CH520097A - Phloroglucic acid derivs - Google Patents
Phloroglucic acid derivsInfo
- Publication number
- CH520097A CH520097A CH9372A CH9372A CH520097A CH 520097 A CH520097 A CH 520097A CH 9372 A CH9372 A CH 9372A CH 9372 A CH9372 A CH 9372A CH 520097 A CH520097 A CH 520097A
- Authority
- CH
- Switzerland
- Prior art keywords
- acid
- trimethoxy
- chloride
- condensed
- phloroglucic
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- 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
- C07C233/12—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 halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
- C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical 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)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
New cpds. of formula : (where X is O or NH; A is a branched or linear divalent alkyl or >6C; R is amino aliphatic gp. or 5,6 or 7-membered N-heterocycle, opt. including a second heteroatom chosen from O, S and N), and their acid addn. salts, are prepd. by condensing trimethoxy-2,4,6-benzoic acid to the chloric acid with HXAR. - Used as antispasmodics and for digestive troubles.
Description
Procédé de préparation d'esters de l'acide phloroglucique La présente invention concerne un procédé de préparation d'esters de l'acide phloroglucique répondant 4 la formule générale
EMI0001.0000
dans laquelle A est un groupe divalent linéaire ou rami fié ayant au maximum 6 atomes de carbone, et R est une fonction amine aliphatique primaire, secondaire ou ter tiaire, ou N-hétérocyclique à 5, 6 ou 7 chaînons, l'hétéro- cycle pouvant contenir un deuxième hétéroatome choisi parmi l'oxygène, le soufre et l'azote, ainsi que leurs sels.
Ces divers composés sont utiles notamment comme antispasmodiques, et vis-à-vis des troubles digestifs.
Le procédé de synthèse des composés de la formule I est caractérisé en ce que l'on condense le chlorure de l'acide triméthoxy-2,4,6 benzoïque avec un amino-alcool HOAR, la base libre obtenue étant transformée si néces saire en sel d'addition d'acide.
Par fonction amine N-hétérocyclique fixée sur la deuxième valence de la chaîne alcoyle de R, on entend les groupes tels que: pipéridino, azépino, pyrrolidino, pi- pérazino, méthyl-4 pipérazino, morpholino, thiomorpho- lino.
On a donné ci-après à titre d'illustration des exem ples non limitatifs de composés selon l'invention. Exemple 1 Chlorhydrate de triméthoxy-2,4,6 benzoate de diéthylamino-2 éthyle
EMI0001.0011
a) On traite 21,2 g (0,l0 mole) d'acide triméthoxy- 2,4,6 benzoïque dans 150 cm3 de benzène avec 35,7 g (0,30 mole) de chlorure de trionyle pour préparer le chlorure d'acide.
b) On dissout le chlorure d'acide dans 100 cm3 de benzène et ajoute lentement 23,4 g (0,2 mole) de diéthyl- amino-2 éthanol, il apparaît une suspension cristalline; on porte au reflux deux heures, laisse refroidir, sature la solution avec HCl gazeux, décante le benzène de l'huile formée; on reprend l'huile par 200 cm3 d'eau, chasse les traces de benzène à 400 C sous pression ré- duite, refroidit et filtre, à .0e, C avec 50 cm3 de lessive de soude, des cristaux jaune orangé précipitent, on les filtre et lave avec un peu d'eau.
c) On sèche les cristaux sous pression réduite, les dissout dans 20 cm3 d'acétone et 50 cm3 d'éther sulfuri que; on ajoute de l'éther chlorhydrique, refroidit dans la glace, filtre le chlorhydrate et le lave à l'éther ; après recristallisation dans 50 cm3 d'éthanol, on obtient 12,85 g (rendement 37 %) d'un produit blanc fondant à 176 1780 C soluble dans l'eau, légèrement soluble dans l'éthanol, insoluble dans les hydrocarbures. Exemple 2 Chlorhydrate de triméthoxy-2,4,6 benzoate de morpholiho-2 éthyle
EMI0002.0007
On suit l'exemple Ne, 1 à partir de 21,2 g d'acide triméthoxy-2,4,6 benzoïque, 35,7 g de chlorure de thionyl et 26,2 g (0,2 mole) de morpholino-2 éthanol.
On obtient 5 g (rendement 13,8 19/o) d'une poudre blanche fondant entre 180-1900 C, soluble dans l'eau, peu soluble dans l'éthanol, insoluble dans les hydrocar bures et l'éther.
L'activité antispasmodique des composés selon l'in vention a été mise en évidence par des tests. Dans ces tests, pour des raisons de commodité, on désignera par composé Ne, 1 le chlorhydrate de triméthoxy-2,4,6 ben- zoate de diéthylamino-2 éthyl, par composé Ne, 2, le chlorhydrate de triméthoxy-2,4,6 benzoate de morpho- lino-2 éthyl.
En ce qui concerne la toxicité aiguë du composé N 1 chez la souris par voie intraveineuse, la DL 50 est de 83 mg/kg, et, par voie gastrique, de 600 mg/kg.
Les essais cliniques ont fourni les enseignements sui vants Le composé Ne, 2 a donné d'excellents résultats dans le traitement des coliques néphrétiques et dans celui des spasmes intestinaux. Il a été utilisé à la dose de 20 mg par 5 ml de soluté isotonique par voie intraveineuse deux à quatre fois par jour et à la dose de 0,25 à 0,50 g par voie buccale sous forme de cachets, 4 à 6 par jour.
Process for preparing phloroglucic acid esters The present invention relates to a process for preparing phloroglucic acid esters having the general formula
EMI0001.0000
in which A is a linear or branched divalent group having at most 6 carbon atoms, and R is a primary, secondary or tertiary aliphatic amine, or 5, 6 or 7 membered N-heterocyclic function, the heterocyclic possibly containing a second heteroatom chosen from oxygen, sulfur and nitrogen, as well as their salts.
These various compounds are useful in particular as antispasmodics, and vis-à-vis digestive disorders.
The process for the synthesis of the compounds of formula I is characterized in that the chloride of trimethoxy-2,4,6 benzoic acid is condensed with an amino alcohol HOAR, the free base obtained being converted if necessary into acid addition salt.
By N-heterocyclic amine function attached to the second valence of the alkyl chain of R, is meant groups such as: piperidino, azepino, pyrrolidino, piperazino, 4-methyl piperazino, morpholino, thiomorpholino.
Non-limiting examples of compounds according to the invention have been given below by way of illustration. Example 1 2,4,6-2-diethylamino-ethyl-trimethoxybenzoate hydrochloride
EMI0001.0011
a) 21.2 g (0.10 mole) of trimethoxy-2,4,6 benzoic acid in 150 cm3 of benzene are treated with 35.7 g (0.30 mole) of trionyl chloride to prepare the chloride of 'acid.
b) The acid chloride is dissolved in 100 cm3 of benzene and slowly added 23.4 g (0.2 mole) of 2-diethylaminoethanol, a crystalline suspension appears; the mixture is refluxed for two hours, allowed to cool, the solution saturated with gaseous HCl, the benzene decanted from the oil formed; the oil is taken up in 200 cm3 of water, the traces of benzene are driven off at 400 C under reduced pressure, cooled and filtered at .0e C with 50 cm3 of sodium hydroxide solution, orange-yellow crystals precipitate, one filter them and wash them with a little water.
c) The crystals are dried under reduced pressure, dissolved in 20 cm3 of acetone and 50 cm3 of sulfuric ether; hydrochloric ether is added, cooled in ice, the hydrochloride filtered off and washed with ether; after recrystallization from 50 cm3 of ethanol, 12.85 g (37% yield) of a white product, melting at 176 1780 C, soluble in water, slightly soluble in ethanol, insoluble in hydrocarbons, are obtained. Example 2 Trimethoxy-2,4,6-2-morpholiho-2-ethyl benzoate hydrochloride
EMI0002.0007
Example Ne is followed, 1 from 21.2 g of 2,4,6-trimethoxy benzoic acid, 35.7 g of thionyl chloride and 26.2 g (0.2 mol) of morpholino-2 ethanol.
5 g (yield 13.8 19 / o) are obtained of a white powder, melting between 180-1900 ° C., soluble in water, sparingly soluble in ethanol, insoluble in hydrocarbons and in ether.
The antispasmodic activity of the compounds according to the invention has been demonstrated by tests. In these tests, for reasons of convenience, by compound Ne, 1 will denote the hydrochloride of 2,4,6-trimethoxy-2-diethylamino-ethyl benzoate, by compound Ne, 2, the hydrochloride of trimethoxy-2,4 , 6 morpholino-2 ethyl benzoate.
As regards the acute toxicity of compound N 1 in mice by the intravenous route, the LD 50 is 83 mg / kg, and, by the gastric route, 600 mg / kg.
The clinical trials have provided the following teachings. Compound Ne, 2 has given excellent results in the treatment of renal colic and in that of intestinal spasms. It was used at a dose of 20 mg per 5 ml of isotonic solution intravenously two to four times a day and at a dose of 0.25 to 0.50 g orally as tablets, 4 to 6 per day.
Claims (1)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR6917561A FR2051486B1 (en) | 1969-05-29 | 1969-05-29 | |
CH695670A CH520114A (en) | 1969-05-29 | 1970-05-11 | Preparation of phloroglucic acid derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
CH520097A true CH520097A (en) | 1972-03-15 |
Family
ID=25700483
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CH9372A CH520097A (en) | 1969-05-29 | 1970-05-11 | Phloroglucic acid derivs |
Country Status (1)
Country | Link |
---|---|
CH (1) | CH520097A (en) |
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1970
- 1970-05-11 CH CH9372A patent/CH520097A/en not_active IP Right Cessation
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Legal Events
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PL | Patent ceased |