IE57094B1 - 1-(2-carbethoxy 4-benzalkylamido phenoxy)3-amino 2-propanols,preparation thereof and use thereof in therapeutics - Google Patents
1-(2-carbethoxy 4-benzalkylamido phenoxy)3-amino 2-propanols,preparation thereof and use thereof in therapeuticsInfo
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- IE57094B1 IE57094B1 IE528/84A IE52884A IE57094B1 IE 57094 B1 IE57094 B1 IE 57094B1 IE 528/84 A IE528/84 A IE 528/84A IE 52884 A IE52884 A IE 52884A IE 57094 B1 IE57094 B1 IE 57094B1
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- carbethoxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
1. Claims for the Contracting States : BE CH DE FR GB IT LI LU NL SE Compounds characterized in that they respond to formula : see diagramm : EP0122827,P20,F2 in which : - R and R' may each designate an atom of hydrogen, an atom of halogen, a nitro group or alkyl or alkoxy radicals with C1-C5, branched or not, or a SCH3 or CF3 group ; - R1 represents a lower alkyl radical with 1 to 5 carbon atoms, branched or not ; - R2 represents a lower alkyl radical with 1 to 5 carbon atoms, branched or not ; and - n designates an integer less than 5. 1. Claims for the Contracting State : AT A process for preparing novel compounds responding to formula see diagramm : EP0122827,P21,F2 in which : - R and R' may each designate an atom of hydrogen, an atom of halogen, a nitro group or alkyl or alkoxy radicals with C1-C5, branched or not, or a SCH3 or CF3 group ; - R1 represents a lower alkyl radical with C1 -C5 , branched or not ; - R2 represents a lower alkyl radical with C1 -C5 , branched or not ; and - n designates an integer less than 5, characterized in that said process comprises the step of reacting a base of formula NH2 -R2 where R2 is as defined hereinabove, on a compound of formula (II) without solvent or in a conventional organic solvent such as alcohols, at a temperature of between 20 degrees C and 150 degrees C, see diagramm : EP0122827,P21,F3 R, R', R1 and n being as defined hereinabove.
Description
The present invention relates as novel products to derivatives of 4-benzalkylamido 2-carbalkoxy phenoxy amino-propanol of genera! formula (I) and to their acid addition salts. The derivatives in question present a highly original and very surprizing pharmacological profile since they are endowed with diuretic properties associated, for certain products, with blocking properties.
The present invention also relates to the process for preparing said products and to the application thereof in therapeutics.
The compounds according to the invention belong to the group 10 < imstitutecl by the products of general formula (I) and their non-toxic acid addition salts :oo r1 R’ CONH .OCH2- CH, CH2-NH,R2 OH (I) In formula (I): - R and R‘ may each designate an atom of hydrogen, an atom of halogen for example fluorine, a nitro group, a straight chain or brmchcd C^— alkyl or C.-Cr alkoxy radical, or an S(1k or CF3 group; -R| represents a straight chain or brandied ‘d-kyl radical advantageously the ethyl radical ; -F<2 represents a straight chain or branched c|~Cg alkyl radical and preferably the isopropyl radical or the terbutyl radical; - n designates an integer less than 5, and preferably equal to 0 or I.
The compounds according to the invention are synthesized by action ot an NH2'R2 base (¾ being defined as hereinabove) on a compound of formula (H) without solvent or in a conventional organic solvent such as alcohols, at a temperature of between 20°C and 150°C.
(ID In formula (II), R, R', R| and n are defined as hereinabove.
The compounds of formula (II) are generally obtained by reaction of a phenol of general formula (III) with an excess of epihalohydrin, particularly epichlorohydrin or epibromohydrin, in the presence of a catalyst such as benzyltrimethylamrnonmm chloride, at a temperature ranging from U0uC to B0"C. This process yields perfectly crystallized compounds with better yields than the processes evoked hereinafter. The compounds of formula (11) may also be obtained by reaction of the phenol of general formula (III) with any epihalohydrin according to the conventional processes. The phenol of formula (111) will then be metalled by conventional metallation agents such as potassium hydroxide, sodium hydroxide, an alkoxide or sodium hydride in a hydroalcoholic solvent, alcohol or dimsthylfomamide (DMF) at a temperature of between 20°C and 150QC. However, these processes yield products which are less well defined.
R’ (HI) In formula (III), R, R’, Rj and n are defined as hereinabove.
The compounds of formula (HI) arc obtained in accordance with known processes of preparation consisting cither in reacting the c hloride 20 of the corresponding arylalkanoic acid with a ^-arnino 2-carbalkoxy phenol in the presence of a base such as triethylamine in a solvent such as acetone or benzene, or in esterifying the corresponding acid (IV) in a sulfuric acidalcohol medium. <1 Ir formula (IV), R, R' and n are defined as hereinabove.
T ie addition salts of the compounds of formula (I) may be obtained by rear tion of these compounds with an inorganic or organic acid in accordance with a me hod known per se. Among the acids which may be used to this end, particular mention will be made of hydrochloric, hydrobromic, acetic, p-toluenc ulfonic, methane sulfonic, oxalic, succinic, maleic, fumaric, cinnamic, malic, aspartic, glutamic, ascorbic, N-aeetyl aspartic and N-acetyl glutamic acids.
The novel compounds according to the invention are endowed with remarkable pharmacological properties and may be used in therapeutics for the treatment of hypertension since, most surprizingly, they present diuretic properties with, for certain of the products, β blocking properties, and low toxicity. These remarkable characteristics seem to be due to the presence in the molecules of the ester function in ortho position arid of the amide function in para position.
In human therapeutics, the compounds of formula (I) and their nontoxic acid addition salts may be administered in particular by th*' oral route.
In that case, the use of gelatin-capsules or of tablets containing from 50 to 300 mg of active ingredient in association with a physiologically acceptable excipient is recommended. The compounds claimed present the advantage of rendering treatment easier. On the other hand, with respect to the bloc king/diuretic associations used in the treatment of hypertension, the compounds of formula (1) have the advantage of single pharmacokinetics.
Angor pectoris and arrhythmia will be mentioned as other possible examples of indications.
Other features and advantages of the invention will appear more clearly on reading the following non-limiting examples of preparation given by way of illustration.
The formulae corresponding to the Examples are given in the single Table .»i the end ol the specification. Εχ.κυρΙο I : l-[ 2-carbethoxy 4-(4-fluoro benzamido) phenoxy] 2,3-epoxy propane Formula II R Fluorine in 4 position Rj '> ΙΓ - Η n - 0 In a flask, the mixture of 34 g of 2-carbcthoxy 4-(4-fluoro benzamido) phenol and 150 ml of epichlorohydrin is heated to 110°C. 2.7 g of benzyltrimethyl ammonium chloride are then introduced. The reaction mixture is heated to i eflux for 1/2 hr. then cooled. Once the temperature has dropped to 50°C, 150 ml of water are added and the mixture is stirred well. The organic phase is decanted and the aqueous phase extracted twice with 50 ml ether. The organic phases are dried over magnesium sulfate then concentrated in vacuo.
The crude residue obtained crystallizes in 200 ml of ether to yield 22 g of 1- 12-carbethoxy 4-(4-fluoro benzamido) phenoxy) 2,3-epoxy propane melting at II5°C.
Example 2 : l-(2-carbethoxy 4-(3-fluoro benzamido) phenoxy] 2,3-epoxy propane Formula fi R = Fluorine in 3 position Rj = R' = Η n - 0 The modus operand! is identical to the one described in Example 1. From 50 g of 2-carbethoxy 4-('i-fluoro benzamido) phenol, 4 g of benzyltrirnethylaminoniuin chloride and 250 ml of epichlorohydrin, 24 g of J-12-carbethoxy 4-(3-fluoro benzamido) phenoxy] 2,3-epoxy propane melting at 100’C are obtained.
Example 3 : 1-12-carbethoxy 4-(2-fluoro benzamido) phenoxy] 2,3-epoxy propane Formula II R = fluorine in 2 position Rj = R* - Η n = 0 The modus operandi is the same as the one described in Example 1. From 36 g of 2-carbethoxy 4-(2-fluoro benzamido) phenol, 3 g of benzyltrimethylammonium chloride and 185 ml of epichlorohydrin, 14 g of 1-(2-carbethoxy 4-(2-1 luoro benzamido) phenoxy] 2,3-epoxy propane melting at 89°C are obtained.
Example 4 : 1-1 2-carbethoxy 4-(4-fluoro benzamido) phenoxy] 3-terbutylamino 2- propanol SH3 I tiiniulu I R lliiui'iiu· in H posilion Rj ^'2^5 \ R’ : Η n . 0 The mixture of 11 g of the product of Example 1, 20 ml of terbutylarnine and 60 rnl of ethanol is heated to 60°C for 8 hrs., then concentrated in vacuo. The residue is taken up in 3 ml of acetic acid in 200 ml of water and 200 ml of isopropyl acetate. The mixture is stirred well and the isopropyl acetate eliminated by decantation. The aqueous phase is then neutralized by ammonia then extracted 3 times with 50 ml of methylene chloride. After drying over magnesium sulfate and concentration in vacuo of the organic phase, a residue is obtained which crystallizes in ether. Recrystallization in isopropyl acetate yields 8 g of l-[2-carbethoxy 4-(4-fluoro benzarnido) phenoxy] 3-ierbutylamino 2-propanol in the form of white crystals melting at 130C. Example\ : l-|2-carb<‘thoxy 4-(4-fluoro benzarnido) phenoxy I 3-isopropylamino 2-propanol zCH3 Formula I R fluorine in 4 position Rj-C^H^ R^- -CH s ch3 R' Η n 0 The modus operandi is identical to the one described in Example 4 but using isopropylamine in place of terbutylamine. From 11 g of the product of Example I, a crude product is obtained whichzecrystallized in isopropyl acetate, yields 6 g of l-[2-carbethoxy 4-(4-fluoro benzarnido) phenoxy] 3-isopropylamino 2-propanol in the form of white crystals melting at J17nC.
Example 6 : 1-|2-carbethoxy 4-(3-fluoro benzarnido) phenoxyl 3-terbutyJamino 2-propanol Formula 1 R .-. fluorine in 3 position RpC^H^ R’ = Η n = 0 pH3 R---C.-CH Lh3 The modus operandi is the same as the one described in Example 4. From 14 g of the product of Example 2 and from 80 ml of terbutylamine, 7 g of l-[2-carbethoxy 4-(3-fluoro benzarnido) phenoxy] 3-terbutylamino 2propanol in the form of white crystals melting at II4°C are obtained after >1. recrystallization in isopropyl acetate.
Example 7 : Hydrochloride of l-[2-carbethoxy 4-(3-fluoro benzamido) phenoxy] 3-isopropylamino 2-propanol ^ch3 Formula 1 R .-. lluorine in 3 position Rj-C^H^ R^-CH ch3 R* - Η n = 0 The modus opcrandi is the same as the one described in Example 4 but from 8 g of the product of Example 2 and 30 ml of isopropylamine, and a white product is obtained which crystallizes in ether. By dissolving this product in acetone (200 ml) and by adding hydrochloric ether up to pH 2, the expected hydrochloride precipitates. After washing with acetone and drying, 3 g of hydrochloride of l-[2-carbethoxy 4-(3-fluoro benzamido) phenoxy] 3-isopropylamine 2-propanol in the form of white crystals melting at 182°C are thus obtained.
Example 8 : l-i 2-carbethoxy 4-(2-flnoro benzamido) phenoxy] 3-terbutylamino 2-propanol FH3 Formula 1 R - fluorine in 2 position R0=-C-CH, I 2 9 2 ι j CH3 R' = Η n - 0 The modus operand! is the same as the one described in Example 4. Starting from 12 g of the product of Example 3, 3.3 g of l-[2-carbethoxy M2-lluoro benzamido) phenoxy] 3-terbutylamino 2-propanol are obtained, in the form of white crystals melting at 124°C.
Example 9 : Hydrochloride of l-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy] 3-isopropylamino 2-propanol CH, / 3 Formula I R - fluorine in 2 position R(-C~Hc R---CH r 12 5 2% CH3 R' .- Η n - 0 The modus operand! is the same as the one described in Example 7 but from 14 g of the product of Example 3. 2 g of hydrochloride of l-[ 2-carbelhoxy 4-(2-fluoro benzamido) phenoxy] 3-isopropylarnino 2-propanol are thus obtained, in the form ol white crystals melLing at 188°C. ¥ Γ-xanipleJO : l-[ 2-carbcihoxy ^-benzamido phenoxyj 2,3-cpoxy propane Imiiiiila II R R’ I I Rj n 0 The modus operand! is identical to that described in Example I but Irom k2 g-of 2-carbethoxy 4-bcnz.ainido phenol, 257 ml of epichlorohydrin and 3,^ g of b^ri/yltriiiiethylarnmonium chloride; 23 g of l-(2-carbethoxy O-benzamido phenoxy) 2,3-cpoxy propane are obtained in the form of white crystals melting at 129°C.
Exumplcjl : l-ί 2-carbcthoxy 4-benzamido phenoxyl 3-tcrbutylamino 2-propanol Formula I R R' - H R^ CH, I 1 n = 0 Rn = -C-CH, The modus operandi is the same as that described in Example 4. Starting from 10 g ol the product of Example 10 and 50 ml oi tcrbutylamine, 3.5 g of I-[2-carbcthoxy ^-benzamido phenoxy] 3-tcrbutylamino 2-propanol arc obtained, in the form of white crystals melting at I2O°C. _lixiunjTleJ2 : l-f2-carbethoxy Q-(Q-mcthyl benzamido) phenoxy] 2,3-epoxy propane Formula II R - CH^ in 4 position R' = H Rj = C2H^ n = 0 The modus operandi is identical to that described in Example 1.
From 27 g of 2-cavbethoxy M^-tnethyl benzamido) phenol, QO ml of epichlorohydrin and 2.3 g of benzyltrimethylammonium chloride, 13.1 g of l-[2-carbethoxy 0-(4-methyI benzamido) phenoxy] 2,3-epoxy propane are obtained, in the form of white crystals melting at II7°C.
Example 13 : l-[2-carbethoxy ^-(4-methyl benzamido) phenoxy] 3-terbutylamino 2-propanol Formula I R = CHj in Q position R| = CjH^ CH3 R' r. H Ro = -C-CH, ίκ, n ~ 0 The modus operandi is the same as that described in Example 4, but starting from 11 g of the product of Example 12 and 60 ml of tcrbutylamine; ti 6.6 g of 1-| 2-carfoethoxy 4-(4-mcthyl benzamide) phenoxy] 3-1erbutylamino 2 propanol are obtained in the form of white crystals melting at 14O"C.
Example 14 l-l 2-carbcthoxy 4-(4-methyl benzamido) phenoxy I 3-isopropylamino 2-propanol ') Formula 1' R Cll^ in 4 position Rj = ZCH R* - H R? = -CH 3 n ^CH, n = 0 3 The modus operandi is the same as the one described in Example 4, but replacing the terbutylarnine by isopropylaminc. Starting from 15 g 10 of the product of Example 12 and 70 ml of isopropylamine, V g of 1-12-carbethoxy 4-(4-methyl benzamido phenoxy] 3-isopropylamino 2-propanol are obtained in the form ot white crystals melting at H4°C.
Example : l-l 2-cui h»*thoxy 4-(0-methoxy benzamido) phenoxy! 2,3-epoxy propane J5 Formula H R - OCH^ in 4 position Rj = C2H3 R' Η n - 0 The modus operandi is identical to that described in Example 1, but from 13.1 g of 2-carbcthoxy 4-(4-methoxy benzoamido) phenol, 66 ml of epichlorohydrin and i g of benzyltrimethylammonium chloride; 8.6 g of J-[ 2-carbethoxy 4-(4-methoxy benzamido) phenoxy] 2,3-epoxy propane are obtained in the lorin of white crystals melting at 126°C. _ExampJe_J6 : l-l 2-carbethoxy 4-(4-mcthoxy benzamido) phenoxy] 3-terbutylamino 2-propanol Formula 1 R - OCH^ in 4 position cn3 R' - H Ro -- -C-CHZ I J n --, 0 CK3 The modus operandi is the same as the one described in Example 4. From 8.6 g of the product of Example 15 and 20 ml of terbutylarnine, .2 g of J-[2-carbcthoxy 4-(4-methoxy benzamido) phenoxy] 3-terbutylamino 2-propanol are obtained, in the form of white crystals melting at I24°C.
Example 17 : l-[2-carbethoxy 4-(2,4-difluoro benzamido) phenoxy] 3-terbutylamino 2-propanol ιο i nimula I It Iluorine in 2 position R’ fluorine in 4 position It n 0 This product is synthesized in the same manner. Prom l-|2-carhcthoxy 4-(2,4- 1- l2-curbethoxy 4 (2,4-difluoro benzamido) phenoxyl 3-terbutylaniino 2-propanol is obtained in act ordanee with thr* modi operandi previously described M.P 138-14O°C Fxamplejjt : I-| 2-carbethoxy 4-(4-fluoro benzacetamido) phenoxy! 3-terbutyIamino 2-propanol Formula 1 R fluorine in 4 position R| CH R1 -= H R. n - 0 CH In the s..mc manner, l-f2-carbethoxy 4-(4-fluoro benzacetamido) phenoxyl 3-terbu vlamino 2-propanol is obtained from 1-( 2-carbethoxy 4-(4fluoro benzacetd· udo) phenoxyl 2,3-epoxy propane and terbutylamine in accordance with a mo ius operandi identical to those described previously M.P 1O9°C. lixarnple 19 : l-l 2-< urbethoxy 4-(4-chloro benzamido phenoxyl 2,3-epoxy propane Formula 11 R - Cl in 4 position Rj - ^H^ R’ = Η n - 0 The modus operandi is identical to that described in Example 1.
From 32 g of 2-carbethoxy 4-(4-chloro benzamido) phenol, 140 ml of epichlorohydrin and 3 g ol ben/yltrimethylnmmonium chloride, 13.2 g of l-f 2-carbethoxy 4-(4-chloro benzamido) phenoxy] 2,3-epoxy propane are obtained, used as such lor subsequent synthesis. _Examp]e_;2_0 : l-| 2-carbethoxy 4-(4-chloro benzamido) phenoxy] 3-terbutylamino 2- propanol -C-.CH.
C2*S Formula 1 P - Cl in 4 position R’ r H 1:η C2H5 I 3 = 5-CH3 R, = C2H5 CH, I 3 -C-CH, I 3 CH3 The modus operandi is the same as that described in Example 4 but, from 13 g of 1-1,2-carbethoxy 4-(4.-chloro benzamido) phenoxy] 2,3-epoxy propane prepared in Example 19, 3.6 g of l-[2-carbethoxy 4-(4-chloro benzamido) phenoxyl 3-terbutylamino 2-propanol in the form of crystals melting al I34°C arc obtained after recrystallization in isopropanol.
I.xaiiiple ?l : l-l? carbethoxy 4-(3-methyl benzamido) phenoxyl 2,3-epoxy JO pi epane Formula 11 R - CH.j in 3 position Rj - C^H^ R1 Η i> 0 According to the modus operandi of Example 1, but starting from II g of 2-carbcthoxy 4-(3-mcthyI benzamido) phenol, 20 cm7 of epichlorohydrin and I g of ben :yltrimethylammoniurn chloride, 15 g of l-[2-carbcthoxy 4-(3rnethyl benzamido) phenoxy] 2,3-epoxy propane are obtained, in the form of oil, used as such.
Example 22 : I-[2-carbethoxy 4-(3-methyl benzamido) phenoxy] 3-terbutylamino 2-propanol CH, I J Formula I R CH^ in 3 position Rj-C^H^ R^'-C-CH^ R' . Η n - 0 CH^ According to the modus operandi ol Example 4, from 15 g of the epoxide prepared in Example 21, 8.6 g of J-| 2-carbethoxy 4-(3-methyJ benzamido) phenoxyj 3-terbutylamino 2-propanol are obtained, in the form of white crystals melting at IO9WC.
Example 23 : l-l 2-carbethoxy 4-(3-methoxy benzamido ) phenoxy] 2,3-epoxy propane Formula 11 R - MeO in 3 position Rj - C^H^ R' . Η n - 0 According to the modus operandi of Example I, but from 16.4 g of 2-carbethoxy 4-(3-methoxy benzamido ) phenol, 50 ml of epichlorohydrin and 1.5 g of benzyltrimethylammonium chloride, 14.5 g of l-[ 2-carbethoxy 4-( 1-rnethoxy benzamido) phenoxy] 2.3-epoxy propane are obtained, in the lorrn of crystals melting at 90°C.
Example 24 : l-l 2-carbethoxy 4-(3-methoxy benzamido ) phenoxy] 3-terbutyIamino 2-propanol CH, I 3 Formula I R - MeO in 3 position Rj-C^H^ R^^-C-CH^ R' - Η n = 0 CH^ According to the modus operandi of Example 4, but from 14.5 g of the epoxide prepared in Example 23, 2.6 g of l-[2-carbethoxy 4-(3-methoxy Ixnzuniido ) phenoxy I V terbutylaniino 2-prnpanol are obtained, in the form ol white crystals melting at 94°C.
Example 2 5 : l-[ 2-carbethoxy 4-(2-rnethyl benzamido) phenoxy] 2,3-epoxy propane Formula II - R = CH^ in 2 position R| R' -- Η n = 0 After having prepared the sodium salt of 20 g of 2-carbethoxy 4-(2methyl benzamido) phenol in ethanol in the presence of the stoichiometric quantity of sodium hydroxide in pastille form, 50 ml of epichlorohydrin are added with stirring and the mixture is taken to reflux for 8 hours. The reaction mixture is cooled then concentrated in vacuo. The residue obtained is taken up in methylene chloride and washed with water. The organic solution is dried over magnesium sulfate, filtered, then concentrated in vacuo. The residue hardens in isopropyl ether. By taking up the solid obtained in a mixture of 100 ml of ethyl ether and 10 ml of isopropyl acetate, 6 g of l-[2-carbcthoxy 4-(2-methyl benzamido) phenoxyl 2,3-epoxy propane are obtained, in the form ol pink crystals melting at 94°C.
Example 26 : l-| 2-carbethoxy 4-(2-methyJ benzamido) phenoxyl 3-terbutylamino 2-propanol Formula I R - CH^ in 2 position R = CH0 » 3 Rn x -C-CH 2 I ch3 R' = Η n - 0 According to the modus operandi of Example 4, starting from J3 g of the epoxide prepared in Example 25, 1.2 g of I-l2-carbethoxy 4-(2-mcthyl benzamido) phenoxyl 3-terbutylarnino 2-propanol is obtained, in the form of white crystals melting at I26°C.
Example 27 : 1-12-<.arbethoxy 4-(4-methylthio benzamido) phenoxy] 2,3-epoxy propane Formula II R - CH^S in 4 position Rj ~ R* - Η n -- 0 According to the modus operandi of Example 25, but from 40 g of 2-carbethoxy 4-(4-methylthio benzamido phenol and 80 ml of epichlorohydrin, 20 g of l-f2-carbcthoxy 4-(4-methylthio benzamido) phenoxy] 2,3-epoxy propane are obtained, in the form of white crystals melting at IO5°C.
Example 78 : l-| 2-< arbethoxy 4-(4-methylthio benzarnido) phenoxy] 3-terbutyl«iinino 2-propanol I’ormula I in 4 position Rj c2n5 R.
FH3 -C-CH I CH3 R’ · Η n 0 According to the modus opcrandi of Example 4, starting from 12 g ot the epoxide prepared in Example 27 and terbutylamine, 6 g of a crude product are obtained which, recrystallized in isopropyl acetate, yields 3.5 g of l-f 2-carbethoxy 4-(4-methyltfuo benzamido) phenoxy! 3-terbutylamino 2-propanol in the form of white crystals melting at I42°C.
Example 29 : l-ί 2-carbethoxy 4-(3-< hJoro benzamido) phenoxy] 2,3-epoxy propane I'onnula 11 R Cl in 3 position R| C^H^ R’ Ιί n - 0 The modus opcrandi is identical to that of Example I. From 7 g ol 2-carbethoxy 4-(3-chloro benzamido) phenol, 30 ml of epichlorohydrin and 0.7 g ol benzyltrimethylamrnonium chloride, 4 g of l-[2-carbethoxy 4-(3(.hloro benzamido) phenoxy] 2,3-epoxy propane arc obtained in the form of white crystals melting at 95°C.
Example 30 : l-f2-carbethoxy 4-(3-chIoro benzamido) phenoxy] 3-terbutylamino 2-propanol Formula 1 R - Cl in 3 position R| = C2H5 R.
CH, I 3 -C-CH, I 3 ch3 R’ .: Η n = 0 According to the modus operand! described in Example 4, 13 g of the epoxide of Example 29 yield 2 g of l-[2-carbethoxy 4-(3-chloro benzamido) phenoxy] 3-terbutylamino 2-propanol in the form of white crystals melting dl 107°C.
Example 31 : Hydrochloride of l-[2-carbethoxy 4-(2-fluoro benzamido) phenoxy] 3-terbutylariuno 2-propanol Formula R lluorine in 2 position R* .. H R. C2H5 CH n . 0 hydrochloride -6-CH t CH, Λ solmι«>η ol 4.5 g of 1-1? raibetlioxy 4-(2-fluoro benzamido) phenoxyl V-hm binvldinino 2-prop.mol prepared in lixarnple 8, in 50 ml of absolute ethanol, is acid 11 ied lo pH 2 by hydrochloric ether. The solvent is evaporated to dryness in vacuo, and the residue is taken up in ether.
Alter draining of the precipitate obtained and washing with ether, 4.6 g of hydrochloride of l-[2-carbcthoxy 4-(2-fluoro benzamido) phenoxy] 3-terbutylamino 2-propanol, melting at 168rtC, are obtained in this way.
Example 32 : l-f 2-carbethoxy 4-(4-trifluoromethyl benzamido) phenoxy] 2,3epoxy oropanc ID Formula II : R - CE^ in 4 position R^ = C^H^ R' - Η n = 0 According to the modus operandi described in Example 25 but from ?0 g of 2-carbelhoxy 4-(4-trifluorornethyl benzamido) phenol and 50 ml of epichlorohydrin, 7 g of l-[2-carbcihoxy 4-(4-trifluorornethyl benzamido) phenoxyl 2,3-epoxy propane in the form of an oil arc obtained, used a·, such for the lollowing.
Example 33 : l-|2-rarbethoxy 4-{4-trifluoromcthyl benzamido) phenoxyl 3terbutylamino 2-propanol formula I : R - CE^ in 4 position Rj ch3 R’ - H R, = -C-CH, ι 3 n =- 0 CH3 According to the modus operandi described in Example 4, starting from 13 g of the epoxide prepared in Example 32, and 50 ml of terbutylamine, 1.5 g of 1-12-carbethoxy 4-(4-trifluoromethyl benzamido) phenoxyl 3-tcrbutylamino 2-propanol melting at 155"C is obtained after crystallization in ether and washing with isopropyl acetate.
Example 34 : 1-( 2-carbethoxy 4-(2-mcthoxy benzamido) phenoxyl 2,3-epoxy propane formula 11 : R - OCH^ in 2 position - C^H^ R' = Η n - 0 According to the modus operandi described in Example I, but from 8.5 g of 2-carbethoxy 4-(4-methoxy benzamido phenol, 50 ml of epichlorohydrin and 600 mg of benzyltrimethyl ammonium chloride, 3.5 g of l-[2-carbethoxy 4-( 2-methoxy benzamido) phenoxy] 2,3-epoxy propane, crystallized in isopropyl ether and melting at 70C are obtained.
Example 35 : l-[2-carbethoxy 4-(2-methoxy benzarnido) phenoxyl 3-terbutylamino 2-propanol Formula I : R . CCH.^ in 2 position Rj C^H,^ R' H CH? N - 0 R- - -C-CH, i 3 CH? According to the modus operandi described in Example 4, but from 3.5 g of the epoxide prepared in Example 34 and 50 ml of terbutylamine, 1.2 g of l-l 2-carbethoxy 4-(2-methoxy benzarnido) phenoxyl 3-terbutylamino 2-propanol, crystallized in pentane and melting at IO7°C, is obtained.
Example 36 : J-[2-carbethoxy 4-(2-chloro benzarnido) phenoxy] 2,3-cpoxy propane Formula 11 : R - Cl in 2 position Rj = *'2^5 K' . Η n .- 0 Λ solution of 10 g (0.03 mole) of 2-carbethoxy 4-(2-chloro benzarnido) js phenol and 2 g of 85% potassium hydroxide (0.03 mole), in 200 ml of ethanol and 30 ml of DMF, is added dropwise over 4.7 cm1 (0.06 mole) of epichlorohydrin in 50 ml of ethanol.
This solution is stirred for 3 hrs. at ambient temperature, then for I hour at 50°, and allowed to stand overnight. It is then concentrated, diluted with water and extracted with ether. After drying and evaporation of the ether, 4 g of an oil are obtained, used as such for the following.
Exampk? 37 : (-12-carbethoxy 4-(2-r hloro benzarnido) phenoxyl 3-tcrbutylamino 2-propanol and hydrochloride Formula 1 R - Cl in 2 position Rj R' - H CH3 n = 0 R-i 2 j 3 ch3 According to the modus operandi described in Example 4, but starting from 4 g of the epoxide prepared in Example 36, 2.5 g of l-[2-carbethoxy 4-(2-chloro benzarnido) phenoxy] 3-terbutylamino 2-propanol, crystallized in an acetone-ether mixture and melting at 113-115°C, are obtained.
Preparation of the hydrochloride g of l-L2-carbethoxy 4-(2-chIoro benzarnido) phenoxy] 3-terbutylii amino 2-propa »oJ are dissolved in 50 ml of acetone, and the solution is acidilied to pH 2 bv hydrochloric ether. 4.5 g of hydrochloride of I-[2-carbethoxy (4-(2-chloro benzamido) phenoxyl 3-tetbutylamino 2-propanol in the form of crystals melting at 158-161° are obtained in this way.
Example 38 : Hydrochloride of l-[2-carbethoxy 4-(2,4-difli;oro benzamido) phenoxy] 3-terbutylamino 2-propanol Formula I = R - fluorine in 2 position Rj = R' -· fluorine in 4 position CH, ι 3 IQ n : 0 ft,.- -C-CH, Z , 5 hydrochloride CH^ Λ solution of 25 g ol l-|2-carbethoxy 4-(2,4-difluoro benzamido) phenoxy) 3-terbutylamino 2-propanol prepared in Example 17 in 100 mt of ethanol is acidified to pH 2 by hydrochloric ether. The precipitate formed j5 is drained, washed with ether. g of crude hydrochloride are thus obtained, which, crystallized in acetonitrile, yield 22 g of hydrochloride of l-[2-carbethoxy 4-(2,4-difluoro benzamido) phenoxyl 3-terbutylammo 2-propanol in the form of white crystals inciting at 15I-152°C.
ExampI ο 1 Example 2 Example 3 Example 4: Example 5 Example 6 Example 7 Example 8 Example 9 TABLE I Example 10 Example 11 Example 12 Example 13 Example L4 Example 15 Example 16 Example 17 Example 18 COO C2H5 \/ 2 0 OH CH.
-CH.
CH. _ coo c2h5 ch3C0NH°CH2ϋη'ΠΙ,> ’N11'C’CH3 ~ nu CH.
' CONII011 COO CZIL CH.
OCH2-CH-CH2-NH-C-C11 OH COO C9H5 CI{2— CONH ^^OCH2-CH-CH2"NH-C-CH nn Example 20 coo-c2h5 ?3 0-CH-s—CH-CIk—NH—C—CH i OH CH3 Example 21 O-CH^—CH—CH. 2 \ /2 COO-C2H5 Example 22 Example 23 Example 24 Example 25 Exainple 26 COO-CJl,.
Exainple 27 S CONihA X— O-Cily—2 \=/ \=/ \/ Example 28 Example 29 Example 30 J.
F :oost PT Example HCl Example F3C COOEt OC0NH J \-0 Cfc—CH-CH\-T 2 V 2 Example Example Example OMe COOEt Example Example Cl 000! .t y-C— NH—V- -CH2-CH-CII,-N1I-J- , HCl Oil Example 38 O-CH.-CH-Clk-NH 2 , 2 HCl
Claims (4)
1. A compound 0.1 the formula: in R' (ch 2 ) which -CONH n -R and R 1 may each designate an atom of hydrogen, an atom of halogen, a nitro group, a straight chain or branched alkyl or C 1 -Cg alkoxy radical, or an SCH^ or CF^ group. -Rjl represents a straight chain or branched C^-C^ alkyl radical; -r< 2 represents a straight chain or branched C ( -C,-> alkyl radical; and -n designates an integer less than 5, or a non-toxic acid addition salt thereof.
2. A compound of Claim 1, wherein R^ represents the ethyl 15 group.
3. A compound of Claim 1 or 2, wherein R 2 represents the isopropyl or terbutyl radical. 4. A compound of any one of Claims 1 to 3, wherein n is equal to 0 or 1. 20 5. A compound of any one of Claims 1 to 3, wherein R = H and R' 1 _ F or R = R' = F.
4. 6. A compound of Claim 1, which is selected from the following: t :: j I-| /-rurbethoxy 4-(4-fluoro benzamido) phenoxy) 3-terbuty, imino 2-propanol, 1-I ar beihoxy 4-(4-,luoro benzamido) phenoxyl 3-isopropy larnino 2-propanol, I 1 2 -cut belhoxy 4-O-lluoro benzamido) phenoxy] 3-terbuty! imino 2-propanol, I lydrochlonde ot l-| ?
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8304150A FR2542737B1 (en) | 1983-03-14 | 1983-03-14 | NOVELS (CARBETHOXY-2 BENZALKYLAMIDO-4 PHENOXY) -1 AMINO-3 PROPANOLS-2, THEIR PREPARATIONS AND THEIR THERAPEUTIC USES |
| FR8318509A FR2555169B2 (en) | 1983-11-21 | 1983-11-21 | NOVEL (CARBETHOXY-2 BENZALKYLAMIDO-4 PHENOXYL) -1 AMINO-3 PROPANOLS-2, THEIR PREPARATIONS AND THEIR THERAPEUTIC USES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE840528L IE840528L (en) | 1984-09-14 |
| IE57094B1 true IE57094B1 (en) | 1992-04-22 |
Family
ID=26223333
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE528/84A IE57094B1 (en) | 1983-03-14 | 1984-03-05 | 1-(2-carbethoxy 4-benzalkylamido phenoxy)3-amino 2-propanols,preparation thereof and use thereof in therapeutics |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0122827B1 (en) |
| KR (1) | KR910002945B1 (en) |
| AT (1) | ATE20879T1 (en) |
| AU (1) | AU567332B2 (en) |
| CA (1) | CA1218378A (en) |
| DE (1) | DE3460323D1 (en) |
| DK (1) | DK117484A (en) |
| ES (1) | ES8504681A1 (en) |
| GR (1) | GR81821B (en) |
| IE (1) | IE57094B1 (en) |
| PH (1) | PH19184A (en) |
| PT (1) | PT78238B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP0617020A1 (en) * | 1992-04-02 | 1994-09-28 | Shudo, Koichi, Prof. Dr. | Carboxylic acid derivatives having retinoic acid-like activity |
| AU4149400A (en) * | 2000-04-19 | 2001-10-30 | Neurotech Co Ltd | Compounds, compositions and methods for preventing neurodegeneration in acute and chronic injuries in the central nervous system |
| US6964982B2 (en) | 2000-04-20 | 2005-11-15 | Neurotech Co., Ltd. | Compounds, compositions and methods for preventing neurodegeneration in acute and chronic injuries in the central nervous system |
| US6927303B2 (en) | 2002-06-19 | 2005-08-09 | Neurotech Co., Ltd. | Tetrafluorobenzyl derivatives and pharmaceutical composition for preventing and treating acute and chronic neurodegenerative diseases in central nervous system containing the same |
| CN103211824B (en) | 2006-04-13 | 2017-04-19 | 纽若泰克制药株式会社 | Pharmaceutical composition for treating or preventing degenerative and inflammatory diseases |
| KR100852962B1 (en) | 2007-11-12 | 2008-08-20 | 주식회사 뉴로테크 | Manufacturing method of 2-hydroxy-5-phenylalkylaminobenzoic acid derivatives and their salts |
| CA2708220C (en) | 2007-12-14 | 2016-04-12 | 3M Innovative Properties Company | Methods of treating subterranean wells using changeable additives |
| CA2708403C (en) | 2007-12-14 | 2016-04-12 | Schlumberger Canada Limited | Proppants and uses thereof |
| CA2708804C (en) | 2007-12-14 | 2016-01-12 | 3M Innovative Properties Company | Fiber aggregate |
| KR101204108B1 (en) * | 2009-02-09 | 2012-11-22 | 주식회사 지엔티파마 | Medicinal use of 5-benzylaminosalicylic acid derivative or its salt |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3852468A (en) * | 1967-02-27 | 1974-12-03 | Ici Ltd | Alkanolamine derivatives as {62 -adrenergic blocking agents |
| MX158644A (en) * | 1982-07-20 | 1989-02-21 | Menarini Sas | PROCEDURE FOR PREPARING A DERIVATIVE 1-ALKYLAMINE-3- (4 (P-ALKYL OXYBENZAMIDE) -PHENOXY) -2PROPANOL |
-
1984
- 1984-02-28 DK DK117484A patent/DK117484A/en not_active Application Discontinuation
- 1984-03-05 IE IE528/84A patent/IE57094B1/en unknown
- 1984-03-12 GR GR74075A patent/GR81821B/el unknown
- 1984-03-12 ES ES530503A patent/ES8504681A1/en not_active Expired
- 1984-03-12 EP EP84400490A patent/EP0122827B1/en not_active Expired
- 1984-03-12 AT AT84400490T patent/ATE20879T1/en active
- 1984-03-12 DE DE8484400490T patent/DE3460323D1/en not_active Expired
- 1984-03-12 PT PT78238A patent/PT78238B/en not_active IP Right Cessation
- 1984-03-13 AU AU25537/84A patent/AU567332B2/en not_active Ceased
- 1984-03-13 KR KR1019840001323A patent/KR910002945B1/en not_active IP Right Cessation
- 1984-03-13 CA CA000449516A patent/CA1218378A/en not_active Expired
- 1984-03-14 PH PH30393A patent/PH19184A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK117484D0 (en) | 1984-02-28 |
| ES530503A0 (en) | 1985-05-01 |
| AU567332B2 (en) | 1987-11-19 |
| EP0122827A1 (en) | 1984-10-24 |
| EP0122827B1 (en) | 1986-07-23 |
| DE3460323D1 (en) | 1986-08-28 |
| PT78238A (en) | 1984-04-01 |
| ATE20879T1 (en) | 1986-08-15 |
| GR81821B (en) | 1984-12-12 |
| KR910002945B1 (en) | 1991-05-11 |
| CA1218378A (en) | 1987-02-24 |
| PT78238B (en) | 1986-04-24 |
| DK117484A (en) | 1984-09-15 |
| ES8504681A1 (en) | 1985-05-01 |
| KR840009078A (en) | 1984-12-24 |
| IE840528L (en) | 1984-09-14 |
| AU2553784A (en) | 1984-09-20 |
| PH19184A (en) | 1986-01-23 |
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