DD204477A5 - PROCESS FOR THE PREPARATION OF BENZO-HETEROCYCLES - Google Patents

Abstract

The invention relates to a process for the preparation of novel benzo-heterocycles having valuable pharmacological, in particular broncholytic properties for use as medicaments, for example for the treatment of asthma, bronchitis, hayfever, cardiovascular disorders and relaxtion of the uterine musculature. The aim of the invention is the provision of new compounds with long-lasting selective broncholytic action and very low side effects on the heart and skeletal muscles. According to the invention, novel compounds of the formula I are prepared in which, for example: A is a single bond, the group -CH deep 2 -CH deep 2 and the like; R deep 1 OH, O acyl, chlorine or hydrogen; R 2 is hydrogen, methyl or ethyl; m is 2,3 or 4; n is 1,2 or 3; R deep 6 hydrogen or methyl.

Description

The invention relates to a process for the preparation of novel benzo-heterocycles having valuable pharmacological, in particular broncho-lytic properties.

The compounds according to the invention are used as medicaments, for example for the treatment of asthma, bronchitis, urticaria, conjunctivitis, hay fever, colds, cardiovascular disorders and »a«

Characteristic of the known technical solution

Bronocholytics are known from DE-OS 2 833 140 and are commercially available, for example isoprenaline, orciprenaline, buterbutalin, salbutamol. However, the known preparations are unsatisfactory with regard to their lifting effects on the heart and the skeletal musculature and / or their duration of action.

Object of the invention

The aim of the invention is the provision of compounds with '' in particular special broths which combine a long-lasting selective bronchiolytic action with very slight lifting effects on the heart and the skeletal musculature.

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Indicate the nature of the invention

The invention has the object of finding new compounds with the desired properties and processes for their preparation.

According to the invention, new compounds of the general formula

(I)

OH

manufactured in the _R

A is a single bond, the group = 0 ^ ρ or the group

-CH ₂ -CH ₂ -,

OH, O acyl, chlorine or hydrogen, R _{2 is} hydrogen, methyl or ethyl,

_{E 22m or} c ( _CH )

3 -C-CH ₀ .- * " I- 2 η

R ⁸

(II) (III)

m 2, 3 or 4 _p

η 1,2 or 3,

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H ^ hydrogen, lower alkyl,

Rc is hydrogen, lower alkyl and also, if R, is hydrogen, phenyl,

Rg is hydrogen or methyl, R ". Hydrogen or methyl, Ro is hydrogen or methyl, Rq is hydrogen, Ar, OAr, IH-CO-Ar

Ar αΧ.ΉΓ) 1 (Γ)] or ! 2

(IY)

R ₁ 1 RI ₂ ^^ ^{e may be the} same or different), hydrogen, hydroxy, methyl, lethoxy, halogen, methylenedioxy,

R - / hydrogenV is acyl or lower alkylsulfonyl; they may be present in the form of racemates, enantiomers and optionally diastereomeric antipode pairs ^: as free bases or as acid addition salts. «

For the purposes of the invention, "lower alkyl" means an alkyl radical having 1 to 4 carbon atoms, "halogen" fluorine, chlorine,

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Bromine and iodine, preferably fluorine and chlorine, "acyl" an optionally substituted radical of an optionally branched aliphatic carboxylic acid having up to 6 carbon atoms or an optionally substituted benzoyl radical »

In a preferred embodiment of the invention

A is a single bond, = CH ₂ , S = CH (CH ₃ ), = C (CH ₃ ) ₂ or -CH (C ₂ H ₅ ),

R _{1 is} OH or OAcyl in the J or p position to the side chain,

R _{2 is} H, CH ₃ or C ₃ H ₅ ,

R- for the above mentioned radicals II and III,

m for 2 or 3,

η for 1, 2 or 3,

Rg, R ₇ , R _{8 is} hydrogen or methyl,

R _{g is} H, Ar, M-CO-Ar,

Ar for the rest of the Ponnel 17, .2-pyridyl or 4-pyridyl,

R ₁₀ for H, OH, CHo, together with R ₁₁ also Methylendiosy,

R ₁₁ for H, OH, CEL, together with R ₁₀ also ethylenediosyl,

R ₁₂ for H,

R "n for acetyl or methanesulfonyl"

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Particularly noteworthy are the compounds in which A is = C (CH ^) ₉ or -CH ₀ -,

> C- C-

R _{1 is} OH in p- or m-position to the side chain, R _{2 is} H, CH ₃ or C ₃ H ₅ ,

R ~ for isopropyl, tert -butyl, cyelopentyl, 1-methylcyelopentyl or the radical of the formula III,

η for 1 or 2,

, Rg is hydrogen or methyl,

Iq is phenyl, 4-hydroxyphenyl, 2-pyridyl, 4-pyridyl, 2-hydroxyphenyl,

, HH-CO tt ^ HJ, _{/ rSK}

~ \ J / " ^0H *

CH ₃

stands.

The new compounds are prepared by methods known per se.

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1. Reduction of compounds of the formula

in which A, R ₁ , R "and R- have the above meaning, although phenolic OH groups can also be protected by a hydrogenolytically removable group.

The reduction is carried out in a solvent sufficiently stable under the reaction conditions, e.g., B, in a lower alcohol such as ethanol. The reducing agents used are hydrogen and hydrogenation catalysts (such as palladium, platinum, Raney nickel) or hydrides (such as sodium borohydride or diborane). By suitable choice of the reducing agent (catalytic reduction or reduction with hydrides) the formation of predominantly the erythro- or threo-form can be achieved «

Any hydrogenolytically cleavable protecting groups present on the central amino group or on a phenolic hydroxyl group, for example benzyl or substituted benzyl, are removed during or after the reduction in the usual way.

L ¹ SL ÖO I α

_ 7 ι «.

61.284 12 15.2.83

The novel compounds of formula Y can be obtained by methods known per se, for example as shown in the following reaction scheme:

OH

Friedel-Crafts HO

-C

Bz-O

Bz = benzyl Ph = phenyl

OH

CO-CH

Bz-O

C0-CH

BT

ClCO-CR ₄ R ₅ Cl

CICO-OPh

HH 0

Bz-O-

CO-CH

61.284-12 15.2 _β 83

O IL

Bz-O-

CO-CH-Br

BzO

CO-CH-Br

(VII)

Corresponding bromoketones having the (protected) OH group in the m-position to the side chain can be obtained as follows;

OH

Bz-O

R, S

CO-CH

CO-CH

OH fl V-CO-CH,

Bz-O

Bz-O

HI 0

Γ ²

CO-CH

Bz-O

Fri.

CO-CH

61284 12 15.2.83

O R

CO-CH-Br

Bz-O

(VIII)

= \ f

(IX)

CO-CH-Br

The bromoketones of the formula O obtained in this way or by other customary methods

R

CO-CH-Br

in which A, R ₁ and H _{2 have} the abovementioned meaning, but where phenolic OH groups can be protected by hydrogenolysis cleavable groups, such as benzyl, can be obtained by reaction with amines of FormsI

R *

wherein R- has the above meaning and R ^{1 is} hydrogen or a hydrogenoIytisch cleavable radical such as benzyl or substituted benzyl, be obtained »The reaction is carried out in suitable inert solvents, such as acetonitrile, ethyl acetate, in the presence of an acid scavenging

s υ

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By means of "sodium carbonate or excess of amines". Schu.tagru.ppen present in the reaction product can subsequently or subsequently be removed during the further reaction or afterward,

2, reaction of phenylglycosides or hemiacetals of the formula

(XII)

in which R ₁ and A have the above meaning and Q is -CHO or

CH

O-Liederalkyl stands, with amines of the formula

H ₂ Ii-R ₃ (XIII),

in which R- has the above meaning, under the conditions of the "reductive" amination ·

Instead of the components XII and XIII, the optionally occurring as an intermediate Schiff's bases of the formula

υ υ ι

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15 * 2.83

m 0

/ ', X-OO-OH = HE ₃ (XIT),

in the 1, R ₁ and R - have the above meaning _{s undergo} a reduction.

As the reducing agent, complex hydrides, preferably sodium borohydride, or hydrogen and hydrogenation catalysts such as platinum, palladium, nickel are used.

Phenolic hydroxy groups contained in the starting materials may be protected by conventional hydrogenolysis cleavable groups. These protecting groups can be removed by hydrogenolysis during or after reduction in the usual way.

One obtains end products with R ₃ equal to hydrogen ·

The compounds used as starting materials Poline1 XII. can out. Acetophenone derivatives of Porinel

COCH ₃ (Σ7),

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in.der R ^ and A have the above meaning be obtained by oxidation with selenium dioxide in aqueous dioxane. »Depending on the crystallization from water or lower alcohols, glyoxals or hemiacetals are obtained.

The amines of formula XEII are known or easy to obtain by conventional methods »

3. Removal of hydrogenoIytisch cleavable protecting groups of compounds of the formula

R ₀ H ·

I ² I

r-CH-CH-IR ₃ OH

in which A and R _{2 have} the above meaning and R. * for B .. or protected by a hydrogenoIytisch cleavable protecting group protected OH group, R ~ »is R ~, wherein, however, in Β, about OH group contained may be protected by a cleavable hydrogenoIytisch Schutsgruppe, ⁵ and R 'is hydrogen or a removable protecting group hydrogenoIytisch. As hydrogenoIytisch cleavable protecting groups are mainly benzyl and substituted benzyl into consideration.

If desired, after 1 ·. to 3 »obtained compounds by conventional methods in the enantiomers,

LUU ι

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if appropriate also separated into the diasteremor antipode pairs, first obtained bases in acid addition salts _s first obtained acid addition salts converted into bases or salts with other acids.

The compounds of the invention are useful as drugs. They have u, a * broncholytisehe, spasmoIytische and anti-allergic effect and increase the Ciliartätigkeit and reduce inflammatory-essudative reactions »They are therefore applicable to - all forms of asthma and bronchitis, in urticaria, Kon) unktivitis, hay fever and colds, They are also relaxants of the uterine musculature, which are suitable for preventing discomfort before birth. The compounds may also be used for the treatment of cardiovascular disorders such as hypertension, peripheral vascular diseases and arrhythmias. Other effects include inhibition of gastric secretion and in the ZlS observed antidepressant effects.

The therapeutic and prophylactic dose "depends on the nature and severity of the disease.

For one sirloin, the following doses are indicated for each of the following indications.

As broncholytic agents oral 0.05 to 5 sig, 0.01 to 1.0 mg by inhalation and 0.02 to 0.5 Hg are taken subcutaneously.

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As a uterine agent, 10 to 50 mg orally as an infusion solution of ampoules (10 ml) containing 0.1 to 1 mg are used.

For vasodilatation, 20 to 100 mg ampoules are used orally for i.m. "injection with 20 to 40 mg._. The antihypertensives are to be dosed orally with 200 mg to 1.8 g »

The pharmaceutical preparations contain active substances, pharmaceutically acceptable excipients and optionally other therapeutic ingredients,

Thus, the broncholytic agents can be combined with theophyllines, parasympatholytics (z, B "ipratropium bromide), secretolytics, (z, B, bromohexine), musculotropic antispasmodics (eg, papaverine), corticosteroids and antiallergic drugs. Combinicoids can be combined with the ünterusrelaxantia.

For oral administration, capsules, tablets, solutions and suspensions are suitable. In pulmonary administration, dry powders with particle diameters of 0.5 to 7yU are preferably brought into the bronchial area by means of propellant gases. The parenteral administration is expediently carried out in the form of sterile isotonic aqueous solutions; for local application, lotions, creams, ointments, emulsions and sprays are taken.

The compounds of the present invention may also be used to increase the rate of increase of meat-producing animals, eg, pigs, cattle, sheep, chickens, geese. The use of the putter is greatly improved.

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Furthermore, the meat has a higher quality and a lower fat content than without the use of the new compounds »

fformulierunffsbeispiele;

Tablets Composition of a tablet

Active substance according to the invention 20 mg

colloidal silica 10 mg

Lactose 118 mg

Potato starch 60 mg

Polyvinylpyrrolidone β mg

Ha-cellulose glycolate 4 mg

Magnesium stearate 2 mg

220 mg

Ampoules Composition of the solution per ampoule

Active substance according to the invention 10 mg

Sorbitol 40 mg

distilled water ad '10 ml

Sup pöaitorien

Composition per suppository

Active substance according to the invention 100 mg

Suppository mass (cocoa butter) 1600 mg

1700 mg

fc. f. V V i

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Inhalation powder

0.5 g of active ingredient according to the invention and 19 mg of lactose with a particle diameter of between 0.5 and 7 μm are introduced per h gelatin capsule;

For the pharmacological tests, the customary (test methods and experimental animals or organs are used.) Pharmacologically, the compounds according to the invention are in some cases very clearly differentiated from commercial products of the same indication.Having a good duration of action z, B shows a particularly clear selectivity in the broncholysis ratio Increase in heart rate * Thus, for example, for the compound according to Example 1 on the guinea pig, the EDf-Qi.v * // Ug / & 7 of the heart rate increase is more than ten times as large as the EDc ₀ -Lv./7ug / kg7 of the broncholysis. which is only 0.045 / ug / kg · In general, the absorption ratios are also favorable.

₀ Lv, z, B, for Compound 7 of Table 3 only 1.1, so that the oral effect is practically as great as the intravenous. The LDe ₀ values are, for. B, on the mouse, so far above the therapeutic dose that a favorable therapeutic range is given,

embodiment

The examples below are intended to illustrate the processes of the invention without limiting them, since the reactions

&, ι ί, Μ V ι

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tion conditions can be varied considerably with a similar result.

Depending on the solvent from which the substances mentioned below are crystallized, some of them still contain defined amounts of the solvent bound in the crystal. The melting points given are uncorrected.

For method 1 example 1

HCIxH ₂ O

1.6,1. g 5'-Benzyloxy-8 ^L - (1-.o-2-bromo-butyl) -2H-1,4-benzo2; azine-3- (4H) -one and 7.5 g. isopropylamine are dissolved in 100 mL acetonitrile stirred for 4 hours at 60 ⁰ C, laughing acidification with concentrated hydrochloric acid und_Zugabe *; to the 100 ml of water that crystallizes

5 * -Benzylosy-8 '- (1-oxo-2-isopropylamino-butyl) -2H-T, 4-benzoxazine <3- (4H) -one hydrochloride (Pp «229 bis _; 232- ⁰ C) aus ,.

6 g of these compounds werderi ^: in methanol with the addition of palladium-carbon as a catalyst to S'-hydroxy-S'-d-osio-S-isopropylamino-butyl) -2H-1,4-benzoxazine-3- (4H) - one hydrochloride dihydrate (Pp, 242-245 ⁰ C) debenzylated *

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By hydrogenation of 3 »3 g of this compound in methanol with platinum as a catalyst to obtain 3 g of erythro-5 -Hydro3jy ^{f-8 f} - (1-hydro ^ -2-isopropylamino-butyl) -2H-1,4-benzo: Xazin-3 '»(4H) -one hydrochloride hydrate (yield 90 % of theory), which melts at 208 to 210 ⁰ G.

Example 1a Method 3

CH-CH-BH-CH (GH ₃ ) ₂ χ HCl (threo) OH

32.4 g of 5 ^l -Benzylo2y-8 ^t - (1-o2; o-2-bromo-batyl) -2H-1,4-benzo2: azin-3- (4H) -one and 72 g of benzyl isopropylamine become 15 hours stirred at 100 ⁰ C. After adding water, the precipitated oil is taken up with ether and diluted with petroleum ether; crystallization of 5'-benzyloxy-8 '- (1-oxo-2-benzylisopropylamino-butyl) -2H-1,4-benzoxazine-3- (4H) -one •;

11.6 g of this compound are mixed in a mixture of 60 ml of ethanol / 60 ml of acetonitrile with 1 g of sodium borohydride and stirred for 3 hours. Then 250 ml of sis water and 100 ml of Bssigester are added, after the decomposition of the sodium borohydride with concentrated acetic acid with stirring is made alkaline with concentrated ammonia solution,

L τ L υ υ ι

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the ethyl acetate phase is separated off, dried and

concentrated vapor »The oily residue is dissolved in ether,

and the precipitated threo-5 ^f -benzyloxy-8 ^f - (1-hydroxy-2-benzylisopropylaiaino-butyl) -2H-1,4-benzoxazine-> 3- (4H) -one (Pp, 89-92 ⁰ C) sucked off »

4.8 g of this compound are hydrogenated in 100 ml of methanol with palladium carbon as a catalyst, lach ended recording the catalyst is filtered off with suction, the mother liquor is concentrated on a rotary evaporator, the oily residue is dissolved in Äceton / ethanol and acidified with the calculated amount of hydrochloric acid, Die solution is diluted with ether, and the precipitated threo-5'-hydrosyl-e'-C1-hydroxy-2-isopropylamino-butyl) -2H-1,4-benzo2azin-3- (4H) -one hydrochloride (yield 74 % of theory) is sucked off; after precipitation from methanol / ether it melts at 202 to 205 ⁰ C,

Example 2

CH-CH ^ -SH-C-CH

HCl

10 g of 5'-benzylp.xy-S * -t 1 -oxo-2-bromo-ethyl) .- 2H-1 »4-benzoxazine ·» 3- (4H) -one and 8.75 g of benzyl-tert .-Butylamine are refluxed in 100 ml of acetonitrile for 3 hours, After cooling, the precipitated crystals are filtered off with suction and with 200 ml of warm

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Water, The crystals are acidified in acetonitrile with ethereal hydrochloric acid; after dilution with ethyl acetate 5 ^t -Benzylos: y-8 ⁱ - (1-o2; o-2-benzyl-tert-butylamino-ethyl) -2H-1,4-benzo2azin ~ 3- (4H) -one hydrochloride (mp, 185 to 189 ⁰ C) aas. ,

7 g of this compound are at 5 bar end 50 ⁰ C in 100 ml of methanol with the addition of palladium-carbon as a catalyst to 5'-hydroxy-8 ^f - (1-oxo-2-tert-butylamino-ethyl) -2H- 1,4-benzosazin-3- (4H) (237 Pp, to 240 ⁰ C) debenzylated -one hydrochloride.

By catalytic hydrogenation of 2.2 g of this compound in methanol with platinum, 1.6 g of 5 * -hydroxy-8 ^f - (1-hydro-3cy-2-tert-butylamino-ethyl) -2H-1, 4-Benzoxazin-3- (4H) -one hydrochloride (yield: 72.5 % of theory), which melts at 185 to 187 ⁰ G.

According to the given examples are synthesized: Table 1

Hr «, structural formula

Yield % of Th. Salt with Melting point ⁰ C 66 hydrochloric acid 230 χ 2 water (Dec.) 63 hydrochloric acid I 163 to 165 ^ χ 1 water 1

, OH ₂ -CH ₃

CH-OH,

Oh hh-c (ch-.

Hl O

GH GH.

OH TSIH-CH (CH ₃ )

OH

HN 0

OH

CH-CH

OH HH-C (CH ₃ > ₃

83

Hydrochloric acid 259 to 261

ro ro

Ur. structural formula

Yield % d. Th.

Salt with melting point

⁰ o

ENT

HO-4, V-CH-CH, OH.

vO

₃ ) ₂

HMT)

CH-CH OH.

j CHp-OHo

m o

HO

OH-CH-MHOH (GH ₃ ) OH

Hydrochloric acid 230 bis

Hydrochloric acid 256 bis

χ 1 water '

HCl

244

χ 1/2 H ₂ O

Nr, Strukturformel Yield salt with melting point % d. Th, ^ ⁷ C

HO

2

OH-GH-KH OH

86 HCl 243 to 245 χ 1/2 H ₂ O *

GH-OH-NH-CH ₀ -CH ₂

^0H *

73.5 BG 206 to 209

HN

CH-CH-NH-CH ₂ -CH ₂ -O

OH

COM

52 HGl

170 to 173

cn

ro ro «ω

• CD-Ρ *

Yield salt with melting point% <U 07h · ⁰ O

OH ₃ SO ₃ H 197 to 201

x H ₂ O

83 OH ₃ SO ₃ H 187 to 190

54 HOl 208 to 211

CD -fa-VjJ

Ur, structural formula

HW

HO

2 ^H 5 f ^H 3

OH-CH-NH-CH-CH

OH

OH

-J ₁ .Γ ~~ \

II utit t

HN 0

HO- <V-CH OH

! -OH-BH-CJH ₂ -OH ₂

<( ^2H 5

OH-CH-NH-OH ₂ -CH ₂ OH

NH-C-CH

ITr * Structural formula Yield salt with melting point% d. Th * ⁰ C

13A

HN O

HO

OH

OH

• ΜΗ,

HO

OH

70 HCl 155 to 159

90 HOl 234 his 236 CH ₃ SO ₃ H x H ₂ O 92 his 94

15 H ^ C 3 \ O Il 11, C-C-C-O ³ δΉ

CH-CH-NH-CHOH

Nr, structural formula Yield salt with melting point

W-C-o - \ y CH-OH-M-CHOH

CH.

ch

0 HN

HO

^2H 5

CH-CH-NH. OH

90

HCl

CH ₃ SO ₃ HXH ₂ O

234 to 236 92 to 94

rv>

co

U)

r \ 3

ro

£ * y

61284 12 15.2.83

To practice 2

Example 3

GH ₃ GH-CH ₂ -IH-C-CH ₂ -CH ₂

x HCl

5 g of 5- ^t- benzyloxy-8 '- (1-o3: o-2-hydroxy-2-ethoxy-ethyl) -2H-1- _i- 4-benzoxazine-3- (4H) -one, 2.2 g of 1, i-Dimethyl-3-phenylpropylamine and 50 ml of alcohol are heated to 50 to 60 ⁰ C for 3 hours. Bach cooling the reaction mixture, the precipitated Schiff base (mp 138 to 140 ⁰ C) is filtered off with suction.

4.5 g of this compound are mixed in 100 ml of alcohol with T g sodium borohydride and stirred for 2 hours at room temperature, after the addition of 100 ml of water, the precipitated 5 ^f -Benzyloxy-8 ^f - / T-hydroxy-2- (4- phenyl-2-methyl-bg.tylamino) -äthyl7-2H-1, ^ - benzoxazine- (4H) -one (Pp 162 to 164 ⁰ C) and filtered off with suction with _ethereal: manufactured das.Hydrochloride hydrochloric acid (m.p. 205 to.. 207 ⁰ C).

By catalytic hydrogenation of this compound in 50 ml of methanol under Uormalbedingungen with palladium-carbon as a catalyst to obtain 2.7 g of 5'-hydroxy-8 ^l - / T-Hydro2y-2- (4-phenyl-2-methyl-butylamino) - äthyl7-2H-1,4-benzosazin-3- (4H) -one hydrochloride (Pp 159-161 ⁰ C, yield:. 90% of theory).

τ u yw ι

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Example 4

W OH ₃

/ VCH-CH ₂ -UH-C-CH ₃ χ HCl \ -1 / OH CH ₃

σι

5.8 g of 6 ^l -chloro-8 ^f - (1-oxo-2-hydroxy-2-ethoxy-ethyl) -2H-1,4-benzoxazine-3- (4H) -one, 1.5 g of tert. -Butylamih, 60 ml of dioxane and 6p ml of alcohol are heated for 2 hours at 50 ⁰ C * Then it is cooled and the solution at 10 to 20 ⁰ C with 2 g of sodium borohydride. The solution is stirred for one hour at room temperature, then added to 500 ml of ice water and covered with 150 ml of acetic ester. lach decomposition of the Hatriumborhydrids under stirring with conc. Acetic acid is made alkaline with aqueous ammonia, the ethyl acetate phase separated, dried with sodium sulfate and concentrated on a rotary evaporator. The oily residue is dissolved in 15 ml of alcohol, acidified with ethereal hydrochloric acid and the precipitated 6 ^f -chloro-8 '- / T-hydroxy-2- (tert-butyl-amino) -ethyl 7-2H-1,4-benzo : Azin-3- (4H) -one hydrochloride (yield: 38 % of theory) aspirated. Fach twice'Umfallen from methanol with the addition of activated carbon, the substance has a melting point, which is above 300 ⁰ C (Pp. Of the base: 173-177 ⁰ C).

In an analogous manner, the following compounds are prepared:

Table II

Structural formula Yield salt with melting point

HN 0

OH ₃

OH-CH ₂ -NH-C-

Hydrochloric acid 252 to

Hydrochloric acid 185 to

hydrochloric acid 205 to 208 • ro • ω VjJ 284 ο χ 1 ethanol

ro

Structural formula Yield salt with melting point % of Th. ° C

HO

OH

HN

OH

HH

CH ₃

CH-CH ₉ -NH-CH-CHOH

₉ - / 42

Hydrochloric acid 155 to 160 χ 1/2 water

Hydrochloric acid 226 to 229

Hydrochloric acid 206 to 209

ro ro • ω

Structural formula Yield salt with melting point % ά. TTL. '° C

ΗΝΌ

OH

CH ₃

OH-CH ₂ -ITH-O-CH ₃ OH 26

Hydrochloric acid out of focus

A 1 Ace- 195 ⁰ C Zers.

tonitril

HN

HO

CH-CH ₂ -NH-CH-CH ₂ OH

OH

, HCl

130 to 133

₃ CH ₃ OH

m o

HO

CH ₃

OH-CH ₂ -NH-C-CH ₂ -OH ₂ (5h CHo

HCOOH 120 to 124

x H ₂ O

vn

co

vj

€ 0 I

ΓΟ

S tr oc tive high yield salt with melting point % a. iEh · ⁰ C

HO

CH-CH ₀ -WH-C-CH 1 CH,

G I

OH

* d CH

HN

HO

CH.

H-CH ₀ MC-CH ₀ -CHp-O * -

OH CH,

COHH,

40

CH ₃ SO ₃ H 192 to 195

35 HCl 205-208

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To method 3

Example 5

CH-CH ₂ -IHC ₂ H ₅ OH

χ HCl

4.3 g ^5-f -Benzylosy 8 ^l - (1-hydro2y-2-'benzyläthylamino-ä "thyl) -2H-1,4-benzo2azin-3- (4H) -one hydrochloride (Pp, 232-235 ⁰ CT) are in 125 ml of methanol with the addition of 0.5 g of 5% palladium-carbon hydrogenated compartment intake of the calculated amount of hydrogen, the catalyst is filtered off and the solution is distilled off under., Reduced pressure by Yerreiben: the residue with acetonitrile to obtain 2.5 g of 5α-hydroxy-8 ♦ - (1-hydroxy-2-ethylamino-ethyl) -2H-1,4-benzosazine-3- (4H) -one-hydrochloride (yield: 86.7 %). the theory), which melts after being precipitated from methanol / ether at 240 to 242 ⁰ C,

Example 6

-IHC - / "^

HC

ΌΗ

L o ο S

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δ, 3 g 4 ^l -Benzyloxy-7 ^l ~ / T-hydro 2-yl-2- (4-picolinamido-2-methyl-2-butylamino) -ethyl 7-2-benzo-sazolinone (pp. 130 to 133 ⁰ C) are hydrogenated in 125 ml of methanol with the addition of 1 g 5 ^ iger palladium carbon. After completion of the recording, the catalyst is filtered off and the clear solution on a rotary evaporator under reduced pressure evaporated. The oily residue is dissolved in 10 ml of alcohol and treated with 0.58 g of formic acid. After 5 hours, the precipitated 4'-hydroxy-7 • - / T-hydroxy-2- (4-picolinic acid-2-methyl-2-butylamino) -2-benzoxazolinone formate (yield: 78.5 % of the Theory, pp. 166 to 168 ^° C.),

Table III According to the given examples were synthesized:

structural formula

HO

CH-OH ₀ -NH-C-OH ^ j .2,

OH CH ₃

OH

₃ '-CH ₀ ^ IH-C-Often,

Cl ι ·?

CH,

OH

2Λ-yield salt with melting point % d. ¹ Zh.

Hydrochloric acid 205 to χ 1 ethanol

Hydrochloric acid 246 to χ 1 ethanol

hydrochloric acid 120 to 123 VJL χ 1 Etha • nol

00

Structural formula Yield salt with melting point % dTtu ^ ⁵ G

CH ₃ H-OH ₂ -NH-J-CH ₃

OH

CH-ants-189 to 192 acid χ water

HN JD

CH ^

CH-CH ₂ -NH OH

OH hydrochloric acid 226 to 229

OH

GH ₃

CH-CH ₂ -NH-CH-CH ₂ -AOH

78.5 hydrochloric acid 206 to 209

VJl _i

ro ro • co

cn -F *.

vj

-ι

ro

structural formula

Yield salt with melting point % d. Th. - ^σ 0

HO

OH ₃

OH

CH

75

Hydrochloric acid 174 bit 175

Ηϊί ^

HO

CH-

CH-CH ₀ -BII-C-CH ₀ CH ₀ 2 -TVI ι 2 2 χ "./

OH

Hydrochloric acid 155 bites 16O χ 1/2 water

CH-CH ₂ -M- (J-CH ₂ -CH ₂

OH

CH,

1/2 fumar 175 to 178 -A VJI * ro CO U) ON KS ro co Φ » Γ * acid (170 to 173 4 base ^} C

Hr, structural formula

Yield salt; with melting point % d. Ih. 0 °

0 HN Ό

HO

f ^H 3

OH

Hydrochloric acid 143 to 146

HN O

OH

CH.

CH-CH ₂ -NH-C-CH ₃ OH 5

Hydrochloric acid out of focus χ 1 Ace- 195 Zers, Tonitril

V \

HH O

OH

CH ₃ -

CH-CH ₂ -HH-C-CH ₂

OH OH.

^J CH

CH ₃ SO ₃ H χ 1 H ₂ O

252 to 254

UI

ro ro

• co:

CO LP ». U)

S tr u c t ur f or me 1 Yield salt with % do Th.

Sohmelzpunkt ⁰ C

OH,

: Ι · · ·; J

CH-CH ₀ -NH ^ cUCIH ₀ -CH ₀ -NH-C '2. ι 2 2 κ

_? 0H

71

CH ₃ SO ₃ H x ¹ / 2H ₂ O

178 to

HN Ό

HO

,! ^H 3 CH-CH ₀ -KH-C-CH ₀

2 s

OH CH ₃

OH

HCl x 159 to 1.5 H ₂ O

V,

HN 0

CD-I * VjJ

structural formula

Yield salt with melting point % d. Th. ⁰ G

% - \

HN O

HO

2 ^H 5 CH-GH-BH-CH ,, OH

2Λ-

M-NH-O-CH

^2H 5

ΗΝΌ

CH-OH-MH-CH ₀ -CH ₀ - ^ ι 2 2

OH

? 2 ^H 5

CH-CH-NH-CH ₀ -CH ₀ OH

' ^2H 5

-α cn

ro w

• oo

03 .4s «

ro

Structural formula Yield salt with melting point % d. Th. ° C

-in OHo O

¹⁹ BLO \ I ³ B

Vn

HIT O

^H 3 °

G-O-O-4, VOH-GH-M-OH

CO VjJ

JL ^ L O U I '

- A & - 61.284 12

⁹¹ 15.2.83

below are intermediates of. Formula 7, which can be obtained according to the above scheme.

The compounds themselves can also be used as drugs because they have similar pharmacological properties as the end products of formula I.

formula

Salt with melting point C

ηϊΓό

G ₀ H ₁ - | 2

HO -KA-0-.0H-NH-OH (GH ₃ ) ₂

HGL χ 2 H ₂ O

to 242

HN O

? 2 ^H 5

P o

to 222

HO

? -0H

) M-OH (OH ₁ )

to 254

ro ro

• Go

00 Φ »

vj

ro

formula

Salt with melting point C

HFX)

HO

GH, -.- Clio

ι ² if-? ^H

OUTH-C (CHo:

250 to 253

HH

C-QH O

HO

M

HO <\ /> ~C-CH-MC (CH ₃ ) ₂

217 to 223

156 to 161

VJl -J.

ro ro

• ω

co -ρ »

formula

Salt with melting point

_CH3 HCl

243 to

HOl

254 to

HOl

250

Claims (2)

61284 15.2,83 Claim for invention 1 · Process for the preparation of compounds of the general formula HS "O CH-CH-IJH-R ₃ (I), OH ^Λ 1 in the., R _n A is a single bond, the group = Cv or the group -Γ ~~ ' OH, O acyl, chlorine or hydrogen, Hydrogen, methyl or ethyl, CH ₂ - (CH ₂ ) _a - ^ E ₇ -C - CH ₂ --- ^ or C- (CH ₂ ) _n -Rq ^E 6 (II) (III) Jn 2, 3 or 4, η 1,2 or 3, R> hydrogen, lower alkyl, Rc is hydrogen, lower alkyl and also, if R, is hydrogen, phenyl, 61 284 12 15.2,83 Hg hydrogen or methyl »
R _{7 is} hydrogen or methyl, R _{0 is} hydrogen or methyl,
ο Hydrogen, Ar, OAr, ITH-CO-Ar 10 Ί1 ^XV 12 , R ₁₁ , R _1? (which may be the same or different), hydrogen, hydroxy, methyl, hethoxy, halogen, me- thylendioxy, COIH R ₁ ^ is hydrogen, acyl or lower alkylsulfonyl, in the form of racemates, enantiomers and optionally diasteremic antipode pairs, in each case as free bases or as acid addition salts, characterized in that a) a compound of the formula 61 284 15.2.83 in which A, E ₁ , R "and R ^ have the abovementioned meaning, where phenolic OH groups may also be protected by hydrogenolytically removable protective groups, reduced and, if appropriate, subsequently cleaving off any protecting groups present
or that one b) a phenylglyoxal or hemiacetal of the formula (XII) in which R ₁ and A have the above meaning, but phenolic OH groups may be protected by hydrogenolytically removable protecting groups, and Q is -CHO or -CHCOEO-O-Siiederalkyl, with an amine of the formula H ₂ IR ₃ (XIII), wherein R- has the above meaning, wherein any OH groups contained may be protected by hydrogenolytically cleavable protective groups, under the conditions of the reductive amination and, if appropriate, then splits off any remaining protective groups or that c) from a compound of the formula 61,284 12 15/2/83 (STI), in which A and R _{2 have} the abovementioned meaning and R, * stands for S ^ or a protected by a hydrogenolytically removable protecting group OH group ₉ E- ♦ for R, but wherein in R, about OH group contained by a hydrogenolytically removable protective group can be protected, and R ^{1 is} hydrogen or a hydrogenolytically removable protective group, and wherein at least one protecting group to be removed is present in the compound of the formula X7I, the protective group is split off by customary methods and if desired, the to c) compounds are separated by conventional methods into the enantiomers, if appropriate also into the diastereomeric pairs of antipodes, bases initially obtained in acid addition salts, initially obtained acid addition salts are converted into bases or salts with other acids *.