IE53615B1 - Benzo heterocycles - Google Patents
Benzo heterocyclesInfo
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- IE53615B1 IE53615B1 IE2105/82A IE210582A IE53615B1 IE 53615 B1 IE53615 B1 IE 53615B1 IE 2105/82 A IE2105/82 A IE 2105/82A IE 210582 A IE210582 A IE 210582A IE 53615 B1 IE53615 B1 IE 53615B1
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- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
Compounds of the formula (A represents a single bond, -CH2-CH2-or R4 represents hydrogen or alkyl, and R5 represents hydrogen or alkyl or, when R4 represents hydrogen, phenyl; R1 represents hydroxy, acyloxy, chlorine or hydrogen; R2 represents hydrogen, methyl or ethyl; R3 represents m represents 2, 3 or 4, n represents 1,2, or 3, R6-8 represent hydrogen or methyl, R9 represents hydrogen, Ar, OAr, or -NH-CO-Ar R10, R11, R12 are hydrogen, hydroxy, methyl, methoxy, halogen, -CONH2 or NH-R13, R13 is hydrogen, acyl or alkylsulfonyl, or any two of R10, R11, and R12 represent methylenedioxy), their acid addition salts, and corresponding compounds in which the CHOH group is replaced by CO (phenolic groups may be protected) are suitable for treating asthma, bronchitis, hay fever, cardiovascular disorders, for relaxation of the muscles of the uterus, and for improving flesh production and fodder utilisation in animals.
Description
Benzo Heterocycles The invention relates to benzo heterocycles.
More particularly it relates to benzo heterocycles having useful therapeutic properties.
According to the invention, we provide compounds of general formula (X) wherein A represents a single bond, a group -CHj-CHj- , ZR5 or a group =C\ wherein R. represents hydrogen R4 or lower alkyl, and Rg represents hydrogen, or lower 25 alkyl or, when represents hydrogen, a phenyl group; represents a hydroxy or acyloxy group or a chlorine or hydrogen atom; Rj represents hydrogen, or a methyl or ethyl group, and Rg ?H2-(CH2’q *7 represents a group -C-CHj———’ or -C-(CH2)n-RgR6 *8 (II) (III) wherein m represents either 2, 3 or 4 n represents either 1,2 or 3, Rg represents hydrogen or methyl, R? represents hydrogen or methyl, Rg represents hydrogen or methyl, and Rg represents hydrogen, or a group Ar, -OAr, or -NH-CO-Ar, wherein Ar represents one of the groups 40j or Rn R12 (IV) in which R1Q, Ru, and R12, which may be the same or different, are each selected from hydrogen, hydroxy, methyl, methoxy, halogen, -C0NH2 and NH-R^3 the group r13 representing hydrogen, acyl or a lower alkylsulfonyl group, or any two of R^q, R·^ and R^2 may represent a methylenedioxy group.
The compounds may occur in the form of racemates, enantiomers and possibly diastereomeric pairs of enantiomers, as free bases or as acid addition salts, and all are included within the scope of this invention.
As used herein, the term lower alkyl denotes an alkyl group with 1 to 4 carbon atoms; the term halogen denotes fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine, and the term acyl denotes an optionally substituted, optionally branched aliphatic acyl group with up to six carbon atoms or an optionally substituted benzoyl group.
Preferred are compounds of the invention wherein A represents a single bond, or a group =CH2, =CH(CH3), =(CH3)2 or =CH(C2H5), represents hydroxy or acyloxy in the m- or p-position relative to the side-chain; - 3 r2 represents hydrogen or a methyl or ethyl group; R3 represents one of the groups of formula (II) or (III) above, in which m represents 2 or 3, n represents 1, 2 or 3, Rg, R^ and Rg represent hydrogen or methyl, Rg represents hydrogen or a group Ar or NH-CO-Ar, wherein Ar represents a 2-pyridyl or 4-pyridyl group or a group of formula (IV), in which R^g represents hydrogen, hydroxy, methyl or a group -NHR^g, the group R-^g representing acetyl or methanesulfonyl or, R^g together with R^ represents a methylenedioxy group, R^ represents hydrogen, hydroxy, methyl or a group -NHR^g, the group R13 representing acetyl or methanesulfonyl or, together with R^g, represents a methylenedioxy group, R12 represents hydrogen.
Particularly preferred are compounds wherein A represents a group =C(CHg)2 or -CH.J-, R1 ‘represents hydroxy in the p- or m-position relative to the side-chain, R2 represents hydrogen, or a methyl or ethyl group; Rg represents isopropyl, tert.-butyl, cyclopentyl, 1- methylcyclopentyl, or a group of formula (III) wherein n represents 1 or 2, R? and Rg represent hydrogen or methyl, and Rg represents one of the groups phenyl, 4-hydroxyphenyl, 2- pyridyl, 4-pyridyl, 2-hydroxyphenyl, 2,6-dimethyl4-hydroxy phenyl, 2-methyl-4-hydroxyphenyl, NH-CO- - 4 According to a further aspect of the invention, we provide a process for the preparation of compounds of formula (I) as defined in claim 1 wherein either a) a compound of formula (V) wherein A, R^, R2 and R3 are as defined in claim 1, any phenolic hydroxyl groups present being optionally protected by hydrogenolytically cleavable protecting groups, is reduced followed, if necessary by deprotection; or b) a phenylglyoxal or hemiacetal of formula (XII) wherein R^ and A are as defined in claim 1, any phenolic hydroxy groups present being optionally protected by hydrogenolytically cleavable protecting groups, and Q represents -CHO or -CH(0H)-0-lower alkyl, is reacted under conditions of reductive amination with an amine of formula (XIII) h2h-r (XIII) wherein R3 is as hereinbefore defined, any hydroxyl groups contained therein being optionally protected by hydrogenolytically cleavable protecting groups, followed, if necessary or if desired, by deprotection; or c) deprotecting compound of formula (XVI) OH R» wherein A and are as defined in claim 1, R£ represents R^ or a hydroxyl group protected by a hydrogenolytically cleavable protecting group, Rj represents R^, any hydroxyl group present in R^ being optionally protected by a hydrogenolytically cleavable protecting group, and R represents hydrogen or a hydrogenolytically cleavable protecting group, at least one protecting group which is to be split off being present in the compound of formula (XVI), after which, if necessary and if desired the compounds obtained according to reactions a) to c) are resolved by conventional methods into their enantiomers, optionally into diastereomeric pairs of enantiomers, any bases initially obtained are converted into their acid addition salts, and/or any acid addition salts initially obtained are converted into bases or salts of other acids.
In reaction a), the reduction is preferably effected in a solvent which is sufficiently stable under the reaction conditions, e.g. in a lower alcohol such as ethanol. As the reducing agents, water and hydrogenation catalysts (such as palladium, platinum, Raney nickel) or hydrides (such as sodium borohydride or diborane) may be used. By a suitable choice of reducing agent (catalytic reduction or reduction with hydrides) it is possible to prepare predominantly either the erythro- or threo-form of an optically active compound of the invention. Any hydrogenolytically cleavable protecting groups present on the nuclear amino group or on a phenolic hydroxyl group, such as benzyl or substituted benzyl group, may be removed in the usual way during or after the reduction reaction.
The compounds of formula (V) used as starting materials which are new compounds may be obtained according to methods known per se, as shown in the following reaction scheme, which is by way of examples CICO-OFh Bz = Benzyl (VI) L (VII) Corresponding bromoketones with an optionally protected hydroxyl group in the m-position relative to the side-chain may be obtained by the following reaction procedure, which is also by way of example: I Bz-0 I 04 *2 -CO-CH-Br \, \-CO-CH-Br Bz° (VIII'' The bromoketones of Bz-0 (IX) formula (X) (X) 3 61S - 8 obtained in this way or by other conventional methods, wherein A, R^ and R2 are as hereinbefore defined but wherein phenolic hydroxyl groups may be protected by hydrogenolytically removable groups, such as benzyl, may then be converted into the compounds of formula (V) by reaction thereof with amines of formula R' HN-R3 (XI) wherein R3 is as hereinbefore defined and R* represents hydrogen or a hydrogenolytically cleavable group, such as benzyl or substituted benzyl. The reaction is preferably carried out in suitable inert solvents such as acetonitrile or ethyl acetate, in the presence of an acid-binding agent, such as sodium carbonate or excess amine. Any protecting groups present in the reaction product may be removed subsequently or as the reaction continues.
In reaction (b), instead of reagents of formulae (XII) and (XIII), it is also possible to reduce the Schiff bases of formula (XIV) wherein A, and R3 are as hereinbefore defined, which may occur as intermediates during the reaction.
Complex hydrides, preferably sodium borohydride or hydrogen and a hydrogenation catalyst such as platinum, palladium or nickel may be used as the reducing agent.
Any phenolic hydroxy groups contained in the starting materials may be protected by means of conventional . S361S - 9 hydrogenolytically cleavable groups. These protecting groups may be removed by hydrogenolysis in the usual way during or after the reduction.
The final products of this reaction are compounds of 5 formula (I) wherein R2 represents hydrogen.
The compounds of formula (XII) used as starting materials may be obtained from acetophenone derivatives of formula (XV) wherein and A are as hereinbefore defined, by oxidation e.g. with selenium dioxide in aqueous dioxan. Depending on whether the product is crystallised from water or lower alcohols, either glyoxals or hemiacetals are obtained.
The amines of formula (XIII) are known or may readily be obtained according to conventional methods.
In reaction c), the compounds of formula (XVI) may be obtained by reducing compounds of formula (V) by a process as described above. Examples of hydrogenolytically cleavable protecting groups include, in particular, benzyl and substituted benzyl.
If desired, the compounds obtained according to reactions (a) to (c) may be resolved into their enantiomers, optionally into diastereomeric pairs of enantiomers, by conventional methods. Any bases initially obtained may be converted into their acid addition salts, and/or any acid addition salts initially obtained may be converted into bases or salts of other acids.
The compounds according to the invention have pharmaceutical application. They have, inter alia, - 10 a broncholytic, spasmolytic and antiallergic activity, and they increase ciliary activity and reduce inflammatory exudative reactions. They are therefore suitable for use in all forms of asthma and bronchitis, and in urticaria, conjunctivitis, hay fever and colds and chills. They also act as relaxants on the muscles of the uterus and are therefore capable of minimising labour pains. The compounds may also be used for the treatment of cardiovascular disorders, e.g. high blood pressure, diseases of the peripheral blood vessels and arrhythmia. Further activities which have been observed are inhibition of gastric secretion and antidepressant effects in the CNS.
According to the further aspect of the invention, we provide pharmaceutical compositions comprising a compound of formula (I) as defined above in association with a carrier, excipient or diluent.
The therapeutic and prophylactic dosage suitable depends on the nature and gravity of the complaint and the method of administration.
In adults, the following dosages are recommended for the following indications.
As broncholytics, the compositions may be taken orally in a dosage of from 0.05 to 5 mg; by inhalation from 0.01 to 1.0 mg; and subcutaneously from 0.02 to 0.05 mg.
When used as uterine agents, the pharmaceutical compositions may be taken orally in a dosage of from 10 to 50 mg or, in the form of a solution for infusion, ml ampoules containing from 0.01 to 1 mg may be used.
For vasodilation, 20 to 100 mg may be taken orally or ampoules containing 20 to 40 mg are used for i.m. injection. The hypotensive agents should preferably be taken orally in a dose of from 200 mg to 1.8 g.
The pharmaceutical compositions may also contain other therapeutic ingredients. Thus, the broncholytics - 11 can be combined with theophyllines, parasympatholytics (e.g. ipratropium bromide), secretolytics (e.g. bromhexine), musculotropic spasmolytics (e.g. papaverine), corticosteroids and antiallergics. In the uterus relaxants, combinations with corticoids are possible.
The compositions may take the form of capsules, tablets, solutions and suspensions which are suitable for oral administration. In pulmonary administration, dry powders preferably with a particle size diameter of from 0.5 to 7p are introduced into the bronchial region by means of aerosol propellents. For parenteral administration, the compositions are preferably in the form of sterile isotonic aqueous solutions.
For topical use, lotions, creams, ointments, emulsions and sprays may be used. Methods of preparing and formulating such compositions are known per se.
The compounds according to the invention may also be used to increase the growth rate of meatproducing animals, e.g. pigs, cattle, sheep, chickens and geese. The utilisation of fodder is improved substantially and furthermore the meat obtained is of higher quality and has a lower fat content than that obtained when the compounds of the invention . are not used.
Aspects of the invention will now be illustrated in the following Examples, which should not be considered as limiting. - 12 Pharmaceutical Examples Tablets Composition of a tablet Active substance according to invention 20 mg 5 Colloidal silicic acid 10 mg Lactose 118 mg Potato starch 60 mg Polyvinylpyrrolidone 6 mg Na-cellulose glycolate 4 mg 10 Magnesium stearate Ampoules Composition of the solution per ampoule 2 mg 220 mg Active substance according to invention 10 mg 15 Sorbitol 40 mg Distilled water ad Suppositories Composition of each suppository 10 ml 20 Active substance according to invention 100 mg Suppository mass (cocoa butter) Powder for inhalation 1600 mq 1700 mg Each bard gelatine capsule is packed with 0.5 mg of active substance according to the invention and 19.5 mg of lactose with a particle diameter of between 0.5 and 7 pm.
For the pharmacological tests, the usual test methods and test animals or organs are used. From a pharmacological point of view the compounds according to the invention are, in some respects, very different from commercially available products used for the same indications. In addition to having a good duration of activity, they have a particularly sharp selectivity, for example, in their broncholytic effect in relation to the increase in heart rate. Thus, for example, for the compound of Example 1, in guinea pigs the EDggi.v. Iyig/kg] of the increase in heart rate is $3615 - 13 more than ten times the EDggi.v. [jig/kg] of broncholysis, which is only 0.045 jig/kg. The resorption characteristics are generally favourable as well. Thus, the resorption quotient ED5Qp.o. "so1·’· is only 1.1, for example, for compound 7 in Table 3, which means that the oral activity is virtually as great as the intravenous activity. In the mouse, for example, the LD5Q values are so much higher than the therapeutic dose that a favourable therapeutic range is provided.
The following Examples illustrate the processes according to the· invention more fully without restricting them, since the reaction conditions may be varied considerably with similar results.
Depending on the solvent from which the substances mentioned hereafter are crystallised, some of them still contain defined quantities of the solvent bound in the crystal. The melting points given are uncorrected 536X5 - 14 Example 1 Q 16.1 g of S'-benzyloxy-S'-Cl-oxo-a-bromobutyl)2H-l,4-benzoxazin-3-(4H)-one and 7.5 g of isopropylamine are stirred in 100 ml of acetonitrile for 4 hours at 60°C. After acidification with cone, hydrochloric acid and addition of the mixture to 100 ml of water the 5'-benzyloxy-8'-(l-oxo-2-isopropylamino-butyl)2H-l,4-benzoxazin-3-(4H)-one hydrochloride (melting point 229 - 232°C) crystallises out. g of these compounds are debenzylated in methanol, with the addition of palladium/charcoal as catalyst, to yield 5'-hydroxy-8'-(l-oxo-2-isopropylaminobutyl)2H-l,4-benzoxazin-3-(4H)-one hydrochloride dihydrate (melting point 242 - 245°C).
By hydrogenating 3.3 g of this compound in methanol with platinum as catalyst, 3 g of erythro-5'-hydroxy25 8'- (l-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxaz in3-(4H)-one hydrochloride hydrate are obtained (yield: 90% of theory), which melts at 208 - 210°C.
Example la H0- F2H5 -CH-CH-NH-CH(CH3)2 X HCl (threo) OH 32.4 g of 5'-benzyloxy-8'-(l-oxo-2-bromo-butyl)~ 2H-l,4-benzoxazin-3-(4H)-one and 72 g of benzylisopropyl35 - 15 amine are stirred at 100°C for 15 Hours. After the addition of water the oil precipitated is taken up in ether and diluted with petroleum ether; crystallisation of 5'-benzyloxy-81-(l-oxo-2-benzylisopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one takes place. 11.6 g of this compound are combined with a mixture of 60 ml of ethanol and 60 ml of acetonitrile with 1 g of sodium borohydride and the resulting mixture is stirred for three hours. Then 250 ml of ice-cold water and 100 ml of ethyl acetate are added and, after the sodium borohydride has been decomposed with concentrated acetic acid, with stirring, the mixture is made alkaline by the addition of concentrated ammonia solution, the ethyl acetate phase is separated off, dried and concentrated by evaporation in the Rotavapor. The oily residue is dissolved in ether and cooled and the threo-5*-benzyloxy-8*-(1-hydroxy2- benzylisopropylamino-butyl)-2H-1,4-benzoxazin-3(4H)-one precipitated (melting point 89 - 92°C) is suction filtered. 4.8 g of this compound are hydrogenated in 100 ml of methanol with palladium/charcoal as catalyst. After uptake has ended, the catalyst is removed from suction filtering, the mother liquor is concentrated . by evaporation in the Rotavapor and the oily residue is dissolved in acetone/ethanol and acidified with the calculated quantity of hydrchloric acid. The solution is diluted with ether and the threo-5*-hydroxys'- (l-hydroxy-2-isopropylamino-butyl) -2H-1,4-benzoxazin3- (4H)-one hydrochloride precipitated (yield: 74% of theory) is suction filtered; after being re-precipitated from methanol/ether it melts at 202 -205°C.
S3615 g of 57-benzyloxy-8'-(l-oxo-2-bromo-ethyl)2H-l,4-benzoxazin-3-(4H)-one and 8.75 g of benzyltert.-butylamine are refluxed in 100 ml of acetonitrile for 3 hours. After cooling, the crystals precipitated are suction filtered and washed with 200 ml of warm water. The crystals are acidified in acetonitrile with etheric hydrochloric acid; after dilution with ethyl acetate, 5'-benzyloxy-8’-(l-oxo-2-benzyl-tert.20 butylaminoethyl)-2H-l,4-benzoxazin-3-(4H)-one hydrochloride is precipitated (melting point 185 - 189°C). g of this compound are debenzylated at 5 bar and at 50°C in 100 ml of methanol, with the addition of palladium/oharcoal as catalyst, to yield 5'-hydroxy25 8'-(l-oxo-2-tert.-butylamino-ethyl)-2H-l,4-benzoxazin3-(4H)-one hydrochloride (melting point 237 - 240°C).
By catalytic hydrogenation of 2.2 g of this compound in methanol with platinum, 1.6 g of 5'-hydroxys' - (l-hydroxy-2-tert.-butylamino-ethyl) -2H-1,4-benzoxazin30 3-(4H)-one hydrochloride are obtained (yield: 72.5% of theory), melting at 185 -187°C. -17 The following were synthesised as described in the Examples mentioned: Melting point °C 230 (decomp .) tn to r" 1 m to 259 - 261 o u 0 Μ M •ri M 4J Ή r-1 4J r4 0 H s ϋ S ϋ H Λ Ό 0 -H 4J r4 Μ < N ‘3 *0 0 0 Μ < nJ V} £ * & s >1 o Λ Yield % of 1 to ID cn to cn co n CM n n X C*> X X n cj x *** CJ X I o CJ 1 Formul X X CJ s \/ X cj X X CJ X \z X (J "\Z X CJ 1 ructural X X CJ -o χό 1 X X cj -O o«Q0U CJ -O o00u X 4J cn = T - X X 0 S H CM m S361S $3615 Melting point °C VO- . $ 4 J ά m σ> C4 J3 I I •H £ n\ jJ W_ JN Sail H S o « & Ό £ Η ΨΙ o 0 0 •H X dfi CA - η n X X <-> U \x fd F-l 3 S M 5 1 X in z X 1 CM X ........J........ 0 fe ( CH-l OH 1 ms H 3 M 3 +> Χύ ®N3! °-7 K S3 0 3 0 1 II C-0 X° JJ W 0 I •4« O X § 6 £5 U3 H Ϊ-) - 22 5 3 615 Example 3 g of 5'-benzyloxy-8'~(l-oxo-2-hydroxy-2-ethoxyethyl)-2H-l,4-benzoxazin-3-(4H)-one, 2.2 g of 1,1dimethyl-3-phenylpropylaraine and 50 ml of alcohol are heated to 50 - 60°C for 3 hours. After the reaction mixture has been cooled, the Schiff base precipitated (melting point 138 - 140°C) is suction filtered. 4.5 g of this compound are added to 100 ml of alcohol and mixed with 1 g of sodium borohydride and the mixture is stirred for 2 hours at ambient temperature. After the addition of 100 ml of water the 5'-benzyloxy-8'-[l-hydroxy-2-(4-phenyl-2-methylbutylamino)-ethyl]-2H-l,4-benzoxazin-3-(4H)-one precipitated (melting point 162 - 164°C) is suction filtered and the hydrochloride (melting point 205 - 207°C) is prepared using etheric hydrochloric acid.
By catalytic hydrogenation of this compound in 50 ml of methanol under normal conditions, using palladium charcoal as catalyst, 2.7 g of 5’-hydroxy8'-[l-hydroxy-2-(4-phenyl-2-methyl-butylamino)-ethyl]2H-l,4-benzoxazin-3-(4H)-one-hydrochloride are obtained (melting point 159 - 161°C, yield; 90% of theory). x HCL - 23 5.8 g of 6'-chloro-8’-(l-oxo-2-hydroxy-2-ethoxyethyl)-2H-l,4-benzoxazin-3-(4H)-one, 1.5 g of tect.butylamine, 60 ml of dioxan and 60 ml of alcohol are heated to 50°C for 2 hours. The solution is then cooled and 2 g of sodium borohydride are added thereto at 10 to 20°C. The solution is stirred at ambient temperature for 1 hour, then poured on to 500 ml of ice-cold water and 150 ml of ethyl acetate are added. After the sodium borohydride has been decomposed with cone, acetic acid, with stirring, the mixture is made alkaline with aqueous amonia, the ethyl acetate phase is separated, dried with sodium sulphate and concentrated by evaporation in the Rotavapor. The oily residue is dissolved in ml of alcohol, acidified with etheric hydrochloric acid and the 6,-chloro-8’-[l-hydroxy-2-(tert.-butylamino) ethyl]-2H-1,4-benzoxazin-3-(4H)-one-hydrochloride precipitated (yield: 38% of theory) is suction filtered. After being re-precipitated twice from methanol, with the addition of active charcoal, the substance has a melting point of over 300°C (melting point of base: 173 - 177°C).
S3615 - 53615 I +j c •rl Ο Oj σ» c? •Η U Ο »—I Ο ♦Η S r—( w 0) H Ή M q -μ •H -H $4 a o o rM 44 Utf U ο ή a ? * u QJ Λ U rH IW Φ O Ή >» dP to X no <*» x ’ x o - V -O I. β S M Cu nJ M a ϋ a P W - 28 5 Example 5 4.3 g of 5'-benzyloxy-8(l-hydroxy-2-benzylethylamino15 ethyl)-2H-1,4-benzoxazin-3-(4H)-one-hydrochloride (melting point 232 - 235°C) are hydrogenated in 125 ml of methanol with the addition of 0.5 g of 5% palladium/ charcoal. After the calculated quantity of hydrogen has been taken up, the catalyst is filtered off and the solution is distilled under reduced pressure.
By triturating the residue with acetonitrile 2.5 g of 5'-hydroxy-8'-(l-hydroxy-2-ethylamino-ethyl)2H-l,4-benzoxazin-3-(4H)-one-hydrochloride are obtained (yield: 86.7% of theory), which melts at 240 to 242°C after being re-precipitated from methanol/ether.
Example 6 ch3 ch-ch2-nh-c-ch2-ch2-nhc OH CH3 0 x HC OH 6.3 g of 4'-benzyloxy-7'-[l-hydroxy-2-(4-picolinic acid-amido-2-methyl-2-butylamino)-ethyl]-2-benzoxazolinone (melting point 130 - 133°C) are hydrogenated in 125 ml of methanol with the addition of 1 g of 5% palladium/ charcoal. When the uptake of hydrogen has ended, the catalyst is filtered off and the clear solution is concentrated by evaporation in the Rotavapor under reduced pressure. The oily residue is dissolved in 10 ml of alcohol and 0.58 g of formic acid are 53613 - 29 added. After 5 hours, the 4'-hydroxy-7'-[1-hydroxy2-(4-picolinic acid amido-2-methyl-2-butylamino)2-benzoxazolinone-formate precipitated (yield: 78.5% of theory, melting point 166 - 168°C) is suction filtered. 53815 τ3 φ •rl •rl ϋ Φ Οι U1 Φ Φ rP Β1 Φ * Φ Φ χ3 Ρ Ο Ρ cn β •rl Ό Ρ Ο ο ϋ φ Ό Φ ω •r| W Φ Λ Ρ β >1 0} Φ Ρ Φ Cn β •Ρ Ο ip ίΡ Ο Μ-Ι Η Η Η ω CQ Εμ Ρ β •Ρ ο CU & β •r| Ρ ο ιΡ β co ο CM un ο CM r< CM I VO *r CM CO CM I o CM xi P •rl ρ H Φ W Ρ φ Ρ Ρ *ϋ Η Ρ Φ ο •Η >1 t/P ϋ •rl P rp □ •P P rp XJ TJ Δ ϋ ·Ρ Ρ 0 0 0 P rfj τι r>1 W X XJOX U ·Η P Ο ϋ Φ P < Ό vJ^1 X •P r-l ρ 2 ο β r—I Λ Ό -C OPP 0 Ο Φ Ρ < Ό <« X r*» co m ρ-* ο •r* H-CH,-NH-C-CH,-CH JJ fi Ή 0 Λ CP c Ή 4J O O Φ s CM cn r— 1 cn co σ> CM CM 1 IO CM CM 206 - 209 Salt with Formic Acid x 1 water Hydrochloric Acid Hydrochloric Acid Yield % of theory * o K. CO co tn co n»» Structural Formula n X σ5 O CO X l X 0-0-0 f X z 1 · CM X O I X X 0-0 X s X z 1 CM X x£ X X O Φ ‘cm X o cn i X X 0-0 I X z 1 CM X χδ, X No. ‘53615 5361S - 37 Intermediate products of formula (V) which can be obtained according to the above scheme are listed below.
The compounds of formula (V) may also be used 5 as pharmaceutical compositions themselves, since they have similar pharmacological properties to the compounds of formula (I).
S3615 Melting point CM J· CM ί CM CM CM a> d in CM I o in CM CC4 r4 CM <·> m W Ϊ u>S S I CJ S3 CM KS U s-z u S3615 - 39 Melting point •H S rH nJ ω a ε *4 O b S3615 Formula I Salt with I Melting point Melting point
Claims (15)
1. Compounds of formula (I) (I) wherein A represents a single bond, the group -CH 2 -CH 2 -, R the group =c' wherein R^ represents hydrogen or a lower alkyl group, and Rg represents hydrogen, or a lower alkyl or, when R 4 represents hydrogen, a phenyl group; R^ represents a hydroxy or acyloxy group or a chlorine or hydrogen atom; R 2 represents hydrogen, or a methyl or ethyl group; ? H 2-f CH 2>m| R 7 25 and Rg represents a group -C-CH 2 ——** or -C-(CH 2 ) n -Rg R 6 r 8 (II) (HI) 30 wherein m represents either 2, 3 or 4, n represents either 1,2 or 3, Rg represents hydrogen or methyl, R? represents hydrogen or methyl, Rg represents hydrogen or methyl, 35 Rg represents hydrogen, or a group Ar, OAr, or -NHCO-Ar, wherein Ar represents one of the groups R.
2. - pyridyl, 4-pyridyl, 2-hydroxyphenyl, 2,6-dimethyl4-hydroxy phenyl, 2-methyl-4-hydroxyphenyl,
3. Compounds of formula (I) as claimed in claim 1 wherein A represents a group =C(CH 3 ) 2 or -CH 2 ~5 R| represents hydroxy in the p- or m-position relative to the side-chain;
4. 5 1 -Hydroxy-8'-(l-hydroxy-2-iSopropylamino-butyl)2H-1,4-benzoxazin-3-(4H)-one and salts thereof. 30 5. Pharmaceutical compositions comprising a compound as claimed in any one of claims 1 to 4 in association with a pharmaceutically acceptable carrier, diluent or excipient.
5. Examples. 5 R 12 represents hydrogen.
6. A process for the preparation of compounds 35 of formula (I) as defined in claim 1 wherein either a) a compound of formula (V) Ο (V) wherein A, R^, R^ and R 3 are as defined in claim 1, any phenolic hydroxyl groups present being optionally protected by hydrogenolytically cleavable protecting groups, is reduced followed, if necessary by deprotection; or b) a phenylglyoxal or hemiacetal of formula (XII) —CO—Q R. wherein R^ and A are as defined in claim 1, any phenolic hydroxy groups present being optionally protected by hydrogenolytically oleavable protecting groups, and Q represents -CHO or -CH(0H)-0-lower alkyl, is reacted under conditions of reductive amination with an amine of formula (XIII) (XIII) wherein Rj is as hereinbefore defined, any hydroxyl groups contained therein being optionally protected by hydrogenolytically cleavable protecting groups, followed, if necessary or if desired, by deprotection; or o) deprotecting compound of formula (XVI) 53815 46 Ο ?2 (XVI) -CH-CH-N-Rj OH ΙΟ wherein A and Rj ace as defined in claim 1, Rj represents or a hydroxyl group protected by a hydrogenolytically cleavable protecting group, Rj represents R 3 , any hydroxyl group present in R 3 being optionally protected 15 by a hydrogenolytically cleavable protecting group, and R' represents hydrogen or a hydrogenolytically cleavable protecting group, at least one protecting group which is to be split off being present in the compound of formula (XVI), after which, if necessary 20 and if desired the compounds obtained according to reactions a) to o) are resolved by conventional methods into their enantiomers, optionally into diastereomeric pairs of enantiomers, any bases initially obtained are converted into their acid addition salts, and/or 25 any acid addition salts initially obtained are converted into bases or salts of other acids.
7. A process as claimed in claim 6 substantially as hereinbefore described.
8. A process as claimed in claim 6 substantially 30 as hereinbefore described with reference to the Examples.
9. Compounds of formula (V) as defined in claim 6. -£-ch-nk-r 3 II *1 10. Prophylaxis of the human or animal body to combat asthma, bronchitis, urticaria, conjunctivitis, hay fever, colds, chills, labour pains and cardiovascular disorders or to relax the uterus.
10. A process for the preparation of compounds of formula (V) as defined In claim 9 substantially as hereinbefore described. 10 Rj represents hydrogen, or a methyl or ethyl group; R 3 represents isopropyl, tert.-butyl, cyclopentyl,
11. A process for the preparation of compounds of formula (V) as defined in claim 9 substantially as hereinbefore described with reference to the
12. Compounds of formula (1) as defined in claim 1, whenever prepared by a process as claimed in any of claims 6 to 8. ‘12 or (IV) in which Η^θ, R^, R^ 2 (which may be identical or different, are each selected from hydrogen, hydroxy, methyl, methoxy, halogen, -C0HH 2 and NH-Rjj, the group r 13 representing hydrogen, acyl or a lower 15 alkylsulfonyl group, or any two of Rj_q, R^j. and R 12 may represent a methylenedioxy group, the compounds being in the form of their racemates, enantiomers or diastereomeric pairs of enantiomers, or their acid addition salts. 20 2. Compounds of formula (I) as claimed in claim
13. Compounds of formula (1), as defined in claim 1, and physiologically acceptable acid addition salts thereof for use in a method of treatment or
14. Compositions for improving the production of flesh and the utilisation of fodder in meat-producing animals which contain a compound of 15 formula (I) as defined in claim 1.
15. The use of compounds of formula (I) as defined in claim 1 for improving flesh production and the utilisation of fodder in meat-producing animals, particularly poultry, cattle, pigs and sheep.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19813134590 DE3134590A1 (en) | 1981-09-01 | 1981-09-01 | NEW BENZO HETEROCYCLES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE822105L IE822105L (en) | 1983-03-01 |
| IE53615B1 true IE53615B1 (en) | 1988-12-21 |
Family
ID=6140603
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2105/82A IE53615B1 (en) | 1981-09-01 | 1982-08-31 | Benzo heterocycles |
Country Status (25)
| Country | Link |
|---|---|
| EP (1) | EP0073505B1 (en) |
| JP (1) | JPS5852278A (en) |
| KR (1) | KR890000380B1 (en) |
| AR (2) | AR231976A1 (en) |
| AT (1) | ATE16703T1 (en) |
| AU (1) | AU553589B2 (en) |
| CA (1) | CA1180012A (en) |
| CS (1) | CS236679B2 (en) |
| DD (1) | DD204477A5 (en) |
| DE (2) | DE3134590A1 (en) |
| DK (1) | DK158664C (en) |
| ES (3) | ES515380A0 (en) |
| FI (1) | FI78475C (en) |
| GB (1) | GB2106105B (en) |
| GR (1) | GR77275B (en) |
| HU (1) | HU186112B (en) |
| IE (1) | IE53615B1 (en) |
| IL (1) | IL66683A0 (en) |
| NO (1) | NO157738C (en) |
| NZ (1) | NZ201777A (en) |
| PL (1) | PL139375B1 (en) |
| PT (1) | PT75478A (en) |
| SU (1) | SU1149876A3 (en) |
| YU (1) | YU42794B (en) |
| ZA (1) | ZA826349B (en) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4554284A (en) * | 1984-09-12 | 1985-11-19 | Smithkline Beckman Corporation | 7-(2-Aminoethyl)-1,3-benzthia- or oxa-zol-2(3H)-ones |
| DE3743265A1 (en) * | 1987-12-19 | 1989-06-29 | Boehringer Ingelheim Kg | NEW AMMONIUM COMPOUNDS, THEIR MANUFACTURE AND USE |
| TW372967B (en) * | 1994-12-27 | 1999-11-01 | Kanebo Ltd | 1,4 benzoxazine derivative, pharmaceutical composition containing the same and use thereof |
| US7056916B2 (en) | 2002-11-15 | 2006-06-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Medicaments for the treatment of chronic obstructive pulmonary disease |
| DE10253282A1 (en) * | 2002-11-15 | 2004-05-27 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Treatment of chronic obstructive pulmonary disease, using new or known N-substituted 2-amino-1-(benz-(1,4)-oxazin-3-on-8-yl)-ethanol derivative beta-mimetic agents, suitable for once-daily administration |
| PE20040950A1 (en) | 2003-02-14 | 2005-01-01 | Theravance Inc | BIPHENYL DERIVATIVES AS AGONISTS OF ß2-ADRENERGIC RECEPTORS AND AS ANTAGONISTS OF MUSCARINAL RECEPTORS |
| GB0307856D0 (en) * | 2003-04-04 | 2003-05-14 | Novartis Ag | Organic compounds |
| BRPI0409198A (en) | 2003-04-04 | 2006-05-02 | Novartis Ag | quinolin-2-one derivatives for the treatment of airway diseases |
| WO2005110990A1 (en) * | 2004-05-13 | 2005-11-24 | Boehringer Ingelheim International Gmbh | Hydroxy-substituted benzo-condensed heterocycles for use as beta agonists in the treatment of respiratory diseases |
| US7307076B2 (en) | 2004-05-13 | 2007-12-11 | Boehringer Ingelheim International Gmbh | Beta agonists for the treatment of respiratory diseases |
| DE102004024453A1 (en) * | 2004-05-14 | 2006-01-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New long-acting bronchodilators for the treatment of respiratory diseases |
| DE102004024454A1 (en) * | 2004-05-14 | 2005-12-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Novel enantiomerically pure beta agonists, process for their preparation and their use as pharmaceuticals |
| US7220742B2 (en) | 2004-05-14 | 2007-05-22 | Boehringer Ingelheim International Gmbh | Enantiomerically pure beta agonists, process for the manufacture thereof and use thereof as medicaments |
| DE102004024451A1 (en) * | 2004-05-14 | 2005-12-22 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Powder formulations for inhalation containing enantiomerically pure beta agonists |
| US7745621B2 (en) | 2004-05-14 | 2010-06-29 | Boehringer Ingelheim International Gmbh | Long acting bronchodilators for the treatment of respiratory diseases |
| DE102004024452A1 (en) * | 2004-05-14 | 2005-12-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Aerosol formulation for the inhalation of beta agonists |
| MX2008001976A (en) * | 2005-08-15 | 2008-03-25 | Boehringer Ingelheim Int | Method for producing betamimetics. |
| TWI389692B (en) * | 2005-10-10 | 2013-03-21 | Boehringer Ingelheim Int | Aerosol formulations for the inhalation of beta-agonists |
| GB0602778D0 (en) | 2006-02-10 | 2006-03-22 | Glaxo Group Ltd | Novel compound |
| EP2057152A1 (en) * | 2006-08-07 | 2009-05-13 | Boehringer Ingelheim International GmbH | Single enantiomer beta-agonists, methods for the production thereof and the use thereof as medication |
| UY30543A1 (en) * | 2006-08-18 | 2008-03-31 | Boehringer Ingelheim Int | AEROSOL FORMULATION FOR INHALATION OF BETA- AGONISTS |
| JP5409387B2 (en) * | 2007-01-25 | 2014-02-05 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Method for producing β-mimetic |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2035749A1 (en) * | 1969-02-06 | 1970-12-24 | Bellon Labor Sa Roger | |
| DE2429253A1 (en) * | 1974-06-19 | 1976-01-15 | Boehringer Sohn Ingelheim | PHENYLAL CANOLAMINE |
-
1981
- 1981-09-01 DE DE19813134590 patent/DE3134590A1/en not_active Withdrawn
-
1982
- 1982-08-27 SU SU823483451A patent/SU1149876A3/en active
- 1982-08-28 AT AT82107919T patent/ATE16703T1/en not_active IP Right Cessation
- 1982-08-28 EP EP82107919A patent/EP0073505B1/en not_active Expired
- 1982-08-28 DE DE8282107919T patent/DE3267702D1/en not_active Expired
- 1982-08-30 YU YU1949/82A patent/YU42794B/en unknown
- 1982-08-30 PT PT75478A patent/PT75478A/en not_active IP Right Cessation
- 1982-08-30 FI FI822985A patent/FI78475C/en not_active IP Right Cessation
- 1982-08-30 AR AR290473A patent/AR231976A1/en active
- 1982-08-30 PL PL1982238077A patent/PL139375B1/en unknown
- 1982-08-30 DD DD82242881A patent/DD204477A5/en unknown
- 1982-08-31 GR GR69166A patent/GR77275B/el unknown
- 1982-08-31 NO NO822932A patent/NO157738C/en unknown
- 1982-08-31 IL IL66683A patent/IL66683A0/en not_active IP Right Cessation
- 1982-08-31 CA CA000410462A patent/CA1180012A/en not_active Expired
- 1982-08-31 IE IE2105/82A patent/IE53615B1/en not_active IP Right Cessation
- 1982-08-31 HU HU822793A patent/HU186112B/en not_active IP Right Cessation
- 1982-08-31 CS CS826329A patent/CS236679B2/en unknown
- 1982-08-31 AU AU87874/82A patent/AU553589B2/en not_active Ceased
- 1982-08-31 ZA ZA826349A patent/ZA826349B/en unknown
- 1982-08-31 GB GB08224810A patent/GB2106105B/en not_active Expired
- 1982-08-31 ES ES515380A patent/ES515380A0/en active Granted
- 1982-08-31 JP JP57151626A patent/JPS5852278A/en active Granted
- 1982-08-31 NZ NZ201777A patent/NZ201777A/en unknown
- 1982-08-31 DK DK389082A patent/DK158664C/en not_active IP Right Cessation
- 1982-09-01 KR KR8203945A patent/KR890000380B1/en active
-
1983
- 1983-04-27 ES ES521870A patent/ES521870A0/en active Granted
- 1983-04-27 ES ES521871A patent/ES521871A0/en active Granted
- 1983-11-17 AR AR294856A patent/AR231977A1/en active
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| MM4A | Patent lapsed |