NZ201777A

NZ201777A - Benzoheterocyclic compounds and pharmaceutical compositions

Info

Publication number: NZ201777A
Application number: NZ201777A
Authority: NZ
Inventors: K Schromm; A Mentrup; E-O Renth; A Fugner
Original assignee: Boehringer Ingelheim Int
Priority date: 1981-09-01
Filing date: 1982-08-31
Publication date: 1985-08-30
Also published as: DK158664C; AU553589B2; JPH035392B2; ES515380A0; DK389082A; DE3267702D1; NO822932L; DD204477A5; GR77275B; YU194982A; AU8787482A; PT75478A; NO157738B; FI822985A0; KR890000380B1; PL139375B1; FI78475B; ZA826349B; GB2106105B; IE822105L

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £01 111 201 7 7 NO DRAWIKGS -GO Patents Form No. 5 NEW ZEALAND PATENTS ACT 195 3 COMPLETE SPECIFICATION "BENZO HETEROCYCLES" -J-,V7E BOEHRINGER INGELHEIM INTERNATIONAL GMBH, a German company, of D-6507 Ingelheira am Rhein, Federal Republic of Germany, hereby declare the invention, for which ->/we pray that a patent may be granted to mc/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- -1- (followed by page 1 A.) 201777 - i/l- 1M139-0 47 "Benzo Heterocycles" The invention relates to benzo heterocycles. 5 More particularly it relates to benzo heterocycles having useful therapeutic properties. According to the invention, we provide compounds general formula (I) 10 0 ii A HN//" 0 >=/ fl2 ID / \ -ch-ch-nh-r -2 X_/ °h 3 Ri wherein A represents a single bond, a group -CE^-CI^- , 20 R5 or a group =c{ wherein R. represents hydrogen R4 or lower alkyl, and R^ represents hydrogen, or lower 25 alkyl or, when R^ represents hydrogen, a phenyl group; R^ represents a hydroxy or acyloxy group or a chlorine or hydrogen atom; 30 R2 represents hydrogen, or a methyl or ethyl group, and ?H2-(CH2)m] ?7 represents a group -C-CI^ —" or (CI^) n~R<j R6 R8 35 (II) (III) wherein m represents either 2, 3 or 4, - 2 - 201777 10 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 15 20 25 30 35 L11 12 (IV) in which R^q, R-j^r and R12' which may be the same or different, are each selected from hydrogen, hydroxy, methyl, methoxy, halogen, -CONI^ and NH-R^ the group R^^ representing hydrogen, acyl or a lower alkylsulfonyl group, or any two of R^q , R^ and R^ 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 wherei A represents a single bond, or a group =(^2' =CH(CH3) ^ =C(CH3)2 or =CH(C2H5) , 9f^AYf9i R^ represents hydroxy or acyloxy in the m- or p-posit relative to the side-chain; 10 201777 - 3 - 1*2 represents hydrogen or a methyl or ethyl group; 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^0 represents hydrogen, hydroxy, methyl or a group -NHR^/ the group R^j representing acetyl or methanesulfonyl or, R1q together with R^ represents a methylenedioxy group, R11 rePresents hydrogen, hydroxy, methyl or a group 15 -NHR^j/ the group R^ representing acetyl or methanesulfonyl or, together with R^q/ represents a methylenedioxy group, R12 rePresents hydrogen. Particularly preferred are compounds wherein 20 A represents a group or -CI^-, R^ 'represents hydroxy in the p- or m-position relative to the side-chain, R2 represents hydrogen, or a methyl or ethyl group; R^ represents isopropyl, tert.-butyl, cyclopentyl, 25 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-dimethyl-30 4-hydroxy phenyl, 2-methyl-4-hydroxyphenyl, -NH-CO-/ ( ) \ , -NH-CO- 201777 - 4 - According to a further aspect of the invention, we provide a process for the preparatidn of compounds of formula (I) as defined in claim 1 wherein either a) a compound of formula (V) (V) 10 wherein A, , R2 and R^ are as defined in claim 1, any phenolic hydroxyl groups present being optionally 15 protected by hydrogenolytically cleavable protecting groups, is reduced followed, if necessary by deprotection; or b) a phenylglyoxal or hemiacetal of formula (XII) 20 (XII) -co-q 25 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(OH)-0-lower alkyl, is 30 reacted under conditions of reductive amination with an amine of formula (XIII) h0n-r, 0 (XIII) 35 wherein R^ is as hereinbefore defined, any hydroxyl groups contained therein being optionally protected 201777 r) 5 by hydrogenolytically cleavable protecting groups, followed, if necessary or if desired, by deprotection; or c) deprotecting compound of formula (XVI) 5 )-K 10 oh 3 (XVI) r1 1 15 wherein A and R2 are as defined in claim 1, R| represents R^ or a hydroxyl group protected by a hydrogenolytically cleavable protecting group, R^ represents R^, any hydroxyl group present in R^ being optionally protected by a hydrogenolytically cleavable protecting group, 20 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 25 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 30 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 35 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 201777 - 6 - 10 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 example: 15 h0- Friedel-Crafts h0- 02n oh hon oh 20 Bz-0- bz-0-, C1C0—CR^R^Cl, bz = benzyl -c0-ch2 Br, Bz-0— r, ^-co-ch2 ClCO-OFh -co—ch, v 35 ° r. x"— hn 0 bz-0-, r, ,-co-ch-br bzo- ?2 —co—ch—br 40 (VI) (VII) 201777 - 7 - 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: oh oh r2 I ,-co-ch, /r \ FL ^-co-ch2 oh Bz-0 02N OH h2n oh r, >-co-ch2 >-CO-CH-Br bz~° (viii) The bromoketones of formula (X) 0 La. hn \ \ \-CO-CH-Br 201777 - 8 - obtained in this way or by other conventional methods, wherein A, and R2 are as hereinbefore defined but wherein phenolic hydroxyl groups may be protected by hydrogenolytically removable groups, such as benzyl, 5 may then be converted into the compounds of formula (V) by reaction thereof with amines of formula R' HN-R3 (XI) 10 wherein R^ 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 15 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 20 (XII) and (XIII), it is also possible to reduce the Schiff bases of formula (XIV) 25 30 \^0-CH=N-R, <XIV> / 3 R1 wherein A, R^ and R^ 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 10 15 201777 hydrogenolytically cleavable groups. These protecting groups may be removed by hydrogenolysis in the usual I way during or after the reduction. The final products of this reaction are compounds of formula (I) wherein Rj represents hydrogen. The compounds of formula (XII) used as starting materials may be obtained from acetophenone derivatives of formula (XV) (XV) Ri wherein R^ and A are as hereinbefore defined, by oxidation e.g. with selenium dioxide in aqueous dioxan. 20 Depending on whether the product is crystallised from water or lower alcohols, either glyoxals or herciacetals 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 30 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 35 other acids. The compounds according to the invention have pharmaceutical application. They have, inter alia. 201777 - 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 5 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 10 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, 15 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 20 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 25 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, 30 10 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 35 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 777 - li - 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 5 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 10 of from 0.5 to Ip. 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 15 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 meat-producing animals, e.g. pigs, cattle, sheep, chickens 20 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. 25 Aspects of the invention will now be illustrated in the following Examples, which should not be considered as limiting. «) 201777 - 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 2 mg 220 mg Ampoules Composition of the solution per ampoule Active substance according to invention 10 mg 15 Sorbitol 40 mg Distilled water ad 10 ml Suppositor ies Composition of each suppository 20 Active substance according to invention 100 mg Suppository mass (cocoa butter) 1600 mg 1700 mg Powder for inhalation Each hard gelatine capsule is packed with 0.5 25 mg of active substance according to the invention and 19.5 mg of lactose with a particle diameter of between 0.5 and 7 p.m. For the pharmacological tests, the usual test methods and test animals or organs are used. From 30 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, 35 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 EDgqi.v. [jig/kg] of the increase in heart rate is 201777 - 13 - more than ten times the ED^gi.v. [jag/kg] of broncholysis, which is only 0.045 jig/kg. The resorption characteristics are generally favourable as well. Thus, the resorption quotient ED^gp.o. EDj-gi. v. 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 values are so much higher than 10 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 15 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. 201777 14 Example 1 0 5 Ht) OH /cm9-ch3 x Hci x h2o CH \nhch(ch3)2 10 16.1 g of 5'-benzyloxy-8'-(l-oxo-2-bromobutyl)- 2H-1,4-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 conc. hydrochloric acid and addition of the mixture to 100 ml of water 15 the 5'-benzyloxy-81 -(l-oxo-2-isopropylamino-butyl)-2H-1,4-benzoxazin-3-(4H)-one hydrochloride (melting point 229 - 232°C) crystallises out. 6 g of these compounds are debenzylated in methanol, with the addition of palladium/charcoal as catalyst, 20 to yield 5'-hydroxy-8'-(l-oxo-2-isopropylaminobutyl)-2H-1,4-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'-hydroxy-25 81 -(l-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxaz in-3-(4H)-one hydrochloride hydrate are obtained (yield: 90% of theory), which melts at 208 - 210°C. Example la 0 30 ho- 35 32.4 g of 5'-benzyloxy-8(l-oxo-2-bromo-butyl)-2H-1,4-benzoxazin-3-(4H)-one and 72 g of benzylisopropyl- 20177? - 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 51-benzyloxy-8'-(l-oxo-2-benzylisopropylamino-5 butyl)-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 10 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 15 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-hydroxy-2-benzylisopropylamino-butyl)-2H-1,4-benzoxazin-3-(4H)-one precipitated (melting point 89 - 92°C) is 20 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 25 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'-hydroxy-8'-(l-hydroxy-2-isopropylamino-butyl)-2H-1,4-benzoxazin-30 3-(4H)-one hydrochloride precipitated (yield: 7 4% of theory) is suction filtered; after being re-precipitated from methanol/ether it melts at 202 -205°C. 35 201777 16 Example 2 0 5 CH3 HO CH-CH2-NH-C-CH3 x HC1 OH CH3 10 10 g of 5*1 -benzyloxy-81 -(l-oxo-2-bromo-ethyl)- 2H-1, 4-benzoxazin—3-(4H)-one and 8.75 g of benzyl-tert.-butylamine are refluxed in 100 ml of acetonitrile 15 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-1,4-benzoxazin-3-(4H)-one hydrochloride is precipitated (melting point 185 - 189°C). 7 g of this compound are debenzylated at 5 bar and at 50°C in 100 ml of methanol, with the addition of palladium/charcoal as catalyst, to yield 5'-hydroxy-25 8'-(l-oxo-2-tert.-butylamino-ethyl)-2H-1,4-benzoxaz in-3-(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'-hydroxy-81 -(l-hydroxy-2-tert.-butylamino-ethyl)-2H-1,4-benzoxaz in-30 3-(4H)-one hydrochloride are obtained (yield: 72.5% of theory), melting at 185 -187°C. • • : The following were synthesised as described in the Examples mentioned: TABLE" I No. Structural Formula Yield % of theory Salt with Melting point : yCH«-CHn ^ch-CH/ OH NH-C(CH3)3 66 Hydrochloric Acid x 2 Water 230(decomp.) 0 H H_ - Q-™-ch\ OH X ch9-ch. / 2 3 OH OH NNH-CH(CH3)2 CH-CH CH9-CH, X 2 3 \. OH NH-C(CH3)3 63 03 Hydrochloric Acid Hydrochloric Acid 163 - 165 259 - 261 vj i No. Structural'formula Yield c^-n- ,,h+-k Melting point % of theory Salt Wlth °c k 0 /ch2"ch3 ho-/ v-ch-ch^ oh \lh-ch(ch3)2 67 Hydrochloric Acid 230 - 232 5 v/ .ch2-ch3 V>iH-CH\ OfH oh xnh-ch(ch3)2 71 Hydrochloric Acid ' x 1 Water 256 - 259 / No . Structural Formula 8 >-\ HN 0 ru 3 ho- >-ch-ch-nhch(ch3)2 oh 0 )—\ HN 0 r u W ,2 5 h0-<( a-ch-ch-nh oh ■0 Hr? Ko ?2H5 HO-^ VcH-CH-NH-CH0-CH0-<^VoH '2 2 oh 3 Yield % of theory 88 86 73,5 Salt with HC1 x 1/2 H20 HC1 x 1/2 H20 HC1 Melting poin-t 244 243-245 206-209 vo I 0 HN^O ?2H5 H°"V /^-CH"CH"NH"CH2"CH2"0_<(3' oh conh2 52 HC1 170-173 ^ o 10 Hl/~\) c9h(- ch, ,25 i J -ch-ch-nh-ch-ch2h^-oh oh 64 CH,S0,H 3 3 X HO NJ 197-201 VJ / Yie Id No. Structural formula % of theinr„ Salt with Melting point 0 r 11 *C,° CH \ / ,2 5 H0-O -ch-ch-nh-ch2-ch2-<£hh-so2ch3 oh 83 CH3S03H 187-190 12 0 HC° y5 » H0"<CI/~CH"^H"NH"CH2"CH2~O"NH"C"CH3 oh 54 HC1 208-211 13 0 H</° f* . ho-^~}-ch-ch£nh-C~-ch2-^-nh2 oh 70 HC1 155-159 14 K V ?ZHS HO"<C^/-CH"^H"NH"CH2"CH2"0"OH oh qs 90 HC1 CH^SO^H x H20 234-236 92-94 15 i 0 h3c ^^ 0 hn' 0 r h \ „ w i2 5 ch., hjc-c'c-o'c vch-ch-nh-ch^ ch^ oh ch3 fO o ro vi VI VI Yield % of theory Salt with Melting point 90 HC1 ch3SO3H x H20 234-236 92-94 No, 16 17 Structural Formula K ,DV CoH CH. 2 1 -ch-nh-ch oh \ CH. h/~> W p2H5 HO- / i ^H-CH-NH- ( H OH 2 017 77 - 22 - Example 3 ch3 ch-ch2-nh-c-ch2-ch2 oh ch, O x HCI 10 5 g of 5'-benzyloxy-8' -(l-oxo-2-hydroxy-2-ethoxy- ethyl)-2H-1,4-benzoxazin-3-(4H)-one, 2.2 g of 1,1-dimethyl-3-phenylpropylamine 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 15 (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 20 the 5'-benzyloxy-8'-[l-hydroxy-2-(4-phenyl-2-methyl- butylamino)-ethyl]-2H-1,4-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. 25 By catalytic hydrogenation of this compound in 50 ml of methanol under normal conditions, using palladium charcoal as catalyst, 2.7 g of 5'-hydroxy-8'-[l-hydroxy-2-(4-phenyl-2-methyl-butylamino)-ethyl]-2H-1,4-benzoxazin-3-(4H)-one-hydrochloride are obtained 30 (melting point 159 - 161°C, yield: 90% of theory). Example 4 2017 - 23 - 5.8 g of 6'-chloro-8'-{l-oxo-2-hydroxy-2-ethoxy-ethyl)-2H-1,4-benzoxazin-3-(4H)-one, 1.5 g of tert.-butylamine, 60 ml of dioxan and 60 ml of alcohol are heated to 50°C for 2 hours. The solution is 5 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 10 decomposed with conc. 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 15 15 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, 20 with the addition of active charcoal, the substance has a melting point of over 300°C (melting point of base: 173 - 177°C). / / No. Structural Formula Yield % of theory Salt with Melting point * ch3 ch-ch2-nh-c-ch2-ch2 oh ch. o 42 Hydrochloric Acid x 1/2 water 155 - 160 ch3 H-CH2»nh\^3 oh 52 Hydrochloric Acid 226 - 229 to U1 oh ch 3 ch-ch2-nH- in-CHz{y oh oh 16 Hydrochloric Acid M 206 - 209 © VJ >4 / Mo Structural Formula Yield % of theory Salt with Melting point °C ; 7 HNM ^ OH 0H 26 Hydrochloric Acid x 1 acetonitrile Imprecise 195°C Decomp. I to CM I h) O s/ NJ • • • • • • • • J r No. Structural Formula Yield % Salt with Melting point °C" 8 0 " W CH3 H0Vy CH"CH2"NH"crH~CM2"C3*0H OH 42 HC1 xCHjOH 130-133 i 9 HV^O • ri, W . H°-\_^-CH-CH2"NH"c"CH2'CH2"C^ 0H CH3 OH 48 HCOOH x H20 120-124 K) ~-J 0 CH3 1 10 H0-^^-CH-CH2-NH-C-CH2CH2-/^\ 0H ch3 CJ/ 40 CH,SO,H 3 3 192-195 NJ 11 0 H^O ch HO-Z^VCH-C^-NH-C-CHg-CHg-O-^^. oh CH3 ml- 1 35 HC1 205-208 O N/ SJ VJ 2 017 7 7 - 28 - 5 Example 5 10 h ij— C- --.2 -2"5 -CH-CH0-NHC0Hc x HC1 dn °H 4.3 g of 5'-benzyloxy-81 -(l-hydroxy-2-benzylethylamino-15 ethyl)-2H-1,4-benzoxaz in-3-(4H)-one-hydrochlor ide (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 20 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-1,4-benzoxazin-3-(4H)-one-hydrochloride are obtained (yield: 86.7% of theory), which melts at 240 to 242°C 25 after being re-precipitated from methanol/ether. Example 6 30 ch- :CS ch-ch2-nh-c-ch2-ch2-nhc. oh ch, 0 x HC \ oh 6.3 g of 41-benzyloxy-71 -[l-hydroxy-2-(4-picolinic 35 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 40 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 2017 - 29 - added. After 5 hours, the 4'-hydroxy-7'-[1-hydroxy-2-(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. V v e. e i>'t, „ e following were synthesised according to the examples specified; TABLE III : No, Structural Formula Yield % of theory Salt with Melting point °C Q CH ch3 h-ch2-nh-c-ch3 h ch. 37 Hydrochloric Acid x 1 ethanol 205 - 203 ch3 ch-ch2-nh-c-ch3 oh ch, 75 Hydrochloric Acid x 1 ethanol 246 - 247 w O ch3 h-ch2-nh-c-ch2-ch2^3 ch, 70 Hydrochloric Acid x 1 ethanol 120 - 123 O Zi i 1 No. Structural Formula i Yield % of theory Salt with Melting point °C 4 0 HjL? CHi ho-hTJ)—ch-ch2-nh-c-ch3 OH CH3 70 Formic Acid x 1 water 189 - 192 5 - CH 2 - (fa OH 88 Hydrochloric Acid 1 i i 226 - 229 6 Hu)o CH3 __ /^V C H - C H 2 - N H - C H - C H o H o7 iH < 78.5 Hydrochloric Acid 206 - 209 u> I O VI S| SI / No. Structural Formula Yield % of theory Salt with Melting point °C ch 3 h-ch„-nh-c-ch.,-ch oh ch. z"0 75 Hydrochloric Acid 174 - 175 a ch. ch-ch2-nh-c-ch2~ch2 oh ch, O 90 Hydrochloric Acid x 1/2 Water co K) 155 - 160 i CH3 h(u a-ch-ch2-nh-c-ch2-ch2 oh ch, 75 1/2 Fumaric Acic 175 - 178 ( 170 - 173 Ba.seO .M VI N • •• • • • • • / No. Structural Formula Yield % of theory. Salt with Melting point °C 10 0 hm° ch CH-CH 2-NH- C-CH 2-CH 2-^^ OH CH3 60 Hydrochloric Acid U3 - 146 11 H|=? CH3 {)>-i:H-CH2-NH-C-CH3 oV °H 76 Hydrochloric Acid x 1 Acetonitrile Imprecise 195 Decomp. o VI V| VI • • • • • •• t / 1 No. Structural Formula Yield % of theory Salt with Melting point °C 12 0 O . fH3 /^>-CH-CH2-NH-C-CH2-/~\-OH °H 0H CH3 ch" 91 CH3SO3H x 1 H20 252-254 13 0 n^o CH3 HO-<r=\-CH-CH2-NH-C-CH2-CH2-NH-C-/~^ II ^ OH CH3 0 • 71 CHjSO^H x 1/2 H20 - i co 178-180 14 0 ^ \ HN 0 \ / CH3 HO-/ \ -CH-CH9-NH-C-CH0-< / \ -OH V_/ (» \2 \=/ 72 HC1 x 1,5 H20 159-162 ^ o SJ SJ SI No.. Structural Formula Yield % of theory Salt with Melting point °C 15 0 /'— hn 0 V / c9h„ ho-/ \ -ch-ch-nh-ch0-ch9- / \-nh-s0och, 2 2\=/ 2 3 16 J-v hn y c2h5 / ""v i / \ ^ ho- \-ch-ch-nh-ch0-ch,r</ ^k-nh-c-ch, X^/Idh 2- 2\=w/ •3-' 17 hn 0 V=\ ?2H5 / \ ho-/ \ -ch-ch-nh-ch2-ch2->-nh2 \ • •• • •••• / No. Structural Formula 18 hn ho-, N 7 c2h5 , -ch-ch-nh-ch2-ch2-< oh ,-qh X c2h5 Yield % of theory Salt with TT 19 o H^C I * (f ^ - c ^ hn ^ H^C - 0-, /H3 -ch-ch-nh-ch i n:h, oh j Melting point ^ u> o> ro Vi VI VI 201777 - 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). / Formula 0 s=/ c2h5 H0- ^ -jjJ-CH-NH-CH (CH3) 2 HN y p2H5 HO-,/ ^ -J-CH-NH-CH ( CH3) 2 HN X C0H(-I 2 5 yi"FH J' O NH-CH(CH3)2 HO Salt with 1 HCl x 2H20 HCl HCl Melting point °C 240-242 218-222 250-254 u> 00 M O "N4 SI / Formula HN HO CH0-CH-r I 2 3 ,-ff-CH -0 ^H-C(CH3)3 0 HN 0 7 p2H5 •ir-CH 0 NH-CH(CH3)2 HO Salt with HCl HCl Melting point 250-253 217-223 w vr> IS) O VI VI Formula Salt with Melting point °C y ■ HN \ V -< p2H5 HCl 156-161 HO-/ \ / ft 3 0 > HN V • \ / HO-^" \ CH3 \ -<jj-CH-NH-CH( CH3) 2 P 0 HCl 243-247 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> Formula Salt with Melting point °C 0 11 f \ HN 0 /*=A HCl 254-258 ■J \ V==\ p2H5 / \ HO-/ \ -C-CH-NH- / H > VV1 v_/ HCl 250 201777 42 VVHAT CLAIM IS:. ■claims

1. Compounds of formula (I) 0 5 hn 9 (I) 10 wherein A represents a single bond, the group -CE^-C^-, Rr 15 the group =c' , wherein R. represents hydrogen R4 or a lower alkyl group, and R^ represents hydrogen, or a lower alkyl or, when R^ represents hydrogen, a phenyl group; 20 R^ represents a hydroxy or acyloxy group or a chlorine or hydrogen atom; R2 represents hydrogen, or a methyl or ethyl group; 30 wherein m represents either 2, 3 or 4, n represents either 1,2 or 3, Rg represents hydrogen or methyl, Rj represents hydrogen or methyl, Rg represents hydrogen or methyl, 35 Rg represents hydrogen, or a group Ar, OAr, or -NH-CO-Ar, wherein Ar represents one of the groups CH2-(CH2) 25 and R^ represents a group -C-CHj—■— 2'ml * or (ii) (III) - 43 - 201777 or 10 20 25 30 35 'll 12 (IV) in which R 10 lll' 12 which may be identical or different, are each selected from hydrogen, hydroxy, methyl, methoxy, halogen, -CONH2 and NH-R^r the group R^^ representing hydrogen, acyl or a lower 15 alkylsulfonyl group, or any two of R 10 R11 and R12 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.

2. Compounds of formula (I) as claimed in claim 1 wherein A represents a single bond, or a group =ch2, =ch(ch3), =c(ch3)2 or =ch(C2h5), R^ represents hydroxy or acyloxy in the m- or p-position relative to the side-chain; R2 represents hydrogen or a methyl or ethyl group; R^ represents one of the groups of formula (II) or (III) , 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 gr<?up of formula (IV) , in which R^q represents hydrogen, hydroxy, methyl or a group -NHR^, the group R^3 representing acetyl or methanesulfonyl, or, R1q together with R^ represents a methylenediox group, nL' V£ 201777 - 44 - 10 15 R^ represents hydrogen, hydroxy, methyl or a group -NHR^2, the group R^ representing acetyl or methanesulfonyl, or, together with R-^g' represents a methylenedioxy group, R^2 represents hydrogen.

3. Compounds of formula (I) as claimed in claim 1 wherein A represents a group or -C^-; R^ represents hydroxy in the p- or m-position relative to the side-chain; R2 represents hydrogen, or a methyl or ethyl group; R^ represents isopropyl, tert.-butyl, cyclopentyl, 1-methylcyclopentyl, or a group of formula (III) wherein n represents 1 or 2, and Rg represent hydrogen or methyl, and Rg represents one of the groups phenyl, 4-hydroxyphenyl, 2-pyridyl, 4-pyridyl, 2-hydroxyphenyl, 2,6-dimethyl-4-hydroxy phenyl, 2-methyl-4-hydroxyphenyl, 20 25 -NH-CO- -NH-CO-

4. 5'-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.

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) "■ A \' V- .-..X 201777 - 45 - -c-ch-nh-r- (V) 15 20 25 wherein A, R. R2 and R^ are as defined in claim 1, any phenolic hydroxyl groups present being optionally 10 protected by hydrogenolytically cleavable protecting groups, is reduced followed, if necessary by deprotection; or b) a phenylglyoxal or hemiacetal of formula (XII) (XII) —co—q 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(OH)-O-lower alkyl, is reacted under conditions of reductive amination with an amine of formula (XIII) 30 h2n-r3 (XIII) 35 wherein Rg is as hereinbefore defined, any hydroxyl groups contained therein being optionally protected by hydrogenolytically cleavable protecting groups, followed, if necessary, by deprotection; or c) deprotecting compound of formula (XVI) Z°/ 91^7 - 46 - R2 ?' (XVI) -ch-ch-n-r; l 3 oh 10 wherein A and R2 are as defined in claim 1, R| represents R^ or a hydroxyl group protected by a hydrogenolytically cleavable protecting group, Rg represents Rg, any hydroxyl group present in Rg 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 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 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. //%• V, N\ ' & 2.01777 - 47 -

10. A process for the preparation of compounds of formula (V) as defined in claim 6 substantially as hereinbefore described.

11. A process for the preparation of compounds 5 of formula (V) as defined in claim 6 substantially as hereinbefore described with reference to the Examples.

12. Compounds of formula (I) as defined in claim 1 whenever prepared by a process as claimed in any of claims 6 to 8. 10

13. A method of treatment or prophylaxis of the non-human animal body to combat asthma, bronchitis, urticaria, conjunctivitis, hay fever, colds, chills, labour pains and cardiovascular disorders or to relax the uterus which comprises administer-15 ing. an effective amount of a compound of formula (I) or formula (V) as defined in claim 1 or claim 6 respectively or a physiologically acceptable acid addition salt thereof.

14. Compounds of formula (I) (as defined in claim 20 1) and physiologically acceptable acid addition salts thereof for use in a method of treatment or 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 25 the uterus.

15. Compositions for improving the production of flesh and the utilisation of fodder in meat-producing animals which contain a compound of formula (I) as defined in claim 1. 30

16. 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. BALDWIIN^SQN 8l_CAREY </div>