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  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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  • C07C43/02—Ethers
  • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
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  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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  • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
  • C07C45/562—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with nitrogen as the only hetero atom
  • C07C45/565—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with nitrogen as the only hetero atom by reaction with hexamethylene-tetramine
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  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
  • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
  • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
  • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C47/00—Compounds having —CHO groups
  • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
  • C07C47/56—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups
  • C07C47/565—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups all hydroxy groups bound to the ring
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C47/00—Compounds having —CHO groups
  • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
  • C07C47/56—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups
  • C07C47/57—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups polycyclic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C47/00—Compounds having —CHO groups
  • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
  • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D233/22—Radicals substituted by oxygen atoms
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
  • C07D243/04—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 3

Definitions

• New di-orthosubstituted phenols of which one of the substitutions is a heterocycle their process of preparation, drugs containing them in particular antihypertensives and new synthesis intermediates.
• the present invention relates to the amino phenols of formula (I) and their acid addition salts. It also relates to the process for the preparation of said products and their application in therapeutics. It also relates to new intermediate compounds allowing the synthesis of said products.
• the new compounds according to the invention are chosen from the group consisting of: a) the compounds of general formula (I):
• X represents a halogen atom, a nitro, methoxy, thiomethyl group, SO CH 3 , SO 2 CH 3 , acetamido or allyl.
• R represents a hydrogen atom, an alkyl radical in particular the terbutyl or isobutyl radical, a cycloalkyl radical in particular the cyclohexyl radical, an alkylcycloalkyl radical in particular the methylcyclopentyl radical, an alkoxy radical, a thioalkyl radical or a halogen atom, n is an integer equal to 0, 1 or 2 b) their acid addition salts.
• the compounds of formula (I) according to the invention can be synthesized: 1 - Either by the action of a halogen or of a halogen chloride on a compound of formula (II) in a solvent such as for example the acid acetic acid, at room temperature, or by the action of an N-halosuccinimide on the compound of formula (II) in a solvent such as dimethyl formamide, at temperature ambient temperature, either by the action of sulfuryl chloride in a solvent such as, for example, acetic acid, 1 ambient temperature, or by nitration using nitric acid in acetic acid, at ambient temperature.
• a solvent such as for example the acid acetic acid, at room temperature
• an N-halosuccinimide on the compound of formula (II) in a solvent such as dimethyl formamide
• R and n are defined as above.
• the compounds of formula (II) can be obtained by reaction of a compound of formula (III) with a diamine of formula:
• R is defined as above.
• nitriles of formula (III) can be obtained from aldehydes of formula (IV) by methods known per se such as, for example, the action of formic acid, hydroxylamine hydrochloride and sodium formate. reflux.
• R is defined as above.
• the aldehydes of formula (17) can be prepared by conventional methods such as the Sommelet reaction: action of hexamethylene tetramine on the chloromethylated derivatives of formula (V) or also the action of the sodium salt of nitropropane on the same derivatives of formula (V):
• R is defined as above.
• the chloromethylated derivatives of formula (V) are prepared by a conventional reaction of white chloromethylation: action of formalin in the presence of hydrochloric acid on the derivatives of formula (VI):
• R is defined as above. 2 - Or by action of a diamine of formula: H 2 N - CH 2 - (CH 2 ) n - CH 2 - NH 2 where n is defined as above, at a temperature between 160 ° C and 250 ° C in a sealed tube if necessary on an ortho nitrile phenol of formula (VII):
• R and X are defined as above.
• nitriles of formula (VII) can be obtained from aldehydes of formula (VIII) by methods known per se such as, for example, the action of formic acid, hydroxylamine hydrochloride and sodium formate. reflux or by heating in acetic anhydride the oxime obtained from the aldehyde of formula (VIII)
• R and X are defined as above.
• R in the formula (IX), R and X are defined as above.
• the acid addition salts of the compounds of formula (I) can be obtained by reaction with a mineral or organic acid, according to a method known per se.
• acids which can be used for this purpose, mention may in particular be made of hydrochloric and hydrobromic acids; sulfuric, phosphoric, oxalic, succinic, methane sulfonic, cyclohexylsulfamic, formic, aspartic, glutamic, N-acetyl aspartic, N-acetyl glutamic, ascorbic, maleic, malic, fumaric, lactic, benzoic, cinnamic, p-toluene sulfonic.
• compositions useful in particular for the treatment of hypertension contain, in association with a physiologically acceptable excipient, at least one compound of formula (I) or one of its non-toxic acid addition salts.
• the invention further relates to the new intermediate products of formula (II), (III) and (VII) in particular.
• a mixture of 120 g of p-cyclohexylanisole, 17.1 g of formalin (trioxymethylene) and 190 ml of 36% hydrochloric acid is brought to 60 ° C. for 26 h.
• reaction mixture is then cooled and extracted with ether.
• reaction mixture is then concentrated under vacuum, taken up in water and extracted with ether.
• the ethereal phase is carefully washed with water, 10% sodium hydroxide and again with water, then dried over sodium sulfate.
• reaction mixture is then subjected to steam entrainment.
• the entrained phase is then extracted with ether which is carefully washed with water, 5% sodium hydroxide and again with water, then dried over sodium sulfate.
• Example 8 According to the procedure of Example 8, but using 85 g of 2-methoxy 5-isobutylbenzonitrile prepared in Example 6 and 206 ml of ethylenediamine, 72.3 g of 2- (2'-imidazolinyl) are obtained. 4-isobutylphenol in the form of crystals with a melting point of 185-187 ° C.
• Example 8 According to the procedure of Example 8, but using 49 g of 2-methoxy 5-cyclohexylbenzonitrile prepared in Example 7 and 118 ml of ethylenediamine, 47.1 g of 2- (2'-imidazolinyl) are obtained. 4-cyclohexylphenol in the form of melting point crystals 194-196oC.
• Example 12 According to the procedure of Example 12, but using 10 g of 2- (2'-imidazolinyl) 4-isobutylphenol prepared in Example 9 and 7.5 g of iodine chloride, after recrystallization from chloroform 8.2 g of 2- (2'-imidazolinyl) 4-isobutyl 6-iodophenol hydrochloride monohydrate in the form of white crystals with a melting point of 170-172 ° C.
• a mixture of 15 g of 2-methoxy 5-Isobutylbenzonitrile prepared in Example 6 and 125 ml of 1,3-diaminopropane is brought to 165 ° C. in a sealed tube for 8 h.
• 6-iodophenol in the form of white crystals with a melting point of 190-192 ° C.
• Example 18 According to the procedure of Example 18, but using 5 g of 2- (2'-tetrahydro-3 ', 4', 5 ', 6' pyrimidinyl) 4-ter butylphenol prepared in Example 20 and 1, 1 ml of bromine, 7.6 g are obtained which, recrystallized from acetonitrile-isopropanol 7-3, give 4.7 g of 2- (2'-tetrahydro-3 ', 4', 5 ', 6 hydrobromide 'pyrimidinyl) 4-ter butyl 6-bromophenol in the form of white crystals with a melting point of 210-211 ° C.
• Example 19 According to the procedure of Example 19, but using 6 g of 2- (2'-tetrahydro-3 ', 4', 5 ', 6' pyrimidinyl) 4-terbutylphenol prepared in Example 20 and 4.2 g of iodine chloride, 8.5 g are obtained which, recrystallized from acetonitrileisopropanol 7-3, gives 5.9 g of 2- (2'-tetrahydro 3 ', 4', 5 ', 6' hydrochloride pyrimidinyl) 4-ter butyl 6-iodophenol in the form of white crystals with melting point 207-209 ° C decomposition.
• Example 18 According to the procedure of Example 18, but using 7.5 g of 2- (2'-tetrahydro-3 ', 4', 5 ', 6' pyrimidinyl) 4-cyclohexylphenol prepared in Example 23 and 1 , 5 ml of bromine, 10.9 g of crystals are obtained which, recrystallized from 60 ml of isopropanol, give 8.9 g of 2- (2'-tetrahydro-3 ', 4', 5 ', 6 hydrobromide 'pyrirmidinyl) 4-cyclohexyl 6-bromophenol in the form of white crystals with a melting point of 195-197 ° C.
• Example 19 According to the procedure of Example 19, but using 7.5 g of 2- (2'-tetrahydro-3 ', 4', 5 ', 6' pyrimidinyl) 4-cyclohexylphenol prepared in Example 23 and 4 , 7 g of iodine chloride, 9.6 g of crystals are obtained which, recrystallized from 100 ml of isopropanol, lead to 6.9 g of 2- (2'-tetrahydro-3 ', 4', hydrochloride 5 ', 6' pyrimidinyl) 4-cyclohexyl 6-iodophenol in the form of white crystals with a melting point of 203-205 ° C decomposition.
• a mixture of 40 g of 2-methoxy 5-ter butylbenzonitrile prepared in Example 5 and 96 ml of 1,4-diaminobutane is brought to 160 ° C. in a flask with good stirring for 8 h.
• reaction mixture is then cooled and the crystals formed are drained and carefully washed with isopropanol then with ether and dried.
• the procedure is as follows: A mixture of 490 g of glycerol and 114.2 g of boric acid is heated to 165 ° C. and the glycerol-water azeotrope is allowed to distill until obtaining a temperature of 165 ° C in the reaction flask. Then let cool to 150oC and an intimate mixture of 81.6 g of 2-fluoro 4-terbutyl phenol and 81.6 g of hexamethylene tetamine is added in small portions while maintaining the temperature of the reaction mixture between 150 ° C and 165 ° C; after the addition is complete this temperature is maintained for 20 minutes.
• Example 30 According to the procedure of Example 30 but using 22.6 g of 2-hydroxy 3-methoxy 5-terbutyl benzaldehyde prepared in Example 40, 20.5 g of 2-hydroxy 3-methoxy 5-terbutyl benzonitrile are recovered. in the form of crystals with melting point 74-76 ° C.
• Example 31 According to the procedure of Example 31 but using 20.5 g of 2-hydroxy 3-methoxy 5-terbutyl benzonitrile prepared in Example 41 and 50 ml of ethylene diamine, 19 g of 2- (2 ') are recovered. -imidazolinyl) 4-terbutyl 6-methoxy phenol in the form of crystals with a melting point of 243-6 ° C. Hydrochloride 10 g of base are dissolved in hot methanol and added with hydrochloric ether until acid pH. The solution is then concentrated in vacuo and taken up in ether and the crystals formed are drained, washed with ether and dried.
• reaction mixture is then brought to dryness under vacuum and the residue crystallizes from acetonitrile.
• the mixture is stirred for 6 h at room temperature and then left to stand overnight.
• reaction mixture is then added with hydrochloric ether and then evaporated to dryness.
• residue is then taken up hot with 100 ml of isopropanol and the crystals formed are drained.
• 2.3 g of 2- (2'-imidazolinyl) 4-terbutyl 6-acetamido phenol hydrochloride are thus recovered in the form of crystals with melting point 149-151 ° C.
• Example 35 According to the procedure of Example 35 but from 16 g of 2- (2'-imidazolinyl) 4-IsobutyI phenol prepared in Example 9 of the 1st text, 6.6 g of 2 are obtained after recrystallization from methanol - (2'-imidazolinyl) 4-isobutyl 6-nitrophenol in the form of crystals with a melting point of 293 ° C decomposition.
• Example 30 According to the procedure of Example 30 but using 34.6 g of 2-hydroxy 3-thiomethyl 5-isobutyl benzaldehyde prepared in Example 51, 27.4 g of 2-hydroxy 3-thiomethyl 5-isobutyl benzonitrile are recovered. in the form of melting point crystals 74-7 ° C
• a mixture of 197 g of p-methylcyclopentyl anisole, 31 g of formalin (trioxy methylene) and 346 ml of 36% hydrochloric acid is brought to 60 ° C. for 14 h.
• reaction mixture is then cooled and extracted with ether.
• Example 31 According to the procedure of Example 31 but using 13.4 g of 2-hydroxy 3-chloro 5-methylcyclopentyl benzonitrile prepared in Example 63 and 32 ml of ethylene diamine, 12.5 g of 2- ( 2'-imidazolinyl) 4-methylcyclopentyl 6-chlorophenol in the form of crystals with a melting point of 288-294 ° C. Hydrochloride These 12.5 g of base are dissolved in methanol and added with hydrochloric ether until acid pH. The solution is concentrated in vacuo and the residue taken up in ether. The crystals formed are drained, washed with ether, with acetonitrile then again with ether and dried. 13.3 g of 2- (2'-imidazolinyl) 4-methylcyclopentyl 6-chlorophenol hydrochloride are thus recovered in the form of crystals with a melting point of 228-232 ° C.
• reaction mixture is stirred again for 6 h and then left to stand overnight.
• Example 58 According to the procedure of Example 58 but using 40 g of 2-methoxy 5-isopropyl benzonitrile prepared in Example 85 and 96 ml of ethylene diamine, 22 g of 2- (2'-imidazolinyl) 4 are obtained. -isopropyl phenol in the form of melting point crystals 175-180oC.
• Example 71 According to the procedure of Example 71 but using 11.7 g of 2- (2'-imidazolinyl) 4-isopropyl phenol prepared in Example 86 and 9.1 ml of sulfuryl chloride, 7.7 is recovered. g of 2- (2'-imidazolinyl) 4-isopropyl 6-chlorophenol in the form of crystals with a melting point of 242-5 ° C. Hydrochloride The 7.7 g of base are dissolved in methanol and added with hydrochloric ether until acid pH. The solution is concentrated in vacuo and the residue taken up in ether crystallizes. The crystals are wrung out, washed with ether and dried.
• ANTI-HYPERTENSIVE ACTIVITY 1- Method Male rats aged 13 to 21 weeks with spontaneous genetically transmissible hypertension (strain OKAMOTO from IFFA-CREDO) are placed in an enclosure thermostatically controlled at 38 ° C. The rats are left free. Blood pressure is measured by a Narco Biosystem sphygm ⁇ manometer. A sleeve is placed at the base of the tail and a sensor registers the pulse downstream of the sleeve. This is inflated until the pulse is removed, then it is gradually deflated. The pressure measured at the resumption of heartbeat is systolic blood pressure. The heart rate is calculated from the recording of the arterial pulse. Products to study are suspended and administered orally in a volume of 1 ml per 100 g of body weight. The measurements are repeated at regular intervals.
• Table II below gives the average of the variations in systolic pressure (mm Hg), of the heart rate (beats / minute) and the deviations from the average obtained 1 h, 3 h and 5 h after oral administration.
• the compounds described have a remarkable hyper tensive activity because they cause little or no reaction tachycardia. They are not very toxic: the lethal doses 50 in the rat intraperitoneally range between 128 and 500 mg / kg or greater than 500 mg / kg.
• the compounds of formula (I) and their non-toxic addition salts can be administered in particular by oral or injectable route.
• oral route capsules or tablets containing 10 to 200 mg of active ingredient are recommended and, by injection, ampoules containing 2 to 50 mg of active ingredient.
• the compounds of formula (I) allow the treatment of hypertension, in particular in the form of capsules or in an injectable form.

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Citations (6)

• 1981
  • 1981-07-17 FR FR8114011A patent/FR2509730A1/fr active Granted
• 1982
  • 1982-07-19 MC MC82FR8200120D patent/MC1517A1/xx unknown
  • 1982-07-19 JP JP57502218A patent/JPS58501127A/ja active Pending
  • 1982-07-19 EP EP82401339A patent/EP0070779A3/fr not_active Withdrawn
  • 1982-07-19 AU AU87316/82A patent/AU8731682A/en not_active Abandoned
  • 1982-07-19 WO PCT/FR1982/000120 patent/WO1983000333A1/fr not_active Ceased
• 1983
  • 1983-03-15 DK DK119783A patent/DK119783A/da not_active IP Right Cessation

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