GB2106105A

GB2106105A - Benzo-heterocycles

Info

Publication number: GB2106105A
Application number: GB08224810A
Authority: GB
Inventors: Armin Fugner; Ernst-Otto Renth; Anton Mentrup; Kurt Schromm
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 1981-09-01
Filing date: 1982-08-31
Publication date: 1983-04-07
Also published as: ES8308318A1; CS236679B2; KR840001560A; CA1180012A; PL238077A1; ES521870A0; DE3267702D1; ES8405778A1; GB2106105B; IE822105L; EP0073505A1; HU186112B; DE3134590A1; IE53615B1; FI78475B; ATE16703T1; NO157738B; SU1149876A3; ES521871A0; PT75478A

Description

1 GB2106105A 1

SPECIFICATION

Benzo Heterocycles The invention relates to benzo heterocycles. More particularly it relates to benzo heterocycles 5 having useful theraputic properties.

According to the invention, we provide compounds general formula (1) 0 A 0 2,CH -Cli-NE-R 3 (1) R,- wherein A represents a single bond, a group -CH2-CH,-, or a group R5 =C R, wherein R, represents hydrogen or lower alkyl, and R, represents hydrogen, or lower alkyl or, 30 when R, represents hydrogen, a phenyl group; R, represents a hydroxy or acyloxy group or a chlorine or hydrogen atom; R2 represents hydrogen, or a methyl or ethyl group, and R3 represents a group CH 2 - (CH) R 7 -C-CH 23 or -C(CH 2 1 2) JR9 R 6 -u) (111) 40 R a wherein m represents either 2, 3 or 4, n represents either 1, 2 or 3, R. represents hydrogen or methyl, R, represents hydrogen or methyl, R. represents hydrogen or methyl, and R, represents hydrogen, or a group Ar, -Oar, or -NH-CO-Ar, wherein Ar represents one of the groups 50 0 ' - -C W 55 or Rio \_---11 R12 (IV) 60 in which R,, IR,, and IR,2, which may be the same or different, are each selected from hydrogen, hydroxy, methyl, methoxy, halogen, -CONH2 and NH-R13 the group R13 representing65 2 GB 2 106 105A 2 hydrogen, acyl or a lower alkylsulfonyl group, or any two of IR,0, IR, and IR, may represent a methylenedioxy group.

The compounds may occur in the form of racemates, enantiomers and possible diastereomeric pairs of enantiomers, as free bases or as acid additon salts, and all are included within the scope 5 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 10 = CH, = CH(CH3), = (CH,), or = CH(C^), 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 (11) or (111) above, in which m represents 2 or 3, 1 n represents 1, 2 or 3, R6, R, and R, represent hydrogen or methyl, R, represents hydrogen or a group Ar or NIHI-CO-Ar, wherein Ar represents a 2-pyridyl or 4 pyridyl group or a group of formula (R), in which IR,, represents hydrogen, hydroxy, methyl or a group -NHIR1, the group R13 representing acetyl or methanesulfonyl or, R10 together with IR, 20 represents a methylenedioxy group, IR, represents hydrogen, hydroxy, methyl or a group -NHIR13, the group R13 represent,ng acetyl or methanesulfonyl or, together with R10, represents a mthylenedioxy group, R12 represents hydrogen.

Particularly preferred are compounds wherein A represents a group = C(CH3)2 or -CH2-, R, represents hydroxy in the p- or m-position relative to the side-chain, R2 represents hydrogen, or a methyl or ethyl group; R3 represents isopropyl, ter.-butyl, cyclopentlyl, 1-methylcyclopentyl, or a group of formula (111) wherein n represents 1 or 2, R, and R. represent 30 hydrogen or methyl, and R, represents one of the groups phenyl, 4-hydroxyphenyl, 2-pyridyl, 4- pyridyi, 2-hydroxy phenyl, 2,6-dimethyi-4-hydroxy phenyl, 2-methyl-4-hydroxyphenyi, PIH-CO- n.,To 1 NH-CO- no.4 According to a further aspect of the invention, we provide a process for the preparation of compounds of formula (1) as defined in claim 1 wherein either a) a compound of formula (V) 0 A 2 -H-NH-R 3 0 (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 phenyigiyoxal or hemiacetal of formula (X11) 3 GB 2 106 105A 3 0 l- 0 -co-a R1 (m) wherein R, and A are as defined in claim 1, any phenolic hydroxy groups present being optionally protected by hydrogenolytically cleavable protecting groups, and G represents -CHO or -CH(OH)-0-lower alkyl, is reacted under conditions of reductive amination with an amine of 15 formula (XIII) H2N-R3 (m 11) wherein R3 is as hereinbefore defined, any hydroxyl groups contained therein being optionally 20 protected by hydrogenolytically cleavable protecting groups, followed, if necessary or if desired, by deprotection; or c) deprotecting compound of formula (XVI) R 12 (XV:E) -CH-CH-N-R b 1 3 OH Rt 1 wherein A and R2 are as defined in claim 1, R,' represents R, or a hydroxyl'group protected by 35 hydrogenolytically cleavable protecting group, R3' represents R3, any hydroxyl group present in R3 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 40 conventional methods into their enantiomers, optionally into diastereomeric pairs of enantiom ers, any bases initially obtained are converted into their acid additon 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, 45 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- 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 new compounds may be obtained according to methods known per se, as shown in the following reaction scheme, which is by way of example:

4 GB 2 106 105A 4 0 02 N OH 2N 1 1 R Friedel-Crafts i 01 HO- -CO-CH2 0 5 Iio- C 0 N OH R, 2 R 12 Bz-0- -CO-CH Bz-0- -CC-CH 2 C1CO-CR R cl C1CO-OPh Bz = Benzyl 15 Ph = Fhenyl 0 R 0.4 R HN HN 0 R2 20 2 1 BZ-0- -co-2 Bz-0_ -CO-CH2 BrP Br. 25 0 0 R 5 0 HN R 30 BZ-O- 2 -CO-Cn-Br Bzo- 2 -CO-CH-Br (V1) (V11) 35 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 40 way of example:

GB 2 106 105A 5 OH OR R R 2 12 -CO.H2 5 Bz-0 OH 0 N OH H 2 N OH R 2 1.2 -CH2 -CO-CH 2 10 Bz-d Bz-0 0 0 R 4 R 15 W / 0 HN 0 R R 2 2 _co--H -COCH 2 2 C5 20 P Bz-0 Bz-0 - t 01 0 R 4 w,5 0 25 R 2 _CO_j -CO-CH-Br H-Br 30 Bz-0 IX) Bz-0 (vili) The bromoketones of formula (X) 0 Fur / LI- A \ 35 R 12 .-CO-CH-Br 40 (X) 6 GB 2 106 105A 6 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 benzyi, may then be converted into the compounds of formula (V) by reaction thereof with amines of formula R 1 1 HN-R, (X 1) wherein R, is as hereinbefore defined and R' represents hydrogen or a hydrogenolytically 10 cleavable group, such as benzyl or substituted benzyl. The reaction is preferably carried out in suitable inert solvents such 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 reacton product may be removed subsequently or as the reaction continues.

In reaction (b), instead of reagents of formulae (Xli) and (Xlil), it is also possible to reduce the 15 Schiff bases of formula (M) 0 11 A, 20 HN 0 R1 (X1v) wherein A, R, and R3 are as hereinbefore defined, which may occur as intermediates during the 30 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 hydrogenolytically cleavable groups. These protecting groups may be removed 35 by hydrogenolysis in the usual way during or after the reduction.

The final products of this reaction are compounds of formula (1) wherein R, represents hydrogen. The compounds of formula (X11) used as starting materials may be obtained from acetophenone derivatives of formula (XV) 0 40 HU IL- A \ 0 -COCH3 (XV) 45 R 1 wherein R, 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 (X111) are known or may readily be obtained according to conventional 55 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, benzyi 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 60 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, 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 65 7 GB 2 106 105A 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 5 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 (1) 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 10 complaint and the method of adminstration.

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 mq; 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, 10 mi ampoules containing from 0.01 to 1 mg may be used.

For vasolidation, 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 20 broncholytics can be combined with theophyllines, parasympatholytics (e.g. ipratropium bro mide), secretolytics (e.g. bromhexine), musculotropic spasmolytics (e.g. papaverine), corticoster oids 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 7tt 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 bompositions 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 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 35 be considered as limiting.

Pharmaceutical Examples Tablets

Composition of a tablet 40 Active substance according to invention 20 mg Colloidal silicic acid 10 mg Lactose 118 mg Potato starch 60 mg Polyvinylpyrrolidone 6 mg 45 Na-cellulose glycolate 4 mg Magnesium stearate 2 mg 220 mg 50 Ampoules Composition of the solution per ampoule Active substance according to invention 10 mg Sorbitol 40 mg Distilled water ad 10 mI 55 Suppositories Composition of each suppository Active substance according to invention 100 mg Suppository mass (cocoa butter) 1600 mg 60 1700 mg Powder for inhalation Each hard gelatine capsule is packed with 0.5 mg of active substance according to the 65 8 GB 2 106 105A 8 invention and 19.5 mg of lactose with a particle diameter of between 0. 5 and 7 jum.

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, their broncholytic effect in relation to the increase in heart rate. Thus, for example, for the compound of Example 1, in guinea pigs the ED,,i.v. [gg/kg] of the increase in heart rate is more than ten times the ED,,i.v. Lug/kg] of broncholysis, which only 0.045 [Lg/kg. The resorption characteristics are generally favourable as well. Thus, the resorption quotient ED,,p.o.

ED,,i.v.

is only 1.1, for example, for compound 7 in Table 3, which means that the oral activity is 15 virtually as great as the intravenous activity. In the mouse, for example, the LD,, 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 simialar 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.

Example 1

H CH-CH/ CH 2_ CH3 X H c-i X H20 H 'mHCH(CH 3)2 16.1 g of 5-benzyioxy-8'-(1 -oxo-2-bromobutyi)-2H-1,4-benzoxazin-3-(4H)- one and 7.5 9 of 35 isopropylamine are stirred in 100 mi of acetonitrile for 4 hours at WC. After acidification with conc. hydrochloric acid and addition of the mixture to 100 mi of water 5'- benzyioxy-8'-(1 oxo-2 isopropylamino-butyi)-2H-1,4-benzoxazin-3-(4H)-one hydrochloride (melting point 229-232'C) crystallises out. 6 9 of these compounds are debenzylated in methanol, with the addition of palladium /charcoal as catalyst, to yield 5'-hydroxy-8-(1-oxo-2- isopropylaminobutyi)-2H-1,4benzoxazin-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-8'-(1-hydroxy-2-isopropylaminobutyi)-2H-1,4-benzoxazin3-( 4H)-one hydro chloride hydrate are obtained (yield: 90% of theory), which melts at 208- 210'C.

Example la

0 H c F2H5 HO- -Cn-CH-NH-CH(CH 3)2 X ",C' (threo) 6H 32.4 g of 5-benzyioxy-81-(1-oxo-2-bromo-butyi)-2H-1,4-benzoxazin-3-(4H)- one and 72 9 of benzylisopropylamine are stirred at 1 OWC for 15 hours. After the addition of water the oil 60 precipitated is taken up in ether and diluted with petroleum ether; crystallisation of W-benzyloxy 8'-(1-oxo-2-benzyiisopropylamino-butyi)-2H-1,4-benzoxoazin-3-(4H)-one takes place.

11.6 g of this compound are combined with a mixture of 60 mi of ethanol and 60 mi of acetonitrile with 1 g of sodium borohydride and the resulting mixture is stirred for three hours.

Then 250 m] of ice-cold water and 100 mi of ethyl acetate are added and, after the sodium 65 9 GB 2 106 105A 9 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'-benzyioxy-8-(1 -hydroxy-2- benzylisopropyiaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one precipitated (melting point 89-92C) is suction filtered. 5 4.8 g of this compound are hydrogenated in 100 m[ 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/eth anol and acidified with the calculated quantity of hydrochloric acid. The solution is diluted with ether and the threo-5'-hydroxy-8'-(1-hydroxy-2-isopropylamino-butyl)-2H-1, 4-benzoxazin-3-( 4H)- 10 one hydrochloride precipitated (yield: 74% of theory) is suction filtered; after being reprecipitated from methanol/ether it melts at 2022OWC.

Example 2

0 Ho H-CH CH3 z-NH--CH3 x HCl OH H3 10 9 of 51-benzyioxy-8'-(1 -oxo-2-bromo-ethyi)-2H-1,4-benzoxazin-3-(4H)- one and 8.75 g of benzyi-tert.-butylamine and refluxed in 100 mi of acetonitrile for 3 hours. After cooling, the crystals precipitated are suction filtered and washed with 200 mi of warm water. The crystals are acidified in acetonitrile with etheric hydrochloric acid; after dilution with ethyl acetate, 51 benzyioxy-81-(1-oxo2-benzyi-tert.-butylaminoethyi)-2H-1,4-benzoxazin-3(4H) -one hydrochloride 30 is precipited (melting point 185-1 WC).

7 g of this compound are debenzy[ated at 5 bar and at WC in 100 mi of methanol, with the additon of palladium /charcoal as catalyst, to yield 5'-hydroxy-8'-(1-oxo- 2-tert.-butylamino-ethyi)2H-1,4-benzoxazin-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 W- 35 hydroxy-8'-(1-hydroxy-2-tert.-butylamino-ethyi)-2H-1,4-benzoxazin-3-(4H)one hydrochloride are obtained (yield: 72.5% of theory), melting at 185-187'C.

0 The following were synthesised as described in the Examples mentioned:

T A B L E 1 No. Structural Formula Yield Salt with Melting point % of theory c 66 Kydrochloric 230(decomp.) 1 CH - CH Acid 2 3 x 2 Water -1 H-CH/ H OH NH-C(CH 3)3 H CH 2- CH 3 63 Hydrochloric 163 165 ROH CH-CH Acid NH-CH(CH OH 3)2 0 A_.

HI CH,-CH 3 83 Hydrochloric 259 - 261 Acid 3 CH_CH 1 04 OH NH-C(CH 3)3 Structural formula Yield of theory Salt with 0 Ho H_CH,/CH2-CR3 67 Hydrochloric Acid \NH-CH(CH 3)2 71 Hydro chloric CH 2- CH 3 Acid H-CH/ X Water %H-CH(CH 3)2 0 HN 0 CH 88 HCI 1 3 x 1/2 H 2 a HO- -CH-CH-NHCH(CH 3)2 OH Melting point c 230 - 232 256 - 259 244 K) FNI T-St tural Formu'la Yield Salt with Melting point] % of theory 0C 0 7 HN 0 86 Hcl 243-245 2H5 HO- H-CH-NH OH x 112 H 20 0 \ MWI 0 8 2H5 73.5 Hcl 2o6-9-og Ho_b -H-CH-4H-CH 2- CH 2-F\'-OH OH CC 3 0 Ht 0 9 2 H 5 52 HCI 170-173 HO-b-H-CH-t'4H-CH 2- CH2- /-N OH C Pti H 2 2H5 64 CH H 197-201 C,3 3S03 -CH-CH-NH-CH-CH2-H X H 20 6H G) W rli 0 0) 0 W m CA) Structural formula 0 C H 12 5 -CH-CH-NH-CH 2-CH CH 1 2-Cl \-'H-502 3 0 Hte o 5"S Yield -L-aL-hhearll_ 83 12 HO-\l CH-CH-NH-CH2-CH2 _Al-\\_NH-C -CH 54 1. 3 UM i U 13 CH3 -o HO-rb-CH-CH;OH -CH2-C-NH 6H -11 2 C113 14 H 0 c 2H 5 HO H-CHAH-CH 2-CH 1 \ 2-n-OH OH t-H/ Salt with Melting poin or CH 3503H 187 190 HC 208-211 1 ECI CH 3SO3H X H 20 155-159 234-236 92-94 c) m tli 0 (n (D Cn 1 > W -r- Yield Me iting No. Structural Formula % of theory Salt with point oc H 3 c 0 0 HN 0 C H \ ', - 2_5 CH 3 W3P.CC-0- -CH-H NH-CH/ 1 bp 1 CH OH CH 3 3 P_\ 1,0 H C 2 H 5 CH 3 1 16 0_ H C-f CH CH-NH-CH 3 6H C H 3 RC:1 234-236 0 17 c 2H5 90 CH 3 so 3 H 92-94 1,0 x H 20 OH 0 CF) 0 M 15' GB 2 106 105A 15 CH 3 H-CHZ-NH-C-CHZ-C-H2-0 X Na 9 OH CH 3 9 of 51-benzyioxy-81-(1-oxo-2-hydroxy-2-ethoxy ethyi)-2H-1,4-benzoxazin-3(4H)-one, 2.2 g of 1, 1 -dimethyi-3-phenylpropylamine and 50. m[ of alcohol are heated to 50-60T for 3 hours.

After the reaction mixture has been cooled, the Schiff base precipitated (melting point 1 38-140C) is suction filtered.

4.5 g of this compound are added to 100 mi 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 mi of water the 5'-benzyioxy-8'-[1 -hydroxy-2-(4-phenyl-2-methyl-butylamino)-ethyi]-2H-1,4benzoxazin-3-(4H)-one precipitated (melting point 162-1 64C) is suction filtered and the hydrochloride (melting point 205-207C) is prepared using etheric hydrochloric acid.

By catalytic hydrogeneration of this compound in 50 m] of methanol under normal conditions, using palladium charcoal as catalyst, 2.7 g of 5'hydoxy-8'-[1-hydroxy-2-(4-pheny]-2-methyibutylamino)-ethyi]-2H-1,4benzoxazin-3-(4H)-one-hydrochloride are obtained (melting point 159-161 Q yield: 90% of theory).

Example 4 b_ H CH, 3 p-CH NH-C-CH X HQ t 3 OH CH, 5.8 g of 61-chloro-81-(1-oxo-2-hydroxy-2-ethoxy-ethyi)-2H-1,4-benzoxazin3-(4H)-one, 1.5 g of tert,butylamine, 60 mi of dioxan and 60 mi of alcohol are heated to WC for 2 hours. The solution is then cooled and 2 g of sodium borohydride are added thereto at 10 to WC. The solution is stirred at ambient temperature for 1 hour, then poured on to 500 mi of ice-cold water and 150 mi of ethyl acetate are added. After the sodium borohydride has been 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 mi of alcohol, acidified with etheric hydrochloric acid and the 6-chloro-8'-[1-hydroxy-2-(tert.butylamino)-ethyl]-2H-1,4-ben- 40 zoxazin-3-(4H)-one-hydrochloride precipitated (yield: 38% of theory) is suction filtered. After being re-precipitated twice from methanol, with the additon of active charcoal, the substance has a melting point of over 300C (melting point of base: 173-1 77C).

The following comp. ounds were prepared analogously:

T A B L E II No. Structural Formula Yield with ofd V. Salt Melting point % of theorv H Hydrochloric 3 40 Acid 252 255 CH-CH NH-C-CH 3 39 Hydrochloric 4CM3 Acid 185 187 H 0-CH-CH NH-C-CH 2 3 6H CH 3 CH 3 Hydrochloric CH 3 40 Acid 205 208 3 x 1 ethanol HO CH-CH NH-C-CH 2 3 6H CH 3 G) CD K) 0 (7) 0 M 6 1 structural Formula CH 3 -H-CH NH-C CH CH,;/ \.F ON N 3 \==1 H CH3 H-CH -NH 0 ON CH. 3 CH-CH27NH-CH-CH \OH GH ON j Yield t of theory ----------42 52 16 Salt with Hydrochloric Acid X 1/2 water Hydrochloric Acid Hydrochloric Acid Melting point QC.

---------- - - 160, 226 -225 206 - 209 G) m NJ 0 0) 0 (n blo 7 1 Go structural Formula HN CH 1 3 H-CH 2- NH7c-CH3 OH OH IA3 Melting point.c Yield f Salt with th % of; eory liy aydrochloric r2 6 d Acid x 1 acetonitrile Imprecise 195-C DecCUP.

00 (D No. Structural Formula Yield Salt with melting poin& c CH 42 BC1 HO_CH_CH2_NH_ v 3 X CH CH-CH ON OH 2 3 130-133 un 0 - 9 lio C 1 3 NO-CH-CH2-NH-C-CH 2 _M 2-0 48 HCOOH 120-124 un CH X H20 3 ON 0 m CH 40 CH 3 sop 192195 Rob 1 3,2CH2_n CH-CH 2-NH-C-CH ON CH 3 0 jib 0 CH 3 35 HCl 205-208 Ho_b 1 12_CH2_ CH-CH 2-NH-C-CH ON CH3 C6NH 2 G) m K) 0 m 0 M (D GB 2 106 105A 20 Example 5

0 5 H -CH-CH - NHC,H X HU H 6H 2 1 5 4.3 g of 5-benzyloxy-8'-(1 -hyd roxy-2-benzyl ethyl am in o-ethyl)-2 H- 1, 4-benzoxazi n-3-(4 H)-onehydrochloride (melting point 232-235C) are hydrogenated in 125 mi 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-(1 hydroxy-2-ethylamino-ethyi)-2H- 15 1,4-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 H CH-CH 4.-C-CH,-CH x H c Hn-/ 2- N H C OH c H, n ",j 6.3 g of 4-benzyioxy-7'-[1-hydroxy-2-(4-picolinic acid-amido-2-methyi-2butylamino)-ethyi]-2- 30 benzoxazolinone (melting point 130-1 33'C) are hydrogenated in 125 mi of methanol with the additon 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 mi of alcohol and 0.58 9 of formic acid are 35 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 166-1 68C) is suction filtered.

bi The following were synthesised according to the examples specified:

T A B L E Ill No. Structural Formula Yield of theory Salt with Melting point 0 CH 3.

3 Hydrochlo ric H 87 Acid 205 203 H x 1 3 ethanol H-CH NH-C-CH 2- 3 CH 3 Hydrochloric 2 3 Acid 246 247 CH-CH NH-C-CH X 1 ethanol A 3 H OH CH 3 H Hydrochloric CH 3 70 Acid 120 123 H-CH NH-e'-CH CH X 1 ethanol H ON CH G) CD rli 0 C3) 0 M N.) N.) No.

0 4 Structural Formula H-CH CH 3 2-NH--CH 3 0 H CH 3 c CH-CH N H H GH CH, 3 CH-CH NH-CH-CH OH 1 DH OH Yie ld % of theary 1 Salt with rormic Acid X 1 water 88 78.5 1 Rvdrochloric Acid Hydroch1Pric Acid Melting point c 189 -]g,, 226 - 229 206 - 209 G) m NJ 0 0) 0 M h.) NJ K) (A) No.

7 a 9 Structural Formula 0 _ H p CH 3 H H-CH - NH--CH CH 2 0 2 2-0 CH 3 0 -HO GH p3.

H H-CH 2-NH-C-CH CH 2- 2 OH H3 (1 CH3 HG_ H-CH NH-.-CH - CH 2 2 OH CH 3 Yield % of theory Sal with Hydrochloric' Acid Acid X 112 Water 1/2 Fu 1 maric Acid Kelting poi,t Iz 174 - 175 - 160 - 178 (170-173 Base) G) m C M m W N) -P- No. Structural Formula Yield Salt with Melting point % of theory. 0C CH Hydrochloric 3 H: -CH-CH NH--CH C H 47W 60 Acid 143 - 146 2 2 H Hydrochloric Imprecise CH 3 76 Acid 195 Decomp.

1 X 1 Acetonitrile H-CH 2- NH-C-CH 3 OH 'OH H 3 bi.P.

N) (n No.

12 13 14 Structural Formula Yield of theor%7 Salt with 0 HN IY-\ 0 CH 3 H C 1 91 CH so H CH-CH 2- NH-C-CH 2 OH 3 3 0-1 1 x 1 H 2 0 OH OH CH3 CH 3 0 H 0 CH 3 HO- -CH-CH 2-NH-C-CH 2-CH 2 -N H -CC CH3S03 H X 1/2 H OH CH 3 0 20 0 HU>-_\0 CH 1 3 72 HC.1 HO-; 5-CH-CH 2-NH -CH 2 X 1,5 H20 bH 1H 3 Malting'point C 252-254 178-180 159-162 M Im NJ 0 0) 0 M N (n No.

16 17 Structural Formula Yield Salt with % of theory C2 H 5 1 -CH-CH-NH-CH 2 -CH 2 RH-SO 2CH 3 OH HN c 2H5 H 2 2 -3 OH Melting point OC HO HN 1C2H5 H-CHNH-CH -CH OH G) m 1 C M CD W N) 0) No. Structural Formula Yield % of 7 Salt wi ing poin % of theory th Melt 0C --------------- 0 HN c H 2 5 11-CH-NH-CH -CH Oil OH -c C H 2 HN 19 CH3 /1 H c c 3 25 /CS C 0-CH-.Clii-IIH-.CH H C 1 "CH 3 3 OH J c) m pi 0 C) 0 C71 28 GB 2 106 105A 28 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 as pharmaceutical compositions themselves, since they have similar pharmacological properties to the compounds of formula (1).

Formula Salt wtth 0 W/1o.

c H 1 2 5 HO- x -C-CH-i'W-CH(CH 3)2 0 ' It HN--- 0 - 1\ F2'S HO --CH-ifH-CH (Ct'13) 2 HN c H j2 H 0 NH-CH(CH 3) 2 0 HCl x 2H 2 o HCl HCl-N C.0 Melting point oc 2.4o-242 218-222 250-254 G) W m 0 0) 0 cr m (0 Formula 0 HN 1 CH 2 -CH 3 -C-CH 0" H-C (CH 0 3)3 HO 0 HN 0 0 NH-CH(CH 92 HO W (D Salt with Hcl HC I Melting point c 1 250-253 217-223 c) W m 0 a) W 0 Formula p.it f Saltith HN H HS O_. -C--CH-i4HC (CH 3 2 HN 0 3 CH HO -q-CH--,4H-Cn.(CH 3) 2 HC-V 156161 243-247 c) W NJ 0 m (D M W W rli Formula Salt with Melting point - 1 1. - 1 0 HN, C 2H 5 -CH-UH- C2H 5 HO1 HCl 254-25s HCI 250 G) CD I bi 0 0) 0 cn W N.) 33 GB2106105A 33

Claims

1. Compounds of formula (1) 0 0 2 >_<-CH-CHNE-R 3 OR R 1 (1) wherein A represents a single bond, the group -CH2-CH2-, the group / R5 =C R4 wherein R4 represents hydrogen or a lower alkyl group, and R5 represents hydrogen, or a lower 25 alkyl or, when R, represents hydrogen, a phenyl group; R1 represents a hydroxy or acyloxy group or a chlorine or hydrogen atom; R2 represents hydrogen, or a methyl or ethyl group; and R3 represents a group CH 2_ (CE 2)m R.7 -C,-CH 2D or -C-(CH -Rg 1 2 2)n . 6 R (T- 1) (Ill) 35 wherein m represents either 2, 3 or 4, n represents either 1, 2 or 3, R6 represents hydrogen or methyl, R, represents hydrogen or methyl, R, represents hydrogen or methyl, R, represents hydrogen, or a group Ar, 0Ar, or -NH- CO-Ar, wherein Ar represents one of the groups or 50 RIO R R12 55 in which 1110, R,,, R12 (which may be identical or different, each are selected from hydrogen, hydroxy, methyl, methoxy, halogen, -CONH2 and NI- I-RU, the group R13 representing hydro- gen, acyl or a lower alkylsulfonyl group, or any two of R10, R, and R12 may represent a methylenedioxy group, the compounds being in the form of their racemates, enantiomers or diastereomeric pairs of enantiorners, or their acid addition salts.

2. Compounds of formula (1) as claimed in Claim 1 wherein A represents a single bond, or a group = CH2, = CH(CH3), = (CH1 or = CH(C21-15), R, represents hydroxy or acyloxy in the m- or p-position relative to the side-chain; 34 GB 2 106 105A 34 R3 represents hydrogen or a methyl or ethyl group; R, represents one of the groups of formula (11) or (111), in which m represents 2 or 3, n represents 1, 2 or 3, R, R, and R, represent hydrogen or methyl, R, represents hydrogen or a group Ar or NH-CO-Ar, wherein Ar represents a 2- pyridyl or 4pyridyl group or a group of formula (R), in which R10 represents hydrogen, hydroxy, methyl or a group -NHR1, the group R, representing acetyl or methanesulfonyl, or, R, together with IR, represents a methylenedioxy group, R, represents hydrogen, hydroxy, methyl or a group -NHIR,, the group R, representing acetyl 10 or methanesulfonyl, or, together with R10, represents a methylenedioxy group, R12represents hydrogen.

3. Compounds of formula (1) as claimed in claim 1 wherein A represents a group = C(CHI or -CH2_; 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 isopropy], tert.-butyi, cyclopentyl, 1-methylcyclopentyl, or a group of formula (111) wherein.

n represents 1 or 2, R, and R, represent hydrogen or methyl, and R, represents one of the groups phenyl, 4-hydroxyphenyl, 2-pyridyl, 4pyridyl, 2-hydroxy- 20 phenyl, 2,6-dimethyi-4-hydroxy phenyl, 2-methyl-4-hydroxyphenyi, 0 U A \ -arlll- 0 2 -CH-CH-NH-R f 3 OH (I) R

4. 5-Hydroxy-8'-(1-hydroxy-2-isopropylamino-butyi)-2H-1,4-benzoxazin-3(4H)-one and salts thereof.

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 of formula (1) as defined in claim 1 wherein either a) a compound of formula (V) 0 ---CH-NH-R 3 0 50 R, (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 55 necessary by deprotection; or b) a phenyigiyoxal or hemiacetal of formula (X11) GB 2 106 105A 35 0 MI/1o 17 -CO-Q \V X R1 10--- - - (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 G represents -CHO or -CH(OH)-0-lower alky], is reacted under conditions of reductive amination with an amine of 15 formula (X111) H,N-R3 (X111) wherein R3 is as hereinbefore defined, any hydroxyl groups contained therein being optionally 20 may be protected by hydrogenolytically cleavable protecting groups, followed, if necessary or if desired, by deprotection; or c) deprotecting compound of formula (XVI) A R 2 R' XVI) b-CH-WI-1N-R 1 3 OH R# 1 wherein A and R2 are as defined in claim 1, R' represents R, or a hydroxyl group protected by a hydrogenolytically cleavable protecting group, R3 represents R' any hydroxyl group present in 31 R3 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 40 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 enantiom ers, 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.

7. A process as claimed in claim 6 substantially as hereinbefore described.

8. A process as claimed in claim 6 substantially as hereinbefore described with reference to the Examples.

9. Compounds of formula (V) wherein A, R, R, and R, are as defined in claim 1.

10. A process for the preparation of compounds of formula (V) as defined in claim 9 substantially as hereinbefore described.

11. A process for the preparation of compounds of formula (V) as defined in claim 9 substantially as hereinbefore described with reference to the Examples.

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

13. 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 the uterus which comprises administering to said body an effective amount of compound of formula (1) or formula (V) as defined in claim 1 or claim 9 respectively or a physiologically acceptable acid addition salt thereof.

14. Compounds of formula (1) (as defined in claim 1) and physiologically acceptable acid 60 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 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 (1) as defined in claim 1.

36 GB 2 106 105A 36

16. The use of compounds of formula (1) as defined in claim 1 for improving flesh production and the utilisation of fodder in meat- producing animals, particularly poultry, cattle, pigs and sheep.

Printed for Her Majesty's Stationgry Cf;ce by Burgess & Son (Abingdon) Ltd -1983Published at The Patent Office, 25 Southampton Buildings, London, WC2A l AY, from which copies may be obtained.