CS273616B2 - Method of 1,3-oaazolidine-2-onane's derivatives preparation - Google Patents

Abstract

Method of preparation of 1,3-oxazolidine-2-one derivates of general formula I, where R means alkyl group C3-8, X is hydrogen, halogen, alkyl group C1-3 or alkoxy group C-3, and n is from 4 to 6, in which a compound of general formula II, where R and X are of the above mentioned meaning, is introduced into reaction with compound of general formula III, where Z is halogen or tosyloxy, mesyloxy or acetoxy group and n has the above mentioned meaning. The obtained substance has extraordinary blocking effect on glutamic acid and also relaxing effect on neuraxial muscles.<IMAGE>

Description

The invention relates to a process for the preparation of 1,3-oxazolidin-2-one derivatives, in particular 1,3-oxazolidin-2-one derivatives of the general formula I

in which it means

R is a straight or branched alkyl group having from 3 to 8 carbon atoms,

X is hydrogen, halogen, (C 1 -C 3) alkyl or (C 1 -C 3) alkoxy, n is an integer from 4 to 6, as well as acid addition salts derived from these compounds.

It is well known in the art that glutamic acid acts as an excitatory neurotransmitter in the central nervous system of higher animals and in neuromuscular junctions in lower animals (Glutamate as and Neurotransmitter published by GD Chiara and Gl Gessa, Raven Press , Nevr York, 1981 and JM Gershanfeld: Physiol. Rev., 53, 1-119 (1973). It has also been reported that distrophilia, rigidity, tremor, seizures and the like are caused by the administration of kainoic acid, i.e. 2-carboxy-4- (1-methyl-ethyl) -3-pyrrolidineacetic acid

COOH

CH 1 = C CH ₉ COOH

AND

CH-2-carboxy-4- (5-carboxy-1-methyl-1,3-hexydienyl) -3-pyrrolidinacetic acid

COOH>

chischvalic acid, i.e. (S) -e6-amino-3,5-dioxo-1,2,4-oxadiazolidine-2-propanoic acid

COOH - 'and ibotonic acid

O-O, -amin o-2,3-dihydro-3-oxo-5-isoxa per 1 o v.

CHCOOH

L ₂ and the like, these acids are potent agonists for glutamic acid in animals (see Cleny et al. Brain Brain, 77, 507-512, 1974).

It is also well known that with aging, the central and peripheral nervous system is subject to hypoergy, including Parkinson's disease, neuromotor disorders, demenoea, tremor, cerehrospinal degeneration and the like. The cause of this onemoonine is considered to be a grain of equilibrium between excitatory nerves and inhibitory nerves (for example, the balance between glutamic acid and GABA), which occurs due to neuronal loss at certain speolfiococcal sites or in the ocular hypoergil of the nervous system (see Toshishoge Hirai, Shinkei Shl. (1973, 69).

In view of the above, it is for theorailed neuropathies, the most common of which is senility, including dizziness, back pain, convulsions, tremor and the like, and these problems occur as a result of the nervous system being unbalanced or hyperstenle in the muscular tissue. releases, suitable drugs that selectively block glutamic acid.

Glutamic acid acts as an excitatory neurotransmitter in neuromuscular joints in insects * Chemlocs that are capable of blocking glutamic acid are also suitable for agricultural use due to their ability to reduce and attenuate insect activity (see Horifusa Eto: Kagaku to Seibutsu, 21, 725, 1983),

There are known compounds which are structurally similar to the compounds of the invention, such as 4-methyl-5-phenyl-3- (2-plperldinetbyl) -1,3-oxazolidin-2-one (see Zikolova et al. Parmatslya (Sofia), 14, 16-21, (1964) and Movova Izv Inst, Piziol., Bulg, Akad., 12, 217-226 (1969) and 4-methyl-5-phenyl-3- (2-pyrrolidinethyl) -1,3-oxazolidin-2-one (see Zikolova et al., Parmatsiya (Sofia), 14, 16-21 (1964)).

In these publications nothing is reported by the authors (Zikolova et al.) About the pharmacological effects of these compounds. Hlkolova reports that 4-methyl-5-phenyl-3- (2-piperldinethyl (-1,3-oxazolidin-2-one) has an analgesic effect but does not exhibit any anticouvulsive or any other relaxing effect on the neuraxial muscles. It has been found by the inventors that the compounds are extremely weak in terms of neuraxial muscle relaxant.

It is an object of the present invention to provide a process for the preparation of novel 1,3-oxazolidin-2-one derivatives having excellent blocking effects on glutamic acid and having a suppressing and releasing effect on rigidity and which, for this reason, are useful as pharmaceuticals. .

The invention relates to a process for the preparation of the above-mentioned 1,3-oxazolidin-2-one derivatives of the general formula I.

The process consists in reacting a compound of formula II 'X in the presence of potassium carbonate or sodium carbonate

(II) wherein R and X have the same substituents as mentioned above, that the compound of formula III is z-ch ₂ ch ₂ ch ₂ -n

(III) t

in which it means

Z is halogen, toayloxy, mesyloxy or oethoxy and n is the same as above, whereupon the product thus obtained is optionally converted into an acid addition salt.

An advantage of the process according to the invention is that new 1,3-oxazolidin-2-one derivatives of the formula I have an excellent blocking effect on glutamic acid as well as a relaxing effect on neuraxial muscles, i.e. the effect of suppressing and releasing rigidity on an anemic decerebral rigidity sample. The actual process is very simple.

Accordingly, the compounds of the present invention are useful for therapies which generally include spastic paralysis and rigidity, and are particularly effective in suppressing or releasing discinesia, athetosis, myclonia, tic. tremor, dystenia, and neuropathy ballism related to such diseases as Parkinson's disease, chorea, epilepsy and the like.

The compounds obtained by the process of the invention have the general formula I above.

The straight or branched chain alkyl radicals which have been mentioned for R in formula I include, for example, propyl, butyl, pentyl, hexyl, heptyl, octyl, 1-methylethyl , 1-methylpropyl, 2-methylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-methylpentyl, 4-methylpentyl, 1-methylbexyl, 5-methylhexyl, 1-methylheptyl , 6-methylheptyl, 1,1-dimethylpropyl, 1-ethylbutyl, and the like. The lower alkyl groups mentioned for substituent X include, for example, methyl, ethyl, n-propyl, and isopropyl. The alkoxy radicals which are also mentioned when defining the substituent X include, for example, methoxy, ethoxy and n-propyloxy. Halogen X atoms are, for example, chlorine, bromine and fluorine.

Each of the compounds of the present invention prepared by the process of the invention may exist in the form of different stereoscopic isomers, i.e. cis-isomers (4RS,

5SR) and trans-isomers (4RS, 5RS), and in the form of the optical isomers (4R, 5S), (4S, 5R), (4R-

5R) and (4S, 5S). It is to be understood that all such types of isomers are within the scope of the invention.

With respect to the practice of the present invention, the following may be performed:

The compound of formula (11) is reacted with a compound of formula (111) to form a compound of formula (1), wherein the reaction scheme is as follows:

JO \ / + Z-CH ₉ CH ₉ CH _r -N (CH)

About NH

Y

in which it means

Z is halogen, tosyloxy, mesyloxy or oethoxy and R, X and n are as defined above.

This reaction of a compound of formula II with a compound of formula III ae is carried out in the presence of a weak basic compound such as potassium carbonate or sodium carbonate, and in an organic solvent such as acetone, methyl ethyl ketone or methyliaobutyl ketone. 50 ° C to reflux temperature. In a preferred embodiment of the process of the invention, the compound of the formula III and the weak base are used in amounts which are from one to two times greater or less than about 1 to about 2 times. at least twice the molar amount of the compound of formula (II), wherein the reaction time ranges from 2 to 50 hours. The compound of formula (III) is preferably used in the form of the hydrochloride salt, which salt is more stable.

The compound of formula (II) which is the starting material for the process according to the invention can be prepared, for example, according to the reaction scheme:

NaB (CN) Hj or Al (OCH / CH _3/2)

Ψ

NOH (VIII)

Cl - C -

II (X) or

II

X

O

NH (II) wherein R, X, Z and n are as defined above.

The compound of formula VI can be prepared by reacting the compound of formula IV with potassium phthalimide or by Friedel-Crafts acylation reaction of acid chloride and benzene in the presence of an aluminum chloride catalyst. The acid chloride is derived from the compound of formula V and obtained by treatment with thionyl chloride.

The compound of formula VII is prepared by reducing the compound of formula VI with a reducing agent such as sodium cyanoborohydride or aluminum isopropoxide.

The compound of formula VIII is obtained by hydrazinolysis of a compound of formula VII or by hydrogenation of a compound of formula IX in the presence of palladium catalyst.

The compound of formula II is prepared by reacting a compound of formula VIII with a compound of formula X or a compound of formula XI.

The corresponding isomer of the compound of formula (I) is obtained either by a process in which one of the isomers is obtained predominantly or by resolution of a mixture of isomers of the compound of formula (VII).

The abovementioned 1,3-oxazolidin-2-one derivatives of formula (I) obtained by the above process can be converted into their acid addition salts and acids using conventional methods. The acid addition salts of the invention are hydrochloride, hydrobromide, sulfate, p-toluenesulfonate, fumarate, citrate, maleate, oxalate or the like,

In the following summary, the compounds that are particularly typical of the invention are listed:

compound 1: (4RS, 5SR) -4- (1-methylethyl) -5-phenyl-3- (3-piperidinopropyl) -1,3-oxazolidin-2-one, compound 2: (4RS, 5RS) -4- (l-methylethyl) -5-phenyl-3- (3-piparidinpropyl) -l, 3-oxazolidin-2-one compound 3: (4RS _ý 5SR) -4- (2-msthylpropyl) -5-phenyl-3 - (3-piperidinopropyl) -1,3-oxazolidin-2-one, compound 4i (4RS, 5RS) -4- (2-methylpropyl) -5-phenyl-3 '(3-piperidinopropyl) -1,3- oxazolidin-2-one, compound 5: (4S, 5R) -4- (2-methylpropyl) -5-phenyl-3- (3-piperidinopropyl) -1,3-oxazolidin-2-one, compound 6: (4R, 5S) -4- (2-methylpropyl) -5-phenyl-3- (3-piperidinopropyl) -1,3-oxazolidin-2-one, compound 7 »(4S, 5S) -4- (2- methylpropyl) -5-phenyl-3-C3-pipetidin-1-propyl) -1,3-oxazolidin-2-one, compound 8: (4R, 5R) -4- (2-methylpropyl) -5-phenyl-3- ( 3-piperidinopropyl) -1,3-oxazolidin-2-one, compound 9: (4R, 5SR) -4- (1-methylethyl) -5-phenyl-3- (3-pyrrolidinpropyl) -1,3-oxazolidin- 2-one, compound 10: (4RS, 5RS) -4- (1-oetbylethyl) -5-phenyl-3- (3-pyrrolidinopropyl) -1,3-oxazolidin-2-one, compound 11 '(4RS, 5SR) -4- (1-oethyl) ethyl) -3- ^(3-PE2, bydroazepín-yl) píopyl) -5-phenyl-1,3-oxa-ol of id in-2-one,! Compound 12: (4RS, 5RS) -4- (1-Methyl-ethyl) -3- (3- (piperidroazepin-1-yl) propyl) -5-phenyl-1,3-oxazolidin-2-one, Compound 13 N - (4RS, 5SR) -4- (2-Methylpropyl) -5-phenyl-3- (3-pyrrolidinopropyl) -1,3-oxazolidin-2-one, Compound 14: (4RS, 5RS) -4- (2 -methylpropyl) -5-phenyl-3- (3-pyrrolidinpropyl) -1,3-oxazolidin-2-one, compound 15: (4RS, 5SR) -4- (2-methylpopyl) -3- (3- / perbydroazepine) 1-yl / propyl) -5-phenyl-1,3-oxazolidin-2-one, compound 16 '(4RS, 5RS) -4- (2-oetbylpropyl) -3- (3-perhydroazepin-1-yl) (propyl) -5-phenyl-1,3-oxazolidin-2-one, compound 17: (4S, 5R) -4- (2'-methylpropyl) -3- (3- (perbydroazepin-1-yl) propyl) -5-phenyl-1,3-oxazolidin-2-one, compound 18: (4R, 5S) -4- (2-methylpropyl) -3- (perhydroazepin-1-yl) propyl) -5-phenyl-1 , 3-oxazolldin-2-one, compound 19: (4S, 5S) -4- (2-methylpropyl) -3- (3- (perhydroazepin-1-yl) propyl) -5-phenyl-1,3-oxazolldin-2 -one, compound 20: (4R, 5R) -4- (2-methylpropyl) -3- (3- (perhydroazepin-1-yl) propyl) -5-phenyl-1,3-oxazolidin-2-one, compound 21: (4RS, 5SR) -5- (2-Methylphenyl) -4- (2-methyl); thylpropyl) -3- (3-piperidinopropyl) -1,3-oxazolidin-2-one, compound 22: (4RS, 5RS) -5- (2-ethylphenyl) -4- (2-methylpropyl) -3- (3 -piperidinopropyl) -1,3-oxaaolidin-2-one, compound 23: (4RS, 5SR) -5- (3-phenylethylphenyl) -4- (2-methylpropyl) -3 - ((3-piperidinopropyl) -1), 3-Oxazolidin-2-one, Compound 24: (4RS, 5RS) -5- (3-methylphenyl) -4- (2-methylpropyl) -3- (3-piperidinopropyl) -1,3-oxaaolidin-2-one compound 25 «(4RS, 5SR) -5- (4-methylphenyl) -4- (2-methylpropyl) -3- (3-piperidinopropyl) -1,3-oxazolidin-2-one, compound 26 compound 27 compound 28 compound 29 compound 30 compound 31 compound 32 compound 33 compound 34 compound 35 compound 36 compound 37 compound 38 compound 39 compound 40 compound 41 compound 42 compound 43 compound 44 compound 45 compound 46 compound 47 compound 48 compound 49 compound 50 compound 51 compound 52 compound 53 Compound 54 Compound 55 (4RS, 5RS) -5 '(4-Methylphenyl) -4- (2-methylpropyl) -3- (3-piperidine) propyl) -1,3-oxazolidin-2-one, (4RS, 5SR) -5- (4-methoxyphenyl) -4- (2-ethylpropyl) -3 '(3-plpardinylpropyl) -1,3-oxazolyl-2-one -one, (4RS, 5R3) -5- (4-netboxyphanyl) -4- (2-methylpiperyl) -3- (3-piparidinopropyl)

-1,3-oxazolidin-2-one, (4RS, 5SR) -5- (4-fluorophenyl) -4- (2-methylpropyl) -3- (3-piperidinopropyl) -1,3-oxazolidin-2-one (4RS, 5RS) -5- (4-Fluorophenyl) -4- (2-methylpropyl) -3- (3-piperidinyl) -1,3-oxazolidin-2-one, (4RS, 5SR) -5 - (4-chlorophanyl) -4- (2-methylpropyl) -3- (3-piparidinopropyl) -1,3-oxazolidin-2-one, (4RS, 5RS) -5- (4-chlorophenyl) -4- ( 2-methylpropyl) -3- (3-piperidinopropyl) -1,3-oxazolidin-2-one, (4RS, 5RS) -5-phenyl-3- (3-piparidinopropyl) -4-propyl-1,3-oxazolidine -2-one, (4RS, 5SR) -5-phenyl-3- (3-piperidinopropyl) -4-propyl-1,3-oxazolidin-2-one, (4RS, 5RS) -4-butyl-5-phenyl -3- (3-Piparidinopropyl) -1,3-oxazololidin-2-one, (4RS, 5SR) -4-butyl-5-phenyl-3- (3-piperidinylpropyl) -1,3-oxazolidin-2-one (4RS, 5RS) -4-Pentyl-5-phenyl-3- (3-piparidinopropil) -1,3-oxazolldin-2-one, (4RS, 5SR) -4-Pentyl-5-phenyl-3- ( 3-plparldinopropyl) -1,3-oxazolidin-2-one, (4RS, 5RS) -4- (3-phenylethylbutyl) -5-phenyl-3- (3-piporidinopropyl) -1,3-oxazolidin-2-one , (4RS, 5SR) »4- (3'-ethylbutyl) -5-phenyl-3- (3-plparidinopropyl) -1,3-oxazolldin-2-one, (4RS ₅ 5RS) -4-hexyl-5- phenyl 3- (3-pi peridinpropyl) -1,3-oxazolidin-2-one, (4RS, 5SR) -4-hexyl-5-phenyl-3- (3-piperidinopropyl) -1,3-oxa-pyrrolidin-2-one, (4RS, 5RS) 4-Hexyl-5-phenyl-3- (3-pyrrolidinopropyl) -1,3-oxazolindin-2-one, (4RS, 5SR) -4-hexyl-5-phenyl-3- ( 3-pyrrolldinpropyl) -l, 3-oxazolidin-2-one, (4RS »5RS) -4-hexyl-3- (3- / perhydroazepln-yl / propyl) -5-phenylsulfanyl-l _L 3-oxazolidin 2-one, (4RS, 5SR) -4-hexyl-3- (3- (perhydroazepin-1-yl) propyl) -5-phenyl-1,3-oxaaolidin-2-one,

C4R, 5R5-4-HE3 (Phenylalanine-yl-5-3- (3-pl.P «rt ^(11npropyl) -l, 3-oxezol ldin-2-one, (4R» 5S) -4-baxyl-5-phenylsulfanyl -3- (3-Piparidinopropyl) -1,3-oxzolidin-2-one, (43,5S) -4-bexyl-5-phenyl-3- (3-piperidinopropyl) -1,3-oxazolidin-2-one (4S, 5R) -4-Hexyl-5-phenyl-3- (3-piperidinyl) -1,3'-oxzolidin-2-one, (4RS, 5RS) -4-heptyl-5-phenyl-3- ( 3-piperidinopropyl) -1,3-oxazolinyl

-2-one (4RS, 5SR) -4-beeptyl-5-phthyl-3- (3-piperidinyl) -1,3-oxazolidin-2-one, (4RS, 5RS) -5-phanyl-3- ( 3-piperidinopropyl) -4-octyl-1,3-oxazolidin-2-one, (4RS, 5SR) -5-phenyl-3- (3-plparidinpropyl) -4-octyl-1,3-oxazolidin-2-one , (4RS, 5RS) -4- (1-Phenylbutyl) -5-phenyl-3- (3-piperidinopropyl) -1,3-oxazolidin-2-one »

J

Compound 56: (4RS, 5SR) -4- (1-methylbutyl) -5-phenyl-3- (3-piperidinopropyl) -1,3-oxazolidin-2-one, compound ⁹ : (4RS) , 5RS) -4- (4-methylpentyl) -5-phenyl-3- (piperidinopropyl) -1,3-oxazolidin-2-one, compound 58: (4RS, 5SR) -4- (4-methylpentyl) -5 -phenyl-3- (3-piperidinopropyl) -1,3-oxazolidin-2-one, compound 59: (4RS, 5RS) -4- (1-methylpentyl) -5-phenyl-3- (3-piperidinopropyl) - 1,3-oxazolidin-2-one, compound 60: (4RS, 5SR) -4- (1-methylpentyl-5-phenyl-3- (3-piperidinopropyl) -1,3-oxazolidin-2-one, compound 61 : (4RS, 5RS) -4- (5-Methylhexyl) -5-phenyl-3- (3-piperidinopropyl) -1,3-oxazolidin-2-one, Compound 62: (4RS, 5SR) -4- (5 -methylhexyl) -5-phenyl-3- (3-piperidinopropyl) -1,3-oxazolidin-2-one, compound 63: (4RS, 5RS) -4- (1-methylhexyl) -5-phenyl-3- ( 3-piperidinopropyl) -1,3-oxazolidin-2-one, compound 64: (4RS, 5SR) -4- (1-methylhexyl) -5-phenyl-3- (3-piperidinopropyl) -1,3-oxazolidin- 2-one, compound 65: · (4RS, 5RS) -4- (6-methylheptyl) -5-phenyl-3- (3-piparidinopropyl) -1,3-oxazolidin-2-one, compound 66: (4RS, 5SR ) -4- (6-methylheptyl) -5-phenyl-3- (3-piperidinopropyl) -1,3-oxazolidin-2-one, compound 67: (4RS, 5RS) -4- (1-methylheptyl) -5 -phenyl-3- (3-piperidinopropyl) -1,3-oxazolidin-2-one, compound 68: (4RS, 5SR) -4- (1-methylheptyl) -5-phenyl-3- (3-piperidinopropyl) - 1,3-oxazolidin-2-one, compound 69: (4RS, 5RS) -4- (1,1-dimethylpropyl) -5-phthyl-3- (3-piperidinopropyl) -1,3-oxa olefinine -2-one, compound 70: (4RS, 5SR) -4- (1,1-dimethylpropyl) -5-phenyl-3- (3-piperidinopropyl) -1,3-oxazolidin-2-one, compound 71: ( 4RS, 5RS) -4- (1-Ethylbutyl) -5-phenyl-3- (3-piperidinopropyl) -1,3-oxazolidin-2-one, Compound 72: (4RS, 5SR) -4- (1-ethylbutyl) -5-phenyl-3- (3-plperidinopropyl) -1,3-oxazolidin-2-one.

The activity of the compounds of the formula I according to the invention was determined on the basis of glutamic acid blocking activity, relaxation effect on nauraxial muscles (an effect of suppressing and releasing rigidity on anemic decerebral rigidity samples) and the level of toxicity was further adjusted. The following comparative compounds were used for comparison:

Comparative Compound 1:

Tolueprisone hydrochloride Comparative Compound 2:

δ 4RS, 5SR-4-methyl-5-phenyl-3- (2-piperidinethyl) -1,3-oxazolidin-2-one hydroxide, comparative compound 3s hydrochloride 4RS, 5RS 4 -4-methyl-5-phonyl- 3- (2-piperidinomethyl) -1,3-Oxazolidin-2-one, Comparative Compound 4:

4RS, 5R-4-Methyl-5-phenyl-3- (2-pyrrolidinetbyl) -1,3'-oxazolldin-2-one hydrochloride, Comparative Compound 5:

4RS, 5R5, 4-Methyl-5-phonyl-3- (2-pyrrolidinethyl) -1,3-oxazolidin-2-one hydrochloride.

Referring to the examples, FIGS. 1 and 2 are also provided, wherein FIG. 1 is a diagram illustrating the initiation rate of cortical neurons during administration of L-glutamic acid with a constant constant current using a compound of the invention, and FIG. the initiation rate of cortical neurons excited by the glutamate phase using the compound of the invention.

Test 1

Effects on anemic decerebral rigidity.

An anemic decerebral rigidity sample was prepared in essentially the same manner as described by Pukuda et al. / see Japan J. Bhrarmacol. 24, 810 (1974)]. According to this procedure, male Wlstar rats (body weight in the range of 270 to 350 g) were placed on the hindparts and incised under the etherization in the neck region. After the trachea and carotid artery were exposed, the trachea was cannulated and then the double-sided carotid artery and esophagus were double-ligated and dissected. The cranial base was then exposed, and a circular hole was drilled into this double-ligated central basilar artery. After the rats began to recover from anesthesia, their forelimbs were rigid. Measurements were performed on each rat to measure the electromyographic response (EMG) of the forelimb muscle (Muscle triceps brachii) in the rigid rat. These EMG pulses were converted to accumulated values every 10 seconds and recorded as a histogram on the recording device.

The effect of each test compound on rigidity was expressed as suppressive ability. This suppressive value was calculated by determining the area of the diminished portion of the EMG pulse on the histogram within a 10-minute interval after the administration of saline containing test compound / 3 mg per kilogram / fetal artery, and calculated according to the equation:

and suppression capability /% / π - ~ -—- - x 100

And where a is the area of reduced EMG pulse as a result of administration of the test compound, and

A is the area of the EMG pulse when no compound (control) was administered.

The results obtained are shown in Table 1.

Table 1

Test compound Suppression ability /% / The compound of the invention 1 12.0 2 19.8 3 18.0 4 21.2 5 37.7 6 14.9 7 64.8 8 12.0 10 18.7 14 10.2 17 93.0 25 10.9 27 Mar: 8.4 29 9.9

Test compound Suppression ability /% / Comparative compound! 1 4.8 2 3.6 3 2.2 4 1.0 5 3.0

T e b t 2 - A

Blocking effects on glutamic acid in neuromuscular connections in cancer.

The method of Ishid et al. (see J. Physiol., 298, 301-319, 1980) and Snihozaki et al. / see Comp. Biochem. Physiol., 70c, 49-58,1981]. This means that the expanding muscles of the first limb of the cancer were used as samples for these observations. The neuromuscular sample was stored in a saline-treated bath [composition of this solution in mM sodium chloride (195), calcium chloride (18), potassium chloride (5.4), trismalate buffer (pH 7.5) 10), glucose (11)] at room temperature and at a constant flow rate. Glass microelectrodes were inserted into the central part of the muscular tissue, each of which was filled with 3M potassium chloride solution to record intracellularly the changes in the potential of the muscular cell membrane.

The blocking effect of each of the test compounds on glutamic acid was expressed as a depolarizing suppressing effect induced by the application of an L-glutamic acid bath (10 ⁴ M concentration) in a 5 minute pretreatment with the test compound solution. The results obtained are shown in Table 2,

Tabelka 2

Test Compound Concentration of Tested Blocking effect on compound in solution /ϊ.ΐ/ glutamic acid /% /

Compound of the Invention No.

3 2 «· lo ⁴ 89 4 2 10 ⁴ 88 5 2 9 10 ⁴ 91 7 2 0 10 ⁴ 92 13 2 10 “ ⁴ 80 17 2 • 10 ⁴ 90 35 2 * 10 ⁴ 68 36 2 10 ⁵ 53 37 2 10 ⁵ 58 40 2 10 ” ⁵ 69 41 2 10-5 69

Comparative compounds:

2. 10 ⁴ 0

2. 10 ⁴ 45

Test 2 - B

Inhibitory effect on the action of L-glutamic acid and its analogues on cortical neurons in rats.

According to this test, I-glutamic acid and the compound of the invention were [(4S, 5R) -4- (2-methylpropyl) -3- (3-perhydroazepin-1-yl) propyl] -5-phenyl-1,3-oxazolidine ” -2-one, iontophoretically applied to cortical neurons in rats using multiple glass micropipettes loaded with L-glutamic acid (1M concentration) and compound prepared according to the invention (0.05 M concentration), see M. Sakurai procedure , Seitsi no Kogaku, 36/4. 416-418 (1985) and T.W., Stona, Hicroiontophoresls Pressure Bjection, IBRO Handbook Series, Vol. 8, Wiky (1985)]. The tip of the nicropipette was fixed using the mlcronsnipulator at the position where the greatest glutamate response occurred, shown by the extracellularly recorded action potentials induced by L-glutamate lontophoretic application. Figure 1 shows the initiation rate of cortical neurons during application Of L-glutanoic acid by constant constant streams in the presence or absence of said compound obtained by the process of the invention, which has been applied in various amounts. To this figure, the action potential frequency value is shown on the ordinate axis and the time is shown on the abscissa axis. From the results shown in FIG. 1, it is evident that the compounds obtained by the process of the invention inhibit the glutamate response in a manner that depends on the amount used. Figure 2 shows the initiation rate of cortical neurons excited by iontophoretic glutamate pulses: Pulse frequency 0.2 Hz, duration of 2 seconds. The compounds obtained by the process according to the invention reduced the frequency of action potentials induced by I-glutamate and also by the three glutamate receptor egonists, i.e. kainic acid, ohischelic acid and K-methyl-D-aspartic acid. From the above results, it was confirmed that the compounds obtained by the process of the invention inhibit the glutamate response in cortical neurons in rats.

Test 3

Acute toxicity.

Male ddK mice were used for this assay, and the acute toxicity of each test compound was determined by a method of monitoring the number of dead and surviving animals. Some of the test compounds were used as dissolved in saline and administered via the caudal artery. The results obtained are shown in Table 3.

Table 3

Test compound ^1d 50 Γ ^{π / 5} «» ^iv J Compound prepared by the process of the invention: 1 »'. 29.7 2 18.8 3 55.5 4 29.9 5 69.0 7 30.4 10 54.6 13 75.1 14 53.2 17 40.1 25 34.9 27 Mar: 39.8 29 66.1 40 53.6

The process according to the invention will be illustrated by means of examples, and reference examples are also included in which the processes for the preparation of the starting materials or substances which are used in this preparation of the starting materials are illustrated (see reaction scheme in the description).

Example 1

4S, 5R1 -4- (2-Methylpropyl) -5-phenyl-3-p-piperidinopropyl-1,3-oxazolidin-2-one Puoarate.

A mixture of 14S, 5R-4- (2-methylpropyl) -5-phenyl-3- (4-piperidinopropyl) -1,3-oxazolidin-2-one (10.37 g, 50 mmol), 3-chloropropyl (piperidine) (12.38 grams, equivalent to 62.5 mmol), anhydrous potassium carbonate powder (17.28 grams, equivalent to 125 mmol), and methyl ethyl ketone (100 mL) was heated to reflux. condenser with stirring for 24 hours. After completion of the reaction, the reaction mixture was cooled and the insoluble matter was filtered off. The insoluble matter was then washed with methyl ethyl ketone. The wash liquid and the filtrate were then combined and evaporated under reduced pressure. The residue was dissolved in toluene (70 ml). The toluene solution was then washed three times with water (70 ml) and the toluene used was then evaporated under reduced pressure. The residue was dissolved in ethanol (50 mL) followed by the addition of fumaric acid (5.80 g, 50 mmol). The resulting mixture was then heated to dissolve the fumaric acid. The solution was allowed to stand overnight at room temperature. The precipitated crystals were collected by filtration, washed three times with ethanol (30 ml) and then dried to give crude crystals (19.04 g). The crude crystals were recrystallized from water (70 ml) to give 16.73 g of the title compound as white crystals. The yield of this procedure was 73%.

Melting point: 174 - 176 ° C (decomposition)

W _D - + 12.0 DEG (c 1.00, CH-OH)

IR 9 KBr,

3560, 3450, 2950, 2640, 2350, 1740, 1725, 1690, 1635, 1540, 1450, 1405, 1240, 1200, 995, 975, 765, 745, 695.

Example 2

Using procedures similar to those described in Example 1, the following compounds were obtained as listed in Table 4 below.

Table 4

Compound

C.

(Example 1)

-ch ₂ ch _x ^ CH.

CH.

* r ’

CH

CH 2

-ch ₂ CH 2, CH.

CH-ch ₂ ch.

CH,

X n Configuration Melting point (° C) IR P _m __ (om ^-1 ) ^¥ max H 5 4S, 5R H ²³ _D -9.7 ° (ol. 14, CHCl 174 - 176 (with decomposition) ) (fumarate) 2920, 2860, 2790, 2760, 1760, 1460, 1440, 1405, 1360, 1245, 1200, 1160, 1110, 1030, 1000, 755, 740, 690 (net) H 5 4RS, 5RS 157-158 (fumarate) 2940, 2860, 2780, 1755, 1604, 1440, 1425, 1230, 1125, 1035, 1025, 750, 695 (pure) H 5 4RS, 5SR 150.5-151.5 (fumarate) 2930, 2800, 2770, 1750, 1490, 1460, 1440, 1410, 1375, 1345, 1315, 1245, 1215, 1170, 1120, 1035, 1010, 755, 695 (KBr). H 5 4 RS, 5RS 137 - 140 (fumarate) 2930, 2810, 2760, 1740, 1435, 1425, 1375, 1315, 1245, 1170, 1150, 1125, 1115, 1055, 1030, 1000, 935, 755, 750, 695 (KBr).

Table 4 (continued)

Compound δ. R X n Configuration Melting point (° C) IR (cm ¹ ) max / ^CH 3 5 -ch5 H 5 4RS, 5SR 142-144 2930, 2860, 2760 'CH, (with decomposition) 1730, 1605, 1440, (fumarate) 1415, 1125, 1030 755,695 (KBr). 6 ch ₃ -CH _? CH 2 H 5 4R, 5S 47 _ 49 2920, 2860, 2790 ^ CH-j {/] D ²³⁺ 9 ^»7 ° 174-176 2760, 1750, 1460, (O! 12, CHCl ₃ ) (with decomposition) 1440 1405 1360 (fumarate) 1245, 1200, 1160

1110, 1030, 1000

755, 740, 690 (KBr) - CH

ch ₃ H, 5S, 5S 160-161 2930, 2760 1750 ch ₃ p, J _D ²³ + 10 ° (fumarate) 1460 1440 1410 (c1.13, CHC1 ₃₎ 1370 1340 1310 1245, 121-0,1655 1130, 1115, 1030, 1005. 750, 690 (pure)

”CHpCH \

ch ₃ H 5 4R, 5R 160-162 2730, 2930, 1750, • ch ₃ PJ ²³ -1O _d, 3 ° (fumarate) 1460 1440 1410, (c1.13, CHC1 ₃₎ 1370 1340 1310, 1245 1210 1165, 1130 1055, 1030 1005 750, 690 (pure)

-CH 3 -, CH,

H 4 4RS, 5RS

145 - 147 (fumarate)

2960, 2880, 2790, 1750, 1445, 1420, 1230, 1030, 754,

700 (pure) .CH,

-CHgCH3

H 4 4RS, 5SR'CH,

169-170 2960 2880 2790. (fumarate) 1750 1605 1450, 1410 1145 1030, 1010 755 700 (Net)

Table 4 (continued)

Slou X security

C.

n Configuration

Melting point IR P _max (cnT ^) (° C)

CH3

-0Η ₂ 0Ηζ 'H ^ OBJ

-CH ₂ CH _x ^ _x cr ₃

CH21

-ch ₂ ch ' _x ch ₃

3η ₃

CH3

-CHaCH ^ ^X CH _Z CH _3.

-CH ₂ CH

On. ^ ³

2-CH,

3-CH-

4 4RS, 5RS 147-148 (fumarate) 2960, 2880, 2790, 1750, 1605, 1450, 1415, 1245, 1145, 1040, 1010, 760, 695 6 4S, 5R pJ _D -10.7 ^O (cl. 15, CHCl ₃ ) 171 - 173 (with decomposition) (fumarate) 2920, 2860, 2810, 1755, 1460, 1445, 1410, 1360, 1025, 1005, 760, 695 5 4RS, 5SR 152 - 153 (fumarate) 2950, 2880, 2820, 2780, 1760, 1445, 1235, 1220, 1130, 1040, 1010, 755 5 4RS, 5SR 142 - 145 (with decomposition) (fumarate) 2930, 2860, 2760, 1750, 1605, 1440, 1405, 1120, 1075, 750. 5 4RS, 5RS _w 2920, 2860, 2760

1750, 1435, 1405, 1370, 1240, 1115, 1030, 775, 750, 690

-CH2H4

X ^CH 3

CH,

-C ^CH ^CH,

4-CH,

4-CH,

5 4RS, 5SR 132-134 2940, 1760, 1125, 815, 2880, 2780, 1445, 1415, 1040, 1015, 760 (pure) 5 4RS, 5RS 2940, 2870 2770

1755, 1605, 1440, 1410, 1250, 1120, 1035, 1010, 810, 755

CH,

Table 4 (continued)

Slou X security

C.

n Configuration

Melting point (° C) raax (cm ^-1 )

X ^CH 3

CH,

4-0CH ₃ 5 4RS, 5SR

127.5-129.5 (fumarate)

2930, 2760, 1750, 1610, 1510, 1435, 1405, 1250, 1170, 1030, 825, 750 (pure) / ^CH3

-CH 2 CH ₃ ^{X X} CH ₃

4-P

4RS, 5SR

140 - 141 (with decomposition) (fumarate)

2930, 2850, 2750, 1720, 1604, 1505, 1445, 1410, 1360, 1225, 1150, 1120, 1030, 990, 845,

810.750 (KBr)

ΌΗ,

-ch ₂ ch;

4-P 5 4RS, 5RS

123-125'CH,

2930, 2870, 2800, 2770, 1750, 1605, 1510, 1470, 1445, 1415, 1225, 1155, 1120, 1030, 1005, 830, 760 (pure)

-CH,

CH,

4-C1 5 4RS, 5SR

141 - 142 (with decomposition) (rubber count)

2940, 2860, 2820 2770 1735 1605, 1495 1450 1425, 1370 1350 1250, 1235 1215 1125, 1090, 1025 1010, 995 945 820, 770 KBr

ΌΗ32 -CHgCH2

4-C1 5 4RS, 5RS

CH-

2940, 2870, 2850, 2810, 2770, 1750, 1600, 1490, 1465, 1440, 1410, 1250, 1120, 1090, 1030,

1005, 820 750 (pure)

- (CH ₂ ) ₂ CH ₃ H 5 4RS, 5RS

198 - 201 2920, 2840, 2760, 1740, 1600, 1440, 1415, 1240, 1120, 1030, 1000, 755,

695 (pure)

Table 4 (continued)

Slou- chenina C. R X n Configuration Melting point (° C) Vδ V (om ¹ ) 34 - (ch ₂ ) ₂ oh ₃ H 5 4RS, 5SR 126-128 2930, 2870, 2770, 1740, 1440, 1410, 1010, 770, 705 (KBr); 35 - (oh ₂ ) ₃ ch ₃ H 5 4RS, 5RS 98 - 100 (fumarate) 2940, 2860, 2770, 1750, 1605, 1450,

1415, 1230, 1120, 1035, 1000, 755, 695 (pure)

- (ch ₂ ) ₃ ch ₃ H

4RS, 5SR 118-120 2930 2860 2760, (fumarate) 1750 1605 1450, 1410 1120 1030, 1010, 755 (pure) 695

4RS, 5RS

- (OH ₂ ) ₄ CH ₃ H

- (OH ₂ ) ₄ GH ₃ H

4RS, 5SR

134 - 136 (oxalate) 2940, 2860, 2800, 2770, 1755, 1450, 1415, 1375, 1240, 1230, 1120, 1035, 1000, 755, 695 113-115 2930 2860 2800 (fumarate) 2760, 1750, 1445, 1410, 1245, 1225, 1120, 1030, 1010, 755, 695

39 - (CH 2) ₉ CH. h ^Χχ 0Η ₃ 5 4RS, 5RS 125 - 126 (maleate) 2940, 1755, 1420, 2870, 1610, 1240, 2780, 1450, 1130, 1040, 1010, 760,

700 (pure)

40 - (ch _? ) ₂ ch _in h ^Χ όη ₃ 5 4RS, 5SR 138 - 139 (fumarate) 2920, 2850, 1740, 1600, 1405, 1115, 2740, 1440, 1025, 1005, 745 (pure) 690

Table 4 (continued)

Slou- chenina C. R X n Configuration Melting point (° C) IcV (cm ¹ ) maz 41 - _(CH?)? CH ₃ H 5 4RS, 5RS 92-94 2920, 2850, 2770, (fumarate) 1750, 16.00, 1450, 1410, 1230, 1120, 1030, 1010, 755, 695 (net) 42 H 5 4HS p 5SR 121 - 123 2930, 2850, 2770, (fumarate) 1750, 1605, 1450, 1410, 1120, 1035, 760, 700 i (net) CH « 1 -cM H 5 4RS, 5SR 142-144 293 0, 2860, (example 1) ^CH 3 (with decomposition) 2760, 1730, (fumarate) 1605, 1440, 1415, 1125, 1030, 755, 695 (KBr) / ^H ) 2 -CH H 5 4-KS $ 5RS 157-158 2940, 2860, 2780, Mh ₃ (fumarate) 1755, 1605, 1440, 1425, 1230, 1125, 1035, 1025, 750, 695 (net) / ^CH 3 3 -CHgCH H 5 4RS, 5SR 150.5-151.5 2930, 2800, 2770, (example 2) (fumarate) 1750, 1490, 1460, 1440, 1410, 1375, 1345, 1315, 1245, 1215, 1170, 1120, 1035, 1010, 755, 695 (KBr) 4 H 5 4RS , 5RS 137-140 2930, 2810, 2760, ch ₃ (fumarate) 1740, 1435, 1425,

1375 1315 1245 1170 1150 1125 1115 1055 1030 1000 935 755

750.695 (KBr)

Table 4 (continued)

Slou- R X n Configuration Melting point čenlna (° c) C.

CH ₃

-CHgCH2H

-CHgCH3

-CH,

CH, CH ₃ ^{, CH} 2 ^CH C ^H 2 CH,

4R, 53 47 - 49 2920, 2860, 2790, f ⁶ ? o ²³ “ 174-176 2760, 1750, 1460, + 9.7 ° (with decomposition) 1440, 1405, 1360, (Art.12, CHC1 ₃₎ (funarát) 1245, 1200, 1160, 1110, 1030, 1000, 755, 740, 690

(KBr)

43, 5S

D +10.3 [deg.] «R

O

160-161 (funarate) • CH _{/ C} h ₃

CH CH ₃ • ₉ H CHF Ύ! Η ₃ • CH ₃ ^CH-X H CHF ₃ 0B (OL, 13, CHC1 ₃₎

2930, 2760, 1750, 1460, 1440, 1410, 1370, 1340, 1310, 1245, 1210, 1165, 1130, 1115, 1055, 1030, 1005, 750,

690 (pure)

4R, 5R 160-162 [ets] iP _e (funarate)

-10.3 ° (cl. 13, I want ₃ )

2930, 2760, 1750, 1460, 1440, 1410, 1370, 1340, 1310, 1245, 1210, 1165, 1130, 1115, 1055, 1030, 1005, 75 0,

690 (pure)

4RS, 5RS

4RS, 5SR

4RS, 5RS

145-147 2960 2880 2790, (funarát) 1750, 1445, 1420, 1230, 1030 755, 700 (pure)

169-170 2960 2880 2790, (funarát) 1750 1605 1450, 1410 1145 1030, 1010 755 700 (net)

147-148 2960, 2880, 2790, (funarát) 1750, 1605, 1450, 1415, 1245, 1145 1040, 1010, 760

695 (pure)

Table 4 (continued)

Sloux X kennel

C.

n Configuration

Mp IR (cm "^) (° C) 3 ^ '2 C ^{2 UH} \ CN3 / ®3

-CH 2 CH 2 -CH ₃ 5 / ^CH 3

-CH 3 CH ₃ -CH ₃ 5 -CH ₂

CH ₃

-CH 3 CH 3 -CH 2, 5 CH ₃

4S, _5R h _d - -10.7 ° (cl, 15, CHC1 ₃₎ 171 - 173 (with decomposition) (fumarate) 2920, 2860, 2810, 1756, 1460, 1445, 1410, 1360, 1025, 1005, 760, 695 (net) 4RS, 5SR 152-153 (fumarate) 2950, 2880, 2820, 2780, 1760, 1445, 1420, 1235, 1220, 1130, 1040, 1010, 750 4RS, 5SR 142 - 145 (with decomposition) (fumarate) 2930, 2860, 2760, 1750, 1605, 1440, 1405, 1120, 1075, 750 4RS, 5RS 2920, 2860, 2760, 1750, 1435, 1405, 1370, 1240, 1115, 1030, 775, 750, 690

/ ^CH 3

-CH 2 CH ₂ 4 -CH ₃ -CH ₃

4RS, 5SR

132-134 2940, 2880 2780 (fumarate) 1760, 1445 1415 1125, 1040, 1015 815, 760 (pure)

-CHgCH _x oh ₃

_4-CH3

4R3,

5RS - 2940, 2870, 2770, 1755, 1605, 1440, 1410, 1250, 1120, 1035, 1010, 810,

755 (Net)

CH ₃

-CH 2 Cl 4 -OCH 3 -CH 2

5RS, 5SR

127.5-129.5 2730, 2930, 1750, (fumarate) 1610 1510 1435, 1405 1250 1170, 1030, 825 750 (net)

Table 4 (continued)

Sloux R Configuration Melting point ΐδΊ? (cm ^-1 ) china (° C)

8.

-CH 2 CH 2, CH

CH,

4-P 5 4RS, 5SR 140 - 141 (with decomposition) 2930 2850 2750 1720 1605 1505 (fumarate) 1445, 1410, 1360, 1225, 1150, 1120, 1030, 990, 845, 810, 755 (KBr)

-ch ₂ ch (?

^ 1 'CH,

CH,

-ch ₂ ch:

.CH,

4-1 ·· 5 4RS, 5RS 123 - 125 (fumarate) 2930, 2870, 2800, 2770, 1750, 1606, 1510, 1470, 1445, 1415, 1225, 1155, 1120, 1030, 1005, 840, 760 (Sown) 4-01 5 4RS, 5SR 141 - 142 (with decomposition) (fumarate) 2940, 2860, 2820, 2770, 1735, 1605, 1495, 1450, 1425, 1370, 1350, 1250, 1235, 1215, 1125, 1090, 1025, 1010, 995, 845, 820, 770 (KBr)

-ch ₂ ch.

.OB,

ΌΗ,

4-Cl. 5 4RS, 5RS - 2940 2870 2850, 2710, 2810 1750, 1600 1490 1465, 1440 1410 1250, 1120 1090 1030, 1005, 820, (Sown) 750

- <ch ₂ ) ₂ ch ₃

- (ch ₂ ) ₂ ch ₃

H 5 4RS, 5RS 198 - 201 (decomposition) (oxalate) 2920, 2840, 2760, 1740, 1600, 1440, 1415, 1240, 1120, 1030, 755, 694 H 5 4RS, 5SR 126 - 128 (fumarate) 2930, 2870, 2770, 1740, 1440, 1410, 1010, 770, 705

(KBr)

Table 4 (continued)

Compound

WITH,

- (CH ₂ ) ₃ CH ₃ H

- (CH ₂ ) ₃ CH ₃ H

- (CH ₂ ) ₄ CH ₃ H

CH 3 ', CH 3 / ^CT 3

-CH _O

- (CH ₂ ) ₅ CH ₃ H 5 4RS,

n Configuration Melting point (° C) ιδ ý (cm * ¹ ) max ⁱⁿ ' 5 4RS „53S 98-100 2940, 2860 2770 (fumarate) 1750, 1605 1450 1415, 1230, 1120 1035, 1000 755 695 (pure) 5 4RS, 5SR 118-120 2930, 2860 (fumarate) 1750, 1605 1450 1410, 1120 1030 1010, 755 695 (net) 5 4RS, 5RS 134-136 2940, 2800, 2800, (oxalate) 2770, 1750, 1450, 1415, 1375 1240 1230, 1135, 1035, 1000, 755,695 (bare) 5 4RS, 5SR 113-115 2930, 2800, 2800, (fumarate) 2760, 1750, 1445, 1410, 1245 1225 1120, 1030, 1010 755, 695 (pure) 5 4RS, 5RS 125–126 2940, 2870 2780 (maleate) 1755, 1610 1450 1420, 1240 1130 1040, 1010 760 700 (pure) 5 4RS, 5SR 138-139 2920, 2850 2740 (fumarate) 1740, 1600 1440 1405, 1115, 1025 1005, 745,690 (net) 5 4RS, 5RS 92-94 2920, 2850, 2770, (fumarate) 1750, 1600 1450 1410, 1230, 1120 1030, 1010 755

695 (pure)

Table 4 (continued)

Slou- R chenina C. X n Configuration Melting point (° C) IR j? (cm ¹ ). ⁱⁿ max 42 - (CH ₂ ) ₅ CH ₃ H 5 4RS, 5SR 121 - 123 (fumarate) 2930, 2850, 2770, 1750, 1605, 1450, 1410, 1120, 1035, 760, 700 Reference Example 1 2- (1,3-Dioxo-2-azaindan-2-yl) -4-methyl-1-phenylpentan-1-one.

Thionyl chloride (34.8 ml, equivalent to 480 mmol) was added to a mixture of 2- (1,3-dioxo-2-szalndan-2-yl) -4-methylpentanoic acid (83.61 g, corresponding to 320 mmol) and benzene (320 mL). The mixture was heated to reflux for 2 hours. The solvent and excess thionyl chloride were removed by distillation under reduced pressure, after which benzene (320 ml) was added. The benzene was then removed and new fresh benzene (480 ml) was added to form a solution. Anhydrous aluminum chloride (106.7 g, 800 mmol) was immediately added to the solution, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then poured into ice water (700 mL). The resulting aqueous layer was then extracted with benzene (200 mL). The organic layer was washed first with water and then with aqueous sodium bicarbonate solution and saturated sodium chloride solution, and the combined organic layers were dried over sodium sulfate and then evaporated under reduced pressure. The residue was treated with ethanol to give crystals. The crystals were dissolved by heating in ethanol (80 ml) and hexane (160 ml) was added. The crystals thus precipitated were collected by filtration and washed first with a 1: 2 mixture of ethanol and hexane (240 ml) and then with hexane. The crystals were air dried to give 74.6 g of the title compound as white crystals. The yield was 73%.

Reference Example 2 (1RS, 2RS) -2- (1,3-Dioxo-2-azaindan-2-yl) -4-methyl-1-phenylpentan-1-ol and 3-Dioxo-2-azaindan-2-yl) -4-methyl-1-phenylpentan-1-ol.

Sodium cyanoborohydride (177 grams, 2.82 moles) was added over 3 hours to a solution of the compound obtained according to Reference Example 1 above (141.4 grams corresponding to 440 mmol) in chloroform (660 milliliters), and in acetic acid (440 mL) while maintaining the reaction temperature below 30 ° C. The resulting mixture was stirred at room temperature for an additional 3 hours and chloroform (1 L) and water (1.4 L) were added. The organic layer was separated and washed twice with water, once with aqueous sodium bicarbonate solution and then once with saturated sodium chloride solution. After drying over sodium sulfate, the organic layer was evaporated under reduced pressure to give white crystals (142 g). The crystals were loaded onto a silica gel chromatography column (silica gel: 2.8 kilograms, solvent: beznene) to obtain at first 94.3 g of isomers as white crystals of the (1RS, 2SR) -isomer, yield 66 %, and then 48.4 g of the (1RS, 2RS) -isomer was obtained as white crystals, the yield of which was 34%,

Reference Example 3 (1RS, 2RS) -2- (1,3-Dioxo-2-azaindan-2-yl) -4-methyl-1-phenylpentan-1-ol.

125.6 g (615 mmol) of aluminum isopropoxide was added to a suspension of 2- (1,3-dioxo-2-azaindan-2-yl) -4-methyl-1-phenylpantan-1-one (72, 3 g, 225 mmol) in isopropanol (1000 mL). The mixture was heated at reflux for 6.5 hours. The isopropanol was removed by distillation under reduced pressure and the residue was taken up in ethyl acetate (800 ml) and aqueous sodium sulfate was added. The organic layer was decanted and the residue was washed twice with ethyl acetate. acetic acid (200 ml). The combined organic layers were then washed with saturated sodium chloride solution. The organic solution was dried and the solvent was removed by distillation under reduced pressure. The residue was recrystallized twice with benzene to give 29.3 g of the title compound as white crystals. The yield was 40%.

Reference Example 4 (1RS, 2SR) -2-Amino-4-methyl-1-phenylpentan-1-ol.

(1RS, 2SR) -2- (1,3-Dioxo-2-azaindan-2-yl) -4-methyl-1-phenylpentan-1-ol in an amount of 80.0 grams (247 mmol) was dissolved by heating ( to 50 ° C) in ethanol (800 mL) followed by the addition of a mixture of 85% hydrazine hydrate (19.0 mL) in ethanol (200 mL). The resulting mixture was then refluxed for 3 hours, cooled on an ice bath, and 4N hydrochloric acid (700 ml) was added. The mixture was stirred at room temperature for 30 minutes. The insoluble material was then collected by filtration through celite and washed with 4N hydrochloric acid (140 ml). The washings were then added to the filtrate and the solution was condensed under reduced pressure to remove ethanol. A 6N sodium hydroxide solution (570 ml) was added under cooling in an ice bath, and the mixture was extracted three times with chloroform. After drying the solution with sodium sulfate, the organic layer was evaporated to give 43.2 g of the title compound as white crystals. The yield was 91%.

Reference Example 5

4-Methyl-1- (4-methylphenyl) -2- (1,3-dioxo-2-azaindan-2-yl) pentan-1-one.

2-Bromo-4-methyl-1- (4-methylphenyl) pentan-1-one (13.5 g, equivalent to 50 mmol) and potassium phthalimide (9.26 g, 50 mmol) were mixed well and heated at 1-60 ° C for 2 hours. After cooling the reaction mixture, ethyl acetate (100 ml) and water (50 ml) were added. The organic layer was separated and washed with saturated sodium chloride solution. The organic solution was dried over sodium sulfate and evaporated under reduced pressure. There was thus obtained a residue which was crystallized by treatment with hexane, and the resulting crystals were crystallized from hexane, whereby

12.2 g of the title compound as white crystals. The yield was 73%.

Reference Example 6 (1RS, 2RS) -2-Amino-1-phenylheptan-1-ol.

Acetic acid anhydride (10 mL) was added to (1RS, 2SR) -2-amino-1-phenylheptan-1-ol (4.15 g, 20 mmol) and the mixture was heated at at 70 ° C for 10 minutes. After cooling, the mixture was poured into water (100 mL) to which chloroform was added, followed by the gradual addition of aqueous sodium hydroxide solution. The solution was then extracted with chloroform and the extract was dried. The solvent was removed under reduced pressure by distillation to give a colorless oil. The oil was cooled in an ice bath, and 20 ml of thlonyl chloride was added. The mixture was stirred at room temperature for 20 minutes. Water (30 ml) was added cautiously in limited amounts to the solution, and the resulting mixture was heated to reflux for 2 hours. The mixture was cooled and water was added. Immediately after washing the mixture, atbar was added and the resulting aqueous layer was separated and basified with aqueous sodium hydroxide solution. The mixture was extracted three times with chloroform and then dried. The organic solution was then evaporated under reduced pressure to give white crystals. The crystals were recrystallized from hexane to give 2.73 g of the title compound as white crystals. The yield was 66%,

Reference Example 7 (1RS, 2SR) -2-Amino-1- (4-methoxyphenyl) -4-methylpentan-1-ol,

2-Hydroxyimino-1- (4-methoxyphenyl) -4-methylpentan-1-one (8.72 grams, which corresponds to 37.1 mmol) was dissolved in acetic acid (88 millimeters). a mixture of 5% or palladium on charcoal (0.87 grams) was added and the reductive components were then catalytically hydrogenated at normal pressure and at 80 ° C until hydrogen was absorbed in a molar amount three times larger than the reactant. The acetic acid was removed under reduced pressure, and the residue was dissolved in 1N HCl (80 mL), washed twice with ether (30 mL) and basified with a 20% aqueous sodium hydroxide solution. The aqueous layer was extracted three times with chloroform and the extracts were combined and washed once with saturated brine. The resulting extract was dried over sodium sulfate and the solvent was removed by distillation under reduced pressure to give pale yellow crystals (6.80 g). The crystals were recrystallized in benzene and hexane to give 5.24 g of the title compound as white crystals. Yield 63

Reference Example 8 (4S, 5R) -4- (2-Methylpropyl) -5-phenyl-1,3-oxazolidin-2-one.

(1R, 2S) -2-Amino-4-methyl-1-phenylpentan-1-ol (96.64 g, equivalent to 0.5 mmol) was dissolved in chloroform (800 mL) and then followed by the addition of water (400 ml), and the statuette thus obtained was cooled in an ice bath. Ethyl chlorocarbonate (47.5 ml) was added dropwise with stirring at temperatures below 10 ° C. Another portion of ethyl chlorocarbonate (47.5 mL) and 7.5 N aqueous sodium hydroxide (150 mL) were added dropwise at the same temperature as above. This dropwise addition was completed simultaneously. The resulting mixture was stirred continuously at the same temperature for a further 30 minutes. The organic layer was separated and the aqueous layer was extracted with chloroform (80 mL). The combined organic layers were then dried over sodium sulfate and then evaporated under reduced pressure. The residue was dissolved in toluene (1.5 L) and then 200 mL of toluene was removed by distillation. Aluminum isopropoxide (2.0 grams) was added to the mixture and the mixture was then heated under reflux for one hour. Then 800 milliliters of toluene was removed by distillation to remove alcohols as by-products. Then n-hexane (600 ml) was added with stirring to the above residue and the solution was allowed to stand over the nose for a period of time. White crystals were formed by punching, which were collected by filtration. The β was then washed twice with a 1: 1 mixture of toluene and n-hexane (300 ml) and then washed once with n-hexane (300 ml). The crystals were dried to give 104.5 g of the title compound. The yield was 95%.

M.p. 163-164 ° C min) ²⁵ - - 0 _137t4 (about 1.016 (about 1.016, CHCl₃)

3260, 2960, 2945 »1750» 1750 »1350» 1250, 1220, 1050, 999 »

975 »950» 740 »725» 696

0.79 (3H, d, J = 6Hz, CH ₃₎

0.81 (3H, d, J = 6Hz, CH ₃₎

0.90 to 1.70 (3H, m, CHgCH (CH _{3) 2)}

II

3.96 - 4.28 (1H, CNHCH)

5.70 (1 H, d, J = 8Hz, PhCH)

6.87 (1H, s-band, NH)

7.32 (5H, m, aromatic protons)

It will be apparent from the foregoing description of the invention that various modifications or modifications may be made therein without departing from the scope of the invention given by the following definition of the subject matter of the invention.

Claims (1)

A process for the preparation of 1,3-oxazolidin-2-one derivatives of the general formula I in which it represents R is a straight or branched chain alkyl group of 3 to 8 carbon atoms, X is a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms or an alkoxy group having 1 to 3 carbon atoms, and an oil number from 4 to 6, as well as acid addition salts of these compounds, characterized in that In the presence of potassium carbonate or sodium carbonate, the compound of formula II (II) in which R and 1 are as defined above is reacted with a compound of formula III: Z-CHgCHgCHg-N (1H) in which is Z is halogen, toxyloxy, mesyloxy or oethoxy, and n is as defined above, whereupon the reaction product obtained is optionally converted into an acid addition salt.