CH648290A5 - COMPOUND WITH PSYCHO-STIMULATING AND ANTIDEPRESSANT ACTIVITY, PROCESS FOR ITS PREPARATION AND RELATIVE PHARMACEUTICAL COMPOSITIONS. - Google Patents
COMPOUND WITH PSYCHO-STIMULATING AND ANTIDEPRESSANT ACTIVITY, PROCESS FOR ITS PREPARATION AND RELATIVE PHARMACEUTICAL COMPOSITIONS. Download PDFInfo
- Publication number
- CH648290A5 CH648290A5 CH398/81A CH39881A CH648290A5 CH 648290 A5 CH648290 A5 CH 648290A5 CH 398/81 A CH398/81 A CH 398/81A CH 39881 A CH39881 A CH 39881A CH 648290 A5 CH648290 A5 CH 648290A5
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- Switzerland
- Prior art keywords
- compound
- aminoadamantane
- preparation
- pharmaceutical compositions
- dose
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- 150000001875 compounds Chemical class 0.000 title claims description 8
- 238000000034 method Methods 0.000 title claims description 6
- 230000008569 process Effects 0.000 title claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title claims description 3
- 230000000694 effects Effects 0.000 title description 7
- 230000001430 anti-depressive effect Effects 0.000 title description 3
- 239000000935 antidepressant agent Substances 0.000 title description 3
- 229940005513 antidepressants Drugs 0.000 title description 3
- 230000002582 psychostimulating effect Effects 0.000 title description 2
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 208000020401 Depressive disease Diseases 0.000 claims description 2
- 208000029808 Psychomotor disease Diseases 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 230000003933 intellectual function Effects 0.000 claims description 2
- CBQJSKKFNMDLON-UHFFFAOYSA-N N-acetylphenylalanine Chemical compound CC(=O)NC(C(O)=O)CC1=CC=CC=C1 CBQJSKKFNMDLON-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 238000001556 precipitation Methods 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 241000700159 Rattus Species 0.000 description 10
- 230000008485 antagonism Effects 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 231100000331 toxic Toxicity 0.000 description 6
- 230000002588 toxic effect Effects 0.000 description 6
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 5
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 5
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 5
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 5
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 5
- 229960003147 reserpine Drugs 0.000 description 5
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 5
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 4
- 229960003805 amantadine Drugs 0.000 description 4
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- WOLHOYHSEKDWQH-UHFFFAOYSA-N amantadine hydrochloride Chemical compound [Cl-].C1C(C2)CC3CC2CC1([NH3+])C3 WOLHOYHSEKDWQH-UHFFFAOYSA-N 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 2
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000027776 Extrapyramidal disease Diseases 0.000 description 2
- 206010022714 Intestinal ulcer Diseases 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 206010042220 Stress ulcer Diseases 0.000 description 2
- 229940025084 amphetamine Drugs 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 2
- 229960002327 chloral hydrate Drugs 0.000 description 2
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 2
- 208000000718 duodenal ulcer Diseases 0.000 description 2
- 229960003878 haloperidol Drugs 0.000 description 2
- 230000002631 hypothermal effect Effects 0.000 description 2
- 230000008991 intestinal motility Effects 0.000 description 2
- 229960002715 nicotine Drugs 0.000 description 2
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 229960005190 phenylalanine Drugs 0.000 description 2
- 235000008729 phenylalanine Nutrition 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 230000004622 sleep time Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010017788 Gastric haemorrhage Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- -1 acetano Chemical compound 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000000648 anti-parkinson Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 230000037007 arousal Effects 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 206010007776 catatonia Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000002911 mydriatic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 231100000161 signs of toxicity Toxicity 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000001562 ulcerogenic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
L'invenzione riguarda un nuovo composto ad attività antidepressiva, e precisamente il D,L-2-acetamido-3-fenilpro-pionato dell'1-amminoadamantano, di formula (I) The invention relates to a new compound with antidepressant activity, namely the D, L-2-acetamido-3-phenylpro-pionate of 1-aminoadamantane, of formula (I)
CH2-CH-C00 CH2-CH-C00
NHCOCH. NHCOCH.
(i) (the)
stati involutivi e depressivi dell'età presenile, delle turbe psicomotorie dell'età senile e — come coadiuvante — dei disturbi delle funzioni intellettuali. involutionary and depressive states of the presenile age, of the psychomotor disorders of the senile age and - as an adjuvant - of the disturbances of the intellectual functions.
L'invenzione riguarda infine un procedimento per la pre-5 parazione del composto (I), consistente nel far reagire quantità sostanzialmente equimoleeolari di acido D,L-2-acetam-mido-3-fenilpropionico e di 1-amminoadamantano in un solvente (costituito preferibilmente da alcoli inferiori, per esempio etanolo, metanolo, propanolo), e nel precipitare il sale io (I) mediante aggiunta di un non-solvente (dietiletere, ace-tano, metiletilchetone). La reazione si effettua opportunamente alla temperatura d'ebollizione della miscela di reazione. Finally, the invention relates to a process for the preparation of compound (I), consisting in reacting substantially equimoleeolar quantities of acid D, L-2-acetam-mido-3-phenylpropionic acid and 1-aminoadamantane in a solvent ( preferably consisting of lower alcohols, for example ethanol, methanol, propanol), and in precipitating the io (I) salt by adding a non-solvent (diethyl ether, acetano, methyl ethyl ketone). The reaction is carried out suitably at the boiling temperature of the reaction mixture.
In alternativa, la reazione può essere effettuata tra un 15 sale (per esempio il sale sodico) dell'acido D,L-2-acetammi-do-3-fenilpropionico e il cloridrato (o altro sale di addizione con acidi) dell'1-amminoadamantano. In tal caso si elimina dapprima per filtrazione il sale inorganico (per esemio cloruro sodico) precipitato dalla soluzione alcolica, e quindi 20 si isola il composto (I) sostanzialmente come sopra indicato. Alternatively, the reaction can be carried out between a 15 salt (for example the sodium salt) of the acid D, L-2-acetams-do-3-phenylpropionic acid and the hydrochloride (or other acid addition salt) of 1 -amminoadamantano. In this case, the inorganic salt (for example sodium chloride) precipitated from the alcoholic solution is first removed by filtration, and then compound (I) is isolated substantially as indicated above.
L'esempio che segue illustra, senza limitarlo, il procedimento dell'invenzione. The following example illustrates, without limiting it, the process of the invention.
Esempio Example
25 41,4 grammi (0,2 moli) di acido D,L-2-acetammido-3-fe-nilpropionico e 30,2 grammi (0,2 moli) di 1-amminoadamantano vengono sciolti in 250 mi di etanolo anidro. La soluzione viene bollita a ricadere per 2-3 ore; dopo raffreddamento si aggiungono 400 mi di etere dietilico, si filtra alla 30 pompa il precipitato ottenuto e lo si lava con dietiletere. Si ottengono 65,88 g di prodotto cristallino, incolore, che fonde a 207-208°C. 25 41.4 grams (0.2 moles) of D, L-2-acetamide-3-fe-nylpropionic acid and 30.2 grams (0.2 moles) of 1-aminoadamantane are dissolved in 250 ml of anhydrous ethanol. The solution is boiled under reflux for 2-3 hours; after cooling, 400 ml of diethyl ether are added, the obtained precipitate is filtered at 30 pump and washed with diethyl ether. 65.88 g of colorless crystalline product are obtained, which melts at 207-208 ° C.
Analisi per: C^H^NaC^ Analysis for: C ^ H ^ NaC ^
Cale. %■. C 70,35 H 8,43 N 7,81 35 Trov. %: C 70,51 H 8,38 N 7,84 Cale. ■%. C 70.35 H 8.43 N 7.81 35 Found %: C 70.51 H 8.38 N 7.84
Il composto è solubile in etanolo, meno solubile in acqua, insolubile in acetone, dietiletere, cloroformio. The compound is soluble in ethanol, less soluble in water, insoluble in acetone, diethyl ether, chloroform.
Le caratteristiche tossicologiche e farmacologiche del 40 composto (I) (che verrà d'ora in poi definito anche con la sigla MR-708) sono state sperimentate come qui sotto descritto. The toxicological and pharmacological characteristics of the compound 40 (I) (which will henceforth also be defined with the abbreviation MR-708) have been tested as described below.
T ossicità Toxicity
45 Tossicità acuta 45 Acute toxicity
I valori ottenuti sul topo e sul ratto sono espressi nella tabella 1. The values obtained on the mouse and the rat are expressed in table 1.
TABELLA 1 TABLE 1
L'1-amminoadamantano (noto come Amantadina) è impiegato da alcuni anni in terapia sia come antivirale nell'influenza di tipo A, sia come antiparkinsoniano. 1-aminoadamantane (known as Amantadine) has been used for some years in therapy both as an antiviral in type A influenza and as an antiparkinsonian.
La limitazione dell'impiego di questo farmaco consiste nel fatto che ai dosaggi pieni previsti dall'impiego terapeutico (400 mg/die) possono insorgere effetti collaterali in misura tale da dover sospendere il trattamento (G. Vallecorsi e coll., La Clin. Ter. 77, 53-60 [1976] - M. Cloarec e coll., Sem. Hôp Paris 5?, 889 [1976]). The limitation of the use of this drug consists in the fact that at the full dosages foreseen by the therapeutic use (400 mg / day), side effects may arise to the extent that the treatment must be stopped (G. Vallecorsi et al., La Clin. Ter 77, 53-60 [1976] - M. Cloarec et al., Sem. Hôp Paris 5 ?, 889 [1976]).
Si è ora sorprendentemente trovato che il sale dello 1-am-minoadamantano con l'acido D,L-acetammido-3-fenilpropio-nico, cioè il composto (I), somministrato a dosaggi equipon-derali rispetto all'Amantadina, presenta un'attività farmacologica perfettamente comparabile in senso psicostimolante, esente però da manifestazioni secondarie, e accompagnata inoltre da una spiccata attività antidepressiva, non posseduta dall'Amantadina. It has now been surprisingly found that the salt of 1-aminoadamantane with D, L-acetamide-3-phenylpropionic acid, i.e. compound (I), administered at equal doses with respect to Amantadine, has a a perfectly comparable pharmacological activity in a psychostimulating sense, however free from secondary manifestations, and also accompanied by a strong antidepressant activity, not possessed by Amantadine.
L'invenzione riguarda pertanto anche composizioni farmaceutiche, contenenti il composto (I), atte alla terapia di so The invention therefore also relates to pharmaceutical compositions, containing compound (I), suitable for so therapy
MR-708 MR-708
Amantadina Amantadine
OS OS
850 850
700 700
Topo ^ Mouse ^
ip ip
365 365
F* F *
205 205
p* p *
OS OS
1020 1020
F* F *
890 890
F* F *
Ratto ^ Rat ^
ip ip
263 263
F* F *
223 223
F* F *
*F = femmina * F = female
Tossicità ripetuta Le prove con somministrazioni ripetute di MR-708 non 65 hanno evidenziato segni di tossicità sui parametri ematochimici, sulla funzionalità epatica e renale, come pure non si sono rilevate alterazioni all'esame micro-macroscopico degli organi. Repeated toxicity Tests with repeated administration of MR-708 not 65 showed signs of toxicity on the blood chemistry parameters, liver and kidney function, as well as no alterations were detected on the micro-macroscopic examination of the organs.
3 3
648 290 648 290
Farmacologia Pharmacology
Azione sulla pressione arteriosa MR-708 somministrato per via endovenosa nel cane anestetizzato, alla dose di 4,5 mg/kg, e nel ratto anestetizzato a vagotomia bilaterale, alla dose di 5 mg/kg, ha determinato una leggera e transitoria ipertensione. Action on blood pressure MR-708 administered intravenously in the anesthetized dog, at the dose of 4.5 mg / kg, and in the anesthetized rat with bilateral vagotomy, at the dose of 5 mg / kg, resulted in a slight and transient hypertension.
Potenziamento degli effetti indotti dalla L-dopa Pretrattando il topo con MR-708 alla dose di 70 mg/kg (per via intraperitoneale) 90' prima della somministrazione intraperitoneale di 500 mg/kg di L-dopa si osserva una notevole eccitazione psicomotoria già prima del 10° minuto dalla somministrazione di L-dopa; somministrando L-dopa da sola anche in dosi di 1000 mg/kg, l'eccitazione appare solo al 25° minuto. Potentiation of the effects induced by L-dopa Pretreating the mouse with MR-708 at the dose of 70 mg / kg (intraperitoneally) 90 'before the intraperitoneal administration of 500 mg / kg of L-dopa, considerable psychomotor arousal is observed already before 10 minutes after L-dopa administration; by administering L-dopa alone even in doses of 1000 mg / kg, the excitation appears only at the 25th minute.
Anche il numero degli scatti è superiore; MR-708 potenzia quindi gli effetti della L-dopa inducendo una stessa sintomatologia con dosi inferiori e facendola manifestare prima nel tempo. Even the number of shots is higher; MR-708 therefore potentiates the effects of L-dopa by inducing the same symptomatology with lower doses and making it manifest earlier in time.
Antagonismo nei confronti dell'azione tossica della nicotina Mr-708, somministrato nel ratto alla dose di 25 mg/kg per via intraperitoneale protegge dall'azione tossica della nicotina. Antagonism towards the toxic action of nicotine Mr-708, administered in the rat at a dose of 25 mg / kg intraperitoneally, protects against the toxic action of nicotine.
Antagonismo nei confronti dell'azione tossica della anfetamina MR-708, somministrato per via intraperitoneale alla dose di 25 mg/kg, protegge dall'azione tossica dell'anfetamina modificando significativamente i valori della DL50. Antagonism towards the toxic action of amphetamine MR-708, administered intraperitoneally at a dose of 25 mg / kg, protects against the toxic action of amphetamine by significantly modifying the LD50 values.
Antagonismo nei confronti dell'azione tossica dell'adrenalina Antagonism towards the toxic action of adrenaline
MR-708, somministrato per via intraperitoneale alla dose di 25 mg/kg, protegge dall'azione tossica dell'adrenalina nel ratto. MR-708, administered intraperitoneally at a dose of 25 mg / kg, protects against the toxic action of adrenaline in the rat.
Antagonismo nei confronti dell'alcool MR-708, alla dose unica di 150 mg/kg/os, riduce di circa il 45 % il tempo di sonno indotto da alcool etilico libero nel ratto Wistar femmina. Antagonism towards alcohol MR-708, at a single dose of 150 mg / kg / os, reduces sleep time induced by free ethyl alcohol in the female Wistar rat by about 45%.
Antagonismo nei confronti del cloralio idrato MR-708, alla dose unica di 150 mg/kg/os, riduce di circa il 26 % il tempo di sonno indotto dal cloralio idrato somministrato nei ratti Wistar maschi alla dose di 300 mg/kg per via intraperitoneale. Antagonism towards chloral hydrate MR-708, at a single dose of 150 mg / kg / os, reduces by about 26% the sleep time induced by chloral hydrate administered in male Wistar rats at a dose of 300 mg / kg intraperitoneally .
Attività bloccante la motilità intestinale MR-708, alla dose di 25 mg/kg per via intraperitoneale nel ratto, dimostra una marcata attività bloccante la motilità intestinale nel test dell'ingestione di carbone, in misura significativa rispetto ai controlli. Intestinal motility blocking activity MR-708, at a dose of 25 mg / kg intraperitoneally in the rat, demonstrates a marked intestinal motility blocking activity in the carbon ingestion test, significantly compared to controls.
Attività midriatica MR-708, alla dose di 25 mg/kg per via intraperitoneale nel ratto, con rilevazioni effettuate dopo 30', 60', 120', 240', pone in evidenza modificazioni del diametro della pupilla lievi rispetto ai controlli, e notevolmente inferiori a quelle provocate da atropina. Mydriatic activity MR-708, at a dose of 25 mg / kg intraperitoneally in the rat, with detections made after 30 ', 60', 120 ', 240', highlights slight changes in the pupil diameter compared to the controls, and significantly lower than those caused by atropine.
Farmacologia speciale Special pharmacology
Antagonismo all'azione ipotermizzante indotta da reserpina Il pretrattamento con MR-708, alla dose di 25 mg/kg/os nel topo, antagonizza in maniera altamente significativa l'azione ipotermizzante indotta da somministrazione di 2,5 mg/kg di reserpina per via intraperitoneale. Reserpine-induced hypothermic action antagonism MR-708 pretreatment, at a dose of 25 mg / kg / os in the mouse, highly antagonizes the hypothermic action induced by administration of 2.5 mg / kg of reserpine per route. intraperitoneal.
Le variazioni risultano più evidenti intorno alla 3a ora e si mantengono significative sino alla 8a ora. The changes are more evident around the 3rd hour and remain significant up to the 8th hour.
Antagonismo all'azione ulcerogena indotta da reserpina s Somministrazioni di MR-708, alla dose di 25 mg/kg/os nel topo un'ora prima del trattamento con reserpina in dosi di 2,5 mg/kg per via intraperitoneale, antagonizzano gli effetti ulcerogeni indotti dalla reserpina. L'esame degli animali sacrificati 22 ore dopo il trattamento ha fatto rilevare nel io 99% degli animali del gruppo di controllo notevoli emorragie gastriche e ulcere intestinali, con presenza di abbondante sangue nelle feci. Nel gruppo trattato con MR-708 solo il 10% presentava ulcerazioni di scarsa entità a livello intestinale. Antagonism to reserpine-induced ulcerogenic action s Administration of MR-708, at a dose of 25 mg / kg / os in the mouse one hour before treatment with reserpine in doses of 2.5 mg / kg intraperitoneally, antagonize the effects ulcerogens induced by reserpine. The examination of the animals sacrificed 22 hours after the treatment revealed 99% of the animals in the control group significant gastric bleeding and intestinal ulcers, with the presence of abundant blood in the stool. In the group treated with MR-708 only 10% had minor intestinal ulcerations.
15 15
Azione protettiva nei confronti dell'ulcera da stress Protective action against stress ulcer
Somministrazioni di MR-708 in dosi di 75 mg/kg consentono di esplicare un'azione protettiva nell'ulcera da stress, altamente significativa rispetto ai controlli. Administration of MR-708 in doses of 75 mg / kg allow to perform a protective action in the stress ulcer, highly significant compared to the controls.
20 20
Azione sulle sindromi extrapiramidali provocate da cloropromazina nel ratto Action on extrapyramidal syndromes caused by chloropromazine in the rat
MR-708 alla dose di 25 mg/kg per via intraperitoneale riduce significativamente le sindromi extrapiramidali indotte 25 da iniezione di cloropromazina alla dose di 10 mg/kg. (Test di Wirth, 1958). MR-708 at the dose of 25 mg / kg intraperitoneally reduces the extrapyramidal syndromes induced by 25 injection of chloropromazine at the dose of 10 mg / kg. (Wirth test, 1958).
Azione sulle sindromi catatoniche indotte da haloperidol nel ratto Action on catatonic syndromes induced by haloperidol in the rat
30 Somministrazioni di dosi da 6,25 a 25 mg/kg di MR-708 per via intraperitoneale pongono in evidenza una significativa opposizione all'accettazione passiva di un'attitudine imposta da somministrazioni di 7,5 mg/kg di haloperidol i.p. (Test di Simon-Boissiet, 1969). 30 Administration of doses from 6.25 to 25 mg / kg of MR-708 intraperitoneally highlight a significant opposition to the passive acceptance of an attitude imposed by administrations of 7.5 mg / kg of haloperidol i.p. (Simon-Boissiet test, 1969).
35 35
Azione sulla risposta all'orientamento dopo elettrochocs ripetuti Action on orientation response after repeated electrochocs
MR-708, somministrato per via intraperitoneale in dosi di 3,125 e 6,25 mg/kg 60 minuti prima del primo elettrodo choc, dimostra di mantenere l'integrità delle strutture cerebrali contro l'azione compromissoria provocata da elettrochocs ripetitivi. (Test di Herold, 1960). MR-708, administered intraperitoneally in doses of 3.125 and 6.25 mg / kg 60 minutes before the first shock electrode, proves to maintain the integrity of the brain structures against the compromising action caused by repetitive electrochocs. (Herold test, 1960).
F armacocinetica 45 La determinazione delle concentrazioni plasmatiche di 1-amminoadamantano nel ratto, dopo somministrazione orale nel topo di MR-708, consente le seguenti osservazioni: Pharmacokinetics 45 The determination of plasma concentrations of 1-aminoadamantane in the rat, after oral administration of MR-708 in the mouse, allows the following observations:
— la cinetica della N-deacetilazione permette alla fenil-alanina di liberarsi progressivamente, il che ne rallenta il so metabolismo epatico e ne potenzia l'azione, in quanto si libera, a poco a poco, nuova fenilalanina pronta per superare la barriera emantoencefalica. I livelli plasmatici di 1-amminoadamantano dopo somministrazione di 190 mg/kg/os di MR-708 nel topo, in confronto a quelli ottenuti con som-55 ministrazione di dosi equimolecolari di 1-amminoadamantano cloridrato (100 mg/kg), in maniera che entrambe le dosi corrispondano a 0,54 mmoli/kg, fanno rilevare una miglior biodisponibilità di MR-708; dal rapporto delle aree sotto la curva dei livelli plasmatici (AUC) si ricava infatti una dif-60 ferenza di biodisponibilità del 29,72% a favore di MR-708. - the kinetics of N-deacetylation allows phenyl-alanine to progressively release, which slows down its liver metabolism and enhances its action, as it gradually releases new phenylalanine ready to overcome the blood-brain barrier. Plasma levels of 1-aminoadamantane after administration of 190 mg / kg / os of MR-708 in mice, compared to those obtained by administering equimolecular doses of 1-aminoadamantane hydrochloride (100 mg / kg), in a manner that both doses correspond to 0.54 mmoles / kg, indicate a better bioavailability of MR-708; from the ratio of areas under the plasma level curve (AUC) a difference of 60.72% bioavailability is obtained in favor of MR-708.
Inoltre la dispersione dei risultati è stata minore nel caso di somministrazione di MR-708 rispetto alla somministrazione di 1-amminoadamantano cloridrato. Furthermore, the dispersion of the results was less in the case of administration of MR-708 than in the administration of 1-aminoadamantane hydrochloride.
Esprimendo infatti la deviazione standard in percentuale 65 rispetto alla media si ottiene una variabilità del 42,7 % nel caso dell'1-amminoadamantano cloridrato, e del 24,6% nel caso di MR-708. Expressing the standard deviation in percentage 65 with respect to the average, a variability of 42.7% is obtained in the case of 1-aminoadamantane hydrochloride, and 24.6% in the case of MR-708.
v v
Claims (5)
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| 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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| CH648290A5 true CH648290A5 (en) | 1985-03-15 |
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| Application Number | Title | Priority Date | Filing Date |
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| CH398/81A CH648290A5 (en) | 1980-02-21 | 1981-01-21 | COMPOUND WITH PSYCHO-STIMULATING AND ANTIDEPRESSANT ACTIVITY, PROCESS FOR ITS PREPARATION AND RELATIVE PHARMACEUTICAL COMPOSITIONS. |
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| Country | Link |
|---|---|
| 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) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
1980
- 1980-02-21 IT IT20075/80A patent/IT1147325B/en active
- 1980-03-05 DE DE3008335A patent/DE3008335C2/en not_active Expired
-
1981
- 1981-01-21 CH CH398/81A patent/CH648290A5/en not_active IP Right Cessation
- 1981-01-26 CA CA000369264A patent/CA1144162A/en not_active Expired
- 1981-01-26 ZA ZA00810523A patent/ZA81523B/en unknown
- 1981-01-27 JP JP1145881A patent/JPS56128745A/en active Granted
- 1981-01-30 GB GB8102912A patent/GB2070004B/en not_active Expired
- 1981-02-03 BE BE2/58995A patent/BE887351A/en not_active IP Right Cessation
- 1981-02-03 NL NL8100510A patent/NL8100510A/en not_active Application Discontinuation
- 1981-02-18 FR FR8103203A patent/FR2476643B1/fr not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS56128745A (en) | 1981-10-08 |
| IT1147325B (en) | 1986-11-19 |
| CA1144162A (en) | 1983-04-05 |
| 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 |
| GB2070004A (en) | 1981-09-03 |
| DE3008335A1 (en) | 1981-08-27 |
| FR2476643A1 (en) | 1981-08-28 |
| FR2476643B1 (en) | 1983-05-13 |
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