GB2070004A - 1-Aminoadamantane D,L-2- acetamido-3-phenylpropionate - Google Patents

1-Aminoadamantane D,L-2- acetamido-3-phenylpropionate Download PDF

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GB2070004A
GB2070004A GB8102912A GB8102912A GB2070004A GB 2070004 A GB2070004 A GB 2070004A GB 8102912 A GB8102912 A GB 8102912A GB 8102912 A GB8102912 A GB 8102912A GB 2070004 A GB2070004 A GB 2070004A
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aminoadamantane
compound
age
acetamido
reaction
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GB2070004B (en
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Medea Research SRL
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Medea Research SRL
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The novel compound is endowed with marked psychostimulant and antidepressive activities, being apparently concurrently devoid of all untoward side effects characteristic of 1-aminoadamantane.

Description

SPECIFICATION Compound with a psychostimulant and antidepressive activity, process for its preparation and related pharmaceutical compositions The present invention concerns a new compound endowed with an antidepressant activity, ie 1amino-adamantane D-L-2-acetamido-3-phenylpropionate, characterized by the following structural formula (I):
1-aminoadamantane (known as amantadine) has been therapeutically used for some years as an antiviral agent in influenza type A as well as an antiparkinsonism agent.
The use of this drug, however, is limited by the evidence that, at the full dosages provided for a therapeutic use, ie 400 mg daily, untoward side effects may arise to such an extent as to require a treatment discontinuation (Vallecorsi G. et al., Clin.Ter.,77,53-60, 1 976-Cloarec M. et al., Sem.Hop.paris,52,889, 1 976).
It has now been surprisingly discovered that the salt of 1 -amino-adamantane with D,L-acetamido3-phenylpropionic acid, ie compound (I), when administered at equiponderal dosages with respect to amantadine, shows a pharmacological activity that, although perfectly comparable with the activity of amantadine from a psychostimulant standpoint, appears to induce definitely no untoward side effects while exhibiting a marked antidepressive activity not encountered in the case of amantadine.
Therefore, the invention concerns also pharmaceutical compositions containing the compound (I), apt to the treatment of all involutional and depressive conditions of the presenile age, all psychomotor disturbances of the elderly age and also, as adjuvant agents, of all disturbances of brain function. Such compositions may contain any suitable conventional pharmaceuticully acceptable liquid or solid carrier or diluent and may be prepared for oral or intraperitoneal dosage, They may further be packaged in unit dosage form.
Finally, the invention concerns a procedure for the preparation of compound (I), that consists in reacting substantially equimolcular amounts of D-L-2-acetamido-3-phenylpropionic acid and 1aminoadamantane in a solvent (consisting preferably of lower alcohols, e.g. ethanol, methanol, propanol), and in precipitating the salt (I) by the addition of a non-solvent agent (e.g. diethylether, acetone, methylethyiketone). The reaction is suitably carried out at the boiling temperature of the mixture.
Alternatively, the reaction may be carried out between a salt (ior example the sodium salt) of D,L2-acetamido-3-phenylpropionic acid and the hydrochloride (or other additon salt with acids) of 1 aminoadamantane.
In said case the inorganic salt, e.g. sodium chloride precipitated from the ethanol solution, is filtered out; thereafter the compound (I) is isolated, according essentially to the above stated procedure.
The following example shows, with no limitation, the procedure of the invention.
EXAMPLE 41.4 grams (0.2 moles) of D,L-2-acetamido-3-phenylpropionic acid and 30.2 grams (0.2 moles of 1 -aminoadamantane are dissolved in 250 ml of anhydrous ethanol. The soiution is allowed to reflux at the boiling temperature for 2-3 hours; after cooling, 400 ml of diethyl ether are added, the precipitate obtained is pump-filtered and washed with diethylether. 65.88 grams of crystalline, colorless product are obtained: the resulting compound melts at 207-2080C.
Analysis for C21H30N2O3 % Calc.: C=70.35; H = 8.43; N = 7.81 % Found: C = 70.51; H=8.38; N = 7.84 The compound is soluble in ethanol, less soluble in water, insoluble in acetone, diethylether, chloroform.
The toxicological and pharmacological characteristics of the compound (I) (that, from now on shall also be defined with the code name MR-708) were evaluated according to the hereinbelow specified procedures.
TOXICITY Acute Toxicity Table 1 shows the values obtained in the mouse and in the rat.
TABLE 1
MR-703 Amantadine wos 850 700 OUS6.
\P 365 F* 205 F'* os 1020 F * 890 F * Rat05 1020F* 890 F* zip 263 Fi 223 Fa Notes: 1. The values are expressed in mg/kg.
2. The symbol F* designates use of a female.
Repeated Toxicity All investigations carried out by repeated administrations of MR-708 could point out neither signs of toxicity of the various blood chemistry parameters, liver and renal function nor micromacroscopic alterations in the various organs examined.
PHARMACOLOGY Action on Blood Pressure MR--708 produced a mild and transient hypertension when given to narcotized dogs at the dosage rate of 4.5 mg/kg, and to rats narcotized by bilateral vagotomy at the dosage rate of 5 mg/kg.
Potentiation of the Effects induced by L-dopa In the mouse, the pretreatment with MR-708, given at the intraperitioneal dosage of 70 mg/kg 90 minutes before the intraperitioneal administration of L-dopa at the dosage of 500 mg/kg, induces a marked psychosomatic excitement that already begins appearing before the 10th minute following the administration of L-dopa, and on the 25th minute when L-dopa is given at a 1,000 mg/kg-dosage. Also the number of fits is higher; MR-708, therefore, potentiates the effects of L-dopa, inducing with lower doses a same symptomatology and causing also its early appearance.
Antagonism versus the toxic action of nicotine MR--708, given intraperitoneally to rats at the dosage of 25 mg/kg, protects from the toxic action of nicotine.
Antagonism versus the Toxic Action ofAmphetamine MR-708, given intraperitoneally at the dosage of 25 mglkg, protects from the toxic action of amphetamine, changing significantly the LD 50 values.
Antagonism versus the Toxic Action ofEpinephrine MR-708, given intraperitoneally at the dosage of 25 mg/kg, protects the rat from the toxic action of epinephrine.
Antagonism versus Ethanol MR-708, given at a single oral dose of 1 50 mg/kg to Wistar female rats, reduces in a 45 percent approximate rate the sleeping time induced by free ethanol.
Antagonism versus Chloral Hydrate MR-708, given at a single oral dose of 1 50 mg/kg, reduces in a 26 percent approximate rate the sleeping time induced by chloral hydrate in male Wistar rats given the intraperitoneal dose of 300 mg/kg.
Activity Blocking the Intestinal Motility MR-708, given to rats at the intraperitoneal dose of 25 mg/kg, shows in the charcoal ingestion test a marked activity, on the intestinal motility block, quite significant in comparison with controls.
Mydria tic Activity MR--708, given to rats at the intraperitoneal dosage of 25 mg/kg with recheck examinations made 30-60-1 20-240 minutes after the adminstration, points out, in comparison with controls, mild changes in the pupil diameter, definitely lower however than those induced by atropine.
SPECIAL PHARMACOLOGY Antagonism versus the Hypothermiant Action induced by Reserpine A pretreatment with MR--708, given to mice at the oral dosage of 25 mg/kg, antagonizes in a highly significant manner the hypothermiant action induced by an intraperitioneal administration of reserpine given at the dosage of 25 mg/kg.
All changes result more evident on the 3rd hour approximately and keep being significant up to the 3rd hour.
Antagonism versus the UlcerogenicAction inducedbyReserpine MR-708, given to mice at the oral dosage of 25 ml/kg one hour before the intraperitoneal administration of reserpine at the dose of 2.5 mg/kg, antagonizes the ulcerogenic effects induced by reserpine. The post-mortem examination of the experimental animals, sacrificed 22 hours after the treatment, could point out in 99 percent of the control animals relevant gastric hermorrhages and intestinal ulcers associated with a copious presence of blood in the stools. In the group given MR-708 only 10 percent of the experimental animals was presenting with scarcely relevant intestinal ulcerations.
Protective Action versus Stress-lnduced Ulcer MR-708, given at the dose of 75 mg/kg, exerts a protective action against stress-induced ulcer in a highly significant rate in comparison with controls.
Action on the Catatonic Syndromes Induced by Haloperidol in the Rat MR-708, given at intraperitoneal doses of 6.25-25 mg/kg, counteracts significantly the passive acceptance of a habit induced by intraperitoneal administrations of haloperidol 7.5 mg/kg. (Test of Simon-Boissiet, 1969).
Action on the Orientation Response after Repeated Electroshocks MR-708, given intraperitoneally at dosages of 3.125 and 6.25 mg-kg 60 minutes before the first electroshock, is shown to maintain the integrity of the brain structures against the impairing action produced by repeated electroshocks (Test of Harold, 1960).
PHARMACOKINETICS The determination of the plasma concentrations of 1 -aminoadamantane in the rat, after oral administration of MR-708 in the mouse, enables to make the following observations: -The N-deacetylation kinetics enables the progressive liberation of phenylalanine: this process slowers the liver metabolism and potentiates the specific action since new phenylalanine is gradually liberated, ready to cross the bloodbrain barrier.After administration of 190 mg/kg/os of MR-708 in the mouse, the plasma levels of 1-aminoadamantane, compared with those resulting from the administration of equimolecular doses of 1 aminoadamantane hydrochloride (100 mg/kg) so that both doses correspond to 0.54 mmoles/kg, point out a better bioavailability of MR-708; actually, the ratio between the plasma ievels Areas Under the Curve (AUC) enables to point out a 29.72 percent difference in bioavailability in favor of MR-708.
Moreover, the dispersion of the results proves lower in the case of the MR--708 administration than in the case of the administration of 1-aminoadamantane hydrochloride.
Actually, when the standard deviation is expressed as percentage versus the mean, a 42.7 percent variability results in the case of 1-aminoadamantane hydrochloride while a 24.6 percent variability is recorded in the case of MR-708.

Claims (8)

1. 1 -aminoadamantane D,L-2-acetamido-3-phenylpropionate characterized by the following formula (I):
2. Process for the preparation of compound I, characterized by the reaction of substantially equimolecular quantities of D,L-2-acetamido-3-phenylpropionic acid (or a related metallic salt) and 1 aminoadamantane (or a related salt resulting from addition with acids) and by the isolation of the reaction product according to already known methods.
3. Process, according to claim 1, characterized by the fact that the reaction is carried out in a lower alcohol.
4. Process, according to claim 3, characterized by the fact that the reaction is carried out in ethanol.
5. Pharmaceutical compositions for the treatment of involutional and depressive conditions of the presenile age, of psychomotor disturbances of the elderly age and, as adjuvant agents, of brain function disturbances characterized by the fact that said compositions contain 1 -aminoadamantane D,L-2acetamido-3-phenylproprionate as the active ingredient.
6. Process for the preparation of compound I conducted substantially as herein described and exemplified.
7. Compound I whenever prepared by the process of any one of claims 2 to 4 and 6.
8. The use of compound I compositions containing same for the treatment of involutional and depressive conditions of the presenile age, of psychomotor disturbances of the elderly age and, as adjuvant agents, of brain function disturbances.
GB8102912A 1980-02-21 1981-01-30 1-aminoadamantane d,l-2-acetamido-3-phenylpropiaonate Expired GB2070004B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
IT20075/80A IT1147325B (en) 1980-02-21 1980-02-21 COMPOUND WITH PSYCHO-STIMULATING AND ANTIDEPRESSANT ACTIVITY, PROCESS FOR ITS PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS

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GB2070004A true GB2070004A (en) 1981-09-03
GB2070004B GB2070004B (en) 1983-10-26

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JP (1) JPS56128745A (en)
BE (1) BE887351A (en)
CA (1) CA1144162A (en)
CH (1) CH648290A5 (en)
DE (1) DE3008335C2 (en)
FR (1) FR2476643B1 (en)
GB (1) GB2070004B (en)
IT (1) IT1147325B (en)
NL (1) NL8100510A (en)
ZA (1) ZA81523B (en)

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JPS5950269U (en) * 1982-09-28 1984-04-03 ダイワ精工株式会社 Level winder with double bearing type reel for fishing
JPS61260824A (en) * 1985-05-15 1986-11-19 株式会社　オリムピツク Production of line guide in parallel winding mechanism of double bearing reel

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JPS56128745A (en) 1981-10-08
IT1147325B (en) 1986-11-19
CA1144162A (en) 1983-04-05
CH648290A5 (en) 1985-03-15
IT8020075A0 (en) 1980-02-21
DE3008335C2 (en) 1982-03-04
NL8100510A (en) 1981-09-16
ZA81523B (en) 1982-02-24
GB2070004B (en) 1983-10-26
BE887351A (en) 1981-06-01
JPS5747178B2 (en) 1982-10-07
DE3008335A1 (en) 1981-08-27
FR2476643A1 (en) 1981-08-28
FR2476643B1 (en) 1983-05-13

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