active ingredient 2.5     Sucrose BP 2750.0     Glycerin BP 500.0     Buffering agent)     Flavoring agent) Required amount     Colorant)     Preservative)     Purified water BP 5.0 ml   Dissolve the active ingredient, buffering agents, flavoring agents, coloring agents and preservatives in a portion of the water and add glycerin. Add phosphorus. The remaining water is heated to dissolve the sucrose and then cooled. Two The two solutions are combined, adjusted to a predetermined volume, and mixed. Clarify syrup by filtration Turn into. B.No sucrose syrup                            mg / 5ml dose     Active ingredient 2.5     Hydroxypropyl methylcellulose USP 22.5       (Viscosity type 4000)     Buffering agent)     Flavoring agent)     Colorant) Required amount     Preservative)     Sweetener)     Purified water BP 5.0 ml   Disperse hydroxypropylmethylcellulose in hot water, cool, and then activate. Mix with the aqueous solution containing the ingredients and other ingredients. Adjust the volume of the resulting solution to the specified volume And mix. The syrup is clarified by filtration.Injection solution for intravenous administration                                             μg / ml (I) Active ingredient 800       Dilute hydrochloric acid BP up to pH 3.5       Sodium chloride injection water BP total volume 1 ml   The active ingredient is dissolved in an appropriate volume of sodium chloride water for injection BP and the solution obtained is The pH was adjusted to pH 3.5 with dilute hydrochloric acid BP, and then the solution was added with sodium chloride injection water B. Make a predetermined volume with P and mix well. 5ml ampoule of type I transparent glass And sealed under the air in the headspace by melting the glass, then 12 Sterilize by autoclaving at 0 ° for 15 minutes or more.                                         μg / ml (Ii) Active ingredient 56.2       Sodium chloride BP required       Water for Injection BP Total volume 1.0 ml   The tonicity of the solution may be adjusted by adding sodium chloride, and the pH may be acid or alkali. To achieve pH of maximum stability and / or to facilitate dissolution of the active ingredient. You may arrange. On the other hand, suitable buffer salts may also be used.   Melt the glass by preparing the solution, clarifying, filling in ampules of appropriate size Seal with. Injection solution is autoclaved using one of the allowed cycles Sterilize by heating at. On the other hand, the solution is sterilized by filtration and sterilized under aseptic conditions. It may be filled in the ampoule. Solution is an inert atmosphere of nitrogen or other suitable gas May be filled below.Suppository for rectal administration       Active ingredient 49.0mg       Witepsol^*H15 total amount 1.0g^* Adeps Solidus Ph. Eur. Proprietary grade   Make a suspension of the active ingredient in molten Witepsol and use a suitable machine to prepare 1g suppositories. Fill the mold.

[Procedure for Amendment] Patent Law Article 184-8 [Submission Date] April 13, 1995 [Amendment Content] 14. The use according to claim 13, wherein the compound of formula (I) or a physiologically acceptable salt or solvate thereof is selected from the compound of formula (II) below and physiologically acceptable salts and solvates thereof. . (In the above formula, one of R ¹¹ and R ¹² represents a hydrogen atom, the other of R ¹¹ and R ¹² represents a group —CH ₂ CO ₂ H, and R ¹⁴ represents a chlorine, fluorine or bromine atom, methyl or Represents a trifluoromethyl group) 15. R ¹¹ is -CH ₂ CO ₂ H, The use according to claim 14. 16. The compound of formula (I) is (R, R)-[4- [2- [2- (3-chlorophenyl) -2-hydroxyethylamino] propoxy] phenyl] acetic acid, any of claims 13-15. Use according to paragraph 1. 17． Use according to any one of claims 13 to 16, wherein the inflammatory gastrointestinal disorder is an inflammatory bowel disease selected from ulcerative colitis, ileitis, Crohn's disease and proctitis. 18. The use according to any one of claims 13 to 16, wherein the inflammatory gastrointestinal disorder is a symptom of gastrointestinal ulcer, and the symptom is caused by a nonsteroidal anti-inflammatory drug.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, M C, NL, PT, SE), OA (BF, BJ, CF, CG , CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AT, AU, BB, BG, BR, BY, CA, CH, CN, CZ, DE, DK, ES, FI, G B, GE, HU, JP, KE, KG, KP, KR, KZ , LK, LU, LV, MD, MG, MN, MW, NL, NO, NZ, PL, PT, RO, RU, SD, SE, S I, SK, TT, UA, US, UZ, VN (72) Inventors Foxton and Mikle Walter             Greensex, Middlesex, England             Road, Greenford, Road             Shi) Glaxo, Research, And, Di             Within Velopment, Limited (72) Inventor Hartley, Charles David             Greensex, Middlesex, England             Road, Greenford, Road             Shi) Glaxo, Research, And, Di             Within Velopment, Limited (72) Inventor Green, Richard Howard             Greensex, Middlesex, England             Road, Greenford, Road             Shi) Glaxo, Research, And, Di             Within Velopment, Limited (72) Inventor Traverse, Stuart             Greensex, Middlesex, England             Road, Greenford, Road             Shi) Glaxo, Research, And, Di             Within Velopment, Limited

Claims (1)

[Claims]   1. Human or non-human mammals with or susceptible to inflammatory gastrointestinal disorders A method of treating an object,   An effective amount of the compound of the following formula (I) and a pharmaceutically acceptable salt thereof for the above mammals , Or a physiologically acceptable salt or solvate thereof. How to do. [In the above formula,   R⁰Is a hydrogen atom, a methyl group or a hydroxymethyl group,   R¹Is the substitution C_1-12An alkyl group, which is substituted with at least one of the following substituents A It is)   R²And R³Is a hydrogen atom, halogen atom, hydroxyl group, C_1-5Arco Xy, carboxy, C_2-7Alkoxycarbonyl group, C_1-5Alkyl group, nit B group, halo C_1-4Alkyl group or substituted C_1-12Alkyl groups (at least 1 Substituted with one of the following substituents A),   X is an oxygen atom or a sulfur atom,   Ar is a group of the following formula (C) or (D): (In the above formula:   R^FourIs a hydrogen atom, a halogen atom, a hydroxy group, a hydroxymethyl group, C_1-5A Lucoxy group, C_1-5Alkyl group, aliphatic carboxylic acid C_1-6Acyloxy group, nitro Group, cyano group, aralkyloxy group (aralkyl part is as follows), Aryloxy groups (where the aryl portion is as follows), aryls such as Group or halo C_1-4Is an alkyl group,   R^FiveIs a hydrogen atom, a halogen atom, a hydroxy group, C_1-5Alkoxy group, C_1-5A Is a rualkyl group or a nitro group,   R⁶Is a hydrogen atom, a halogen atom, a hydroxy group, C_1-5Alkoxy group or C_{1- Five} Is an alkyl group),   The above aralkyl moiety is C substituted with one or two aryl groups as follows:_1-3 Is an alkyl group,   The aryl group is unsubstituted or substituted with at least one of the following substituents B Carbocyclic C_6-10An aryl group,   The substituent A is a carboxy group, C_2-7Alkoxycarbonyl group, aryloxy Cycarbonyl group (aryl part is as above), aralkyloxycal Bonyl group (aralkyl part is as described above), C_1-6Alkyl carbamoy Group, dialkylcarbamoyl group (each alkyl moiety having 1 to 4 carbon atoms ), Carbamoyl group, hydroxycarbamoyl group, hydroxy group, 1-6 Carboxylic acid acyloxy groups having carbon atoms and 2,4-dioxothiazolidi Selected from the group n-5-yl,   The substituent B is a halogen atom, C_1-4Alkyl group, C_1-3Alkoxy group, nitro Group, halo C_1-4Selected from an alkyl group and a hydroxy group]   2. A compound of formula (I) or a physiologically acceptable salt or solvate thereof Selected from compounds of formula (II) below and their physiologically acceptable salts and solvates It The method of claim 1, wherein the method comprises: (In the above formula, R¹¹And R¹²One of them represents a hydrogen atom, R¹¹And R¹²Nou The other is group -CH₂CO₂Represents H, R¹⁴Is a chlorine, fluorine or bromine atom or Represents a methyl or trifluoromethyl group)   3. R¹¹Is -CH₂CO₂The method of claim 2, wherein H is H.   4. The compound of formula (I) is (R, R)-[4- [2- [2- (3-chlorophene Nyl) -2-hydroxyethylamino] propoxy] phenyl] acetic acid, The method according to any one of claims 1 to 3.   5. Inflammatory gastrointestinal disorders from ulcerative colitis, ileitis, Crohn's disease and proctitis The method according to any one of claims 1 to 4, which is a selected inflammatory bowel disease.   6. Inflammatory gastrointestinal disorder is a symptom of gastrointestinal ulcer, and the symptom is non-steroidal anti-inflammatory drug. The method according to any one of claims 1 to 4, which is caused by an inflammatory agent.   7. An effective amount of a compound of formula (I) or a physiologically acceptable salt thereof or Is a therapeutic agent for the treatment of inflammatory gastrointestinal disorders, which comprises a solvate. [In the above formula,   R⁰Is a hydrogen atom, a methyl group or a hydroxymethyl group,   R¹Is the substitution C_1-12An alkyl group, which is substituted with at least one of the following substituents A It is)   R²And R³Is a hydrogen atom, halogen atom, hydroxyl group, C_1-5Arco Xy, carboxy, C_2-7Alkoxycarbonyl group, C_1-5Alkyl group, nit B group, halo C_1-4Alkyl group or substituted C_1-12Alkyl groups (at least 1 Substituted with one of the following substituents A),   X is an oxygen atom or a sulfur atom,   Ar is a group of the following formula (C) or (D): (In the above formula:   R^FourIs a hydrogen atom, a halogen atom, a hydroxy group, a hydroxymethyl group, C_1-5A Lucoxy group, C_1-5Alkyl group, aliphatic carboxylic acid C_1-6Acyloxy group, nitro Group, cyano group, aralkyloxy group (aralkyl part is as follows), Aryloxy groups (where the aryl portion is as follows), aryls such as Group or halo C_1-4Is an alkyl group,   R^FiveIs a hydrogen atom, a halogen atom, a hydroxy group, C_1-5Alkoxy group, C_1-5A Is a rualkyl group or a nitro group,   R⁶Is a hydrogen atom, a halogen atom, a hydroxy group, C_1-5Alkoxy group or C_{1- Five} Is an alkyl group),   The above aralkyl moiety is C substituted with one or two aryl groups as follows:_1-3 Is an alkyl group,   The aryl group is unsubstituted or substituted with at least one of the following substituents B Carbocyclic C_6-10An aryl group,   The substituent A is a carboxy group, C_2-7Alkoxycarbonyl group, aryloxy Cycarbonyl group (aryl part is as above), aralkyloxycal Bonyl group (aralkyl part is as described above), C_1-6Alkyl carbamoy Group, dialkylcarbamoyl group (each alkyl moiety having 1 to 4 carbon atoms ), Carbamoyl group, hydroxycarbamoyl group, hydroxy group, 1-6 Carboxylic acid acyloxy groups having carbon atoms and 2,4-dioxothiazolidi Selected from the group n-5-yl,   The substituent B is a halogen atom, C_1-4Alkyl group, C_1-3Alkoxy group, nitro Group, halo C_1-4Selected from an alkyl group and a hydroxy group]   8. A compound of formula (I) or a physiologically acceptable salt or solvate thereof Selected from compounds of formula (II) below and their physiologically acceptable salts and solvates The therapeutic agent according to claim 7, which is (In the above formula, R¹¹And R¹²One of them represents a hydrogen atom, R¹¹And R¹²Nou The other is group -CH₂CO₂Represents H, R¹⁴Is a chlorine, fluorine or bromine atom or Represents a methyl or trifluoromethyl group)   9. R¹¹Is -CH₂CO₂The therapeutic agent according to claim 8, which is H.   10. The compound of formula (I) is (R, R)-[4- [2- [2- (3-chlorophenyl Phenyl) -2-hydroxyethylamino] propoxy] phenyl] acetic acid, The therapeutic agent according to any one of claims 7 to 9.   11. Whether inflammatory gastrointestinal disorders are ulcerative colitis, ileitis, Crohn's disease and proctitis Treatment according to any one of claims 7 to 10, which is an inflammatory bowel disease selected from: Agent.   12. Inflammatory gastrointestinal disorder is a symptom of gastrointestinal ulcer, which is non-steroidal The therapeutic agent according to any one of claims 7 to 10, which is caused by an anti-inflammatory agent.   13. A compound of the following formula (I) or a physiologically acceptable salt or solvent thereof Use of a Japanese product for the manufacture of a medicament for treating inflammatory gastrointestinal disorders. [In the above formula,   R⁰Is a hydrogen atom, a methyl group or a hydroxymethyl group,   R¹Is the substitution C_1-12An alkyl group, which is substituted with at least one of the following substituents A It is)   R²And R³Is a hydrogen atom, halogen atom, hydroxyl group, C_1-5Arco Xy, carboxy, C_2-7Alkoxycarbonyl group, C_1-5Alkyl group, nit B group, halo C_1-4Alkyl group or substituted C_1-12Alkyl groups (at least 1 Substituted with one of the following substituents A),   X is an oxygen atom or a sulfur atom,   Ar is a group of the following formula (C) or (D): (In the above formula:   R^FourIs a hydrogen atom, a halogen atom, a hydroxy group, a hydroxymethyl group, C_1-5 Alkoxy group, C_1-5Alkyl group, aliphatic carboxylic acid C_1-6Acyloxy group, nit B group, cyano group, aralkyloxy group (aralkyl part is as follows) , An aryloxy group (where the aryl part is as follows), an ant as shown below Group or halo C_1-4Is an alkyl group,   R^FiveIs a hydrogen atom, a halogen atom, a hydroxy group, C_1-5Alkoxy group, C_1-5A Is a rualkyl group or a nitro group,   R⁶Is a hydrogen atom, a halogen atom, a hydroxy group, C_1-5Alkoxy group or C_{1- Five} Is an alkyl group),   The above aralkyl moiety is C substituted with one or two aryl groups as follows:_1-3 Is an alkyl group,   The aryl group is unsubstituted or substituted with at least one of the following substituents B Carbocyclic C_6-10An aryl group,   The substituent A is a carboxy group, C_2-7Alkoxycarbonyl group, aryloxy Cycarbonyl group (aryl part is as above), aralkyloxycal Bonyl group (aralkyl part is as described above), C_1-6Alkyl carbamoy Group, dialkylcarbamoyl group (each alkyl moiety having 1 to 4 carbon atoms ), Carbamoyl group, hydroxycarbamoyl group, hydroxy group, 1-6 Carboxylic acid acyloxy groups having carbon atoms and 2,4-dioxothiazolidi Selected from the group n-5-yl,   The substituent B is a halogen atom, C_1-4Alkyl group, C_1-3Alkoxy group, nitro Group, halo C_1-4Selected from an alkyl group and a hydroxy group]   14. Compound of formula (I) or physiologically acceptable salt or solvate thereof Is selected from the compounds of formula (II) below and their physiologically acceptable salts and solvates. Use according to claim 13, which is selected. (In the above formula, R¹¹And R¹²One of them represents a hydrogen atom, R¹¹And R¹²Nou The other is group -CH₂CO₂Represents H, R¹⁴Is a chlorine, fluorine or bromine atom or Represents a methyl or trifluoromethyl group)   15. R¹¹Is -CH₂CO₂Use according to claim 4, which is H.   16. The compound of formula (I) is (R, R)-[4- [2- [2- (3-chlorophenyl Phenyl) -2-hydroxyethylamino] propoxy] phenyl] acetic acid, Use according to any one of claims 13-15.   17． Whether inflammatory gastrointestinal disorders are ulcerative colitis, ileitis, Crohn's disease and proctitis Use according to any one of claims 13 to 16, which is an inflammatory bowel disease selected from: for.   18. Inflammatory gastrointestinal disorder is a symptom of gastrointestinal ulcer, which is non-steroidal Use according to any one of claims 13 to 16, which is due to an anti-inflammatory agent.   19. A compound of the following formula (I) or a physiologically acceptable salt or solvate thereof , Non-steroidal anti-inflammatory agents and physiologically acceptable carriers therefor A pharmaceutical composition comprising: [In the above formula,   R⁰Is a hydrogen atom, a methyl group or a hydroxymethyl group,   R¹Is the substitution C_1-12An alkyl group, which is substituted with at least one of the following substituents A It is)   R²And R³Is a hydrogen atom, halogen atom, hydroxyl group, C_1-5Arco Xy, carboxy, C_2-7Alkoxycarbonyl group, C_1-5Alkyl group, nit B group, halo C_1-4Alkyl group or substituted C_1-12Alkyl groups (at least 1 Substituted with one of the following substituents A),   X is an oxygen atom or a sulfur atom,   Ar is a group of the following formula (C) or (D): (In the above formula:   R^FourIs a hydrogen atom, a halogen atom, a hydroxy group, a hydroxymethyl group, C_1-5A Lucoxy group, C_1-5Alkyl group, aliphatic carboxylic acid C_1-6Acyloxy group, nitro Group, cyano group, aralkyloxy group (aralkyl part is as follows), Aryloxy groups (where the aryl portion is as follows), aryls such as Group or halo C_1-4Is an alkyl group,   R^FiveIs a hydrogen atom, a halogen atom, a hydroxy group, C_1-5Alkoxy group, C_1-5A Is a rualkyl group or a nitro group,   R⁶Is a hydrogen atom, a halogen atom, a hydroxy group, C_1-5Alkoxy group or C_{1- Five} Is an alkyl group),   The above aralkyl moiety is C substituted with one or two aryl groups as follows:_1-3 Is an alkyl group,   The aryl group is unsubstituted or substituted with at least one of the following substituents B Carbocyclic C_6-10An aryl group,   The substituent A is a carboxy group, C_2-7Alkoxycarbonyl group, aryloxy Cycarbonyl group (aryl part is as above), aralkyloxycal Bonyl group (aralkyl part is as described above), C_1-6Alkyl carbamoy Group, dialkylcarbamoyl group (each alkyl moiety having 1 to 4 carbon atoms ), Carbamoyl group, hydroxycarbamoyl group, hydroxy group, 1-6 Carboxylic acid acyloxy groups having carbon atoms and 2,4-dioxothiazolidi Selected from the group n-5-yl,   The substituent B is a halogen atom, C_1-4Alkyl group, C_1-3Alkoxy group, nitro Group, halo C_1-4Selected from an alkyl group and a hydroxy group]   20. Compound of formula (I) or physiologically acceptable salt or solvate thereof Is selected from the compounds of formula (II) below and their physiologically acceptable salts and solvates: The pharmaceutical composition according to claim 20, which is (In the above formula, R¹¹And R¹²One of them represents a hydrogen atom, R¹¹And R¹²Nou The other is group -CH₂CO₂Represents H, R¹⁴Is a chlorine, fluorine or bromine atom or Represents a methyl or trifluoromethyl group)   21. R¹¹Is -CH₂CO₂The pharmaceutical composition according to claim 20, which is H.   22. The compound of formula (I) is (R, R)-[4- [2- [2- (3-chlorophenyl Phenyl) -2-hydroxyethylamino] propoxy] phenyl] acetic acid, The pharmaceutical composition according to any one of claims 19 to 21.