DE3145473A1 - 2-Substituted 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-one compounds, processs for their preparation and medicaments containing them - Google Patents

Description

. ■. '. 3 1 4 υ μ / 3

Kefalas A / S Copenhagen-Valby, Denmark

2 ~ substituted 4,5,6,7-tetrahydrolsoxazolo j5,4-cjpyridln ~ 3 cm compounds, Process for their manufacture and medicinal products dispensing them

-H-

description

The invention relates to heretofore unknown compounds the general formula

0
/ I

* ■ ^c

in which R is a branched or unbranched alkyl group with 1 to 17 carbon atoms inclusive, a phenyl group, optionally with 1 or 2 groups, selected is substituted from lower alkyl groups, lower alkyloxy groups and halogen atoms, a phenylalkyl group, a

1 1 lower alkyloxy group or a group -NHR, in which R Is hydrogen, a lower alkyl, phenyl or cyclohexyl group, and their pharmaceutically acceptable ones Acid addition salts, of which it could be shown that they have a compound with ^ f-aminobutyric acid (GABA) have a standing effect and are indicated for use in the treatment of diseases dLe with a defective Function of the GABA system related, such as epilepsy, parkinsonism, schizophrenia, Huntington's chorea (Chorea chronica progressiva hereditaia), diseases that are based on the malfunctioning of pituitary hormones and cerebral arteriosclerosis.

In addition, the compounds show strong analgesic properties and myotonic effects,

The compound 4,5,6,7-tetra-hydro-isoxazolo p, 4-cjpyridin-3-ol (hereinafter referred to as TIP for short) has been shown to have an activity related to GABA, such as this e.g. in the European patent application No. 78 100 191.2. is described. However, it has a relatively short duration of action and also some side effects.

t / K '"V" p

According to the invention it has surprisingly been found that
Compounds of the formula I and how their pharmaceutically acceptable acid addition salts have an activity of the same order of magnitude related to GABA,
as is the case with the connection THIP and some
of the new compounds according to the invention even show
a prolonged effect compared to IHIP. In addition, these compounds show pronounced analgesic and
myotonic effects.

The invention also relates to new drugs that are used as
Active ingredient a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof. ^:

The invention also includes a method of making the

Compounds of formula I and methods of treating ''

Diseases associated with the malfunctioning of the GABA system \

connected, a matting to facilitate \

Pain of varying etiology and a procedure for the [

development of Myjbonic states (e.g. to induce the \

Muscle relaxation or treatment "of muscle cramps or \ muscular Krampferseheinungen).

The terms "lower alkyl groups" and "higher alkoxy groups" \

include those groups that one 1 to 6 carbon atoms \

finally have. ι

Examples of pharmaceutically acceptable salts of compounds I of the formula I are salts with inorganic acids, e.g. Hydro-I chlorides, hydrobromides, nitrates, sulfates, phosphates and der- | same or with organic acids such as acetates, propionates, |

I glycolates, malonates, maleates, succinates, fumarates, tartrates, * citrates, oxalates, benzoates, pamoates, methanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates and the like, where
these salts can be prepared by processes known per se, e.g. by adding the acid in question to the base,
preferably in a solvent.

According to the method of the invention, a compound the general formula

2
in which R is a protecting group for the amino group which can be easily removed with a reactive derivative of an acid of the formula R · COOH, where R has the stated meaning

2 has acylated, after which the protective group R is split off and the compound of the formula I is isolated as a free base or as a pharmaceutically acceptable acid addition salt will.

When R is an -NHR group, it has been found to be particularly advantageous proved to be an isocyanate as a reactive derivative

-1

of the formula R -N = C = O to be used.

2
Groups which can then easily be split off, such as alkyloxycarbonyl groups, are preferably used as the protective group R. Preferably, substitution with tertiary butyloxycarbonyl groups was used according to the method of Tarbell et al, in Proc.Nat.Acad.Sei., Vol. 69 (3), p. 730, 1972.

The N-acylation according to the process of the invention is carried out in the usual manner in an organic solvent at reflux temperatures.

Some of the starting materials of the formula II are expediently prepared by reacting 4,5,6,7-tetrahydroisoxazolo [5,4-cjpyridin-3-ol (hereinafter abbreviated as THIP) with a dialkyl dicarbonate, preferably made ditertiary butyl dicarbonate. After acylation according to the invention '

2
the protective group R is optionally under mild conditions

·.: - ·.: 3H5473

conditions such as controlled hydrolysis.

2 carbonyl

when R is a tertiary-butylox group, it can conveniently by reaction with anhydrous trifluoroacetic acid
be removed at about 0 ^{0 C.}

The method of the invention is carried out by the following
Working examples explained, which, however, are not intended to be limiting.

example 1

3-hydroxy-6- (t-butyloxycarbonyl) -4,5,6,7-tetrahydroisoxazolo
[5,4-cJpyrldiri (t-BOC THIP).

There were 11.1 g of THIP χ HBr in 50 cm ^{5 of} dioxane and 25 cm ⁵
Suspended in water. By adding 4.0 g of NaOH in 25 cm
A clear solution was obtained with water while cooling with ice.
11.0 g of di-t-butyl dicarbonate were then added and
let the temperature rise to 25 ^{0 C.} The mixture
was stirred vigorously for a further 1.5 hours. After that were
300 cm ^{5 of} ethyl acetate and 100 cm of water were added and the
pH of the aqueous solution to ~ 3.0 with a

Solution discontinued. The Äthylacetal.phase was separated i-

and washed with 2 × 25 cnr water, over anhydrous ■ '[

Magnesium sulfate dried and the solvent removed. ₅

evaporated leaving 11.8 g (98 %) of product. ,

M.p. 134-136 ° C, IR (KBr): ^ 2400-3200 (broad, complex * |

Bands), "V _nn 1690 cm" ¹ . . -.i

BeisiJel 2 ■: l

j = ^

r Ί ^] '\

2-Benzoyl-4,5,6,7-tetrahydroisoxazolo [5,4-cJ pyridin-2-one J

and its oxalate. "; j.

There were 2.4 g of butyloxycarbonyl-THIP with 2.5 g of benzoin . ')

Acid anhydride in 40 cm ⁵ CHCl, 13 hours under reflux- ^ f

conditions heated. The organic solution was with ice fi

3 chilled 0.1 m potassium carbonate solution: (2 × 25 cm) washed,

η- ο * f "Y * o CK QP * fc

Evaporated off over anhydrous magnesium sulphate; / and the chloroform. The remaining oil was dissolved in 20 cnr of a mixture of ether and η-hexane in a ratio of 1: 1. After stirring and cooling for a while, 2-benzoyl-6- (t-butyloxycarbonyl) -4,5,6,7-tetrahydroisoxazolo i5,4-cjpyridin-3-one precipitated, yield: 1.3 g (38% ). F. 126-128 ⁰ C.

This product was added to 10 cm ^{5 of} ice-cold anhydrous trifluoric acid. The mixture was stirred until the evolution of carbon dioxide had ceased, excess trifluoroacetic acid was evaporated and the resulting oil was dissolved in a few cubic centimeters of dead acetone. 2 g of anhydrous oxalic acid in 10 cm of dry acetone were added. With stirring and cooling, the oxalate of 2-benzoyl-4,5,6,7-tetrahydroisoxazolof5,4-cJ-3-one precipitated. Yield: 89 %. F. 210-213 ⁰ C (decomposition). (Found: C 53.22; H 4.45; N 8.08; _{calculated for C 15} H ₁₄ N ₂ O: C 53.89; H 4.23; N 8.38 %).

Example 3

2-acetyl-4,5,6,7-tetrahydroisoxazolo | _5,4-c) pyridin-3-one and its oxalate.

7.2 g of t-butyloxycarbonyl-THIP were heated under reflux conditions with 5.0 g of acetic anhydride in 50 cm of chloroform for 2 hours. 2-Acetyl-6- (t-butyloxycarbonyl) -4,5,6,7-tetrahydroisoxazolo [5,4-cJpyridin-3-one was obtained as an oil in a yield of 6.4 g (76 %) by column chromatography ( isolated on silica gel 60 "Merck") after elution with a mixture of ether and CH ₂ Cl ₂ in a ratio of 1: 3. The t-butyloxycarbonyl group was split off as in Example 2, 73 % of the oxalate being obtained. F. 177-178 ⁰ C (decomposition) (Found: C 44.32; H 4.70; N 10.58; H ^ _1n C for _{0 0} N O ₇ Calculated: C 44.12; H 4.45; N 10.29 %).

WPP ■■ * "t'i ar. *». ¹ "* '

. . . ■. 3U5473

Example 4

2-isobutyryl-4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-one
and de ss en oxalate.

The intermediate, 2-isobutyryl-6- (t-butyloxycarbonyl) - i

4p5, .6,7-tetrahydroisoxazolo ^ 5,4-c] pyr: ÜLn-3-one was according to,

Example 3 prepared and isolated in a yield of [

82 %. 118-119 ° C. The t-butyloxycarbonyl group was according to; Example 2 split off and there were 94 % yield of the oxa

get lats. F. 174-176 ⁰ C (decomposition) (Found: C 47.72;?

H 5.50; N 9.45; for C ₁₂ H ₁₆ N ₂ O ₇ calcd C 47.99; H 5.38; \

N 9.33 %). ·

Example 5 *

■. .- ■. i

2-carbemoyl-4,5,6,7-tetrahydroisoxazolo ^ 5,4-c \ pyridin-3-one |

ynä its oxalate. |

To a suspension of "-5.2 g of potassium uracyanate in 50 cm of CH ₀ Cl->

was added a solution of 4.0 g of trifluoroacetic acid in 50 cnr \

CH ₂ Cl ₂ at O ⁰ C added. 4.8 g * |. Were slowly obtained with cooling

t-Butyloxycarbonyl-THIP, dissolved in 100 cm ⁵ CH ₃ Cl _{2, was} added. f

The mixture was further allowed to stand at room temperature for 0.5 hour

stirs. The entire reaction mixture became the column chroma |

Subjected tography without CH ₂ Cl _{2 being} evaporated. It "|

were with 10 % methanol in ether 4.6 g (81 96) 2-carbamoyl- |

6- (t-butyloxycarbonyl) ~ 4,5,6,7-tetrahydroisoxazolo [_5,4-c ^ ■ t

pyridin-3-one eluted. Yield: 4.6 g (81%). F. 139-131 ⁰ CI

The t-butyloxycarbonyl group is removed according to Example 2 cleave, yield: 87% of the oxalate. F. 209-210 ⁰ C (decomposition) (Found: C 39.48; H 4.24; N 15.31; for C ₉ H ₁₁ N ₃ O ₇
calculated: C 39.56; H 4.07; N 15.38 %).

Example 6

2- (N-methylcarbamoyl) -4 ₉ 5,6,7-tetrijhydroisoxa '/: olo ^ 5, ^/ 4-c ^
pyridin-3-one and its oxalate.

Ea were heated lußbedingungen 4.8 g t-butyloxycarbonyl-THIP with 3.0 g of methyl isocyanate in 50 cm ^ CH ₂ Cl ₂ 1.5 hours unterjRückf. The solvent was evaporated. The remaining solid substance was stirred with cold isopropyl ether, whereby 5.4 g (91 %) of 2- (N ~ methylcarbamoyl) -6- (t-butyloxycarbonyl) -4,5,6,7-tetrahyroisoxazolo [5,4-cJ -pyridin-3-one of m.p. 134-135 ° C. The t-butyloxycarbonyl group was split off according to Example 2, after which 90 % of the oxalate were obtained. M.p. 168-169 ° C (decomposition) (Found: C 41.60; H 4.74; N 14.43; _{calcd for C 10} H ₁₃ N ₃ O ₇ : C 41.81; H 4.57; N. 14.63%). '

Example 7

2 ~ (N-C. Cyclohexylcarbaraoyl) -4,5,6,7-tetrahydroisoxazolo | 5,4-cjpyridin-3-one and its oxalate.

3.6 g of t-loxycarbonyl.-ΐΗΙΡ with 1.9 g of cyclohexyl isocyanate in 50 cm · ⁵ CH ₂ Cl _{2 were} heated under reflux conditions for 2 hours. Most of the CH ₂ Cl ₂ was evaporated and the addition of η-hexane precipitated 2-N-cyclohexylcarbamoyl) -6- (t-butyloxycarbonyl) -4,5,6,7-tetrahydroi soxazolo [5,4-c] pyridin-3-one. Yield: 4.8 g (88%). F. 92-94 ⁰ C. The t-butyloxycarbonyl group was cleaved as described in Example 2, whereby 87% of the oxalate was obtained. M.p. 204-205 ° C (decomposition) (Found: C 50.53; H 6.17; N 11.45; calcd for C ₁₅ H ₂₁ N ₃ O ₇ : C 50.69; H 5.97; N. 11.83%).

Example 8

2- (N-Phenylcarbamoyl) 4,5,6,7-tetrahydroisoxazolo | 5,4-cJ pyridin-3-one and its oxalate.

4.8 g of t-butyloxycarbonyl-THIP, 2.1 g of triethylamine and 2.5 g of phenyl isocyanate in 50 cm x ^{5 of} dry tetrahydrofuran were heated under reflux conditions for 1.5 hours. The volatile material was evaporated and the remaining oil was gelc'-t ^{in 100 cm 5 of ether.} 2- (N-phenyl-

3U5A73

ear'bamoyl ("6 - (t'-butyloxycar'bonyl)" ^, 5,6,7-tetrahydroisoxa g © I © jJ5,4 "G | pyrldin"-;3'-Qn from. Yield: 4 , 9 g (68 %). F ₈ 152-154 ⁶ C.

The t-butyloxyearbonyl group was split off according to Example 2 and gave a 90% yield of the oxalate. F. 214-218 ⁰ C (decomposition) (Found: C 52.02; H 4.40; N 12.01; for C ₁₅ H ₁₅ N ₅ O ₇ calculated C 51.57}; H U, 6h; N 12.05%).

The compounds of formula I were standardized according to reliable test methods, which are described below,

Male mice, 20-25 g
Isoniazid 300 mg / kg subcutaneously
Macrolon cages type II

The test compound is injected intraperetally in doses of 0, 1/2, 1/8 and 1/32 of the intravenously determined LD ₅₀ ,

Dosage: and procedure I

In the case of insoluble substances / the dosages O, 1/4, 1/16 and 1/64 of the intraperetonally determined dosages LD ^ q used.

Five mice were sacrificed for each dose.

Immediately after the administration of the test substances were 300 mg / kg isonlacldl injected subcutaneously. The isoniacid dose induced interrupted tonic clonic convulsions within 60 minutes.

The calculations were carried out using the direct method, "on line "at the terminal of a data processing system. The results were given as the percentage increase in time during the listing of the cramps and in addition the last dose that shows a significant effect was calculated (MED «minimal effective dose), calculated using the Van der Waerden test.

The EP [-q is determined as that dose in mg / kg which allows this time to increase by 50 % .

Grid shock test in mice

Male mice, 20-23 g. '

The mouse grid consists of a cage made of unbreakable plastic glass with a bottom made of wire mesh and a lid from the plastic glass, on which a microphone is attached, which is sensitive to the frequency of mouse screams “A stimulator using a motorized potentiometer brings a sequence of square wave pulses with continuously increasing Current strength (in milliamperes) on the grid. The frequency of the impulses is 20 cycles / sec. for a period of 5 milliseconds. The current in milliamps is shown on a digital ammeter that is connected to the stimulator is. Activating the microphone by screaming a mouse cuts off the current strength and the last current strength appears on the milliampeter.

J. .. -. ■ 3U5473
. / 3 -

Dosage and procedure

The test substance is administered intraperetonially in the dosages
1/2, 1/4 and 1/8 of the intravenously determined LDr _{0 were} administered.
In the case of insoluble substances, the dosages are 1/4, 1/8
and 1/16 of the intraperitoneally determined LD, _ ₀ used.
5 mice are needed for each dose. Each corn serves
as your own control.

Before the administration of the test substance, the animals
(one at a time) placed on the grid and the
Pain threshold is determined by increasing the intensity of the;.

Amperage determined until the mouse screams. The pain threshold
can be read on the milliampane meter.

15 minutes and 30 minutes after the administration of the test substance, the mice are tested again and the pain; threshold measured. In addition, the test substance can be tested after oral administration in doses 1, 1/2 and 1/4 ^ of the intravenously determined LDc ₀ and the pain threshold is determined before and 30 minutes after administration. \ Insoluble test substances are administered orally at doses 2.1, '1/4 and 1/8 of the intraperetonial certain LD ^ tested _0th

The analgesic effect 1st present when the pain '■

threshold above the value before dosing (control value). ^

is increased. The results are expressed as a percentage increase ^

the pain threshold, calculated on the basis of the * j

Control value. You can also register directly on the ^:

Data processing system ("on line") take place. In this case s

wgsxten the punch card instructions / and the punch cards themselves auto-! ' automatically generated and the results are recorded as the minimum effective dose (MED) according to the van der Waerden X-test.

3 *

Determination of the binding of H-GABA to the brain membrane of the ■; Rats

^:: '■■ * ■ -3U5473 A-

Rats weighing 125 - 200 g

0.32 m sucrose (freshly prepared daily) 10 % Triton X-100

0.05 n-Tris-citrate buffer (pH 6.8)

6.05 g Trisma ^ ^R '(base)

3.502 g citric acid. ^ O to 1 liter of water

H-GABA β aminobutyric acid, γ-2, · 3-H (N) (approx.).

35 Ci / mmol (New England Nuclear) (diluted to 1 µM with water daily).

Procedure A. Preparation of the membrane

Rats were killed by a blow to the head, bleeded to death, and the brains removed and placed in freezing cold Chilled saline solution. After rinsing and weighing, two brains were homogenized together in an ice-cold 40 cm 0.32M sucrose solution using a motorized homogenizer and pestle Made of Teflon (6 movements up and down, rotation at slow speed).

The samples were centrifuged for 10 minutes at 900 g and then the supernatants for 20 minutes centrifuged at 17,000 g (4 ° C). To each received

■ χ

Pellet were added to 20 cm 'of water and the samples were homogenized for 30 seconds (Ultra Turrax). After adding the samples were centrifuged for 23 minutes at 8,500 g (4 ° C.) from a further 10 cnr water. 2/3 of the supernatant fluids were discarded and the light brown top of the pellet was whirled up by hand. This protruding Liquid was centrifuged at 37,500 g (4 ° C.) for 30 minutes. The pellet was homogenized in 10 cm of water for 1 minute (Ultra Turrax). The sample was divided into 2 glasses and an additional 25 cnr of water was added to each sample

given. Each glass now contained membranes of a brain in 30 cm of water, these samples are centrifuged for 30 minutes at 37 500 g (4 ⁰ C) and the pellets subsequently frozen in acetone / COp, stoppered and (stored frozen until ready to use at least about Night).

B »Pretreatment of the membrane

On the day on which the measurements are carried out, the pellet is frozen in acetone / dry ice for 20 minutes and 25 cm- ^{5 of} water are added for 1 minute before homogenization (Ultra Turrax). 25 cm of a 0.05 n Tris citrate buffer solution and 0.250 cm ^ of a 10% solution of a surfactant Triton X-100 are added and the sample is ^{incubated for 30 minutes at 37 °} C. and then at 37,500 g for 20 minutes (4 ⁰ C) centrifuged. The supernatant liquid is discarded and the pellet is suspended in 0.05 n-Tris-citrate buffer solution (75 seconds in the Ultra Turrax) up to a concentration of 30 mg original wet weight per cm. The suspension is left to stand for 20 minutes at room temperature and then stored on ice.

C. Test of cohesiveness

780 mm of water, 200 mm of the drug dissolved in water, 20 mm of a solution of 1 μmol HG ⁷ ABA (final concentration of H-GABA in the tube = 10 nmol) and 1000 mm of the membrane suspension are placed in 2 incubation tubes on ice

Samples filled. After incubating for 5 minutes on ice, the / are centrifuged at 31,000 g for 18 minutes. The supernatant liquid is discarded and the pellet is carefully rinsed with 3 × 5 cm ice-cold water. Excess water is carefully wiped off with soft paper. 1 cm of Soluene350 is added and the samples are incubated for 30 minutes at 37 ° C. 10 cm Instagel or Lumagel with a content of 10 cm ⁵ acetic acid per liter are added and

> - * «■ - '; ■ ': "' - ^.: 3H5473

the radioactivity is measured by a liquid scintillation counter measured. The non-specific binding of H-GABA is determined by incubating the samples with 1 mmol of GABA.

Each series of measurements consists of 8 double measurements (1 comparison measurement, 1 sample with 1 mmol GABA and 1 to 2 series of test compounds in 3 to 6 concentrations).

The mean values of controls and samples with 1 mmol GABA were calculated. The measured cpm values were plotted against the drug concentration on semi-logistic paper and the best fitting S-shaped curve was drawn. The IC ₅₀ values were determined as those concentrations at which the binding was 50 % of the total binding minus the non-specific binding.

The results obtained are listed in the following Table I, the test substances by the number of the example, which describe the production of the respective substance.

The corresponding test values for THIP are given as a comparison value.

Table I.

test THIP 2 IsonLa2ld- l ^v luuiii / ,. i iter- ^ H-CJAIiA bond IC ^ _n substance 3 Antagoniiiuiua bchock example 2.0 Il 5 weaker Pure 6th effect effect If 7th 5.8 1.9 Il 1.3 2.7. Il 2.1 A, 3 - 1.3 + ■ 1.7 . "id-? > Vo- ⁴ 10 ~ ⁷ ΙΟ " ⁶ 10 ~ ⁷ 10 " ⁷

The compounds of formula I and the non-toxic acid addition salts These compounds can be animals such as dogs, cats, horses, sheep or the like including humans both orally and parenterally administered and can

': & ' ■ '-' ■
.. _; . ■. -T- ^ g * .- ο 14 ί3 η / ο

for example in the form of tablets, capsules, powders, syrups or in the form of the usual sterile solutions ?: | c / can be used for injections. Results after £ - · '/ its application in humans was ^ very promising.

Most expediently, the compounds of the formula I are administered orally in dosage units such as tablets or capsules, each dosage containing a non-toxic addition salt of one of the compounds with an acid in an amount of about 5 to 10 mg, but most preferably of about 10 to 10 mg mg calculated as free amine, the total daily dose usually ranging from about 20 to about 200 mg. The exact individual dosages as well as the daily dosages in special cases are of course determined according to proven medical principles under the guidance of a doctor.

When making tablets, the active ingredient is usually mixed with common adjuvants such as corn starch, potato starch, Talc, magnesium stearate, gelatin, lactose, guanaene or the like mixed.

When the compound of formula 1 in the form of the free amine is present, preferably K is a higher alkyl group having 8 to 17 carbon atoms, inclusive, wherein the feed, preparation, preferably in the form ei animal oily solution for injections is present and such solutions often have a very prolonged effect compared to the corresponding non-esterified bond.

Typical examples of formulations for drugs that 2-carb ""> & - 4 £, 6> 7-tetrahydrolsoxazolo [5, VcJpyridin-3-one (abbreviated Lu 18-028) as an active ingredient are the following:

1 "Tablets with 10 mg Lu 18-028, calculated as the free base in the form of the Qxalat:

Lu 18-Q? 8: 10 mg

'■ Lactose: Yl mg

. Potato starch: Ik mg
Gelatin: 2 mg

: "■ Talc: 8 mg

Z. capsules containing per capsule:

Lu 18-028; t: Ao mg Lactose: O. mg Magnesium steara b mg

Any other pharmaceutical UiJisuimittel for tabietierung. can be used provided that these Substances containing the active ingredient are compatible, and additional preparations and dosage forms may be similar to those currently used for neuroleptics such as thiolilxene, Clopenthixol or Flupenthlxol, are in use. Even Combinations of the compounds of formula I and their non-toxic acid addition salts with other active ingredients, especially other neuroleptics, thymoleptics, sedatives Or the like fall within the scope of the crisis.

As mentioned earlier this is important when isolating the connections of formula i in the form of an acid addition salt, the acid preferably selected such that it contains an anion, that is non-toxic and pharmacologically harmless, at least in ordinary therapeutic dosages. Representative salts included in this preferred group are hydrochlorides, hydrobroinides, sulfates, Acetates, phosphates, nitrates, methanesulfonates, ethanesulfonates, Lactate, Citrate, Tartral or Bitartrate, Embonate and Maleates of the amines of Formula I. Other acids are also suitable and can be used if necessary. Examples these are: fumaric acid, benzoic acid, ascorbic acid, succinic acid, salicylic acid, bismethylene-salicylic acid, propionic acid, Gluconic acid, malic acid, malonic acid, mandelic acid,

Cinnamic acid / stearic acid, palmitic acid, itaconic acid, glycol-citraconic acid

acid, benzenesulfonic acid and sulfamic acids which can also be used as salt-forming acids for the addition salts. If it is desired to isolate a compound according to the invention in the form of the free bases, this can be done by conventional procedures, such as by dissolving the isolated or non-isolated salt in water, treating with a suitable alkaline material, extracting the released free lens with a suitable organic solvent, drying the extract and evaporating to dryness or fractional distillation to isolate the free basic amine.

The invention also encompasses a method of alleviating, relieving, alleviating or inhibiting the manifestations certain physiological-psychological abnormalities of Animals by administering a compound to a living animal, including man, in an appropriate amount of the formula I or a non-toxic acid addition salt thereof. A reasonable amount would be around 0.5 nag to about 20 mg / body weight per day from about 20 mg to be about 200 mg per day for oral administration.

The invention is not limited to the precise details of the manufacturing process or limited to the exact compound or preparations according to the examples. Obvious Changes and equivalents are apparent to the kachmann.

Claims (4)

.., -. ο I 4 ο '4 / J patent claims ~ Ί 1. 2-Substituted 4, '>, 6,7-Tetrahydroisoxazolo 5,4 - cj pyridin-3-one compounds of the general B formula in which R is a branched or unbranched alkyl group with 1 to 17 carbon atoms including, a phenyl group, which possibly with 1 or? Groups, selected from lower alkyl groups, lower Al.koxytfruppen and halogen atoms is substituted, a pheny1 alkyl group, a lower alkyloxy group or a group -NHR, in which R is hydrogen, a lower alkyl] -, phenyl- or cyclohexyl group, and their pharmaceutically acceptable acid addition salts. 2. Process for the preparation of compounds of the formula I * according to claim 1, as well as their | iurm; izeutisch harmless salts, thereby geke η η ζ e ί ο h π et that *>'- one is a compound of a'l l / ;, Hine ί ni * ri formula in which R is a protecting group for the amino group, the can be easily removed with a reactive derivative of an acid of the formula R.COOH, in which H has the meaning mentioned has, implemented and then split off the protective group IC and the compound of formula I in the form of a free base or in the form of a pharmaceutically acceptable acid addition salt isolated. 3. Medicaments containing as active ingredient a compound of the general formula I according to claim 1 or a pharmaceutically acceptable salt daw, together with a conventional pharmaceutical carrier or excipient. 4 .. Drugs according to claim% thereby g ekennze I think it also contains a small amount of a tranquillizer or neuroleptic.