CH642646A5 - 2-Oxazolidinone derivatives - Google Patents

Abstract

The novel compounds of the formula I <IMAGE> in which R represents a group which is stable in a reductive amination, and in which the hydroxyl group is present in activated or replaced form, in racemic or optically active form, are intermediates for the preparation of useful medicaments having a beta -adreno-receptor- blocking action. They are obtained by activation or replacement of the free hydroxyl group in the corresponding compounds of the formula I, in which the hydroxyl group is present in free form.

Description

The invention relates to the subject-matter defined in the claims.

R represents, for example, an alkyl group. R is preferably branched. Examples of preferred meanings of R are in particular isopropyl and tert-butyl.

The compounds according to the invention are obtained by activating or replacing the hydroxyl group in the compounds of the formula I in which the hydroxyl group is in free form.

The tosyloxy and mesyloxy groups represent examples of activated forms of the hydroxyl group of compounds of the formula I. Halogen with an atomic number from 17 to 53 represents an example of an exchanged form of the hydroxyl group.

The compounds of formula I in which the hydroxy group is in free form are obtained e.g. by cyclization of the compounds of the formula II,

0, 0 iv

35 \ /

/ \

ch3 ch3

40 wherein R has the above meaning.

Examples of suitable meanings of Ra are alkoxy with 1 to 4 carbon atoms, haloalkoxy with 1 to 4 carbon atoms, phenoxy, benzyloxy, through halogen with an atomic number from 9 to 35, alkyl with 1 to 4 carbon 45 atoms or alkoxy with 1 to 4 carbon atoms substituted phenoxy or benzyloxy. Ra preferably means alkoxy with 1 or 2 carbon atoms, 2,2,2-trichloroethoxy, unsubstituted phenoxy, or unsubstituted benzyloxy, in particular ethoxy or unsubstituted benzyl-50 oxy.

The introduction of a -CORa group is carried out under Schotten-Baumann conditions.

The compounds of formula IV are obtained, for example, by reacting in corresponding compounds of formula V,

35 ch9 - ch - ch0

1 1 I

0 0 of

60 / C \

ch3 ch3

introduces group R by reductive amination. 65 The compounds according to the invention can be present in racemic or in optically active form. If they are in optically active form, they preferably have the following configuration:

642646

ch, i '

0

1

h h?

.c.

A

O

V

s

.ch9 1 0

No

The configuration of the starting material is retained. The compounds of the formula I are valuable starting compounds for the preparation of medicaments of the formula VII,

wherein Rb and R have the above meaning, implemented and then saponified the compounds of formula VI thus obtained.

The compounds of formula VI are saponified preferably under basic conditions, e.g. in the presence of an alkali metal hydroxide.

The configuration is also retained when the compounds of the formula I are converted into the compounds of the formula VII. The compounds are preferably in optically active form. They preferably have the following configuration:

15

Rb - OCH2CH (OH) CH2NH - R

VII

ch,

h f

.c.

.ch2n wherein R has the above meaning and Rb represents an optionally substituted aromatic ring.

The compounds of formula VII have a blocker action on the β-adrenoceptors and can therefore, inter alia, for the prophylaxis and therapy of coronary diseases such as angina pectoris, for the treatment of cardiac arrhythmias and for conditions which lead to an undesired mobilization of fatty acid and glucose caused by psychological stress.

One or more aromatic, heteroaromatic, cycloaliphatic or heterocycloaliphatic rings are optionally linked in Rb, it being possible for the linked rings to also be substituted. Rb means e.g. Phenyl.

Preferred residues Rb are residues of phenols, in particular of phenols, which do not contain any groups which are labile towards bases.

Suitable residues Rb include:

a) 4-indolyl, optionally substituted in the 2-position by methyl or COOB, in which B is isopropyl;

b) phenyl, optionally substituted, e.g. by 2-acetyl-4-n-butyramido, allyl in 2-, 3- or 4-division, 2-allyloxy, 2-cyano, 2-chloro-5-methyl, 2-chloro, 3,4-dichloro, 2 , 5-dichloro, 2-ethynyl, 2-ß-chloroallyl, 2-cis-y-chloroallyl, methyl in the 2-, 3- or 4-position, 2,3-dimethyl-3,5-dimethyl, 2-bromo , 2-propynyloxy, 2-hydroxymethyl, 2-methyl-3-nitro, 2-phenoxy, methoxy in 2-, 3- or 4-position, methanesulfonamido, 3-cyclohexylureido, 2-methylthio, 2-tetrahydrofur furyloxy , 3-n-butynyloxy, 2-cyclopropyl, 2-cyclopentyl, 4-methoxyethyl;

c) 2,3-dimethyl-4-benzo [b] furyl;

d) 1-naphthyl or 5,8-dihydro-l-naphthyl;

e) 1,2,3,4-tetrahydro-1,4-ethano-5-naphthyl;

0 8-thiochromanyl;

g) 4-indanyl;

h) 7-indenyl;

i) 2,3-dihydro-1 - (2H) -oxo-5-naphthyl;

j) cis-1,2,3,4-tetrahydronaphthalene-2,3-diol.

Particularly preferred radicals Rb are 4-indolyl and 2-methyl-4-indolyl.

The compounds of formula VII are obtained e.g.

in that the compounds according to the invention are converted into the corresponding compounds of the formula VI,

rl - 0cho - ch - ch,

20th

If the preparation of the starting compounds is not described, they are known or can be prepared by methods known per se or analogously to the methods described here or analogously to methods known per se. 25 In the following examples, which explain the invention in more detail, all temperatures are given in degrees Celsius and are uncorrected.

example 1

30 (5S) -3-isopropyl-5-tosyloxymethyl-2-oxazolidinone

(Compound of the formula I in which the free hydroxyl group is activated in the form of the tosyloxy group)

32.8 g of p-toluenesulfonyl chloride are added over 30 minutes to a solution of 24.8 g of (5S) -5-hydroxymethyl-35 3-isopropyl-2-oxazolidinone in 60 ml of pyridine at -5 ° and overnight at 0 ° kept. The mixture is poured onto ice, the oil is extracted with methylene chloride and the organic phases are washed with 2H HCl and water. After drying over Na ^ SO *, the methylene chloride 40 is removed and the residue is crystallized from methylene chloride ether. The (5S) -3-isopropyl-5-tosyloxy-methyl-2-oxazolidinone (mp 77-79 °) [a] o + 51.8 ° (1% in MeOH) is obtained.

The starting product is obtained as follows:

45

a) (4S) -4-Isopropylaminometh-4-yl-2,2-dimethyl-1,3-dio-xolane

52.5 g of (4R) -2,2-dimethyl-1,3-dioxolane-4-carbaldehyde in 400 ml of methanol (prepared by reacting 1,2,5,6-50 diisopropylidene-D-mannitol with lead tetraacetate) added dropwise to a suspension of 5.25 g of 10% palladium on carbon in 150 ml of methanol and 86 ml of isopropylamine under hydrogen over two hours. The mixture is hydrogenated at 1 atm until no more hydrogen is taken up, the catalyst is filtered off and the methanol is distilled off. The residue is stirred for five minutes with a solution of 95 g of Na2CCb in 500 ml of water, extracted three times with methylene chloride, the organic phases are dried with Na.SO4 and the filtrate is concentrated. The yellowish oil is then distilled 60 at 42 ° (0.1 mmHg). The (4S) -4-isopropylaminometh-4-yl-2,2-dimethyl-1,3-dioxolane (colorless oil) [a® -7.2 ° (2% methanol) is obtained.

i i

Y

n - r b) N - [(4S) -2,2-dimethyl-1,3-dioxolan-4-ylmethyl] -N-iso-vi 65propyl-carbamic acid ethyl ester

150 g (4S) -isopropylaminometh-4-yI-2,2-dimethyl-1,3-di-oxolane are dissolved in 1.51 methylene chloride and cooled to 0 °. This solution takes one hour

642 646

92 ml of ethyl chloroformate and 240 ml of 4N sodium hydroxide solution were simultaneously added dropwise and the suspension was stirred vigorously at 0 ° for 30 minutes. It is then acidified with cold 10% tartaric acid, the phases are separated and the aqueous phase is extracted three times with methylene chloride. The combined organic phases are shaken twice with cold 2N NaOH, washed with water, dried over Na2S04 and concentrated. Distillation of the residue gives the pure N - [(4S) -2,2-dimethyl-1,3-dioxolan-4-ylmethyl] -N-isopropyl-carbamic acid ethyl ester (Sdpo, 6mmHg 96 °), [aß0 -19.2 ° (1% MeOH).

c) (2S) -N- (2,3-dihydroxypropyl) -N-isopropylcarbamic acid ethyl ester

115.6 g of N - [(4S) -2,2-dimethyl-l, 3-dioxolan-4-ylmethyl] -N-isopropylcarbamic acid ethyl ester are stirred in 500 ml of methanol and 115 ml of 4N HCl for two hours at 10 ° and in Vacuum concentrated. The (2S) -N- (2,3-dihydroxypropyl) -N-isopropylcarbamic acid ethyl ester [a] o -19.9 ° (1% in methanol) (crude processed).

d) (5S) -5-hydroxymethyl-3-isopropyl-2-oxazolidinone

(Compound of formula I with free hydroxyl group)

98.7 g of crude (2S) -N- (2,3-dihydroxypropyl) -N-isopropyl-

ethyl carbamic acid are brought to pH 13 with 4N NaOH, left to stand at 20 ° for two hours and extracted three times with methylene chloride. The organic phases are washed with 6M NaCl, dried over Na2SÛ4 and the solvent is distilled off. The (5S) -5-hydroxymethyl-3-isopropyl-2-oxazolidinone (mp. 56-59 ° - from methylene chloride / ether) is obtained [a] ^ + 49.1 ° (1% in methanol).

Example 2

(2S) -l- (Indol-4-yloxy) -3-isopropylamino-2-propanol

(Further processing of the compound of Example 1 to the corresponding compound of the formula VII, in which Rb is indol-4-yl)

a) (5S) -5- (Indol-4-yloxymethyl) -3-isopropyl-2-oxazol-s dinone

(Compound of formula VI)

A solution of 17.4 g of 4-hydroxyindole in 100 ml of N, N-dimethylformamide is added dropwise to a suspension of 6.3 g of sodium hydride (50% dispersion) and 50 ml of N, N-dimethyl-lo formamide under argon over the course of one hour . The temperature must not exceed 35 °. The suspension is stirred for 1.5 hours at room temperature, 41 g of (5S) -3-iso-propyl-5-tosyloxymethyl-2-oxazolidinone in 50 ml of N, N-dimethylformamide are added dropwise and the mixture is stirred at 80 ° overnight under argon. The suspension is poured onto ice, shaken with methylene chloride, the organic phases are washed with 2N NaOH and water, dried over Na2SÖ4 and concentrated on a rotor vapor. The residue is crystallized from methylene chloride ether. The 20 (5S) -5- (indol-4-yloxymethyl) -3-isopropyl-2-oxazolidinone (mp 139-142 °) [a] 2D ° + 56.7 ° (1% in MeOH) is obtained.

b) (2S) -l- (indol-4-yloxy) -3-isopropylamino-2-propanol 25 (compound of the formula VII)

A suspension of 19.5 g (5S) -5- (indo-4-yloxymethyl-3-isopropyl-2-oxazolidinone, 200 ml of ethanol and 180 ml of 4N NaOH is heated under reflux overnight, the solvent is distilled off and the residue is dissolved in Methylene chloride-30 water was taken in. The aqueous phase is extracted with methylene chloride, the combined organic phases are washed neutral with water, dried over NaïS04 and concentrated. The residue is crystallized from benzene. The (2S) -l- (indole-4- yloxy) -3-isopropylamino-2-pro-35 panol (mp. 93-94.5 °) [a] ^ -4.8 ° (1% in methanol).

Claims (10)

642 646 2nd PATENT CLAIMS 1. Compounds of formula I, HIGH2CH (OH) CH2NR-C-Ra O II hoch.-ch- <- i ch9 I L n-r C II 0 worm R stands for a group which is resistant to reductive amination and in which the hydroxyl group is functionally modified, in racemic or optically active form. 2. Compounds according to claim 1 of formula I, in which the functionally modified hydroxyl group is in the form of an activated hydroxyl group. 3. Compounds according to claim 1 of formula I, in which the functionally modified hydroxy group is in the form of an exchanged hydroxy group. 4. Compounds according to claim 1 of formula I, in which the hydroxy group is activated in the form of a tosyloxy group. 5. Compounds according to claim 1 of formula I, in which the hydroxy group is activated in the form of a mesyloxy group. 6. Compounds according to claim 1 of formula I, in which the hydroxy group is replaced in the form of a halogen group with an atomic number of 17 to 53. 7. Compounds according to claims 1 to 6, in which R is alkyl. 8. Compounds according to claims 1 to 6, in which R is isopropyl or tert-butyl. 9. Compounds according to claims 1 to 8, which have the following optically active form: worm s R has the above meaning and Ra means a group which is split off during intramolecular oxazolidinone formation. The cyclization of the compounds of formula II takes place under basic conditions, e.g. in the presence of sodium hydroxide, pyridine or triethylamine. The process is carried out at about 0 ° to about 50 ° C., preferably at room temperature. The solvent used is e.g. Tetrahydrofuran, dioxane, ethanol or methanol, or water. The compounds of formula II are obtained e.g. by splitting off the isopropylidene radical from the corresponding compounds of the formula III, ch, - ch i 2 i 20 0 0 V ch2nr c - r. (1 iii / \ ch, 25 à ch, where Rund Ra have the above meaning. The compounds of formula III are obtained e.g. by introducing a group -CORa, in which Ra has the above meaning 30, into corresponding compounds of the formula IV, ch2 - ch ch2 - nhr hoh2c. H ? , c. 4th 0 , ch9 I * ■ .No C. H 0