CA1180012A

CA1180012A - Benzo heterocycles

Info

Publication number: CA1180012A
Application number: CA000410462A
Authority: CA
Inventors: Kurt Schromm; Anton Mentrup; Ernst-Otto Renth; Armin Fugner
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 1981-09-01
Filing date: 1982-08-31
Publication date: 1984-12-27
Also published as: PT75478A; CS236679B2; DE3134590A1; NO822932L; PL238077A1; ES8402279A1; DK389082A; ATE16703T1; DE3267702D1; NO157738B; GR77275B; GB2106105B; HU186112B; IE822105L; KR890000380B1; NO157738C; ZA826349B; ES515380A0; ES8405778A1; GB2106105A

Abstract

Abstract New benzo-heterocycles of formula (I) (I) are described, wherein A represents a single bond, the group -CH2-CH2- or, the group , wherein R4 represents hydrogen or a lower alkyl group, and R5 represents hydrogen, or a lower alkyl or, when R4 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 or (II) (III) wherein m represents either 2, 3 or 4, n represents either 1,2 or 3, R6 represents hydrogen or methyl, R7 represents hydrogen or methyl, R8 represents hydrogen or methyl, R9 represents hydrogen, or a group Ar, OAr, or -NH-CO-Ar, wherein Ar represents one of the groups , or (IV) in which R10, R11, R12 which may be identical or different, are each selected from hydrogen, hydroxy, methyl, methoxy, halogen, -CONH2 and NH-R13, the group R13 representing hydrogen, acyl or 3 lower alkylsulfonyl group, or any two of R10, R11 and R12 may represent a methylenedioxy group, the compounds being in the form of their racemates, enantiomers or diastereomeric pairs of enantiomers, together with their acid addition salts.
The preparation and use of the new compounds as active substances for pharmaceutical compositions and as intermediate products for pharmaceutical substances are also disclosed. The new compounds are particularly suitable for treating asthma, bronchitis, hayfever, cardiovascular disorders and for the relaxation of the muscles of the uterus, and are also suitable for improving the flesh production and fodder utilisation in meat-producing animals.

Description

lM139~047 "Benzo_Heterocycles'I

The invention relates to benzo heterocycles. -More particularly it relates to benso heterocycleshaving useful therapeutic properties.
According to the invention, we~provide compounds general formula (I) ' O
Il A~
- H~ O
/ ~ \ 1 2 (I~
~ 5~ X-R~
~ OH
R

wherein A represents a single bond, a group -C~2-CH2~, R
or a group =C~ S wherein R4 represents hydrogen or lower alkyl, and R5 represents hydrogen, or lower alkyl or, when R4 represents hydrogen, a phenyl grou~;

Rl represents a hydroxy or acyloxy gro~p or a chlorlne or hydrogen atom;

R2 represents hydrogen, or a m~thyl or ethyl group, and R3 C~12-(C ~ R7 represents a group -C-CH2 or ~C~(CH2)n~Rg R6 R~
(II~ (III) wherein m represents either 2, 3 or 4, n represents either 1, 2 or 3, R6 represents hydrogen or methyl, R7 represents hydrogen or methyl, R8 represents hydrogen or methyl, and Rg represents hydrogen, or a group Ar, -OAr, or -NH-CO-Ar, wherein Ar represents one of the groups ~ ' ~
Rlo or ~ R12 (IV) in which Rlo, Rll, and R12, which may be the same or different, are each selected from hydrogen, hydroxy, methyl, methoxy, halogen, -CONH2 and NH-R13 the group R13 representing hydrogen, acyl or a lower alkylsulfonyl group, or any two of Rlo, Rll and R12 may represent a methylenedioxy group.
~ he 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 ~ carbon atoms; the term "halogen" denotes fluorine, chlorine, bromine or lodlne, preferably fluorine and chlorine, and the term "acyl" denotes an optionally substltuted, optionally branched aliphatic acyl group with up to six carbon atoms or an optionally substitued benzoyl group.
Pre.~erred are compounds of the lnvention wherein A
represents a slngle bond, or a group aCH2, =CH(CH3), =C(CH3)2 or ~i CH ( C 2H 5 ) , Rl represents hydroxy or acyloxy in the m- or p-position relative to the side-chain;

-2a-~2 represents hydrogen or a methyl or ethyl group;
R3 rep.eesents one of -the groups of formula (II) or (III) above, in which m represents 2 or 3, n represents 1, 2 or 3, R6, R7 and R8 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 Rlo represents hydrogen, hydroxy, methyl or a group -NHR13, the group R13 representing acetyl or methanesulonyl or, Rlo together with Rll represents a methylenedioxy group, Rll represents hydrogen, hydroxy, methyl or a group -NHR13, the group R13 representing acetyl or methanesulfonyl or, to.gether with Rlo, represents a methylenedioxy group, R12 represents hydrogen.
Particularly preferred are compounds wherein A represents a group =C(CH3)2 or -CH2-, Rl'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, tert.-butyl, cyclopentyl, l-methylcyclopentyl, or a group of formula (III) wherein n represents 1 or 2, R7 and R8 represent hydrogen or methyl t and Rg represents one of the groups phenyl, 4-hydroxyphenyl,

2-pyridyl, ~-pyridyl, 2-hydroxyphenyl, 2,6-dimethyl-4-hydroxy phenyl, ~-methyl-4-hydroxyphenyl, ~' "
NH-C0--< ~ rH-C0~ N

4 _ According to a further a~pect of the invention/
we provide a process for the preparati~n of compounds of formula (I) as defined iEI claim 1 wherein either a)a compound of formula ~V) O
~ A
~ b (v) ~2 10~ ~ ~ -C~-NH-~3 Rl wherein A, R1, 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) A
H~ O
/ (XII) ~ -CO-Q

Rl wherein Rl 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 o ~ormula (XIII) (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) A

~ 12 R (XVI
~ IH-CH-N_R3 R' lS wherein A and R2 are as defined in claim 1, R1 represents Rl or a hydroxyl group protected by a hydrogenolyticallv 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 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 pre~erably e~fected in a solvent whlch is sufficiently stable under the reaction conditions, e.g. in a lower alcohol such as ethanol. As thq reducin~ 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 (catalytlc reduction or reduction 9 ~8~

with hydrides) it is possible to prepare predominantly either the erythro- or threo-form of an optically active compo~nd 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 re~oved in the usual way during or after the reduction reaction.
The compounds of formula lV) used as starting materials which are new compounds may be ob~ained according to methods known per se, as shown in the following reaction scheme, which is by way of example:
02N Q~ O~N OH R

HO- ~ = HO ~ l2 ~2N OH H2N ~ R2 20 ~Z-O- ~ -cO-cH2 ________~ BZ-O- ~ ~CO-CX2 Clco-c~4R5 ~ 1 ClCO-OPh Bz = Benzy' , ~
Ph = Phenyl o 33z_~o_C22 ~Z~~/~~CO~C~2 ~ ar2 ~,, Br2 o B2~0~ C0-C~-Br Bzû~ CC-C~-Br (VI ) ~VI~ ) Correspondina bromoketones wit:h ~?n option;,lly protected hydroxyl ~Jroup in the m-position relative to the side-chain may be obtained by t~lf=? :'-ol].ow.ing reaction procedure, which ls ~].so by way of exampLe:
OH OH
1 ~2 ~ ~ -CO-C~2 Bz-O

O2~J OH H2N OH
CH2 ~ ,R2 ~ /' Bz-O / ~?~_0 ~ O ~

~ CO-CH2 ~-CO-C~2 Bz-O ¦ Bz-O ,1-o R4 "L~ R5 ~ /~
HN' ~ ~ ~
\"e< R2 ~ ~o-CH-Br ~-CO~H-Br ~/
~ ' /
~ (VIII~
Tlle h:romolceton~-?s o:E Eormula (X) (~

/o ~,~ F~ 2 ~, -CO-CH-Br f~

obtained in this way or by other conventional methods, wherein A, Rl 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 ~' HN-R3 (XI~

wherein R3 is as hereinbefore defined and R' represents hydrogen or a hydrogenolytically cleavable group, such as ben~yl 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 contlnues.
In reaction (b), instead of reagents of formulae (XII) and (XIII), it is also possible to reduce the Schiff bases of formula (XIV) o ~ A
~7 ' -cO-CH=N-~3 (XIV~

wh~rein A, Rl and R3 are as hereinbefore defined, whlch 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 hydrogenolytically cleavable groups. These protecting groups may be removed by hydrogenolysis in the usual way cluring or after the reduction.
The final products of this reaction are compounds of formula (I) wherein R2 represents hydrogen.
'I'he compounds of formula (XII) used as starting materials may be obtained from acetophenone derivatives of formula (XV) ~ A
l-IN O

1 /> ~ COCH3 (XV) wherein Rl 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 kno~l 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) Inay be resolved into their enantiomers, optionally into diastereomeric pa:irs of onantlolnors J by conventional metllods. ~ny bases initially ob~ained may bc convortecl:illto their acid a(lclition salts, and/or any acicl addition salts ini-tially obtained nlay be convertecl into bases or salts ot other acids.
Tllo compounds accorcli.ng to the invention hlve phlrnlaceutical 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 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 lahour 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 ~he complaint and the method of administration.
In adults, the following dosages are recommended for the ~ollowing 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, 10 ml ampoules containing from 0.01 to 1 mg may be u ed.
For vasodila~ion, 20 to L00 mg may be tak~n orally or ampoules containing 20 to 40 mg are u~ed 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 con-tain other therapeutic ingredients Thus, the broncholytics 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 7/u 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 formulatir.g 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 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.

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 mq 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 Suppositories 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 mg of active substance according to the 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 Erom 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, Eor example, for the compound of Example 1, in guinea pigs the ED50i.v. [~g/kg] of the increase in heart rate is :

- 13 - i more than ten times the ED50i.v. ~g/kg3 of broncholysis, which is only 0.045 ~g/kg. The resorption characteristics are generally favourable as well. Thus, the resorption quotient ED50p.o.
ED50i-V

is only l.l, 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 LD50 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 de~ined quantities of the solvent bound in the crystal. The melting points given are uncorrected.

Example 1 -H ~
H0 ~ OH ~ NHCH~CH3)2 x HCi x H20 16.1 g of 5'-benzyloxy-8'~ oxo-2-bromobutyl)-2H-1,4-b~nzoxazin-3-(4E)-one and 7.5 g of isopropylamine are stirred in 100 ml of acetonitrile for 4 hours at 60C. After acidification with conc. hydrochlor:ic acid and addition of the mixture to 100 ml of water the 5'-benzyloxy-8'-(1-oxo-2-isopropylamino-butyl~-2~-1,4-benzoxazin-3-(4H)-one hydrochloride (melting point 229 - 232C~ crystallises out.
6 g of these compounds are debenzylated in methanol, with the addition of palladium/charcoal as catalyst, to yield 5'-hydroxy-8'-(1-oxo-Z-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one hydrochloride dihydrate ~melting point 242 - 245C).
By hydrogenating 3.3 g of this cvmpound in methanol with platinum as catalyst, 3 g of erythro-5'-hydroxy-2S 8'-(l-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxa2in-3-(4H)-one hydrochloride hydrate are obtained (yield:
9o% of theory), which melts at 208 - 210C.
_xample la O

H~l/ C~
\~=< F2H~

3S H0~ H-CH-l~H-CH(CH3)2 x HCl (~hreo) 32.4 g of S'-benzyloxy-8'-(1-oxo-2-bromo-butyl)-2H-1,4-benzoxazin-3-(4H)-one and 72 g of benzylisopropyl-amine are stirred at 100C 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-8'~ oxo-2-benæylisopropylamino-butyl)-2~-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 25~ 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-hydroxy-2-benzylisopropylamino-butyl)-2H-1,4-benzoxazin-3-(4H)-one precipitated (melting point 89 - 92C) is suction filtered.

4.8 g of this compound are hydro~enated in 100 ml of methanol with palladium/charcoal as catalyst.
After uptake has ended, the catalyst is removed from suction filtering, the mother liquor i5 concentrated by evapofation 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~ hydroxy-2-isopropylamino-butyl)-2H-1,4-benzoxazin-3-(4H)-one hydrochloride precipitated (yield: 74%
o~ theory) is suction filtered; after being re-precipitated from methanol/ether it melts at 202 -205C.

Example 2 H ~ CH3 HO CH-CH2-NH-C-CH3 x HCl 10 g of 5~-benzyloxy-8'-(1-oxo-~-bromo-ethyl)-2H~1,4-benzoxazin-3-(4H~-one and 8.75 9 of benzyl-tert.-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'-(1-oxo-2-benzyl-tert.-butylaminoethyl)-2~-1,4-benzoxazin-3-(4H)-one hydrochloride is precipitated (melting point 185 - 189C).
7 g of this compound are debenzylated at 5 bar and at 50C in 100 ml of methanol, with the addition of palladium/charcoal as catalyst, to yield 5'-hydroxy-8'-~1-oxo-2-tert.-butylamino-ethyl)-2H-1,4-benzoxazin-3-(4H)-one hydrochloride (melting point 237 - 240C).
By catalytic hydrogenation of 2.2 g of this compound in methanol with platinum, 1.6 g of 5'-hydroxy-8'-(1-hydroxy-2-tert.-butylamino-ethyl)-2H-1,4-benzoxazin-3-(4H)-one hydrochloride are obtained (yield: 72.S%
o~ theory) t melting at 185 -187C.

- _ --17 --._ C _ . , _ C ' O ' ~ ~o -1 ~ ~ ~ ~
o . ~_ ~o ~
~ _ .

~ ~ O V
S ~ 3 j C ~ 3 ~ ,Uc a c aJ , o ~ . ~ . .. _._............ ........
C ~ ~O C~
.

m~

~c ~ .

1 ~ ~ T _ ~ T

tD t4 _ \ /

~ 1-1 1~ - Cl I X t_~ - O
O ~ ~ ~ 0~
h ~ .. x :~:
. ____ _ , _ ., Z; . ,_~

- 18 ~
1' ~,, X I

T

. O " ~

.- 1 9 - ~` L~

N
~10 ~ ;~ , O) O - ~_ , _ _ _ - r __ _ _ !
~ 0~ 0~ ~ 5~ ;
~ ~ ~I ~
V~ O~
_ _ __ _ _ _ _ _ 0~ ~ . .
~V .
a~o, ~ ~ . .~

_ ._. ______ .~.___.____ _ _ _ _ - . __.
~ ll ~ ~ ~ I

r~ ~ I ~J
_-I I ~ , ~.) ~: I
Z u~ z u~ z u z Ll ~ I I I I I ~: I
I ~ - ~.) ~ ~ - c_) ~ - ~_) ~1 T 3:: I :~: I I I ~ ~ T
~_) - O (~ ~ - O t_) - O
.~J o~ ~ oJ~ l o~ 3 ~C~ 0~
t/~ T ~ C T ~
~ _. . _ _.__. ___ _ O ' l L ~
. _. . ~ .__ .

~ .
.

~ I N ~ N 0~
~ ,tt~- a~ ~ ~1 ___ _ _ _ 0~ ,~
3 ~ X
~ U~ ~ . ~0~ . 1 ~ . ~ _ __ . !
C . .
,c a~' ;t t- o .
. . _ -I

T t .
V~ 0 t_~ N
Z I T T
d ~1 ~ (~3 ~ x I .
~1~I ~ I~ ~:~J ,:~

E N T ~ ~; N

~ C~ ~ - ~ . ~ ~ J O I - O
O ~ ~ T _ TT '~ :1 I ~ ~q ~ ~ o C_~ I=) C~ -O t~ ~ ~' ~J
U c;~ ~ ~ ~ ~ 0~(~1 T O
~ O . _ O ~0 ~
______ _.~ . ~ _.___ _ .
q ~ ~3 _~ I

1s r I ~

. --_ - ....................... , U~ ~3 . 0~,~
L ~

Exam~le 3 H ~ CH
H ~ CH-CH2-NH-C-CH2-CH2 ~ x HC

5 g of 5'~benzyloxy-8'-~1-oxo-2-hydroxy-2-ethoxy-ethyl)-2H-1,4-benzoxazin-3-t4H)-one, 2.2 g of 1,1-dimethyl-3-phenylpropylamine and 50 ml of alcohol are heated to 50 60C for 3 hours. After the reaction mixture has been cooled, the Schiff base precipitated (melting point 138 - 140C) 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'-[1-hydroxy-2-~4-phenyl-2-methyl-butylamino)-ethyl]-2~-1,4-benzoxazin-3-(4H)-one precipitated (meltin~ point 162 - 164C) is suction filtered and the hydrochloride (melting point 20S - 207C) 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 5l-hydroxy-8'-[1-hydroxy-~2-~4-phenyl-2-methyl-butylamino)-ethyl.]-2H-1,4-benzoxazin 3-(4H)-one-hydrochloride are obtai.ned ~melting point 15~ - 161C, yield: 90~ of theory).

H~ \P CH3 C ~ C H - C H - N H - C - C ~13 x H Cl .

5.8 g of 6'-chloro 8'-(1-oxo-2-hydroxy-2-ethoxy- -ethyl)-2H-1,4-benzoxazin-3-(4~)-one, 1.5 g of tert.-butylamine, 60 ml of dioxan and 60 ml of alcohol are heated to 50C for 2 hours. The solution is then cooled and 2 g of sodium borohydride are added thereto at lO 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 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 ml of alcohol, acidified with etheric hydrochloric acid and the 6'-chloro-8'-[1-hydroxy-2-(tert.-butylamino)-ethyl]-2~-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 300C (melting point of base: 173 - 177C~.

~5C~

. ~ ,,, v _ ~ 3 h o O

. 3 O-U. OU Ot)O

. rd ~ h ~ ~1: X

o O ,~0 ~ . _.
. . .

h ~

~ I :~:
~ ~ r~
O ~ X I X
O . , -/ C~ ~ ~ ~ ~ ~ ~
.o ~

~0 r/

I ~O~ ~ I - 25 l ~ ___ . ' __ __ _ C~ .0 ,t~ j 3 So~3 ~ s~ . I
~ ~ X . ~ ~: ' _ _ .. .

,0 . . . i -~

Z~ .

~ ~ Y - ~
~ ~- ~ o~ 3 lo~ o~o.
_._ . ___ _ -" ~; .. ~

~o ~ 26_ :~ ~
's~

3 Jo~ U
j ~ ' I :

~O~ U~
~ C~
~0 . .' ~o\
_~

,_1 ~O,, S
~ lc-L~a __o _ ~ _ --. 27 --_ _ _ U C O O N O
l :::3. __ 'I l . 'I I _.

3 ~ . 5: o ~ ~ o ~ o ~ ~X ~X ~ ~ :
. ___ _ _ .

~P J ~ O u~
_~ . _ ~. ._ _ _ ~2 . ~ ~IJ

~J I .:~:
n~ ~ ~ ~ ~ V
U X ~ 2 O ~ ~) 3: ~ X

~-1 ~ ~ X
I'~J X T I _ o 3~ X
~ ~--o o I ~ o C~ ~ o U ,, o O ~ 0 ~ ~
._._ __ _ . . _ O 0 O~ O r~

.

Example 5 H ~
~ CH-CH2-NHC2H5 x HCl ~H ~

4.3 g of 5'-benzyloxy-8'~ hydroxy-2-benzylethylamino-ethyl)-2H-1,4-benzoxazin-3-t4H)-one-hydrochloride (melting point 232 - 235C) are hydrogenated in 125 ml of methanol with the addition of 005 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-ethyl)-2H-1,4-benzoxazin-3-t4H)-one-hydrochloride are obtained (yield: 86.7% of theory), which melts at 240 to 242C
after being re-precipitated from methanol/ether.
Example 6 ' ~ ' H~ $ CH-CH2~NH-C-CH2-CH2-NHC ~ 3 \
OH ~H3 0 OH

6.3 g o 4'-benzyloxy-7'-~1-hydroxy-2-(4-picolinic acld-amido-2-methyl-2-butylamino~-ethyl]-~-benzoxa~olinone (melting point 130 133C) are hydrogenated in 125 ml of methanol with the addition of 1 g of 5~ palladium/
charcoal. When the uptake o~ hydrogen has ended, the catalyst is filtered off and the clear solution is concentrated hy 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 ~l8~

2g 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 - 168C3 is suction filtered.

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Intermediate products of formula (V) which can be obtained according to the above scheme are listed belowO
The compounds of formula (V) may also be used as pharmaceutical compositions themselves, since they have similar pharmacological properties to the compounds of formula (I~.

. - 38 -_ ~rl 3 ~ ~3 ~
~ I
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Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of compounds of formula I, in the form of their racemates, enantiomers, or diastereomeric pairs of enantiomers, and the acid addition salts thereof, (I) wherein A represents a single bond, the group -CH2-CH2-, the group , wherein R4 represents hydrogen or a lower alkyl group, and R5 represents hydrogen, or a lower alkyl or, when R4 represents hydrogen, a phenyl group;
R1 represents a hydroxy or acyloxy group or a chlorine or hydrogen atom;
R2 represents hydrogen, a methyl, or an ethyl group;
R3 represents one of the groups (II) or (III) (II) (III) wherein m represents either 2, 3 or 4, n represents either 1, 2 or 3, R6 represents hydrogen or methyl, R7 represents hydrogen or methyl, R8 represents hydrogen or methyl, R9 represents hydrogen, or a group Ar, OAr, or -NH-CO-Ar, wherein Ar represents one of the groups , or (IV) in which R10, R11, R12 (which may be identical or different, are each selected from hydrogen, hydroxy, methyl, methoxy, halogen, -CONH2 and NH-R13, the group R13 representing hydrogen, acyl or a lower alkylsulfonyl group, or any two of R10, R11 and R12 may represent a methylenedioxy group, which process comprises:
(a) a compound of formula (V) (V) wherein A, R1, R2 and R3 are as defined above, 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) (XII) wherein R1 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) H2N-R3 (XIII) wherein R3 is as hereinbefore defined, any hydroxyl groups contained therein optionally may be protected by hydrogenolytically cleavable protecting groups, followed, if necessary or if desired, by deprotection; or (c) deprotecting compound of formula (XVI) (XVI) wherein A and R2 are as defined in claim 1, R1 represents R1 or a hydroxyl group protected by a 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), and (d) if desired, resolving a thus obtained compound either into its enantiomers or into diastereomeric pairs of enantiomers; and (e) if desired, converting a thus obtained compound either into an acid addition salt thereof, or into a different acid addition salt thereof, and (f) if desired converting a thus obtained compound in the form of a salt into the corresponding free base.

2. A benzoheterocyclic compound of formula I as defined in claim 1 whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

3. A process according to claim 1 wherein:
A represents a single bond, or a group =CH2, =CH(CH3), =C(CH3)2 or =CH(C2H5), R1 represents hydroxy or acyloxy in the m- or p-position relative to the side-chain;
R2 represents hydrogen or a methyl or ethyl group;
R3 represents one of the groups of formula (II) or (III), in which m represents 2 or 3, n represents 1, 2 or 3, R6, R7 and R8 represent hydrogen or methyl, R9 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 R10 represents hydrogen, hydroxy, methyl or a group -NHR13, the group R13 representing acetyl or methanesulfonyl, or, R10 together with R11 represents a methylenedioxy group, R11 represents hydrogen, hydroxy, methyl or a group -MHR13, the group R13 representing acetyl or methanesulfonyl, or, together with R10, represents a methylenedioxy group, and R12 represents hydrogen.

4. A benzoheterocyclic compound of formula I as defined in claim 1 in which A, n, m, R1, R2, R3, R6, R7, R8, R9, R10, R11, R12 and R13 are as defined in claim 3, whenever prepared by the process of claim 3 or by an obvious chemical equivalent thereof.

5. A processs according to claim 1 wherein:
A represents a group =C(CH3)2 or -CH2-;
R1 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, tert.-butyl, cyclopentyl, 1-methylcyclo-pentyl, or a group of formula (III) wherein n represents 1 or 2, R7 and R8 represent hydrogen or methyl, and R9 represents one of the groups phenyl, 4-hydroxyphenyl, 2-pyridyl, 4-pyridyl, 2-hydroxyphenyl, 2,6-dimethyl-4-hydroxy phenyl, 2-methyl-4-hydroxyphenyl, , or

6. A benzoheterocyclic compound of formula I as defined in claim 1 in whlch A, Rl, R2, R3, R7, R8, R9, and n are as defined in claim 5, whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

7. A process for the preparation of erythro-5'-hydroxy-8'-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one hydrochloride hydrate which comprises reacting 5'-benzoyloxy 8'-(1-oxo-2-bromobutyl)-2H-1,4-benzoxazin-3-(4H)-one with isopropyl-amine; by dibenzylating the thus obtained product in methanol using a palladium/charcoal catalyst; and then hydrogenating using a platinum catalyst.

8. Erythro-5'-hydroxy-8'-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one hydrochloride hydrate whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.

9. A process for the preparation of threo-5'-hydroxy-8'-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one hydrochloride which comprises reacting 5'-benzyloxy-8'-(1-oxo-2-bromobutyl)-2H-1,4-benzoxazin-3-(4H)-one with benzylisopropylamine;
reducing the thus obtained product with sodium borohydride;
hydrogenating the reduced product using palladium/charcoal catalyst; and converting the thus obtained free base into its hydrochloride salt.

10. Threo-5'-hydroxy-8'-(1-hydroxy-2-isopropy1aminobutyl)-2H-1,4-benzoxazin-3-(4H)-one hydrochloride whenever obtained by the process of claim 9 or by an ohvious chemical equivalent thereof.