DE2062620A1 - Optical isomers and processes for their cleavage - Google Patents

Description

The present invention relates to a process for the resolution of racemic 2- (o-chlorophenyl) -2-methylaminocyclohexanone, the optical isomer of 2- (o-chlorophenyl) -2-methylaminocyclohexanone, which is levorotatory in ethanol, and the non-toxic, pharmaceutically acceptable salts thereof.

According to the present invention, racemic 2- (o-chlorophenyl) -2-methylaminocyolohexanone is used (Ketamine) cleaved using tartaric acid, producing an optical isomer is that as a base in ethanol levorotatory and as the hydrochloride salt is clockwise in water. It has been found that this isomer is present in various animal species as well as in

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ι People have improved anesthetic and anticonvulsant activity.

Bacemic 2- (o-chlorophenyl) ~ 2-niethylaiQinocyclohexanone (Ketamine) and its hydrochloride salt and related compounds are described in U.S. Patent 3,254,124.

ι Ketamine has the following structural formula:

Cl

* the so-called carbon atom is asymmetric.

The activities of ketamine hydrochloride on the central nervous system and in particular its anesthetic activity in various animal species has been described by D ₈ A. McCarthy, Gr. Chen, JD ₀ H ₉ Kaump and O. Ensor in J. Hew Drugs, 5,11 (1965). The good analgesic and anesthetic activity has been confirmed in initial clinical investigations (cf., E ₈ S ¹ * Domino, P ₉ Chodoff and G. Corssen, Clin. Pharmacol. Ther., 6, 279 (1965)). The main disadvantage of ketamine hydrochloride as an injectable anesthetic is its occasional adverse psychological effects. This is shown by the fact that the patient goes through a lively phase of space with or without psychomotor activity when he wakes up from anesthesia, which manifests itself in confusion and unreasonable behavior.

The splitting of ketamine has not yet been described «, While, in general, optical isomers are the same

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physicochemical properties (with the exception of their Dre hung of plane-polarized light), their "biological activities" might be expected to be different however, a racemate with many activities cannot do that biological activity can be predicted, which is assigned to the respective optical isomers.

According to the invention, a method for the cleavage of racemic 2- (o-chlorophenyl) -2-methylaminocyclohexanone with the structural formula

wherein * means an asymmetric carbon atom, created, which is characterized in that one is an enantiomorph The form of tartaric acid is added to a solution of the racemic 2- (o-chlorophenyl) -2-methylaminoeyclohexanone the tartaric acid salt of 2- (o-chlorophenyl) -2-methylaminocyclohexanone to form, and then an isomer of 2- (o-chlorophenyl) -2-methylaminocyclohexanone isolated.

The present invention also relates to the optical isomer of 2- (o-chlorophenyl) -2-methylaminocyclohexanone.

solid, Preferred embodiments of the present invention are / essentially pure 2- (o-chlorophenyl) -2-methylaminocyclohexanone with a negative [a} jj greater than 50 ° at a concentration of 2.00 g / 100 ml in ethanol and solid, essentially pure 2- (o-Chlorphejiyl) -2-methylaminocyclohexanone hydrochloride with a positive [a] _D greater than 91 ° "

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a concentration of 2.00 g / 100 ml in water.

The pharmaceutically acceptable non-toxic salts include the organic and inorganic acid addition salts, "For example, from acids such as hydrochloric acid, sulfuric acid, sulfamic acid, tartaric acid, fumaric acid, hydrogen bromide acid, glycolic acid, citric acid, maleic acid, Phosphoric acid, succinic acid, acetic acid, nitric acid and the like can be produced.

The compounds according to the invention and especially the very Water-soluble hydrochloride are used in animals and in particular Used in humans as aqueous solutions, for example the equivalent of 5, 10 or 50 mg of the free Base per ml included. Such solutions can also contain a preservative, for example ΙϊΙΟ 000 benzethonium chloride, may be made isotonic with sodium chloride and, if necessary, to a slightly acidic pH, for example 3.5 to 5.5j can be set.

To induce surgical anesthesia for a short period of time such as 5 to 25 minutes, an intravenous dose of about 1 to 2 mg / kg or an intramuscular dose of about 5 to 15 mg / kg is used. When a longer effect is desired , including periods of 6 hours or more, additional portions may be given to supplement the anesthesia maintain.

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Ketamine is split as follows: Q I ü

H OH *

• (+) - tartaric acid + mother liquor

HaOH

! (3) ⁰¹

: counterclockwise in ethanol

(+) * and $ 44> Racemate [-) - tartaric acid

H _n OH ₃

W ■

• KOI

(-) - tartaric acid

(6)

BI-2706, clockwise in _{water H x} JDH,

NaOH

clockwise in ethanol 0

BL-2705, counter-clockwise in What Bar una AtKa

HOl

Hol

anol

109829/1324 ORIGINAL INSPECTED

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The treatment of 'ketamine (1) with (*) - tartaric acid gives the (+) - ¥ one acid salt of (")" - 2 - (o-chlorophenyl) -2-nietliylaiDino ~ cyclohexanone (2) _o The decomposition of this diastereoisomer Salt (2) with sodium hydroxide gives the free base (3) which is converted to its hydrochloride salt BL-27Q6 (5) for testing.

Similarly, Bl-2705 (8) is carried from mother liquors, formation of a diastereoisomeric salt with (-) - tartaric acid iso "'lines. Alternatively, it can be expected that the treatment of ketamine with (-) - tartaric acid led to the preferential crystallization of (-) - tartaric acid, salt of (+) ~ 2- (o-chlorophenyl) -2 ~ methylamino- ι cyclohexanone (β)

When they are converted into their respective hydrochlorides, the sense of rolation of the free bases (3) and (7) »therefore changes the prefixes (+) and (-) should only be used with the full lamen to avoid confusion «,

Preliminary pharmacological results indicate that BL-2706 in different tests using different animal species the more effective optical isomer is «, This makes the process particularly interesting in that the more potent isomer is isolated using a readily available cleavage agent (natural tartaric acid) which is itself a non-toxic, pharmaceutically acceptable substance. It can thus in an essentially one-step process, the more effective isomer im Ketamine can be isolated in a suitable form »

The ease with which the cleavage of ketamine is accomplished is extremely surprising. If you look at the previous unsuccessful attempts at this split

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contemplates involving the following cleavage agents have been used:

(1) 1-a-Bromocampfer-V -sulfonic acid,

(2) d-camphor acid,

(3) d-10 camphor sulfonic acid,

(4) (+) - 5-Cyolohexyl-l-indanecarboxylic acid,

(5)! -Mandelic acid,

(6) 1-malic acid,

(7) l ^ -pyrrolidone-S-carboxylic acid, (B) 1-quininic acid,

(9) (2R: 3R) -2'-bromo tartaranilic acid,

(10) (2R: 3R) -4 ^t -Bromo-tartaranilinic acid monohydrate,

(11) (2R: 3R) -2 * -Ohlorweinanilinic acid,

(12) (2R: 3R) -2 ^t -troweinanilic acid,

(13) (2R: 3R) -2 *, 4 ', 6 ^f -iDribromo-tartaric acid and

(14) (2R: 3R) -2 ^! , 4 ', ö'-IDrichlorotartaranilic acid.

Pharmacological results ;

Some detailed pharmacological comparisons of the anesthetic and anticonvulsant activities of (+) - 2- (o-chlorophenyl) -2-methylaminocyclohexanone hydrochloride (Ketamine «HOl), (+) - 2- (o-Chlorophenyl) -2-methylaminocyclohexanone hydrochloride (BL-2706) and (-) - 2- (o-Chlorophenyl) -2-methylaminocyclohexanone hydrochloride (BL-2705) if there are multiple idier types are as follows specified.

Preferred embodiments of the present invention are described below. The specified melting points are uncorrected. The temperatures are measured ^{in 0 O.}

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example 1

(+) - Tartaric acid salt of (-) - 2- (o-Glilorplienyl) -2-methylaminocyclOj hexanone (2) ' i

10.3 g (0.0686 mol) of (+) - tartaric acid are added to a solution of 16.3 g (0.0686 mol) of racemic 2- (o-chlorophenyl) -2-methylaminocyclohexanone in 200 ml of acetone The mixture is heated to boiling and then clarified at the boiling point by adding 13 ml of water. The hot solution is partially cooled and then inoculated with the (+) - tartaric acid salt of (-) - 2- (o-oleophenyl) -2-methylaminocyclohexanone (The seed crystals are obtained from a small preliminary experiment.) The mixture is allowed to cool slowly and then left to stand for 17.5 hours at 25 C. The colorless needles are collected and washed with cold acetone, giving 19.68 g of a mixture of Salts with a T? = 89 to 95 ⁰ O. Twice _: Total recrystallization from acetonitrile gives 10.4 g of the ■ (+) - tartaric acid salt of (-) - 2- (o-chlorophenyl) -2-methylaminocyclohexanone with a T? = 140 to 142 ⁰ C.

The acetone water and the first acetonitrile mother liquors are used for the eventual isolation of (+) - 2- (d-chlorophenyl) -2-methylaminocyclohexanone retained.

Example 2

(-) - 2-Co-0hlorphen.vl,) - 2-methylaminocyclohexanone (3)

4 g (+) - tartaric acid salt of (-) - 2- (o-chlorophenyl) -2-methylaminocyclohexanone are distributed between 150 ml of diethyl ether and 120 ml of 0.5N sodium hydroxide. The ethereal layer is washed with 60 ml of water and then with 60 ml of water saturated with sodium chloride and washed over sodium sulfate dried. The ethereal solution is concentrated to dryness,

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where 6.15 g of (-) - 2- (o-chlorophenyl) -2-met] iylaminocyclohexanone with a melting point of 109 to 118.5 ⁰ G with previous shrinkage and a [α ~ \ ψ = -50.30 ° ( . c = 2.00, ethanol] are obtained recrystallization from cyclohexane gives 5.16 g long colorless needles with an F = 120 to 122 ⁰ g, [a] |. ⁵ = -56.35 ° (c = 2.00 , Ethanol).

Example 3

(+) - 2- (o-Chlorophenyl) -2-methylaminocyclohexanone hydrochloride BL-2705 (5)

21.0 ml of 1.0N hydrochloric acid (0.021 mol) are added to a mixture of 4.93 g (0.0208 mol) of (-) - 2- (o-chlorophenyl) -2-me- | added thylaminocyclohexanone and 21 ml of water. The mixture is heated on a steam bath for 2 minutes until almost completely dissolved. 40 ml of ethanol are added to the warm mixture and the resulting solution is concentrated to dryness, with (+) - 2- (o-chlorophenyl) -2-methylaminocyclohexanone hydrochloride in the form of colorless crystals with a Έ = 265 to 266.5 ⁰ C (dec.) And an O] ^ ⁵ = + 91.88 ° (c = 2.00, water) remains. Recrystallization from ethanol gives 4.15 g of colorless needles with a

^ ⁵

Ϊ ¹ = 259 to 261 ⁰ C (dec.) And a water).

= + 92.48 ° (c = 2.00,

analysis

calculated: found:

Cl

56.95 6.25 25.86
56.70 6.47 26.00

5.11 5.10

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Example 4

(-) - Tartaric acid salt of (+) - 2- (o-chlorophenyl) -2 ™ methylamino c ycl ohexanone (6) ' l ^^^^^ - ^ - ^^ - ^^^^ --- ^ _______

The acetone-water and the first acetonitrile mother liquors from Example 1 are combined and concentrated to dryness, 15.6 g of a colorless foam remaining. The foam is partitioned between 250 ml of diethyl ether and 200 ml of 0.5NN atrium hydroxide. The ethereal layer is washed with 100 ml of water and then with 100 ml of water saturated with sodium chloride. The ethereal solution is dried over sodium sulphate, filtered and the filtrate is added dryness to yield 8.7 g of a partially digested mixture of bases having a F = 91 remains to 17O ⁰ C, where [+) - 2- (o-chlorophenyl) -2-methylaminocyelohexanon, [α] - = x ³ + 31.88 ° (c = 2.00, ethanol) is enriched.

S? »5 g (0.0367 mol) (-) - tartaric acid are added to a solution of 8.7 g (0.0367 mol) of this partially split mixture in 100 ml of acetone. The mixture is heated to the boil and then clarified at the boiling point by adding 65 ml of water. The solution is allowed to cool slowly and then ^{stored at 25 °} C. for 21 hours. The colorless crystals are collected, washed with cold acetone and dried, 12.43 g of the (-) - tartaric acid salt of (+) - 2- (o -Chlorophenyl) -2-methylaminocyclohexanones with an F = 143 to 148 C with partial melting at 96 ⁰ C result. Recrystallization "from acetonitrile gives 10.06 g of colorless crystals with an F = 144 to 148 ^° C.

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example

(+) - 2- (o-Chlorophenyl) -2-methylaminocyclohexanone (7)

In a manner similar to Example 2, 10.06 g of (-) - tartaric acid salt of (+) - 2- (o-chlorophenyl) -2-methylaminocyclohexanone (E = 144 "to 148 ⁰ O) are decomposed with aqueous sodium hydroxide and the free Base is extracted into ether. Upon removal of the ether, 5.82 g of (+) - 2- (o-chlorophenyl) -2-methylaminocyclohexanone with a P = 119 Ms 122 ^° C. and an [α] ,, · ^{3 result} = + 56.5 ° (c = 2.00, Ithanol), recrystallization from cyclohexane gives 5.42 g long colorless needles with an F = 120 to 122 ⁰ C and a 0Ip ⁵ = + 56.78 ° (c = 2 , 00, ethanol) *

Example 6

(-) - 2- (o-Chlorophenyl) -2-methylaminocyclohexanone hydrochloride 1 ΒΙ £ 7Ο5 (8) ; ___ i

In a manner similar to Example 3, 5.21 g of (+) - 2- (o-chlorophenyl) -2-methylaminocyclohexanone are treated with 1 equivalent of aqueous hydrochloric acid, whereby (-) - 2- (o-chlorophenyl) -2- methylaminocyclohexanone hydrochloride with a J = 265 to 266 ⁰ C (decomp.) and an O] ^ ⁵ = -92.18 °

(c = 2.00, WasserΧ recrystallization from ithanol gives 4.43 g of colorless needles having a i ¹ = 259-261 C (dec.) and [α] ^{2. 5} = -91.88 ° (c = 2, 00, water). / Surrender

Analysis C-, JELgClNO • HC1: 56
56 C. να vo H Cl VO O
CO VD 5
5 H calculated:
found : , 95
, 80 , 25
, 35 25,
25, , 11
, 17th

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Pharmacological studies

Some comparisons between the racemate of 2- (o-chlorophenyl) -2- (methylamino ^ cyclohexanon- j hydrochloride (ketamine), its dextrorotatory isomer (BL-2706) and its levorotatory isomer (BL-2705) passed through leads. ι

The main purpose of the investigation is to "determine whether there is a separation of the activities observed for ketamine between the two optical isomers.

materials

All doses given relate to the hydrochloride salt and not on the free base. The isomers BL-2705 and BL-2706 j are used as the solid hydrochloride and solutions in saline are prepared immediately before use.

.χ.

represents /. For convenience is in the following Tables the dextrorotatory hydrochloride in water is designated as BL-2706, while the less effective in water is levorotatory Isomer of ketamine hydrochloride is designated as BL-27Ö5.

The acute toxicity of the three compounds are determined in mice \ using different routes of administration.! The LD ^ ₀ values are determined using the method of Weil and groups of four animals. The results

are compiled in Table I.

j / *

■ 'All three compounds were freely soluble in water.

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T a b e lie I j, mg / kg path Zetamine HCl BI-2705 orally 539 625 intraperi-
toneal 213 263 intravenous 68 68

BI-2706 559

236

54

These toxicities are because of the small number of used (Eggs are not regarded as distinctly different ".

Anticonvulsant examinations

Two studies are carried out on mice. In the first investigation, the ED ™ will be in terms of each drug intended for protection against tonic extensor muscle spasms, induced by maximum electric shock. The electric shock is generated at 8 mA and lasts 0.5 seconds and is applied through corneal electrodes. The animals will Shocked 5 minutes after intravenous dosing. 10 animals per group are used and the values of the EDt-Q are determined by a log-probit diagram. The values the ED ™ for the three compounds with their normal errors are the following:

Ketamine wood: 2.85 + 0.37 mg / kg; BI-2705: 4.6 + 0.74 mg / kgj BI-2706: 2.25 + 0.43 mg / kg.

The second test is used to produce a tonic extension of the hind limbs of 50% Animals pretreated with various intravenous doses of the three compounds required electricity certainly. The electric shock lasts 0.5 seconds

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and is applied in the manner described above. It groups of 10 mice are used and the dose is given intravenously 5 minutes before shock. The value of the "Tonic Current ™" is determined by a log-probit diagram. The results of this study are shown in Table II. This investigation will also Sodium Diphenylhydant-oin Included To Show that the curves obtained with ketamine are for anticonvulsant Means are typical. The diphenylhydantoin is administered intraperitoneally 30 minutes before the shock. It is found that it is a critical one with ketamine HCl and BL-2706 Dose above which the anticonvulsant properties of the compounds increase markedly. The same is also the case with diphenylhydantoin. With the connection BL-2705 however, this pronounced increase does not occur and doses higher than 20 mg / kg intravenously may be toxic in terms of toxicity Not used. The 5 minute pre-dose time has been found to be critical as it has been shown has that the anticonvulsant activity decreases when the animals are left longer.

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Tabel

II

The current (mA) required to generate a
50 #igen tonic extension after administration
various drugs and postures

Drug / dose mg / kg

7.5

10

15th

20th

! ι Ul

Ketamine HCl iv 6.4 + 0.29 Bl-2705 iv 6.4 + 0.29 O
ίο BL-2706 iv 6.4 + 0.29 OO
NJ
CO Diphenylhydane
toin ip_ 6.4 + 0.29

9.3 + 0.72 - 34.4 + 4.8 106 + 14

8.0 + 0.52 - 12.6 + 1.4 - 19.4 + 4.7

10.8 ± 0.59 12.5 + 1.8 116 + 15

7.0 + 0.45 - 7.2 + 0.54 - 26.0 + 4.3 150 + 27

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Hypnotic effects in rats ■

In all three connections the intfaperitoneal do-; sis determined which causes the rats at 50 fo a loss of up \ righting reflex. The righting reflex is called
considered lost if a rat remains on its back for more than 10 seconds j. The intraperitoneal HD, - ₀ values
are the following:

Ketamine HCl: 50.4 mg / kgj BI-2705: 76.1 mg / kgj
BI-2706: 4.40 mg / kg (insufficient delivery). In contrast
to larger test animals produce all three compounds
in rats a general behavior profile that is more similar to that which results with classic anesthetics,
insofar as the animals are very relaxed with low muscle tone.

Anesthetic effect in cats

Three examinations are carried out. In the first study, three cats are cross-tested on consecutive days using a dose of
10 mg / kg im performed by each dose. Three times are recorded: The time from injection to loss
of the righting reflex (induction), the time from loss to! for the return of the righting reflex (anesthesia) and the: time from the return of the righting reflex to the
Time at which the animal stands on all four feet (recovery). The results of this experiment are shown in Table III
compiled.

16 -

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! EaI) el 1 e

III

Cross-over experiment with three cats using a dose of 10 mg / kg im. The time spans of the different levels are given in minutes

induction Ketamine HOl recreation Cat no. 3
9
2 anesthesia 8th
36
IO 472
476
481 50
24
32

Average

35

18th

induction BL-2705 BL-27O6 recreation Cat Mr. 7th anesthesia anesthesia 5 472 0 * 10 37 0 476 0 ** 0 29 14th 481 2 0 32 6th
- Average 3 33 induction recreation Cat kr, 5 15th 472 4th 40 476 4th 10 481 4th 22nd Average

* When this cat receives the product BL-2705, it is showing Extreme ataxia for 45 minutes, but still remains,

** This cat could after receiving. Bi> -2705 do not stand, however was never anesthetized,

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BATH

In a second investigation, "which is not one Cross-examination, each drug is administered at a dose of 10 mg / kg iv into the headache of four cats. In this experiment, induction was immediate and only two levels are recorded: The time from injection until the righting reflex returns (anesthesia) and the time from the return of the righting reflex to the time the animal stands on all four feet (Recreation). The results of this experiment are shown in Table IV.

25th Erho
lung T a b e 1 le IV recreation BI-27O6 15th 12th 15th Ketamine and
Time spans 4th Γ4 26th 13th Isomers in cats with
are given in minutes 7th 6th 6th 21st BIi-2705 10 27 Mean value 17 17th Anesthesia 13th Anesthetic recovery 15th Investigation of
IO mg / kg iv. the
ben 16 12th 8th 26th Ketamine HCl 10 15th Experi- anesthet.
ment 9 15th 1 8th 20th 2 10 19th 3 4th

In a third study, 6 cats (3 males and females) are used in a crossover experiment and 4 days are allowed to elapse between doses. It is verwendeb a dose of 20 mg / kg Lv of each compound, there are three levels recorded time at which the head is lifted from the bottom of the injection to the time (anesthesia 1), time of lifting of the head to au the time when the katae lifts her shoulders (anesthesia 2) and time from the lift

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/ 3

the shoulder to the point in time when the cat stands on all ■ four feet (recovery). The results of this study are summarized in Table Y.

Table V

Cross-examination with ketamine and Isomers -J-9 - recreation in cats with Σ 10 mg / kg iv. The time spans 8/11? : ■ if 26th are in minutes specified 37 Ketamine HCl 20th Cat no. Anesthesia 1 Anesthesia 2 36 - 471 20th 26th 6th 472 30th 42 16 476 14th 14th 23 I. 481 26th 50 479 37 69 Recovery i 482 32 * . 52 18th Average 26th 42 23 BL-2705 18th Cat no. Anesthesia 1 Anesthesia 2 15th 471 0 10 10 472 0 10 4th 476 4 ' 9 15th 481 0 0 479 11 21st recreation 482 15th 18th 25th Average VJl 11 45 BL-2706 55 Cat no. Anesthesia 1 Anesthesia 2 .8th 471 32 40 56 472 40 45 43. 476 29 34 39! 481 37 69 479 50 58 BATH ORIGINAL 482 32 45 Average 37 48 1098y

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* Cat # 482 has "respiratory inhibition when administering ketamine and is "artificially" ventilated for 2 minutes.

Salivation is observed in all cats, with the extent seems to correlate well with duration of anesthesia. Considerable muscle tone is always observed, most of all at the front legs. The cats' posture is similar to that observed after brain extension will. Anaigesia is only observed when anesthesia occurs. All of the reflexes examined are present throughout, with the exception of pupillary constriction in strong light. It Extreme mydriasis is always observed.

Anesthetic effect in monkeys

The effect of the three compounds is on plumb monkeys (Saimiri sciureus) examined. The monkeys are considered anesthetized considered if they can be put on their sides. The recovery level is assumed to be the point in time from which the animal rolls on its chest until it either stands or moves in a crouched position.

At a dose of 10 mg / kg im, none of the compounds produced anesthesia (loss of the righting reflex). the Monkeys that received ketamine or BL-2706 become extremely atactic, while those monkeys that received BL-2705 have become somewhat atactic.

Produced in four monkeys at a dose of 20 mg / kg im BL-2705 no anesthesia, however considerable ataxia is observed in all cases. The effects of ketamine and BL-2706 at a dose of 20 mg / kg im in a crossover study with 8 monkeys are given in! Table VI.

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Table VI

: Ketamine and BL-2706 , 20 mg / kg im induction anesthesia BL-2706 (intramus 2.5 popular) in monkeys 2.5 17.5 3.5 Ketamine HCl 3 14th 2 Monkey ur. 2.5 27.5 recreation 16.5 ^; 25th 2 6th 7.5 2.5 ! . 26th 3.5 26th 10.5 7th j 40 7.5 4th 1.5 6.5 '44 5.5 4.5 2 7.5 51 3 6.5 1 6th ι 39 3.5 13th 4.5 45 11 48 induction 2.5 Average 4th 5 3.5 J monkey Mr. 2.5 Anas the she recovery \ 23 1.5 28 : 26 £ 2 24.5 40 3 39.5 44 4.5 8.5 51 1.5 25.5 39 3 14th 45 14th 48 14th Average 21 ■

The difference between the mean duration of anesthesia with BI-2706 and ketamine is significant at ρ = 0.1.

In some monkeys, the ketamine or BL-2706 at a dose of 20 mg / kg im. received, salivation is observed.

The anesthetic potential of ketamine is difficult to assess in laboratory animals because it does not

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testifies to what is observed with common anesthetics. However In all experiments carried out, BL-2705 is less active than ketamine, while BL-2706 is more active than the Raeemat.

The results of the studies with cats and monkeys indicate that BL-2706 has a more consistent response can evoke than ketamine. In none of the studies performed is analgesia observed without anesthesia. All three connections result after intravenous or intramuscular Administering an extraordinarily smooth induction of anesthesia.

A dose of 10 mg / kg ketamine or BL-2706 in cats appears to be more active after intramuscular administration than after intravenous administration. No reason can be given to explain this phenomenon other than the fact that after intravenous administration the drug is more rapidly delivered to the liver and kidney for metabolism or excretion.

The recovery period from anesthesia is similar for all compounds and there is no significant relative duration Differences.

One of the "major problems with ketamine in humans is an occurrence of hallucinations during recovery, being natural there is no way of determining this in laboratory animals. However, it can be hypothesized that this is due to the less active isomer of ketamine (BL-2705), which only imperfectly fits receptors in the GNS, which can lead to mental disorders. This can only be studied in humans.

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K / 1137S fc. ²⁰⁶²⁶² °

It is concluded that there is no separation between the optical isomers of ketamine in terms of qualitative activity, but there is separation or a difference in effectiveness. The dextrorotatory isomer (BL-27O6) 'is considerably more potent than the levorotatory isomer (BL-2705) and somewhat more potent than the racemic mixture, as found in animals in the manner described above. The dextrorotatory isomer BL27O6 can produce clearer and more predictable anesthesia in humans than ketamine.

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109829/1824

Claims (1)

-wherein * denotes an asymmetric carbon atom, thereby characterized in that one enantiomorphic form of "tartaric acid to a solution of the racemic 2- (o-chlorophenyl) -, 2-methylaminocyclohexanones adds., The ¥ acid salt. des 2 - '(o-chlorophenyl) -2-methylaminocyclohexanone formed I is, and then an isomer of 2- (o-chlorophenyl,) -2-methylaminocyclohexanone isolated. 2. The method according to claim 1, characterized in that | one (+) - ¥ one acid to a solution of the racemic 2- {o-chloro-; phenyl) -2-methylaminocyclohexanones, where the | (+) - Tartaric acid salt of (-.) - 2- (o-Chlorophenyl) -2-methylaminocyclohexanone is formed ,, and then the optical isomer of 2- (o-chlorophenyl) -2-methylaminocyclohexanone iso- after one a where Smb vgMmsftm BAD ORIGfNAL 2 ° ⁶²⁶² ° 4. The method according to claim 3, characterized in that the decomposition is carried out in the presence of a strongly alkaline material. 5. The method according to claim 3 or 4, characterized that the gekennzeich- '■ net, 2- (o-chlorophenyl) -2-methylaminocyclohexanone hydrochloric acid are added, whereupon the hydrochloride salt is formed, which is dextrorotatory in water (-) -. 6. The method according to claim 2 or 3, characterized in that that the (+) -, tartaric acid salt of (-) - 2- (o-chlorophenyl) -2-methylaminocyclohexa-! nons washes in acetone and then subjected to recrystallization from acetonitrile before the isolation of the optical isomer. 7. The method according to claim 6, characterized in that in the washing process with acetone and in recrystallization resulting mother liquors with a strongly alkaline: see material treated, being a partially split mixture is obtained from bases wherein (+) - 2- (o-chlorophenyl) -2-; methylaminocyclohexanone is enriched. 8. The method according to claim 4 or 7, characterized in that the strongly alkaline material is sodium hydroxide. , 9. The method according to claim 7, characterized in that (-) - tartaric acid is added to the partially split mixture, where the (-) - tartaric acid salt of (+) - 2- (o-chlorophenyl) -2-methylaminocyclohexanone is formed, which after decomposition gives (+) - 2- (o-chlorophenyl) -2-methylaminocyclohexanone, which clockwise in ethanol. 10. The method according to claim 9 _r, characterized in that the (+) - 2- (o-chlorophenyl) -2-methylaminocyclohexanone chlorine - 25 - 109829/1824 M / 11378 H. hydrochloric acid is added, the hydrochloride salt being formed that is left-handed in water and ethanol. 11. Optical isomer of 2- (o-chlorophenyl) -2-methylaminocyclohexanone. 12. A compound according to claim 11 in the form of the levorotatory free base in ethanol. 13. Might-toxic, pharmaceutically acceptable acid addition salts of the compound according to claim 11, which in water: is clockwise. ' 14. The compound according to claim 11 as a solid, essentially pure 2- (o-chlorophenyl) -2-methylaminocyclohexanone with a negative [a] -n greater than 50 ° at a con— concentration of 2.00 g / 100 cnr in ethanol. ■ 15. Hydrochloride salt of the compound according to claim 14. i 16. The compound according to claim 11 as a solid, essentially pure 2- (o-chlorophenyl) -2-methylaminocyclohexa- i non-hydrochloride with a positive [ ⁰ Gj) greater than 91 ° at, a concentration of 2.0 g / 100 cm in water. , 17. A compound according to claim 11 in the form of that in ethanol clockwise free base. 18. Non-toxic, pharmaceutically acceptable acid addition salts the compound of claim 11 which is levorotatory in water. 19. Optically active isomer of 2 - (o-chlorophenyl) -2-methylaminocyclohexanone, isolated by means of a method according to claims 1 to 10. - 26 - 109.829 / 1824 "