DE2535023A1 - NEW OXAZOLIDINONE, THE METHOD FOR THEIR MANUFACTURE AND THEIR USE IN MEDICINAL PRODUCTS - Google Patents

Description

SAU 3

Patent attorney
62 Wiesbaden

Hfflit 22 It). 54 210

1ϊΤ3ΐΙΐϋΐ 1IiIa ¹ IC ^ UL 1/3 IA wA ^ iS L'-J? DS LA i

j .. LDIC ALE

.Ρ a r i s / ff r a η k r e i c h

leue oxazolidinones, process for their preparation, and their use in medicines

The invention relates to new phenoxymethyloxazolidinones which can have one or more tertiobutyl and / or allyl radicals on their phenyl nucleus as substituents, _o

Numerous oxazolidinones have already been described as husky relaxants. In addition to this muscle-relaxing effect, phenoxymethyloxazolidinones also have a calming (tranquilizer) effect; this also applies to the iiephenoxalon and Hetaxalon in the 2-position of the Phenylkerna a methoxy group, or ru in 3.5 IUGthyl'2 position _"0; open carry _o

With all previously known connections the reassuring and the musculoskeletal effect at the same time on <

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- 2 - ■ ■

2635023

The aim of the "; rfiiiaun _: ;; are new oxazolidinones, which show an anxiolytic (: -. Nxiolytic) effect, j ed ο el: vr'2-li ·; free oincl of any Efuskelentscanneiiden or. ;; ar sedative i ± r: -Mnir _a

Diefje-: goal v / ii-d o.i-iiiiuun ^ sgernäß achieved r ^ it Y ^ ruinuuner folyeiidtn .ill clean a formula

de

2 - (j - OH ₉ - GII GH ₉

0. Ϊ7Η
^ he

Il

is henylkern I-H in which for one, of the _o and / or allyl Heste Trä ^ t, where the zv / ei dubstituenten in meta- or para-Stellmi ;: available as .oUDBtituenten one or zviel i'ertiobutyl- each other The preferred compounds according to the present invention are those that either the ^{Tertiobutyl-:} .ebt in ortho, meta or-para positions, or two-i'ertiobutyl üeste in 2,4-, ^{^>} 5- or 3 , 5-3 division, or the allyl red in 2-3 positions and tertiobutyl rieste in 6.5 or 4 positions' tare »

j) The inventive compounds can be prepared by reacting -y; an thenoxyeooxypropane of the formula RO-CH ₀ -GI-I-CH, - with urea

2 ^ ₁ / c

For this purpose is heated with constant llühren an intimate ü-eriisch from 0.1 mol Phenoxyepoxypropan and u, 2 Liol urea at 200 ° C ₀ laughing cooling, constitutes 2üO .ml;! A ^ ser to and extracted with chloroform; then it is dried, the solvent is verdairpit and the? LÜcicstand recrystallized "

jjie compounds obtained according to the invention, their Melting points and their analytical data obtained by thin layer chromatography are shown below Table I summarized:

60 * 810/0932 BAD OFlIQlNAL

Table I.

R-O-

H TT _ PT-

CII ₂ HH

VJ

ff

Γ,

Ooie-Hrο i OH ₃ -C-OH ₃ CH,
I ^ j Schrapc
I (° c) 1 3 172 Solution with
tel fl do
Umkristallο juimsch chromato ^ r-o GH ₅ CH _x -C-CH ₇
⁵ ι - " 134
t
t Pf ₀ Siuier ^ So
not 0 R 1297 p- i 160 './as s he CH, -C-OH,
^J j ^J CE ,, 93 0.36 Ethyl-
acetate IR 1299 174 !,! etha.nol f 3 _/ _ ^ 0.35 11 R 1229 Cyclo-
• heχan ' ³ OH ₇ -O-OI 0.32 t! R 1283 3 Cyclo-
hexane 0.36 Il - R 1319 Heptane! 0.50 Il

0 α 8 1 0 / U9 3 2 BATH ORIGINAL

Code itfr i I. R. OH ₃ (
CH ₃ -C GH ₂ -GH = CHg C.
( ochmp
(° 0) Solution with
tel fd
Umkristallalo Thin so0 chromato- Eluier - i
R 1349 CPU-C-GH,
* \ ■ fa
J-CJi ₃ 3H ₃
⁵ GHg-CH = GHg Pf O R 1565 : R 1526 CH ₃ -C-GH ₅ 204 toluene Ethyl-
acetate OH ₃ 0.46 R 1557 CHg-GH = GHg 85 Hexane M. 0.52 120 Heptane t! 0.47 73 Pentane
50
f hexane
50 benzene
90
Ethanol
10 0.64

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The compounds of the invention are pharmacodynamic 'Tested and compared to the following' known products: Meprobamate, Diazepam, Cresoxypropanediol and mephenoxalone.

The compounds were administered orally in lorin aqueous suspensions to which 0.25% carboxymethyl cellulose had been added. "The various studies were carried out on Swiss mice EoO ₀ PoSo from 18 to 22 g body weight." The DE 50 and DA 50 values were followed the graphic method of TAIFISR u "MILLEH, ProCoSOoExper.BioloMedo1944,57,26i determined. The statistical analysis of the results was carried out after the P-'fest ο

IoToxicity

The acute toxicity was examined in groups of 6 female mice. The animals were observed for one week and the number of dead animals was determined on the 7th day. The toxicity of the compounds examined is weak and is over 1.5 g / kg ₀

Ho effect on the central nervous system

10 "Tige tournant" test, tensile test and test for protective action against the pentetrazole crisis (Table H) ₀ a) "Tige tournanf'-gest (J ₀ R.BOIoSIER, GoDUMONT, RoRATOUIS Uo JoPAGHY, Archo intern ₀ Pharmacodyn ₀ 1961,135,29.)

This test was carried out according to the protocol _{proposed by 30ISSIER u »Hitarb β} , All compounds were administered at a dose of 100 mg / kg 30 min before the start of the experiment to groups of 6 animals» The DE 50 value is the dose which led to the death of 50 % of the animals in a time of 3 minutes or less

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b) Zug - ("tr ac tion") - Te st (J ₀ R ₀ BOISSISR, J. PAGITT U du PIOiIRD therapy 1960, 1_6, 279) »

The tests were performed on the same animals as the "term tournant" j? Were used est "The DE 50 value is the dose that 50 f> of the animals makes incapable of itself sec in less than 5 to recover"

c) Investigation of the protective effect against the pentetrazole crisis »

The pentetrazole was in aqueous solution 30 min after the "administration of the compounds to be tested groups injected by 6 mice »

The number of dead animals was 4 determined to 24 hrs. After starting the test "The DE 50 value the dose 50 ⁰ Yes animals slits" In Table II below are the results achieved with the compounds R 1297 and R 1337 Results listed;

Table II

DE 50- v / er te in mg / kg

Product Uige tournant- tensile test pentetrazole-

Test test

ή 1297 > 1000 > 1GOO > 1000 P. 1337 > 500 > 500 500 Diazepam 4.5. 6.5 1.8 Meprobamate 120 140 70 Cresoxypropane 210 500 700 diol

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2ο The so-called "four plates " (des quatre plaques) -

It was prepared following the experimental protocol τοπ BOISSIER u "Mitar" bc (C. ARON, Po SIMOlT, C ₀ LAE0US3E u "JR ₀ BCIb Heuropharmacolo, 1971,10,459) worked Compounds were 30 min before the start of the test, female mice administered. A comparative experiment was carried out with three further samples of the compound to be tested ο All products were tested in a dose of 100 mg / kg The investigations were only continued with those compounds that cause a significant increase in the number of reactions in this dose _o The DE 50 value is the dose that a 100 ^ »$ 50 of the animals -. cent increase in minutes in one electric shocks occurring causes," the percentage increase was a puncture of the scatter of individual results, eg ₀ 5 (+4.5) for. 174 participants determined »There are therefore only 5 chances that the result obtained with a mouse was not between 0.5 and 9.5. The latter number corresponds to an increase of 95 ° / ° · 100 fo _{0 was chosen here} The results are given below,

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Table III Compound (dose in mg / kg) Increase (, .- j) DE 50 (mg / kg)

R 1297 (25) 25

R 1297 (50) 67

R 1297 (100) 89

R 1297 (200) 128

E 1319 (50) 11.5

R 1319 (100) 70

ß 1326 (100) 67

R 1337 (50) 21

R 1337 (100) 86

R 1337 (200) 121

(25) 20

(50) 67

Meprobamate

(100) 140

(200) 190

(D 25

(2) 65

Diazepam

(4) 98

(8) 116

(25) 9

Cresoxy- W ³²

propane (100) 29

(400) 60

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IIIo Complementary Investigations

The investigations were supplemented by a test which is considered to be sufficiently specific for the anxiolytic effect: the "electric fight" (la bataille electrique); (J _o R ₀ B0ISÖISR, P.SIMON and B ₀ RAULl ¹ , Ann ,, Pharm. Er., 1968, 26, 277) ο

A dose of each compound was given to a group of pairs of male mice 30 minutes before the start of the test The DA 50- '. 7ert is the dose that a 50> i-ige Reduce the number of reactions with regard to the comparative tests «,

The compounds R 1297 and R 1337 exert a detectable antagonistic i / MPACT to the induced by electrical stimulation in the mouse aggressiveness of _o Among the comparison substances have only meprobamate and diazepam proportional one of its dose 7irkung ₀

Table IV "Electric Combat"

Product dose in percentage reduction DA 50 in

mg / kg of the number of reactions mg / kg ' relo z. comparison

Diazepam 1 38 1.4

2 60

4 98

Meprobamat 25 23

50 48

100 75

Gresoxy- 25 26

propane _5Q ■ ""

100 41

200 49

R 1297 25 0

50 23

100 68

R 1337 50. 33

100 50

200 84

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From these various studies, it follows that the compounds neither a sedative nor show an analgesic effect, but prove to be selectively active only in those tests in which an anxiolytic activity is observed ₀ In contrast, the comparison substances additionally show anxiolytic their Effectiveness sedative properties »

The compounds according to the invention, which have anxiolytic, but no muscle-relaxing activity, can be used to treat anxiety and depression can be applied.

You can do this in any suitable oral or parenteral Administration form used »The daily dose can range from 50 to 500 mg in humans.

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Claims (1)

Claims 1 ο Oxazolidinone the formula E-O-CH, CH • CH, - MH in which R is a phenyl nucleus, which as Substituents carries one or two tertiobutyl and / or allyl radicals, the two substituents in meta- or para-position to each other » 2 ο "The compound of the formula V-O - - CH- CH. [I. The compound of the formula (CH. U C The compound of the formula CH, / \ v - O - CH ^ - CH O- OH ₂ -OH [ CH ₂ -CH = CH. CH, NH B09810 / 0932 - ΛΖ - The compound of the formula O - CH ₂ - CH O '3 CI-L Ml 6 ο The compound of the formula O CH ₂ CH ₂ - CH = CII ₂ CH C U CH, 7 ° A method for the preparation of compounds according to claim 1, characterized in that a PhenoxyeOoxypropan the formula RO- CH ₀ - CH - CH ₀ is reacted with urea "O 8. Medicament, characterized in that it contains a compound according to claim 1 as the active ingredient " 609B10 / Ü932