RU860446C - Substituted n-adamantilanilines possessing psychostimulating activity - Google Patents

Description

3 New biologically active compounds substituted with M-adamantylaniline are provided. showing psychostimulant and anticaleptic activity. Various derivatives of adamantane are known to have psycho-stimulating activity, for example, 4-keto-adamantanecarboxylic acid amide having a pronounced immunostimulating activity with a simultaneous increase in physical performance. In addition, N- (2-adamantyl) aniline is known, which, along with psychostimulating properties, has significant toxicity. In medical practice, phenamine is used as a psychomotor stimulator, as well as midantan, which has an anti-cataleptic effect. The aim of the invention is to expand the arsenal of means of influencing a living organism, increasing physical performance, exhibiting anti-catleptic activity and having low toxicity. The goal is achieved by the new substituted N-adamantylaniline of the general formula H-HH-O-yts: where is H; R is CHa (1); Ri "R2 R3 R5-H; R4-OH (2); Ri-R2 R3 R5 is H; R4-OCH3 (3); Ri R3 R4 R5-H; R2-CI (4); Ri R2-R4 R5 is Hr Rs-CI (5); Ri R2 R3 R5-K; R4-CI (6); - H; R4-Br (, Ri R2 R4-R5-H; R3-N02 (8); Ri R2 R3 R5-H; R4-N03 (9); R2 R3-R4 R5-H, -Ri-OH (lO); R2-R3 R5-H; Ri-OH; R4-F (11); R2-R3 R5-H; Ri-CI; R4-F (12) .With psychostimulating and anticaleptic activity. The proposed compounds and their hydrochloride salts are they are white or colored crystalline substances soluble in alcohol or water.They are obtained in a known manner by reacting an appropriate ketone with formic acid and amine or with an formic acid salt of an amine when heated.In the proposed case, a mixture of 1 mol of adamantznoia, 2 mol of aroma amine and 2 mol of formic acid, boiling for 6-10 hours at a temperature of 130-180 ° C, and then for 1-2 hours with an excess of hydrochloric acid.The unreacted adamantanone is extracted with ether or benzene, the acidic aqueous layer is saturated with bicarbonate sodium and extracted with ether or benzene.The extract is dried with magnesium sulfate, the solvent is distilled off and the desired product is obtained in the form of a base. It should be noted that, when K | - (2-adamantyl) -p-bromaniline is isolated, after heating is completed, the cooled reaction mass is acidified with a strictly calculated amount of hydrochloric acid and the precipitates of the target product (they are filtered off as the base (p-bromaniline not reacted) taken in excess, remains in solution as salt) Example 1 Preparation of M- (2-Adamantyl) p-nitroaniline A mixture of 5.5 g (0.04 mol) of p-nitroaniline and 1.85 g 0.04 mol) of 99% formic acid is heated to 100 ° C and at this temperature 3 g (0.02 mol) of adamantane are added The reaction mixture is boiled for 10 hours at a temperature of 150-160 ° C, cooled, 16 ml of dilute hydrochloric acid are added and boiled for 2 hours. The acidic solution is extracted with ether, the aqueous layer is saturated with sodium bicarbonate and the amine base is extracted with ether. The extract was dried with magnesium sulfate, the solvent was distilled off, and 4.1 g of the expected product was obtained (yellow crystals), yield 76%, mp 180-181.5 ° C (from ethanol). Found.%: C 71.00; H 7.47; N10.36. Cl6H2QN202 Calculated.%: 070.56; H, 7.40; N, 10.28. PRI me R 2. Obtaining N- (2-adamantyl) p-anisidine. To a mixture of 9.85 g (0.08 mol) of p-anisidine and 3.68 g (0.08 mol) of 99% formic acid heated to 100 ° C, 6 g (0.04 mol) of adamantanone are added and boiled for 10 hours at a bath temperature of 150 -160 ° C. To the cooled reaction mass, 35 ml of dilute hydrochloric acid was added, boiled for 2 hours, cooled, the precipitate was filtered off and 6.5 g of Y- (2-adamantyl) -p-anisidine hydrochloride were obtained. yield 56%. so pl. 247-248 ° C (from ethanol). Found.%: SP2.87. Ci7H23NO.HCt, Calculated,%: C 12.41, The hydrochloride was dissolved in water, saturated with sodium bicarbonate and extracted with ether amine base, so pl. 106-107 ° C (60% ethanol). Found,%: C80.00; H, 8.93; N, 5.71. C17H23NO-HCI Calculated,%: C 79.33: H 9.01; N, 5.44. PRI me R 3. Obtaining f f ldlmantyl) g p-nitroaniline.

To a mixture of 5.5 g (0.04 mol) of p-nitroaniline and 1.85 g (0.04 mol) of formic acid, heated to 100 ° С, 3 g (0.02 mol) of 1 adamantdnone are added and boiled for 10 hours at a temperature of 150-160 ° C. 18 ml of diluted (1: 1) hydrochloric acid was added to the cooled mass, boiled for 2 hours, from the cooled solution, unreacted ketone was extracted with ether. The aqueous layer was saturated with sodium bicarbonate and extracted with ether, the extract was dried with magnesium sulfate, the solvent was distilled off, and 4 g of base were obtained (orange crystals), yield 74%, mp. 92-93 ° C (from ethanol),

Found,%: C 70.41, - H 7.27: N 10.40,

Cl6H20N202

Calculated,%: C 70.56: H 7.40: N 10.28.

PRI me R 4. Obtaining N- (1-hydroxy-4-adamantyl) aniline.

A mixture of 3 g (0.018 mol) of 1-hydroxy-4-adamantanone, 4.5 g (0.036 mol) of formanilide and 1.1 g (0.024 mol) of formic acid is boiled for 12 hours at a bath temperature, 10 ml of 10% are added. hydrochloric acid and boiled t 1 h ..

The reaction mixture is cooled and extracted with benzene unreacted ketone. The aqueous layer was saturated with sodium bicarbonate and extracted with chloroform, the chloroform extract was dried with magnesium sulfate, the solvent was evaporated, and 2.6 g (59%) of the desired amine were obtained, t. , 188-189 C (from ethanol).

Found,%: C 78.84: H 8.52: N5.75.

C16H21NO

Calculated,%: C 78.97: H 8.70: N 5.76.

Hydrochloride melts at 237-238 C (from ethanol) ..

Found6,%: C112.17.

Ci6H2iNO-HGI

Calculated,%: C1 12.66.

PRI me R 5. Obtaining N- (1-hydroxy-4-adamantyl) -p-fluoroaniline.

To a mixture of 4 g (0.036 mol) of p-fluoroaniline and 1.72 g (0.036 mol) of 99% formic acid heated to 100 ° C, 3 g (0.018 mol) of 1-rxi-4-adamantanone are added over 15 minutes and the mixture is boiled for 15 hours at a temperature of 150-160 ° C. After cooling, 10 ml of 10% hydrochloric acid are added to the reaction mass and boiled for 2 hours. The unreacted ketone is extracted with benzene (3x50 ml). The acidic aqueous solution was saturated with sodium bicarbonate and extracted with chloroform (8x30 ml). The extract was dried with magnesium sulfate and treated with charcoal. Chloroform was distilled off in vacuo to give 2.8 g (75%) of the amine base, mp 98-107 ° C (mixture of stereoisomers, from ethanol).

Found,%: N 5.60.

Ci6h2ono

Calculated,%; N, 5.36.

Hydrochloride melts at 221-223 ° C (from acetone).

Found,%: SP 1.25.

Ci6H2oNO-Ha

Calculated,%: C111.90.

Example 6, Preparation of N- {2-adamantyl) p-chloroaniline.

Knagretoido JO Smemeo 10.02 gSO, 08 mol) p-chloraniline and 3.68 g (0.08 mol) of 99% formic acid are added over 20 m | 47 (6 g (0.04 mol) of adamantanone and the mixture is boiled for 6 hours at a temperature of 150-160 C.

After cooling, 15 ml of 15% hydrochloric acid was added to the reaction mixture, boiled for 2 hours, the initial ketone was extracted with ether (3x50). The aqueous acidic solution was saturated with sodium bicarbonate and extracted with ether (4x80). The ether extract is dried with magnesium sulfate. The ether was distilled off in vacuo to give 7.28 g (70%) of the amine base, mp 82-83 ° C (from alcohol).

Found,%: C113.29.

Ci6H2oNCI

Calculated,%: C113.54.

PRI me R 7. Obtaining N- (2-adamantyl) p-chloroaniline.

A mixture of 10.02 g (0.08 mol) of p-chloroaniline and 3.68 g (0 mol) of 99% formic acid is heated to 100 ° C., at this temperature 6 g (0.04 mol) of adamantanone are added. and boiled for 6 hours at a temperature of 150-TbO C. After cooling, 15 ml of 10% hydrochloric acid were added to the reaction mixture and boiled for 2 hours. The precipitate formed after cooling was filtered off and washed twice with ether. The yield of hydrochloride was 8.1 g (77.8%), mp 195-196 C (from absolute ethanol).

Found,%: C123.32.

Ci6H2oNCr-HCI

Calculated,%: C123.77.

PRI me R 8, Obtaining N- (2-adamantyl) p-bromoaniline.

To a mixture of 13.7 g (0.08 mol) of p-bromoaniline and 3.68 g (0.08 mol) of 99% formic acid, 6 g (0.04 mol) of adamantanone was added and boiled for 6 hours at temperature 150 160 ° С. 15 ml of 15% hydrochloric acid were added to the cooled reaction mixture, boiled for 0.5 h., 9.6 g of N- {2-aAa-amantyl) -p-bromaniline base were cooled and filtered, yield 80%, t .pl. 100-102 ° C (absolute ethanol).

Found,%: C 62.91: And 6.51: N 4.65; Wh 26.11.

Ci6H2oBrN 786044 Calculated.%; C 62.75; H 6.58: N4.57; 8g 26.09. . PRI me R 9. Obtaining M- (1-chloro-4-adamantyl} -p-fluoroaniline. A mixture of 2.38 g (0.021 mol) p-fluoroaniline 5 "m 1.05 g (0.02 mol) 99 % formic acid is heated to 100 ° C. At this temperature, 2 g of 1-chloro-4-adamantione are added and boiled for 10 hours at a temperature of 150-160 ° C. After cooling, 10 ml are added to the reaction mass 10 % hydrochloric acid, boiled for 2 hours, the precipitate was filtered off, washed twice with zeter, the precipitate was dissolved in water, the solution was saturated with sodium bicarbonate and extracted with ether, the ether extract was dried with magnesium sulfate, the ether was distilled off, and 2.4 was obtained. g (8 0%) amine base; t.ri} iii83S5 ° C (from ethanol). Found.%; N 5.23.- F 7.14; О 15.53 .20 CieHigClNF Calculated,%: N 5.25; F 6.91; CI12.71 Hydrochloride melts at 221 222C (from absolute ethanol) Found D: C111.18.25 Ct9Hi9CI Calculated,%: C111.22 Example 10: Preparation of M- {2-adamantyl-p-minofendla .. Mixture 4.36 g (0.04 mRL) p-aminophenol 30 and 2 g (0.04 mol) of 99% formic acid are heated to 1 ° C ° C. At this temperature, 3 g (0.02 mol) of adamantanone are added and boiled for 6 hours at a temperature of 150 -160 ° C. After cooling, 15 ml of 1-5% hydrochloric acid was added to the reaction mixture35, boiled for 1.5 hours, cooled, the precipitate formed was filtered off, washed with ether W to obtain 4 g (80%) of chlorohydrate M- {2-adamantyl) -p -am1 / 1nophenol. After crystallization, 40 from ethanol mp. 275 ° C. 1- found.%: PPE, 03. C16H22CINO Calculated.%: CM2.67. PRI m 8 r 11. Obtaining M- (2-adaman-45 tyl) -o-chloroaniline. To a hot solution of 3.7 g (0.03 mol) of o-chloroaniline in 2.5 ml of 99% formic acid, 3 g (0.02 mol) of adamantanone are added and boiled at a temperature of 50-150 ° C for 5 hours. 10 ml of a 15% hydrochloric acid solution are added to the mass, boiled for 1 hour, unreacted adamantanone is extracted with ether, the aqueous layer is saturated with sodium bi-55 carbonate and the amine base is extracted with ether. The extract was dried with magnesium sulfate, the solvent was distilled off, and 3.2 g of the expected product were obtained, yield 62%, mp 114-115 ° C (absolute ethanol). 68 Found.%: Ct13.55. Ci6H2oCIN. Calculated,%: C1 13.64. PRI me R 12. Obtaining M- (2-adamantyl) -p-toluidine. A mixture of 4.3 g (0.04 mol) of p-toluidine. 2 ml of formic acid and 3 g (0.02 mol) of adamantano boiled for 4 hours at a temperature of 130-150 C. Concentrated hydrochloric acid was added to the solution, boiled for 1 hour and the unreacted adamantanone was extracted with ether. The acid layer was diluted with EODOi and the precipitated hydrochloric acid salt of M- (2-adamantyl-1-p-toluide, ina, yield g (90%). Mp 254-258 ° C (water). Found.%: СМ2.76, CnHzaN.HCI Calculated,%: C 12.80. The hydrochloric acid salt was suspended in water, alkalized with alkali and extracted with ether amine base, mp 48-49 ° C. Found.%: C 84.48; H 9.82 Ci7H23N A study of these compounds shows that they exhibit properties that discourage increased levels of physical performance, increased motor activity, and the elimination of triftazine catalepsy. Compounds of adamantylaniline containing halogen (compounds 4, 5, 6, and 7) have an influence on the level of physical performance. All of the most important compounds of this type of action are more active than the known phenamine and have a significantly greater breadth of therapeutic effect than phenamine These compounds also have a pronounced anti-cataleptic activity (according to the test of trifthazine catalepsy), 9-19 times higher than the activity of midantan (prototype), and 2-30 times less toxic. The most active of the claimed compounds is (2-adamantyl) -p-bromoaniline (bromantane). Bromactan has a pronounced psychostimulating activity, which is manifested in an increase in the level of physical performance, optimization of operant activity, and the elimination of the psycho-depressant effects of tranquilizers. This compound is 83 times less toxic than phenamine. According to the spruce nickname, this compound surpasses phenamine 84 times by the level of physical working capacity. Thus, the maximum increase in the swimming time of mice with the introduction of phenamine is 54% compared with the initial

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level, and after administration of bromantane solution) obtained on the same day. 210% Approved for clinical trials. Test compounds were administered an anthritium drug, adapterin, water (1 second peritoneal 60 minutes before swimming. Advantageously non-derivative adamantane, increases water-prolonged substances as a swimming capacity of mice by 51% (max. 5 suspension in tween -80. Substances were introduced into

)) doses of 1.5.10 and 25 mg / kg,

It should be noted that the positive Another test characterizing the phenamine psihvlenie, as well as other using stimulating effects of the currently identified psycho-stimulus connections, was the level of spontaneous

ra-sydnocarba - on a complex operant TO of motor activity (tentative

the activity of rats is manifested in doses (non-reaction) when animals are placed in the physical activity specimen for growth for 15 min.

properties. Phenamine and Sydnocarb in doses, Spontaneous motor activity

having a positive effect ndizuchadi on the device DAER-20 always in one

level of physical performance, -15 and the same time days. Experienced Results

adversely affect the quality of the operant groups was compared with the control, which is the rat rat infection rate daily. Test substances

Bromantan has the ability to be retracted intraperitoneally 60 minutes before experimenting with complex operative de-ta in doses of 10 ml / kg. The effect of the animals on a wide range of 20 times in two indicated dose tests, including doses that were compared with the action of the well-known psycho-positive effect on the level of the physical-motor stimulator of phenamine, and its working capacity.

This property distinguishes favorably, anti-rkinson action

the claimed bromantane from phenamine and sid-25 were evaluated in rats by the anti-catalepticocarb, since the use of the possible activity of the claimed compounds on

receive 1-b- simultaneously qi stimulus (6 physi models of trifazinov catalyps II 02 mg / kg

mental and mental performance. Intraperitoneally) with an assessment of severity.

The claimed bromantane exerts about ty-catalepsy in points according to the Morpufgo metric.

minimal corrective effect on psychedep-30 Intra-rhyme effects of various peritoneal doses were introduced for the claimed compounds 5 and Yumg / kg

tranquilizers (benzodiazelin, triox-administration of antipsychotics: level of catalepsin, meprobamate, sodium hydroxybutyrate) posium (animal’s ability to hold

, test of disorders of operant activity. given to him an uncomfortable posture based on

The restoration of steps of different heights broken after VVE-35) was evaluated through

days of said operan-bOmin tranquilizers after administration of triftazine. More

your activity with phenamine or the level of catalepsy corresponds to a greater

Sydnocarb occurs in part or with a pro-number of points given to this group

a negative effect of the use of animals. The results obtained in the experiment

psychostimulants in separate 40 groups were compared with the control (input & indicators of this activity of triftazine and physiological

In addition, bromantane has a solution method). .

the ability to remove triftazine-induced catalepsy one of nagaloperidol was used for comparison. In terms of this most active antiparkinsonian action, it is superior to that used in the 45 P | midantane epeparats, which is a hydropractic antiparkinsonian prep-chloride of 1-aminoadamantane. rat midantane 2.5 times. , Besides; In addition, an acute day was examined $ / | to assess the impact of the compounds involved:; This is a new reason for the connection of compounds to the level of a physical working express method. The results obtained used the biological mice swimming test with mice with SO for a load of 10% of body weight until the doses of the claimed laziness compounds were fully studied (diving). Floating animals are represented in the Republic of Belarus. From the data in the table are in a thermostatic bath (temperature indicates that the claimed compounds have 27 ° C). An indicator of the level of physical activity, pronounced biological activity, and working capacity was the time from MO-55, which manifests itself for most of them at the time of placing the animal in water until it increases the level of physical workload to the bottom. Groups of 20 mice were taken to assess the effect of the property, enhancing motor activity. Experiments or removal of triftazine data were compared with catalepsy data. Compounds 4, 5, 6 and 7, which are halo derivatives of anilinoadamantane, have the strongest positive control group (administration by physiological influence on the level of physical performance). All of them are much stronger than the given form of action than phenamine in the optimal dose.

 . ,

At the same time, these compounds are 10-100 times less toxic than 411 phenamine, which has a much greater therapeutic effect than phenamine. The claimed compounds have pronounced anti-cataleptic activity according to the test of trifthazine catalepsy, which significantly exceeds that of midantan at a dose of 5 mg / kg However, these compounds are 2-30 times less toxic than midantan.

It should be noted that the claimed compounds, significantly enhancing physical performance, do not significantly increase the level of motor activity, as is characteristic of phenamine. This property significantly and positively distinguishes the claimed compounds from phenamine.

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(56) Artsimovich N, G. et al. Study of the immunotropic activity of N- {2-adamantyl) aniline on models of cellular and humoral immunity Chem.pharm. Zh., 1979, No. 9, p. 8.

Mashkovsky M.D. Medicines, M: Medicine, 1979, v. 1, p. 110-111,

Chemistry of polyhedranes. Conference abstracts. Volgograd, 1976, p. 131.

. Biological Activity of Substituted Y-Adamantyl Aylinilin 1 RS

-R

NH total T

The compound was tested with poretomomoroimnoy salt.

1fodolheky TaiJanuji