WO1995025104A1 - Novel heterocyclic ethanolamine derivatives with beta-adrenoreceptor agonistic activity - Google Patents
Novel heterocyclic ethanolamine derivatives with beta-adrenoreceptor agonistic activity Download PDFInfo
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- WO1995025104A1 WO1995025104A1 PCT/EP1995/000794 EP9500794W WO9525104A1 WO 1995025104 A1 WO1995025104 A1 WO 1995025104A1 EP 9500794 W EP9500794 W EP 9500794W WO 9525104 A1 WO9525104 A1 WO 9525104A1
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- WIPO (PCT)
- Prior art keywords
- formula
- compound
- pharmaceutically acceptable
- acceptable salt
- alkyl
- Prior art date
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- -1 heterocyclic ethanolamine derivatives Chemical class 0.000 title description 8
- 230000001270 agonistic effect Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 134
- 238000000034 method Methods 0.000 claims abstract description 54
- 150000003839 salts Chemical class 0.000 claims abstract description 42
- 239000012453 solvate Substances 0.000 claims abstract description 32
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 26
- 150000001408 amides Chemical class 0.000 claims abstract description 20
- 150000002148 esters Chemical class 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- 239000000203 mixture Substances 0.000 claims abstract description 15
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 11
- 230000008569 process Effects 0.000 claims abstract description 11
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 4
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 150000002367 halogens Chemical class 0.000 claims abstract description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- 238000011282 treatment Methods 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
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- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
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- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
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- 229910052731 fluorine Inorganic materials 0.000 description 1
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- 239000007952 growth promoter Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
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- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229960001317 isoprenaline Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
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- 239000010410 layer Substances 0.000 description 1
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- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- PUPAWTXNPAJCHR-UHFFFAOYSA-N oxazaborole Chemical compound O1C=CB=N1 PUPAWTXNPAJCHR-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
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- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
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- 239000000843 powder Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
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- 229940095574 propionic acid Drugs 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 239000012047 saturated solution Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000004296 sodium metabisulphite Substances 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000013223 sprague-dawley female rat Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IMCXPAOPGUAZBH-SECBINFHSA-N tert-butyl n-[(2r)-1-(3,4-dihydroxyphenyl)propan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C)CC1=CC=C(O)C(O)=C1 IMCXPAOPGUAZBH-SECBINFHSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
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- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- This invention relates to novel compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine and agriculture.
- These compounds are also indicated to have potential in the treatment of gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis and duodenitis, intestinal ulcerations, including inflammatory bowel disease, and irritable bowel syndrome and also for the treatment of gastrointestinal ulcerations, especially when induced by non-steroidal anti-inflammatory drugs or corticosteroids.
- These compounds also have potential as growth promoters for livestock and for decreasing birth mortality rate and increasing the post-natal survival rate in livestock.
- These compounds may also be of use in increasing the high- density-lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in human blood serum and are therefore of potential use in the treatment and/or prophylaxis of atherosclerosis. They are also indicated to be useful for the treatment of hyperinsulinaemia. They are also indicated to be useful for the treatment of depression.
- HDL high- density-lipoprotein
- X represents a moiety of formula (a):
- a ⁇ represents an oxo or a thioxo group
- a ⁇ represents H or an alkylcarbonyl group
- a 4 represents hydroxy or NR s R l wherein R s and R l each independently represents H or alkyl; R° and R each independently represents hydrogen or an alkyl group; R2 represents OCH2CO2H, or an ester or amide thereof, or R ⁇ represents a moiety of formula (b):
- R ⁇ and R ⁇ each independently represent hydrogen, alkyl, hydroxyalkyl, cycloalkyl or R 4 together with R ⁇ represents (CH2)n wherein n is 2, 3 or 4;
- R3 represents hydrogen, halogen, alkyl or alkoxy or R ⁇ together with R ⁇ represents a moiety of formula (c):
- a ⁇ is oxo
- a 3 is H.
- a 4 is OH, favourably substituted at the 4-position relative to the bond linking X to the CHOH carbon atom.
- R° is hydrogen
- R* is an alkyl group.
- Ri is alkyl
- it is favourably a C ⁇ . alkyl group, especially a methyl group.
- R ⁇ together with R 3 represents a moiety of formula (c).
- the compounds of formula (I) have two or more asymmetric carbon atoms, for example those marked with asterisks in the formula. These compounds may therefore exist in different stereoisomeric forms.
- the present invention encompasses all stereoisomers of the compounds of the general formula (I) whether free from other isomers, or admixed with other isomers in any proportion, such as mixtures of diastereoisomers and racemic mixtures of enantiomers.
- the asymmetric carbon atom indicated by a single asterisk (*) is in the R-conf ⁇ guration.
- the asymmetric carbon atom indicated by two asterisks (**) is in the R-configuration.
- carbon atom in moiety (c) marked with three asterisks (***) may also be chiral when R is different from the other attached substituent (as selected from CO2H or an ester or amide thereof).
- a suitable form of a compound of formula (I) is a mixture of the R(*)R(**) and S(*)S(**) enantiomers
- a preferred form of a compound of formula (I) is the R(*)R(**) enantiomer.
- 'alkyl' when used alone or when forming part of other groups (such as the 'alkoxy' group) includes straight- or branched-chain alkyl groups containing 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms, examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group.
- 'cycloalkyl' includes C3_g cycloalkyl groups, especially C5 or C$ cycloalkyl groups.
- halogen refers to fluorine, chlorine, bromine and iodine, preferably chlorine.
- Suitable esters are pharmaceutically acceptable esters.
- Suitable pharmaceutically acceptable esters of carboxyl groups include alkyl esters, especially C ⁇ . alkyl esters such as methyl.
- Suitable amides are pharmaceutically acceptable amides.
- Suitable pharmaceutically acceptable amides are those of formula - CONRJRk wherein R ) and R ⁇ each independently represent hydrogen, alkyl or alkoxyalkyl.
- Suitable salts are pharmaceutically acceptable salts.
- Suitable pharmaceutically acceptable salts include acid addition salts, salts of carboxy groups and salts of phosphonic acid groups.
- Suitable pharmaceutically acceptable acid addition salts include salts with inorganic acids such, for example, as hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulphuric acid, or with organic acids such, for example as methanesulphonic acid, toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid or acetylsalicylic acid.
- inorganic acids such, for example, as hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulphuric acid
- organic acids such, for example as methanesulphonic acid, toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid or acetylsalicylic acid.
- Suitable pharmaceutically acceptable salts of carboxy groups or phosphonic acid groups include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with C ⁇ .(.
- alkylamines such as triethylamine, hydroxy- C ⁇ _6 alkylamines such as 2-hydroxyethylamine, bis-(2- hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl- ⁇ -phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine or quinoline.
- Suitable solvates are pharmaceutically acceptable solvates.
- Suitable pharmaceutically acceptable solvates are conventional solvates, preferably hydrates.
- the invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, which process comprises reacting a compound of formula (II):
- R°, R* are as defined in relation to formula (I)
- R ⁇ a represents R ⁇ as defined in relation to formula (I) or a protected form thereof
- R 3a represents
- R 3 as defined in relation to formula (I) or a protected form thereof; and thereafter, if necessary, carrying out one or more of the following optional steps:
- reaction between the compounds of formulae (II) and (HI) may be carried out in any suitable solvent, generally being an alkanol such as ethanol, at any temperature providing a suitable rate of formation of the required product, suitably at an elevated temperature, such as the reflux temperature of the solvent and preferably under an inert atmosphere such as argon or nitrogen.
- suitable solvent generally being an alkanol such as ethanol
- an elevated temperature such as the reflux temperature of the solvent and preferably under an inert atmosphere such as argon or nitrogen.
- the compounds of formulae (II) are known compounds or they may be prepared using processes analogous to those used to prepare such compounds, for example by use of the methods or analogous methods to those disclosed in Journal of Medical Chemistry 1987, 30, 1563-1566.
- a chiral compound of formula (II) wherein the C* carbon atom is chiral may be prepared from an activated form of a compound of formula (TV):
- a suitable activated form of a compound of formula (TV) is a salted form such as an alkali metal salted form, suitably a potassium salted form.
- the activated form of a compound of formula (TV) may be prepared by the appropriate conventional process depending upon the particular nature of the activated form, for example when the activated form is a salted form the compound of formula (IV) is treated with an appropriate source of salting ion such as an alkali metal salt; for example potassium carbonate, in any suitable aprotic solvent such as acetone.
- an appropriate source of salting ion such as an alkali metal salt
- potassium carbonate for example potassium carbonate
- the intramolecular displacement reaction of the activated form of the compound of formula (IV) may be carried out in any suitable aprotic solvent, such as acetone, at any temperature which provides a suitable rate of formation of the required product, usually at an elevated temperature such as the reflux temperature of the solvent.
- aprotic solvent such as acetone
- the activated form of the compound of formula (IV) is prepared in situ with respect to the intramolecular displacement reaction for formation of the required compounds of formula (II).
- a compound of formula (IV) may be prepared by the chiral reduction of a compound of formula (V):
- the chiral reduction of the compound of formula (V) may conveniently be carried out using borane, suitably as a tetrahydrofuran complex, in the presence of a chiral reduction catalyst such as those disclosed in Journal of American Chemical Society 1987, 109, 5551-5553.
- Suitable conditions for the reduction of the compound of formula (V) are the appropriate conventional conditions for example the borane reduction may be carried out using the conditions described in Journal of American Chemical Society, ibid.
- a compound of formlula (V) may be prepared by halogenating a compound of formula (VI):
- halogenation of the compound of formula (VI) is conveniently carried out using a benzyltrimethylammonium dihaloiodate as a halogenating agent (for example benzyltrimethylammonium dichloroiodate is used for chlorination) under conditions disclosed in the Synthesis, 1988, 545-546.
- a benzyltrimethylammonium dihaloiodate as a halogenating agent
- the compounds of formula (VI) are known compounds or they may be prepared using methods analogous to those used to prepare such compounds, for example by use of the methods or analogous methods to those disclosed in the European Journal of Medicinal Chemistry, 1984, 19, 341-346
- the compounds of formula (III) are known compounds or they may be prepared according to methods used to prepare known compounds, for example by use of the methods or analogous methods to those disclosed in European Patent Application Number 0023385 (especially for compounds of formula (HI) wherein R ⁇ is OCH2CO2H or an ester or amide thereof) or International Application, Publication Number WO 94/02493 (especially for compounds wherein R ⁇ is a moiety of hereinbefore defined formula (b)).
- a compound of formula (III) wherein R ⁇ and R 3 together represent a moiety of the above defined formula (c) may be prepared by reacting an activated form of a compound of formula (VTJ):
- O- represents a leaving group or atom, suitably a halogen group such as a bromine atom
- R a represents R as defined in relation to formula (I) or a protected form thereof
- T ⁇ represents hydrogen or a carboxyl protecting group
- T s a nitrogen protecting group, such as a tert- butyloxycarbonyl group.
- T ⁇ is a carboxyl protecting group, such as an alkyl group.
- R a represents a protected form of R when required by the particular nature of R, for example when R is carboxyl then R a is a protected carboxyl group such as a group CO2T ⁇ defined above.
- a suitable activated form of a compound of formula (VII) is an ionic form, such as a salted form, for example an alkali metal salted form.
- the activated form of a compound of formula (TV) may be prepared by the appropriate conventional process depending upon the particular nature of the activated form, for example when the activated form is a salted form the compound of formula (VII) is treated with an appropriate source of salting ion such as an alkali metal salt; for example potassium carbonate, in any suitable aprotic solvent such as acetone.
- an appropriate source of salting ion such as an alkali metal salt
- aprotic solvent such as acetone.
- reaction between the compounds of formulae (VTJ) and (V ⁇ l) may be carried out in any suitable aprotic solvent, such as acetone, at any temperature which provides a suitable rate of formation of the required product, usually at an elevated temperature such as the reflux temperature of the solvent.
- suitable aprotic solvent such as acetone
- the activated form of the compound of formula (VD is prepared in situ with respect to the reaction between the compounds of formulae (VTJ) and (V1TJ) which then form the required compounds of formula (HI).
- a compound of formula (VII) is conveniently prepared according to the reaction scheme set out below:
- the C * and C** carbon atom are chiral carbon atoms.
- the compounds of formulae (VIII) are either known commercially available compounds (for example, the compounds wherein R is CO2H) or an ester or amide thereof or they may be prepared from such compounds using routine procedures or they may be prepared using methods or analogous methods to those used to prepare known compounds, for example those disclosed in Bull. Korean Chem. Soc. 1992, 13, 226-227.
- the compounds of formulae (A) are known compounds or they may be prepared by processes analogous to those used to prepare known compounds, for example by use of the methods or analogous methods disclosed in the Journal of Medicinal Chemistry 1973, 16, 480-483.
- Suitable conversions of one compound of formula (I) into another compound of formula (I) include converting one group OR 4 into another group OR 4 and/or converting one group OR ⁇ into another group OR ⁇ .
- Suitable conversions of one group OR 4 into another group OR 4 include: (i) converting OR 4 as hydroxy into OR 4 as alkoxy; (ii) converting OR 4 as alkoxy into OR 4 as hydroxy; (iii) converting OR 4 as alkoxy into OR 4 as another alkoxy group.
- the abovementioned conversion (i) may be carried out under conventional phosphonate alkylation methods, using for example the appropriate alcohol (R 4 OH) in the presence of hydrogen chloride.
- the abovementioned conversion (ii) may be carried out using conventional phosphonate hydrolysis methods, for example by treating the appropriate compound of formula (I) with an alkaline metal hydroxide, such as sodium hydroxide.
- an alkaline metal hydroxide such as sodium hydroxide.
- the abovementioned conversion (iii) may be carried out by first converting OR 4 as alkoxy into OR 4 as hydroxy using the conditions set out in respect of the abovementioned conversion (ii), followed by converting the hydroxy group so formed into another alkoxy group, using the conditions set out in respect of the abovementioned conversion (i).
- Suitable conversions of one group OR ⁇ into another group OR ⁇ include analogous conversions to those mentioned above in regard to converting one group OR 4 into another group OR 4 .
- Suitable protecting groups include those used conventionally in the art for the particular group or atom being protected.
- Protecting groups may be prepared and removed using the appropriate conventional procedure. For example when T* represents a tert- butyloxycarbonyl nitrogen protecting group it may be removed by acidic hydrolysis, using hydrogen chloride in ether/ethyl acetate, or when T ⁇ represents an alkyl group as a carboxyl protecting group it may be removed by catalytic hydrogenation, using a palladium on carbon catalyst.
- a leaving group or atom is any group or atom that will, under the reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Suitable examples of such groups unless othewise specified are halogen atoms, mesyloxy groups and tosyloxy groups.
- salts, esters, amides and solvates of the compounds mentioned herein may be produced by methods conventional in the art: For example, acid addition salts may be prepared by treating a compound of formula (I) with the appropriate acid.
- Esters of carboxylic acids may be prepared by conventional esterification procedures, for example alkyl esters may be prepared by treating the required carboxylic acid with the appropriate alkanol, generally under acidic conditions.
- Amides may be prepared using conventional amidation procedures, for example amides of formula CONRJR ⁇ may be prepared by treating the relevant carboxylic acid with an amine of formula HNRJR ⁇ * wherein RJ and R ⁇ are as defined above. Alternatively, a C ⁇ . ⁇ alkyl ester such as a methyl ester of the acid may be treated with an amine of the above defined formula HNRJR ⁇ to provide the required amide.
- mixtures of isomers of the compounds of the invention may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.
- optically active acids which maybe used as resolving agents are described in Topics in Stereochemistry 1 , Vol. 6, Wiley Interscience, 1971, Allinger, N.L. and Eliel, W.L. Eds.
- any enantiomer of a compound of the invention may be obtained by stereospecific synthesis using optically pure starting materials of known configuration.
- the absolute configuration of compounds may be determined by conventional X-ray crystallographic techniques. As previously indicated, the compounds of the present invention have valuable pharmacological properties:
- the present invention accordingly provides a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.
- the present invention provides a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of hyperglycaemia in human or non-human animals.
- the present invention further provides a compound of formula (I), or pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of obesity in human or non-human animals.
- a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.
- pharmaceutically acceptable embraces compounds, compositions and ingredients for both human and veterinary use: for example the term “pharmaceutically acceptable salt” embraces a veterinarily acceptable salt.
- composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
- compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection, are also envisaged.
- compositions for oral administration are unit dosage forms such as tablets and capsules.
- Other fixed unit dosage forms such as powders presented in sachets, may also be used.
- the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant.
- Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinyipyrrolidone, polyvinylpolypyrrolidone, magnesium stearate or sodium lauryl sulphate.
- composition will be formulated in unit dose form.
- unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 2-100 mg or 0.1 to 500 mg, and more especially 0.1 to 250 mg.
- the present invention further provides a method for treating hyperglycaemia in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, to a hyperglycaemic human or non-human mammal in need thereof.
- the present invention further provides a method for treating obesity or for the treatment and/or prophylaxis of atherosclerosis in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof.
- the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention.
- the compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof may be taken in doses, such as those described above, one to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg.
- the treatment regimens for atherosclerosis are generally as described for hyperglycaemia.
- the active ingredient may be adminstered by mouth, usually once or twice a day and in an amount in the range of from about 0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg.
- the present invention also provides a method for increasing weight gain and/or improving the feed utilisation efficiency and/or increasing lean body mass and/or decreasing birth mortality rate and increasing post/natal survival rate; of livestock, which method comprises the administration to livestock of an effective non-toxic amount of a compound of formula (I) or a veterinarily acceptable acid addition salt thereof, or a veterinarily acceptable solvate thereof.
- the compounds of formula (I) and the veterinarily acceptable acid addition salts thereof or a veterinarily acceptable solvate thereof may be administered to any livestock in the abovementioned method, they are particularly suitable for increasing weight gain and/or feed utilisation efficiency and/or lean body mass and/or decreasing birth mortality rate and increasing post-natal survival rate; in poultry, especially turkeys and chickens, cattle, pigs and sheep.
- the compounds of formula (I) or veterinarily acceptable acid addition salts thereof will normally be administered orally although non-oral modes of administration, for example injection or implantation, are also envisaged.
- the compounds are administered in the feed-stuff or drinking water provided for the livestock.
- these are administered in the feed-stuff at from 10- 3 ppm - 500ppm of total daily fed intake, more usually O.Olppm to 250ppm, suitably less than lOOppm.
- the particular formulations used will of course depend upon the mode of administration but will be those used conventionally in the mode of administration chosen.
- the drugs are conveniently formulated as a premix in association with a suitable carrier.
- the present invention also provides a veterinarily acceptable premix formulation comprising a compound of formula (I), or a veterinarily acceptable acid addition salt thereof; or a veterinarily acceptable solvate thereof, in association with a veterinarily acceptable carrier therefore.
- Suitable carriers are inert conventional agents such as powdered starch. Other conventional feed-stuff premix carriers may also be employed.
- ⁇ l-Adrenoceptor Agonism Female Sprague-Dawley rats (150-250g) are killed by a blow to the head and exsanguinated. Spontaneously beating right atria are removed by the method of Broadley and Lumleyl and mounted on a glass tissue holder. Each tissue is placed in 30 ml organ baths at 37°C containing Kreb's- Henseleit solution. Each atrium is attached to an isometric transducer by cotton and placed under an initial resting tension of lg. Rate recordings from the spontaneous beating atria are obtained from the tension signal using a Lectromed Type 4522 ratemeter.
- ⁇ -adrenoceptor agonists are then added to the Krebs medium in a cumulative fashion and the results expressed as a percentage increase in atrial rate.
- ⁇ 2-Adrenoceptor Agonism Rat uterine horns are removed and bisected longitudinally. Each tissue is tied to a glass tissue holder and placed in Krebs- Henseleit solution in a 30 ml organ bath as before. Tissues are placed under a resting tension of lg and allowed to equilibrate. Each uterine strip is pre ⁇ contracted by the addition of 40mM K + to the bath to produced a steady tonic contraction, ⁇ -agonists are then added to the bath in a cumulative manner and results expressed as percentage inhibition of contraction.
- Adenylyl cyclase activity was assayed by the method of Kirkham et. al. 2 by the addition of 40 ⁇ l (70 -80 ⁇ g protein) to the incubation medium of the above CHO cell plasma membranes transfected with the human ⁇ 3 -adrenoceptor .
- cAMP produced over 20 minutes was separated from ATP by the method of Salomon et alA
- Agonist EC50 values and intrinsic activities were expressed as the concentration of agonist producing 50 % activation of adenylyl cyclase and the maximum response produced by each agonist relative to that produced by (-) isoprenaline respectively.
- X represents a moiety of formula (a):
- a 2 represents an oxo or a thioxo group
- a ⁇ represents H or an alkylcarbonyl group
- a 4 represents hydroxy or NR s R l wherein R s and R l each independently represents H or alkyl; R° and R* each independently represents hydrogen or an alkyl group; R 2 represents OCH2CO2H, or an ester or amide thereof, or R 2 represents a moiety of formula (b):
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Abstract
Description
Claims
Priority Applications (3)
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US08/704,699 US5750701A (en) | 1994-03-15 | 1995-03-03 | Heterocyclic ethanolamine derivatives with β-adrenoreceptor agonistic activity |
EP95912200A EP0750617A1 (en) | 1994-03-15 | 1995-03-03 | Novel heterocyclic ethanolamine derivatives with beta-adrenoreceptor agonistic activity |
JP7523802A JPH09512786A (en) | 1994-03-15 | 1995-03-03 | Novel heterocyclic ethanolamine derivatives having beta-adrenergic receptor agonist activity |
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GB9405019.2 | 1994-03-15 | ||
GB9405019A GB9405019D0 (en) | 1994-03-15 | 1994-03-15 | Novel compounds |
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WO1995025104A1 true WO1995025104A1 (en) | 1995-09-21 |
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PCT/EP1995/000794 WO1995025104A1 (en) | 1994-03-15 | 1995-03-03 | Novel heterocyclic ethanolamine derivatives with beta-adrenoreceptor agonistic activity |
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US (1) | US5750701A (en) |
EP (1) | EP0750617A1 (en) |
JP (1) | JPH09512786A (en) |
GB (1) | GB9405019D0 (en) |
WO (1) | WO1995025104A1 (en) |
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WO2014139485A1 (en) | 2013-03-15 | 2014-09-18 | Zentiva, K.S. | A method for the preparation of 5-[(r)-2-(5,6-diethyl-indan-2-ylamino)-l-hydroxyethyl]- 8-hydroxy-(1h)-quinolin-2-one (indacaterol) |
CN107629000A (en) * | 2017-09-19 | 2018-01-26 | 南京法恩化学有限公司 | The preparation method of 5 chloracetyl of QAB-149 intermediate 8 benzyloxy 2 (1H) quinolinone |
CN109988111A (en) * | 2019-05-06 | 2019-07-09 | 淮北师范大学 | A kind of impurity and its synthetic method of maleic acid datro |
Also Published As
Publication number | Publication date |
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EP0750617A1 (en) | 1997-01-02 |
JPH09512786A (en) | 1997-12-22 |
US5750701A (en) | 1998-05-12 |
GB9405019D0 (en) | 1994-04-27 |
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