WO1995001170A2 - Utilisation des derives de phenethanolamine dans le traitement des troubles gastro-intestinaux - Google Patents
Utilisation des derives de phenethanolamine dans le traitement des troubles gastro-intestinaux Download PDFInfo
- Publication number
- WO1995001170A2 WO1995001170A2 PCT/EP1994/002106 EP9402106W WO9501170A2 WO 1995001170 A2 WO1995001170 A2 WO 1995001170A2 EP 9402106 W EP9402106 W EP 9402106W WO 9501170 A2 WO9501170 A2 WO 9501170A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- groups
- alkyl
- defined below
- substituted
- Prior art date
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- 238000011282 treatment Methods 0.000 title claims abstract description 23
- 208000018522 Gastrointestinal disease Diseases 0.000 title claims abstract description 18
- ULSIYEODSMZIPX-UHFFFAOYSA-N phenylethanolamine Chemical class NCC(O)C1=CC=CC=C1 ULSIYEODSMZIPX-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 67
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 31
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 11
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 30
- 239000012453 solvate Substances 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 125000005843 halogen group Chemical group 0.000 claims description 25
- 125000001424 substituent group Chemical group 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 24
- -1 hydroxycarbamoyl groups Chemical group 0.000 claims description 20
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 15
- 208000025865 Ulcer Diseases 0.000 claims description 13
- 230000002496 gastric effect Effects 0.000 claims description 13
- 230000002757 inflammatory effect Effects 0.000 claims description 13
- 230000036269 ulceration Effects 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 208000010643 digestive system disease Diseases 0.000 claims description 10
- 208000018685 gastrointestinal system disease Diseases 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 229940124597 therapeutic agent Drugs 0.000 claims description 9
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 7
- 208000011231 Crohn disease Diseases 0.000 claims description 7
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 7
- 206010036774 Proctitis Diseases 0.000 claims description 7
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 7
- 208000009326 ileitis Diseases 0.000 claims description 7
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- 125000001931 aliphatic group Chemical group 0.000 claims description 5
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 5
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 5
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 5
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 125000002837 carbocyclic group Chemical group 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
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- 239000011737 fluorine Chemical group 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
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- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 3
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
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- 239000001257 hydrogen Substances 0.000 abstract 2
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 2
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- 125000003545 alkoxy group Chemical group 0.000 abstract 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- 125000001188 haloalkyl group Chemical group 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 125000001624 naphthyl group Chemical group 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 24
- 239000000203 mixture Substances 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000004480 active ingredient Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000003826 tablet Substances 0.000 description 14
- 239000000556 agonist Substances 0.000 description 13
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 12
- 241000700159 Rattus Species 0.000 description 11
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 102000015005 beta-adrenergic receptor activity proteins Human genes 0.000 description 6
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
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- INBMIZHPELSCKR-ACJLOTCBSA-N 2-[4-[(2r)-2-[[(2r)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propoxy]phenyl]acetic acid Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(Cl)C=CC=1)OC1=CC=C(CC(O)=O)C=C1 INBMIZHPELSCKR-ACJLOTCBSA-N 0.000 description 4
- 108060003345 Adrenergic Receptor Proteins 0.000 description 4
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- 208000007882 Gastritis Diseases 0.000 description 4
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- 208000008469 Peptic Ulcer Diseases 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 4
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- YBPAYPRLUDCSEY-UHFFFAOYSA-N 2-(4-hydroxyphenyl)acetamide Chemical compound NC(=O)CC1=CC=C(O)C=C1 YBPAYPRLUDCSEY-UHFFFAOYSA-N 0.000 description 2
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- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical class NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- This invention relates to a new medical use for certain phenethanolamine derivatives and to pharmaceutical compositions containing them.
- the invention relates to the use of such compounds which act as agonists at atypical beta-adrenoceptors (also known as beta-3-adrenoceptors).
- beta-adrenoceptors also known as beta-3-adrenoceptors.
- Such receptors have been described for example by J R S Arch et. al., Nature, 309, 163-165 (1984); C Wilson et. al., Eur. J. Pharmacol., 100, 309-319 (1984); L J Emorine et. al., Science, 245, 1118-1121 (1989); and A. Bianchetti et. al. Br. J. Pharmacol., 100, 831-839 (1990).
- Atypical beta-adrenoceptors belong to the family of adrenoceptors which mediate the physiological actions of the hormones adrenaline and noradrenaline.
- Sub-types of the adrenoceptors, - -, ⁇ -2-, ⁇ , &2" and &3- can be identified on the basis of their pharmacological properties and physiological effects. Chemical agents which stimulate or block these receptors (but not >2) are widely used in clinical medicine. More recently, emphasis has been placed upon specific receptor selectivity in order to reduce side effects caused, in part, by interactions with other receptors.
- Atypical beta-adrenoceptors are known to occur in adipose tissue and the gastrointestinal tract. Compounds which act as agonists at atypical beta- adrenoceptors may be identified using standard tests (see for instance C Wilson et. al., supra).
- R° is a hydrogen atom, a methyl group or a hydroxymethyl group
- R 1 is a substituted C ⁇ alk l group which group is substituted by at least one of the substituents A, defined below
- R 2 and R 3 are each selected from a hydrogen atom, a halogen atom, a hydroxyl group, a C.,.. 5 alkoxy group, a carboxy group, a C 2 _ 7 alkoxycarbonyl group, a Chalky!
- R 4 is a hydrogen atom, a halogen atom, a hydroxy group, a hydroxymethyl group, a C ⁇ alkoxy group, a C ⁇ alkyl group, an aliphatic carboxylic C 1 ⁇ acyloxy group, a nitro group, a cyano group, an aralkyloxy group in which the aralkyl part is as defined below, an aryloxy group in which the aryl part is as defined below, an aryl group as defined below, or a haloC ⁇ alkyl group;
- R 5 is a hydrogen atom, a halogen atom, a hydroxy group, a C- ⁇ alkoxy group, a Chalk ! group, or a nitro group;
- R 6 is a hydrogen atom, a halogen atom, a hydroxy group, a C- ⁇ alkoxy group, or a C ⁇ alkyl group; said aralkyl part is a C ⁇ alkyl group which group is substituted by 1 or 2 aryl groups as defined below; said aryl groups are carbocyclic C 6 _ 10 aryl groups which are unsubstituted or are substituted by at least one of substituents B, defined below; said substituents A are selected from carboxy groups, C 2 _7alkoxycarbonyl groups, aryloxycarbonyl groups in which the aryl part is as defined above, aralkyloxycarbonyl groups in which the aralkyl part is as defined above, C ⁇ alkylcarbamoyl groups, dialkylcarbamoyl groups in which each alkyl part has from 1 to 4 carbon atoms, carbamoyl groups, hydroxycarbamoyl groups, hydroxy groups, carboxylic
- substituents B are selected from halogen atoms, C 1. alkyl groups, C- ⁇ alkoxy groups, nitro groups, haloC ⁇ alkyl groups, and hydroxy groups; and pharmaceutically acceptable salts thereof.
- atypical beta-adrenoceptor agonists have been found to be particularly useful as thermogenic anti-obesity agents and as anti-diabetic agents.
- Compounds having atypical beta-adrenoceptor agonist activity have also been described as being useful in the treatment of hyperglycaemia, as animal growth promoters, as blood platelet aggregation inhibitors, as positive inotropic agents and as antiathereosclerotic agents, and as being useful in the treatment of glaucoma.
- the compounds of general formula (I) which act as agonists at atypical beta-adrenoceptors may be useful for the treatment of gastrointestinal disorders, especially inflammatory gastrointestinal disorders including peptic ulceration, oesophagitis, gastritis and duodenitis (including that induced by H. pylori), intestinal ulcerations (including inflammatory bowel disease, especially, ulcerative colitis, ileitis, Crohn's disease and proctitis) and gastrointestinal ulcerations, especially when induced by non-steroidal anti- inflammatory drugs (NSAIDs) or corticosteroids.
- NSAIDs non-steroidal anti- inflammatory drugs
- a preferred sub-class of the compounds of the general formula (I) for use according to the present invention is that defined by formula (II)
- R 11 and R 12 represents a hydrogen atom and the other of R 11 and R 12 represents the group -CH 2 CO 2 H;
- R 14 represents a chlorine, fluorine or bromine atom or a methyl or trifluoromethyl group.
- R 11 represents the group -CH 2 CO 2 H.
- a particularly preferred compound of general formula (I) for use according to the present invention is:
- Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, naphthoates, hydroxynaphthoates, p-toluenesulphonates, methanesulphonates, sulphamates, ascorbates, tartrates, citrates, oxalates, maleates, salicylates, fumarates, succinates, lactates, glutarates, glutaconates, acetates or tricarballyates.
- the compounds may also form salts with suitable bases. Examples of such salts include alkali metal (e.g. sodium or potassium), alkaline earth metal (e.g. calcium, or magnesium), ammonium and substituted ammonium.
- salts referred to above will be physiologically acceptable, but other salts may find use, for example, in the preparation of the compounds of general formula (I) and the physiologically acceptable salts thereof.
- the present invention provides a method of treatment of a human or non-human mammal, suffering from or susceptible to a inflammatory gastrointestinal disorder, such as peptic ulceration, oesophagitis, gastritis, duodenitis, intestinal ulcerations and gastrointestinal ulcerations, which method comprises administering to said mammal an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof.
- a inflammatory gastrointestinal disorder such as peptic ulceration, oesophagitis, gastritis, duodenitis, intestinal ulcerations and gastrointestinal ulcerations
- a method of treatment of a human or non-human mammal suffering from a condition of intestinal ulcerations wherein said condition is an inflammatory bowel disease, such as ulcerative colitis, ileitis, Crohn's disease or proctitis, which method comprises administering to said mammal an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof.
- a method of treatment of a human or non-human mammal, suffering from a condition of gastrointestinal ulcerations wherein said condition is induced by non-steroidal anti-inflammatory drugs comprises administering to said mammal an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof.
- references in this specification to treatment include prophylactic treatment as well as the alleviation of symptoms.
- the present invention provides a therapeutic agent which comprises an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in medicine, particularly human medicine, for the treatment of inflammatory gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis, duodenitis, intestinal ulcerations and gastrointestinal ulcerations.
- a therapeutic agent which comprises an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in medicine, particularly human medicine, for the treatment of inflammatory gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis, duodenitis, intestinal ulcerations and gastrointestinal ulcerations.
- a therapeutic agent which comprises an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of a condition of intestinal ulcerations wherein said condition is an inflammatory bowel disease such as ulcerative colitis, ileitis, Crohn's disease or proctitis.
- a therapeutic agent which comprises an effective amount of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of a condition of gastrointestinal ulcerations wherein said condition is induced by non-steroidal anti-inflammatory drugs.
- the invention provides for the use of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of inflammatory gastrointestinal disorders such as peptic ulceration, gastritis, duodenitis, intestinal ulcerations and gastrointestinal ulcerations.
- a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of a condition of intestinal ulcerations wherein said condition is an inflammatory bowel disease such as ulcerative colitis, ileitis, Crohn's disease or proctitis.
- a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of a condition of gastrointestinal ulcerations wherein said condition is induced by non-steroidal anti-inflammatory drugs.
- NSAID non-steroidal anti- inflammatory drugs
- the active ingredients may be employed in the form of separate pharmaceutical formulations or a combined formulation may be used. In such a combined formulation, the active ingredients must of course be stable and mutually compatible in the particular formulation employed.
- compositions which comprise at least one compound of general formula (I) or a physiologically acceptable salt or solvate thereof and at least one non-steroidal anti-inflammatory drug, together with at least one physiologically acceptable carrier or excipient are believed to be novel compositions and constitute a further aspect of the present invention.
- compositions comprising at least one compound of general formula (1) or a physiologically acceptable salt or solvate thereof adapted for use in human or veterinary medicine.
- Such compositions may be presented for use in a conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
- the carrier(s) or excipient(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- the compounds for use according to the present invention may be formulated for oral, buccal, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or the nose).
- the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate).
- binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
- fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
- lubricants e.g. magnesium stearate, talc or silica
- disintegrants e.g. potato starch or sodium starch glycollate
- Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
- Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl- ⁇ -hydroxybenzoates or sorbic acid).
- the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
- Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
- compositions may take the form of tablets or lozenges formulated in conventional manner.
- the compounds for use according to the present invention may be formulated for parenteral administration by injection e.g. by bolus injection or continuous infusion.
- Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative.
- the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
- the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
- the compounds for use according to the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
- the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection.
- the compounds for use according to the present invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
- a proposed dose of the compounds for use according to the present invention for administration to a human is 0.1 mg to 1g, preferably to 1mg to 100mg of the active ingredient per unit dose, expressed as the weight of free base.
- the unit dose may be administered, for example, 1 to 4 times per day.
- the dose will depend on the route of administration. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient as well as the severity of the condition to be treated. The precise dose and route of administration will ultimately be at the discretion of the attendant physician or veterinarian.
- the compounds of general formula (I) for use according to the present invention may be prepared by a number of processes which are well known in the art for the preparation of phenethanolamine derivatives. Suitable methods are described, for instance, in European Patent Specification No. 0 543 662-A.
- Atypical beta-adrenoceptor agonists are compounds which demonstrate a pharmacological response (in vitro or in vivo) mediated at atypical beta-adrenoceptors. This activity has been be measured as the ability to stimulate lipolysis by rat adipocytes at sub-micromolar concentrations, in a response that is resistant to blockade by standard beta-adrenoceptor blocking drugs such as propranolol.
- Another useful means of identifying an atypical beta-adrenoceptor agonist involves the measurement of agonist activity at atypical beta-adrenoceptors in the rat isolated lower oesophagus.
- a suitable assay is .described below as Method 1.
- a compound of general formula (I) for use according to the present invention has an equipotent molar ratio (EPMR) relevant to isoprenaline of less than 30.
- the rat oesophagus assay is based upon that described by Ford et. al., Br. J.
- the lower oesophagus is removed from male AH/A rats (100-150g).
- the overlying serosal muscle is removed from the oesophagus to leave the tunis muscularis mucosa.
- Tissues are then placed in Kreb's solution containing the ⁇ 2-antagonist ICI 118,551 (lO ⁇ M), the ⁇ -
- tissues are contracted with a submaximal concentration of carbachol (10 " ⁇ M) and, when a stable increase in tension has been achieved, a cumulative concentration effect curve to isoprenaline is constructed.
- tissues are recontracted with carbachol (lO ⁇ M) and a cumulative concentration effect curve to test agonist is constructed.
- EC50 is the molar concentration of agonist which produces 50% of the maximum possible response for that agonist.
- compounds selective for atypical beta-adrenoceptors should preferably be a minimum of 10-30 times less potent than isoprenaline at or ⁇ 2 ⁇ adrenoceptors and, more preferably, 300-1000 times less potent than isoprenaline at ⁇ -
- Method 2 Food (but not water) is withheld from female random hooded rats (70-120g) for 24 hours and then the rats are re-fed with Rat and Mouse No. 1 Maintenance Diet. After 1 hour of access to food, the rats are dosed orally with either the test compound or solvent (0.5% w/v methyl cellulose in water). 30 minutes later, indomethacin (60mg/kg; dissolved in 1 % w/v NaHCO ⁇ in saline) is administered as a single subcutaneous injection at the back of the neck. Subsequently, the rats are allowed food, but water is withheld, and the animals are humanely killed by cervical dislocation at 6 hours post dose. Control animals received a single subcutaneous dose of the appropriate solvent.
- the rat's stomach is removed (with a small amount of duodenum attached), opened along the greater curvature and the contents removed by washing with 0.9% w/v sodium chloride solution (saline).
- the opened stomach is pinned out (mucosal surface uppermost) on a polystyrene mat and the area of damage assessed by placing a grid (composed of 1 mm squares) over the antral region. Antral damage appears as discrete black or dark brown ulcers. The total area of antral damage is then expressed as a percentage of the total surface area of the antrum.
- Tablets may be prepared by the normal methods such as direct compression or wet granulation.
- the tablets may be film coated with suitable film forming materials, such as hydroxypropyl methylcellulose, using standard techniques.
- suitable film forming materials such as hydroxypropyl methylcellulose, using standard techniques.
- the tablets may be sugar coated.
- the active ingredient is passed through a 60 mesh sieve, blended with the calcium hydrogen phosphate, croscarmellose sodium and magnesium stearate.
- the resultant mix is compressed into tablets using a Manesty F3 tablet machine fitted with 5.5mm, flat bevelled edge punches.
- the active ingredient is passed through a 60 mesh sieve, and blended with the lactose, pregelatinised starch and magnesium stearate.
- the resultant mix is compressed into tablets using a Manesty F3 tablet machine fitted with 7.5mm normal concave punches.
- SYRUP This may be either a sucrose or sucrose free presentation.
- the active ingredient, buffer, flavour, colour and preservative are dissolved in some of the water and the glycerine is added. The remainder of the water is heated to dissolve the sucrose and is then cooled. The two solutions are combined, adjusted to volume and mixed. The syrup is clarified by filtration.
- the hydroxypropylmethylcellulose is dispersed in hot water, cooled and then mixed with an aqueous solution containing the active ingredient and the other components of the formulation.
- the resultant solution is adjusted to volume and mixed.
- the syrup is clarified by filtration.
- the active ingredient is dissolved in a suitable volume of Sodium Chloride Injection BP, the pH of the resultant solution is adjusted to pH3.5 with dilute hydrochloric acid BP then the solution is made to volume with sodium chloride injection BP and thoroughly mixed.
- the solution is filled into Type I clear glass 5ml ampoules which are sealed under a headspace of air, by fusion of the glass then sterilised by autoclaving at 120 ⁇ for not less than 15 minutes.
- Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted, using acid or alkali, to that of optimum stability and/or facilitate solution of the active ingredient.
- suitable buffer salts may be used.
- the solution is prepared, clarified and filled into appropriate size ampoules sealed by fusion of the glass.
- the injection is sterilised by heating in an autoclave using one of the acceptable cycles.
- the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions.
- the solution may be packed under an inert atmosphere of nitrogen or other suitable gas.
- a suspension of the active ingredient in molten Witepsol is prepared and filled using suitable machinery, into 1g size suppository moulds.
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP94923697A EP0706386A1 (fr) | 1993-07-01 | 1994-06-29 | Utilisation des derives de phenethanolamine dans le traitement des troubles gastro-intestinaux |
JP7503267A JPH08512038A (ja) | 1993-07-01 | 1994-06-29 | 胃腸障害の治療に関するフェネタノールアミン誘導体の用途 |
AU73840/94A AU7384094A (en) | 1993-07-01 | 1994-06-29 | Use of phenethanolamine derivatives in the treatment of gastrointestinal disorders |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9313574.7 | 1993-07-01 | ||
GB939313574A GB9313574D0 (en) | 1993-07-01 | 1993-07-01 | Medicaments |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1995001170A2 true WO1995001170A2 (fr) | 1995-01-12 |
WO1995001170A3 WO1995001170A3 (fr) | 2002-02-14 |
Family
ID=10738090
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1994/002106 WO1995001170A2 (fr) | 1993-07-01 | 1994-06-29 | Utilisation des derives de phenethanolamine dans le traitement des troubles gastro-intestinaux |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0706386A1 (fr) |
JP (1) | JPH08512038A (fr) |
AU (1) | AU7384094A (fr) |
GB (1) | GB9313574D0 (fr) |
WO (1) | WO1995001170A2 (fr) |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5635534A (en) * | 1991-11-20 | 1997-06-03 | Sankyo Company, Limited | Aromatic amino-alcohol derivatives having anti-diabetic and anti-obesity properties, their preparation and their therapeutic uses |
US5786356A (en) * | 1995-09-21 | 1998-07-28 | Eli Lilly And Company | Selective β3 adrenergic agonists |
US5808080A (en) * | 1996-09-05 | 1998-09-15 | Eli Lilly And Company | Selective β3 adrenergic agonists |
WO1998043953A1 (fr) * | 1997-04-02 | 1998-10-08 | Glaxo Group Limited | Acides naphtalenesulfoniques ou carboxyliques et leur utilisation en tant qu'agonistes atypiques de beta-adrenorecepteur |
US6046227A (en) * | 1997-12-05 | 2000-04-04 | Eli Lilly And Company | Selective β3 adrenergic agonists |
US6140352A (en) * | 1996-09-05 | 2000-10-31 | Eli Lilly And Company | Carbazolyl-substituted ethanolamines as selective β-3 agonists |
US7045658B2 (en) | 2001-03-22 | 2006-05-16 | Glaxo Group Limited | Formailide derivatives as beta2-adrenoreceptor agonists |
US7135600B2 (en) | 2001-02-14 | 2006-11-14 | Glaxo Group Limited | Phenethanolamine derivatives for treatment of respiratory diseases |
US7144908B2 (en) | 2001-03-08 | 2006-12-05 | Glaxo Group Limited | Agonists of beta-adrenoceptors |
US7361787B2 (en) | 2001-09-14 | 2008-04-22 | Glaxo Group Limited | Phenethanolamine derivatives for treatment of respiratory diseases |
US7402598B2 (en) | 2002-07-25 | 2008-07-22 | Glaxo Group Limited | Arylethanolamine β2-adrenoreceptor agonist compounds |
US7425639B2 (en) | 2001-01-31 | 2008-09-16 | Smithkline Beecham Corporation | Process |
US7538127B2 (en) | 2003-02-14 | 2009-05-26 | Glaxo Group Limited | Medicinal compounds |
US7709677B2 (en) | 2001-01-31 | 2010-05-04 | Glaxosmithkline Llc | Process of preparing arylethanoldiamines |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9016655D0 (en) * | 1990-07-30 | 1990-09-12 | Ici Plc | Therapeutic agents |
GB9111426D0 (en) * | 1991-05-28 | 1991-07-17 | Ici Plc | Chemical compounds |
NO179246C (no) * | 1991-11-20 | 1996-09-04 | Sankyo Co | Aromatiske amino-alkoholderivater og mellomprodukter til fremstilling derav |
ES2174897T3 (es) * | 1992-01-22 | 2002-11-16 | Glaxo Group Ltd | Uso medico de agonistas de beta-adrenoceptores atipicos. |
-
1993
- 1993-07-01 GB GB939313574A patent/GB9313574D0/en active Pending
-
1994
- 1994-06-29 EP EP94923697A patent/EP0706386A1/fr not_active Ceased
- 1994-06-29 JP JP7503267A patent/JPH08512038A/ja active Pending
- 1994-06-29 WO PCT/EP1994/002106 patent/WO1995001170A2/fr not_active Application Discontinuation
- 1994-06-29 AU AU73840/94A patent/AU7384094A/en not_active Abandoned
Cited By (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5635534A (en) * | 1991-11-20 | 1997-06-03 | Sankyo Company, Limited | Aromatic amino-alcohol derivatives having anti-diabetic and anti-obesity properties, their preparation and their therapeutic uses |
US6060492A (en) * | 1995-09-21 | 2000-05-09 | Eli Lilly And Company | Selective β3 adrenergic agonists |
US5786356A (en) * | 1995-09-21 | 1998-07-28 | Eli Lilly And Company | Selective β3 adrenergic agonists |
US6265581B1 (en) | 1995-09-21 | 2001-07-24 | Eli Lilly And Company | Selective β3 adrenergic agonists |
US6093735A (en) * | 1995-09-21 | 2000-07-25 | Eli Lilly And Company | Selective β-3 adrenergic agonists |
US5939443A (en) * | 1995-09-21 | 1999-08-17 | Eli Lilly And Company | Selective β3 adrenergic agonists |
US5977154A (en) * | 1995-09-21 | 1999-11-02 | Eli Lilly And Company | Selective β3 adrenergic agonist |
US7041684B2 (en) | 1996-09-05 | 2006-05-09 | Eli Lilly And Company | Selective β3 adrenergic agonists |
US6075040A (en) * | 1996-09-05 | 2000-06-13 | Eli Lilly And Company | Selective β3 adrenergic agonists |
US5840738A (en) * | 1996-09-05 | 1998-11-24 | Eli Lilly And Company | Selective β-3 adrenergic agonists |
US6140352A (en) * | 1996-09-05 | 2000-10-31 | Eli Lilly And Company | Carbazolyl-substituted ethanolamines as selective β-3 agonists |
US6413991B1 (en) | 1996-09-05 | 2002-07-02 | Eli Lilly And Company | Selective β3 adrenergic agonists |
US6686372B2 (en) | 1996-09-05 | 2004-02-03 | Eli Lilly And Company | Selective β3 adrenergic agonists |
US5808080A (en) * | 1996-09-05 | 1998-09-15 | Eli Lilly And Company | Selective β3 adrenergic agonists |
WO1998043953A1 (fr) * | 1997-04-02 | 1998-10-08 | Glaxo Group Limited | Acides naphtalenesulfoniques ou carboxyliques et leur utilisation en tant qu'agonistes atypiques de beta-adrenorecepteur |
US6617347B1 (en) | 1997-12-05 | 2003-09-09 | Eli Lilly And Company | Selective β3 adrenergic agonists |
US6046227A (en) * | 1997-12-05 | 2000-04-04 | Eli Lilly And Company | Selective β3 adrenergic agonists |
US7425639B2 (en) | 2001-01-31 | 2008-09-16 | Smithkline Beecham Corporation | Process |
US7709677B2 (en) | 2001-01-31 | 2010-05-04 | Glaxosmithkline Llc | Process of preparing arylethanoldiamines |
US7442836B2 (en) | 2001-02-14 | 2008-10-28 | Glaxo Group Limited | Phenethanolamine derivatives for treatment of respiratory diseases |
US7442837B2 (en) | 2001-02-14 | 2008-10-28 | Glaxo Group Limited | Phenethanolamine derivatives for treatment of respiratory diseases |
US7135600B2 (en) | 2001-02-14 | 2006-11-14 | Glaxo Group Limited | Phenethanolamine derivatives for treatment of respiratory diseases |
US7442719B2 (en) | 2001-02-14 | 2008-10-28 | Glaxo Group Limited | Methods using phenethanolamine derivatives for treatment of respiratory diseases |
US7144908B2 (en) | 2001-03-08 | 2006-12-05 | Glaxo Group Limited | Agonists of beta-adrenoceptors |
US7045658B2 (en) | 2001-03-22 | 2006-05-16 | Glaxo Group Limited | Formailide derivatives as beta2-adrenoreceptor agonists |
US7439393B2 (en) | 2001-09-14 | 2008-10-21 | Glaxo Group Limited | Phenethanolamine derivatives for treatment of respiratory diseases |
US7361787B2 (en) | 2001-09-14 | 2008-04-22 | Glaxo Group Limited | Phenethanolamine derivatives for treatment of respiratory diseases |
US7776895B2 (en) | 2001-09-14 | 2010-08-17 | Glaxo Group Limited | Inhalation devices for delivering phenethanolamine derivatives for the treatment of respiratory diseases |
US7982067B2 (en) | 2001-09-14 | 2011-07-19 | Glaxo Group Limited | Phenethanolamine derivatives for treatment of respiratory diseases |
US8198483B2 (en) | 2001-09-14 | 2012-06-12 | Glaxo Group Limited | Phenethanolamine derivatives for treatment of respiratory diseases |
USRE44874E1 (en) | 2001-09-14 | 2014-04-29 | Glaxo Group Limited | Phenethanolamine derivatives for treatment of respiratory diseases |
US7402598B2 (en) | 2002-07-25 | 2008-07-22 | Glaxo Group Limited | Arylethanolamine β2-adrenoreceptor agonist compounds |
US7538127B2 (en) | 2003-02-14 | 2009-05-26 | Glaxo Group Limited | Medicinal compounds |
Also Published As
Publication number | Publication date |
---|---|
GB9313574D0 (en) | 1993-08-18 |
JPH08512038A (ja) | 1996-12-17 |
WO1995001170A3 (fr) | 2002-02-14 |
EP0706386A1 (fr) | 1996-04-17 |
AU7384094A (en) | 1995-01-24 |
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