FR2503143A1 - Tri:methoxy phenacyl alkylamine(s) - having sedative, anti:depressant, and anti:aggressive activity - Google Patents
Tri:methoxy phenacyl alkylamine(s) - having sedative, anti:depressant, and anti:aggressive activity Download PDFInfo
- Publication number
- FR2503143A1 FR2503143A1 FR8106468A FR8106468A FR2503143A1 FR 2503143 A1 FR2503143 A1 FR 2503143A1 FR 8106468 A FR8106468 A FR 8106468A FR 8106468 A FR8106468 A FR 8106468A FR 2503143 A1 FR2503143 A1 FR 2503143A1
- Authority
- FR
- France
- Prior art keywords
- trimethoxyphenacyl
- formula
- addition salts
- sedative
- mole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 methoxy phenacyl alkylamine Chemical class 0.000 title claims abstract description 13
- 239000000932 sedative agent Substances 0.000 title abstract description 5
- 230000001624 sedative effect Effects 0.000 title abstract description 5
- 230000000694 effects Effects 0.000 title description 2
- 230000000994 depressogenic effect Effects 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- HEQOJEGTZCTHCF-UHFFFAOYSA-N 2-amino-1-phenylethanone Chemical class NCC(=O)C1=CC=CC=C1 HEQOJEGTZCTHCF-UHFFFAOYSA-N 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- IVMGRBAONKIFCX-UHFFFAOYSA-N 2-(propan-2-ylamino)-1-(2,4,6-trimethoxyphenyl)ethanone Chemical compound COC1=CC(OC)=C(C(=O)CNC(C)C)C(OC)=C1 IVMGRBAONKIFCX-UHFFFAOYSA-N 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000012429 reaction media Substances 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 239000002253 acid Substances 0.000 abstract description 3
- 238000007912 intraperitoneal administration Methods 0.000 abstract description 2
- 231100001160 nonlethal Toxicity 0.000 abstract description 2
- 231100000636 lethal dose Toxicity 0.000 abstract 1
- BOOAPBRSLNANFQ-UHFFFAOYSA-N 2-(propan-2-ylamino)-1-(2,4,6-trimethoxyphenyl)ethanone;hydrochloride Chemical compound Cl.COC1=CC(OC)=C(C(=O)CNC(C)C)C(OC)=C1 BOOAPBRSLNANFQ-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- FGJFFNYREINBNT-UHFFFAOYSA-N 2-chloro-1-(2,4,6-trimethoxyphenyl)ethanone Chemical compound COC1=CC(OC)=C(C(=O)CCl)C(OC)=C1 FGJFFNYREINBNT-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 206010039897 Sedation Diseases 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- 229940005513 antidepressants Drugs 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000036280 sedation Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LKUDPHPHKOZXCD-UHFFFAOYSA-N 1,3,5-trimethoxybenzene Chemical compound COC1=CC(OC)=CC(OC)=C1 LKUDPHPHKOZXCD-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- 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 1
- VDVNCCLROCXTRX-UHFFFAOYSA-N 2-(propan-2-ylamino)-1-(2,4,6-trihydroxyphenyl)ethanone Chemical compound CC(C)NCC(=O)C1=C(O)C=C(O)C=C1O VDVNCCLROCXTRX-UHFFFAOYSA-N 0.000 description 1
- OFQCQIGMURIECL-UHFFFAOYSA-N 2-[2-(diethylamino)ethyl]-2',6'-dimethylspiro[isoquinoline-4,4'-oxane]-1,3-dione;phosphoric acid Chemical compound OP(O)(O)=O.O=C1N(CCN(CC)CC)C(=O)C2=CC=CC=C2C21CC(C)OC(C)C2 OFQCQIGMURIECL-UHFFFAOYSA-N 0.000 description 1
- MABBYKMGDSGXSL-UHFFFAOYSA-N 2-piperazin-1-yl-1-(2,4,6-trimethoxyphenyl)ethanone Chemical compound COC1=CC(OC)=CC(OC)=C1C(=O)CN1CCNCC1 MABBYKMGDSGXSL-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 102100038916 Caspase-5 Human genes 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 101100112336 Homo sapiens CASP5 gene Proteins 0.000 description 1
- 101100273286 Mus musculus Casp4 gene Proteins 0.000 description 1
- RSDOPYMFZBJHRL-UHFFFAOYSA-N Oxotremorine Chemical compound O=C1CCCN1CC#CCN1CCCC1 RSDOPYMFZBJHRL-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000002539 anti-aggressive effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002631 hypothermal effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229960001317 isoprenaline Drugs 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 230000037023 motor activity Effects 0.000 description 1
- 229940105631 nembutal Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 239000000810 peripheral vasodilating agent Substances 0.000 description 1
- 229960002116 peripheral vasodilator Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 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 1
- 229960003147 reserpine Drugs 0.000 description 1
- 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 1
- 229940125723 sedative agent Drugs 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Nouveaux dérivés de hénacylamine.1airutilisation en thérapeutique et leur procédé de préparation.New derivatives of hénacylamine. 1air use in therapeutics and their process of preparation.
ta présente invention concerne en tant que produits industriels nouveaux des dérivés de phénacylamine. Elle concerne également leur utilisation en thérapeutique ainsi que leur procédé de préparation. Your present invention relates, as new industrial products, to phenacylamine derivatives. It also relates to their use in therapy as well as their preparation process.
On sait que l'on a déjb décrit des dérivés de phénacylamine trihydroxylés et triméthoxylés en positions 2,4 et 6 du groupe phénacyle et étudié leurs propriétés pharmacologiques. On connatt en particulier du brevet britannique nO 1.325.192, du brevet américain n" 3.895.030 et de la demande allemande publiée avant examen (OLS) nO 2.122.144, qui correspondent audit brevet britannique, les N-(2,4,6-trihydroxyphénacylj-isopropylamine et N-(2,4,6- triméthoxyphénacyl)-pipérazine qui ont été proposées en tant qu'agents vasodilatateurs périphériques. We know that we have already described phenacylamine derivatives trihydroxylated and trimethoxylated in positions 2,4 and 6 of the phenacyl group and studied their pharmacological properties. We know in particular of the British patent nO 1,325,192, the American patent n ° 3,895,030 and the German application published before examination (OLS) nO 2,122,144, which correspond to said British patent, the N- (2,4, 6-trihydroxyphenacylj-isopropylamine and N- (2,4,6-trimethoxyphenacyl) -piperazine which have been proposed as peripheral vasodilators.
On vient de trouver de façon surprenante que de nouveaux dérivés de phénacylamine du type N-(2,4,6-triméthoxyphénacyl)- aikylamine (i) possèdent des propriétés très intéressantes sur le plan thérapeutique, (ii) agissent en particulier sur le SNC en tant qu'agents sédatifs et antidépresseurs, et (iii) se distinguent des produits voisina connus et notamment de leur homologue N-(2,4,6trihydroxyphénacyl)-isopropylamine en particulier, par leurs effets sédatifs antidépresseurs du SNC et antiagressifs. We have just surprisingly found that new phenacylamine derivatives of the N- (2,4,6-trimethoxyphenacyl) - aikylamine type (i) have very interesting properties from a therapeutic point of view, (ii) act in particular on the CNS. as sedative agents and antidepressants, and (iii) are distinguished from known neighbor products and in particular from their counterpart N- (2,4,6trihydroxyphenacyl) -isopropylamine in particular, by their sedative effects antidepressants of CNS and antiagressants.
Un nouveau dérivé de phénacylamine selon l'invention est caractérisé en ce qutil est choisi parmi l'ensemble constitué par
(i) les N-(2,4,6-triméthoxyphénacyl)-alkylamines
répondant å la formule générale
(où R représente un groupe isopropyle ou tertiobutyle), et
(ii) leurs sels d'addition.A new phenacylamine derivative according to the invention is characterized in that it is chosen from the group consisting of
(i) N- (2,4,6-trimethoxyphenacyl) -alkylamines
meeting the general formula
(where R represents an isopropyl or tert-butyl group), and
(ii) their addition salts.
L'invention vise donc les N-(2,4,6-triméthoxy- phénacyl)-isopropylamine et N-(2,4,6-triméthoxyphénacyl)-tertiobutyl- amine et leurs sels d'addition. Les composés preférés sont la N-(2,4 > 6-triméthoxyphénacyl)-isopropylamine et ses sels d'addition, notamment le chlorhydrate. The invention therefore relates to the N- (2,4,6-trimethoxyphenacyl) -isopropylamine and N- (2,4,6-trimethoxyphenacyl) -tertiobutylamine and their addition salts. The preferred compounds are N- (2,4> 6-trimethoxyphenacyl) -isopropylamine and its addition salts, in particular the hydrochloride.
Par sels d'addition, on entend ici les sels d'addition d'acide obtenus par réaction d'une base libre de formule (I) avec des acides minéraux ou organiques (tels que notamment les acides chlorhydrique, bromhydrique, nitrique, sulfurique, formique, acétique, propionique, benzotque, fumarique, maléique, oxalique, malique, citrique, lactique, tartrique, ascorbique, cinnamique, méthanesulfonique, p-toluenesulfonique et aspartique), et les sels t'ammonium, notasi-ent ceux obtenus par réaction avec ICH3 et C1CH3. Les sels préférés sont les sels d'addition d'acide, notamment les chlorhydrates. By addition salts is meant here the acid addition salts obtained by reaction of a free base of formula (I) with mineral or organic acids (such as in particular hydrochloric, hydrobromic, nitric, sulfuric acids, formic, acetic, propionic, benzotque, fumaric, maleic, oxalic, malic, citric, lactic, tartaric, ascorbic, cinnamic, methanesulfonic, p-toluenesulfonic and aspartic), and the ammonium salts, notably those obtained by reaction with ICH3 and C1CH3. The preferred salts are the acid addition salts, in particular the hydrochlorides.
Les composés de formule (I) peuvent entre préparés selon une méthode connue par application de mécanismes réactionnels classiques. Le procédé de préparation préconisé selon I1 invention consiste a faire réagir un halogénure de 2,4,6-triméthoxyphénacyle de formule
(où X représente un atome de chlore ou de brome) avec une amine primaire de formule
H2NR (III) (où R représente un groupe isopropyle ou tertiobutyle).The compounds of formula (I) can between prepared according to a known method by application of conventional reaction mechanisms. The preparation process recommended according to the invention consists in reacting a 2,4,6-trimethoxyphenacyl halide of formula
(where X represents a chlorine or bromine atom) with a primary amine of formula
H2NR (III) (where R represents an isopropyl or tert-butyl group).
Cette réaction est mise en oeuvre en faisant réagir 1 mole d'halogénure II avec plus d'une mole d'amine III, et avantageusement avec 1,5 5 moles de III. De façon pratique, on pourra faire réagir l'halogénure Il en solution dans l'acétone avec l'amine III en solution dans un alcool inférieur en C1-C4, la température de reflux du milieu reactionnel, pendant au moins 1 h. This reaction is carried out by reacting 1 mole of halide II with more than one mole of amine III, and advantageously with 1.5 5 moles of III. In practice, it will be possible to react the halide II in solution in acetone with the amine III in solution in a lower alcohol in C1-C4, the reflux temperature of the reaction medium, for at least 1 h.
Les composés de formule (I) et leurs sels sont utiles en neuropsychopharmacologie en raison de leurs propriétés sédatives, antidépressives et antiagressives. Selon l'invention, on préconise une composition thérapeutique qui est caractérisée en ce qu'elle renferme, en association avec un excipient physiologiquement acceptable, au moins un dérivé de N-(2,4,6-triméthoxyphénacyl)- alkylamine de formule (I) ou l'un de ses sels d'addition non toxiques. The compounds of formula (I) and their salts are useful in neuropsychopharmacology because of their sedative, antidepressant and antiaggressive properties. According to the invention, a therapeutic composition is recommended which is characterized in that it contains, in combination with a physiologically acceptable excipient, at least one derivative of N- (2,4,6-trimethoxyphenacyl) - alkylamine of formula (I ) or one of its non-toxic addition salts.
La teneur en ingrédient actif dans une telle composition correspond, bien entendu, å une dose pharmaceutiquement efficace.The content of active ingredient in such a composition corresponds, of course, to a pharmaceutically effective dose.
D'autres avantages et caractéristiques de l'invention seront mieux compris å la lecture de la description qui va suivre d'exemples de préparation nullement limitatifs. Other advantages and characteristics of the invention will be better understood on reading the description which follows of non-limiting examples of preparation.
PREPARATION I
Synthèse totale du chlorhydrate de N-(2,4,6-triméthoxyphénacyl)- isopropylamine
PREPARATION I
Total synthesis of N- (2,4,6-trimethoxyphenacyl) hydrochloride - isopropylamine
(Exemple 1, numéro de code : CRL 40726)
On fait passer un courant de HC1 gazeux jusqu'à saturation dans une solution constituée de 168 g de 1,3,5-triméthoxy- benzène, de 75,5 g de chloroacétonitrile et de 750 ml de chlorobenzène anhydre. On recueille par filtration le précipité de chlorhydrate de cétimine formé, que l'on soumet à une hydrolyse au moyen de 1 litre d'eau au reflux pendant 1 h. On recueille l'insoluble que l'on sèche.(Example 1, code number: CRL 40726)
A stream of HCl gas is passed until saturation in a solution consisting of 168 g of 1,3,5-trimethoxybenzene, 75.5 g of chloroacetonitrile and 750 ml of anhydrous chlorobenzene. The precipitate of ketimine hydrochloride formed is collected by filtration, which is subjected to hydrolysis by means of 1 liter of water at reflux for 1 h. The insoluble material is collected and dried.
On obtient ainsi 183 g (rendement : 74%) de chlorure de 2,4,6-trimé- thoxyphénacyle. F= 920C. 183 g (yield: 74%) of 2,4,6-trimethoxyphenacyl chloride are thus obtained. F = 920C.
On coule goutte à goutte une solution de 61,1 g (0,25 mole) de chlorure de 2,4,6-triméthoxyphénacyle dans l'acétone, dans une solution de 73,8 g (1,25 mole; 105 ml) d'isopropylamine dans 100 ml de méthanol. On porte à reflux pendant 2 h, refroidit ensuite et évapore à sec. On reprend le résidu d'évaporation avec de l'eau et extrait la base [N-(2,4,6-triméthoxyphénacyl)-isopropyl- amine) par de l'acétate d'éthyle. On lave la phase acétate d'éthyle avec de l'eau, puis on la sèche sur MgS04. On précipite le chlorhydrate avec 36 ml d'éthanol chlorhydrique 7N. Par recristallisation dans le mélange acétone-éthanol (1:1) v/v, on obtient 16 g (rendement ; 21%) de CRL 40726. F, 158 C (avec décomposition). A solution of 61.1 g (0.25 mole) of 2,4,6-trimethoxyphenacyl chloride in acetone is poured in dropwise into a solution of 73.8 g (1.25 mole; 105 ml) isopropylamine in 100 ml of methanol. The mixture is refluxed for 2 h, then cooled and evaporated to dryness. The evaporation residue is taken up with water and the base [N- (2,4,6-trimethoxyphenacyl) -isopropylamine) is extracted with ethyl acetate. The ethyl acetate phase is washed with water, then dried over MgSO4. The hydrochloride is precipitated with 36 ml of 7N hydrochloric ethanol. By recrystallization from acetone-ethanol (1: 1) v / v, 16 g (yield; 21%) of CRL 40726 are obtained. F, 158 C (with decomposition).
PREPARiTION II
Obtention du chlorhydrate de N-2,4,6-triméboxyehénacyl)-tertiobutyl- amine
(Exemple 2, numéro de code : CRL 40726A)
En procédant comme indiqué dans la préparation I en faisant réagir le chlorure de 2,4,6-triméthoxyphénacyle avec la tertiobutylantine, on obtint le chlorhydrate de N-(2,4,6-triméthoxy phénacyl) -tertiobutylamine. PREPARATION II
Obtaining N-2,4,6-trimeboxyehenacyl) -tertiobutyl-hydrochloride
(Example 2, code number: CRL 40726A)
By proceeding as indicated in preparation I by reacting 2,4,6-trimethoxyphenacyl chloride with tert-butylantine, N- (2,4,6-trimethoxy phenacyl) -teriobutylamine hydrochloride was obtained.
On a résumé ci-après les résultats des essais qui ont été entrepris avec le produit préféré selon l'invention, le
CRL 40726.The results of the tests which have been carried out with the preferred product according to the invention,
CRL 40726.
1 ) Toxicité et comportement
La dose maximale non mortelle (DL-O) du CRL 40726 chez la souris mâle par administration intrapéritonéale est supérieure å 250 mg/kg et inférieure à 500 mg/kg.1) Toxicity and behavior
The maximum non-lethal dose (DL-O) of CRL 40726 in male mice by intraperitoneal administration is greater than 250 mg / kg and less than 500 mg / kg.
A la dose de 128 mg/kg I.P., le CRL 40726 provoque chez la souris mSle une sédation, une dyspnée d'une duree de 1 heure. At a dose of 128 mg / kg I.P., CRL 40726 causes mice mice sedation, dyspnea lasting 1 hour.
A la dose de 64 mg/kg I.P., le CRL 40726 provoque chez la sourie maie une sédation.At a dose of 64 mg / kg I.P., CRL 40726 causes sedation in the mouse.
A la dose de 64 mg/kg I.P.,le CRL 40726 provoque chez le rat une sédation d'une durée de 2 heures. At a dose of 64 mg / kg I.P., CRL 40726 causes a sedation lasting 2 hours in rats.
20) Action sur le SNC
L'étude neuropsychopharmacologique du CRL 40726 montre
- une augmentation de l'hypothermie induite par
la réserpine et, à un degré moindre, par 1'oxo-
trémorine;
- une diminution de l'agressivité intergroupes chez
la souris male, sans modification nette de
l'activité motrice, et
- une potentialisation des stéréotypies amphétamini
ques et une reprise modérée de la motilité chez
la souris habituée à son enceinte.20) Action on the SNC
The neuropsychopharmacological study of CRL 40726 shows
- an increase in hypothermia induced by
reserpine and, to a lesser degree, by oxo-
tremorine;
- a decrease in intergroup aggressiveness in
the male mouse, without any net change in
motor activity, and
- a potentiation of amphetamini stereotypes
and a moderate recovery of motility in
the mouse accustomed to its enclosure.
On observe par ailleurs que, chez le chien anesthésié au Nembutal, le CRL 40726 administré par perfusion diminue l'action tachycardisante de l'isoprénaline. Ceci implique que le CRL 40726 a un effet ss-bloquant (très vraisemblablement du type
En clinique, on a obtenu de bons résultats chez l'homme apres administration de CRL 40726 en tant que sédatif sous forme de comprimés et de gélules renfermant chacun 10 mg de
CRL 40726, à raison de 3 comprimés ou gélules par jour pendant au moins une semaine. It is also observed that, in dogs anesthetized with Nembutal, CRL 40726 administered by infusion reduces the tachycardizing action of isoprenaline. This implies that CRL 40726 has an ss-blocking effect (very likely of the type
Clinically, good results have been obtained in humans after administration of CRL 40726 as a sedative in the form of tablets and capsules each containing 10 mg of
CRL 40726, at the rate of 3 tablets or capsules per day for at least one week.
Claims (6)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8106468A FR2503143A1 (en) | 1981-03-31 | 1981-03-31 | Tri:methoxy phenacyl alkylamine(s) - having sedative, anti:depressant, and anti:aggressive activity |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8106468A FR2503143A1 (en) | 1981-03-31 | 1981-03-31 | Tri:methoxy phenacyl alkylamine(s) - having sedative, anti:depressant, and anti:aggressive activity |
Publications (2)
Publication Number | Publication Date |
---|---|
FR2503143A1 true FR2503143A1 (en) | 1982-10-08 |
FR2503143B1 FR2503143B1 (en) | 1984-08-31 |
Family
ID=9256833
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
FR8106468A Granted FR2503143A1 (en) | 1981-03-31 | 1981-03-31 | Tri:methoxy phenacyl alkylamine(s) - having sedative, anti:depressant, and anti:aggressive activity |
Country Status (1)
Country | Link |
---|---|
FR (1) | FR2503143A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2555576A1 (en) * | 1983-11-25 | 1985-05-31 | Lafon Labor | N- (METHOXYPHENACYL) -AMINE DERIVATIVES, IN PARTICULAR USE IN THERAPEUTICS AND METHOD OF PREPARATION |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR1023815A (en) * | 1949-04-13 | 1953-03-24 | Philips Nv | Process for the preparation of amino ketones and their derivatives |
GB1325192A (en) * | 1970-05-06 | 1973-08-01 | Orsymonde | Phloroglucinol derivatives |
FR2341308A1 (en) * | 1976-02-20 | 1977-09-16 | Souchard Maddy | (2,4,6)-Trimethoxy-phenacyl-amines - with cardiovascular activity |
-
1981
- 1981-03-31 FR FR8106468A patent/FR2503143A1/en active Granted
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR1023815A (en) * | 1949-04-13 | 1953-03-24 | Philips Nv | Process for the preparation of amino ketones and their derivatives |
GB1325192A (en) * | 1970-05-06 | 1973-08-01 | Orsymonde | Phloroglucinol derivatives |
FR2341308A1 (en) * | 1976-02-20 | 1977-09-16 | Souchard Maddy | (2,4,6)-Trimethoxy-phenacyl-amines - with cardiovascular activity |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2555576A1 (en) * | 1983-11-25 | 1985-05-31 | Lafon Labor | N- (METHOXYPHENACYL) -AMINE DERIVATIVES, IN PARTICULAR USE IN THERAPEUTICS AND METHOD OF PREPARATION |
EP0143711A2 (en) * | 1983-11-25 | 1985-06-05 | LABORATOIRE L. LAFON Société anonyme dite: | Derivatives of N-(methoxyphenacyl)amine, their therapeutical use and process for their preparation |
EP0143711A3 (en) * | 1983-11-25 | 1985-08-07 | Laboratoire L. Lafon Societe Anonyme Dite: | Derivatives of n-(methoxyphenacyl)amine, their therapeutical use and process for their preparation |
Also Published As
Publication number | Publication date |
---|---|
FR2503143B1 (en) | 1984-08-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0233106B1 (en) | (-)-benzhydrylsulfinylacetamide, process for its preparation and its use in therapy | |
FR2500450A1 (en) | NOVEL AMINOMETHYL-5-OXAZOLIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC USE THEREOF | |
EP0362001A1 (en) | N-cycloalkyl benzylamines alpha,alpha disubstituted, the process for their preparation, their use as drugs and their synthesis intermediates | |
CH649994A5 (en) | 4H-1,2,4-TRIAZOLE DERIVATIVES, METHODS OF PREPARATION AND COMPOSITIONS CONTAINING THEM. | |
FR2534915A1 (en) | New 2-(phenoxymethyl)morpholine derivatives, their therapeutic use and process for preparing them | |
FR2658821A1 (en) | NOVEL PROPANAMINES, THEIR PHARMACOLOGICAL PROPERTIES AND THEIR USE FOR THERAPEUTIC PURPOSES, ESPECIALLY ANTIDIARRHEUTICS. | |
EP0037344B1 (en) | Amino-alcoxy pyrazoles, process for their preparation and medicaments containing them | |
FR2503143A1 (en) | Tri:methoxy phenacyl alkylamine(s) - having sedative, anti:depressant, and anti:aggressive activity | |
EP0426562B1 (en) | 1-(4-Aminophenyl)-2-piperidinopropanone derivatives, process for their preparation and their therapeutic use | |
EP0143711B1 (en) | Derivatives of n-(methoxyphenacyl)amine, their therapeutical use and process for their preparation | |
EP0061406B1 (en) | Benzamido-alkyl-hydroxamic-acid derivatives, preparation thereof and therapeutical composition | |
EP0001947B1 (en) | 2-amino-thiazoline derivatives, their preparation and their use in pharmaceutical preparations | |
EP0097546B1 (en) | Benzhydrylsulfinyl ethyl amines, process for their preparation and their use in therapy | |
EP0110747B1 (en) | (2,4,6-trimethoxyphenyl)-(3-piperidinopropyl)-ketone derivatives, their therapeutical use and preparation process | |
EP0123605B1 (en) | N-cyclopropylmethyl-2-oxo-3-diparamethoxyphenyl-5,6-triazines, process for its preparation and their use as pharmaceutical preparations | |
EP0581677B1 (en) | Cycloalkylalkylamines which are sigma-receptor ligands, process for preparing them and their application in therapy | |
FR2486074A1 (en) | FLUOROPHENACYL-AMINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC USE THEREOF | |
FR2690917A1 (en) | New amino-di:chloro-benzyl-propanol ester cpds. - used to treat depression, neuroses, mood disturbance, migraine, insomnia and nausea | |
EP0110748B1 (en) | Derivatives of phenyl-(3-aminopropyl) ketone, their therapeutical use and process for their preparation | |
FR2507180A1 (en) | NOVEL PHENYLALKYLAMINES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINES | |
EP0445116A1 (en) | [(aryl-4-piperazinyl-1)-2 ethoxy]-3 p-cymene, the ortho, meta and para derivatives mono- or disubstituted on the phenyl nucleus of said product, process for preparing said derivatives, and drugs containing said compounds as active ingredients | |
EP0174887B1 (en) | 1-[N-(alpha-amino-alpha-methylacetyl)-aminophenyl]-2-amino propanon derivatives, process for their preparation and their therapeutical use | |
FR2509298A1 (en) | NOVEL CYSTINE DERIVATIVES AND THEIR USEFUL SALTS AS MEDICAMENTS AND PROCESS FOR THEIR PREPARATION | |
FR2515177A1 (en) | 1-Amino:phenyl 2-isopropyl or tert.butyl-amino 1-ethanol derivs. - used as antidepressants, sedatives, vasodilators and hypotensives, without hyper:reactivity and excitation side effects | |
FR2594335A1 (en) | 5-(2-Piperazinoethyl)thiazole derivatives as medicaments for use in urology |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
ST | Notification of lapse |