CA1090812A - Substituted 1,3-diphenoxypropan-2-o1 derivatives and their manufacture and use - Google Patents
Substituted 1,3-diphenoxypropan-2-o1 derivatives and their manufacture and useInfo
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- C07C59/40—Unsaturated compounds
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- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
- C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
- C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
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Abstract
A B S T R A C T
Substituted 1.3-diphenoxypropan-2-ol derivatives of the formula
Substituted 1.3-diphenoxypropan-2-ol derivatives of the formula
Description
This invention relates to 1,3-diphenoxypropan-2-ol derivatives and their manufacture and use.
In our Canadian Patbnt No. 1,065,870, we have described and cIaimed compounds of the general formula .
Rl_ ~ 1 2 ~ (1) O-R
and their therapeutically acceptable salts, in which X
and Y are both -0-, or one of them is -~H-, and the other is -0-, or Y is -O- and X is -S-; Rl = -Cl or C(CH3)3; R2 = -H, or if X and Y denote -O- or Y is -O-: and X is -S-, nicotinoyl; A is a valence bond,. vinylene or ethylene; and R3 = COOH; -COOMe, (wherein M~ is sodium, potassium, magnesium, alwminium or a therapeutically ; acceptable ammonium cation); -COOR' (wherein R' is a ~traight or branched, saturated or unsaturated alkyl radical of l to 3 carbon atoms unsubstituted or bearing a terminal hydroxy, methoxy, chlorine, dimethylamino, or piperidyl-l radical, or R' is pyridyl-3-methyl); -CO~HOH, if X and Y are both -O- or Y iB -O- ~ and X is -S-:
O-R"
-CH , (wherein R" is methyl or ethyl when A
O-R"
;is a ~alente bond, X and Y are both -O or ~ is -0- and X
is -S-); or -CH l . , (where A is a valence bond, X and Y are both -O-, or Y is -O- and X is -S-.
.
3V~
The compounds of the general formula (1) have a good lipid-lowering actionl coupled with go~d tolerance.
They are thus suitable for the therapeutic treatment of hyperlipaemias.
- It Xas now been fow,~d that compoundsof the general formula (2) below also possess a strong lipid-lowering action, coupled with good tolerance.
, The present invention thus provides compounds of the formula R~ o-CH2-CH-cH2-o~
OH
in which Rl and A are as hereinbefore defined, and R4 is -COOR"', wherein Ri" is n-butyl, n-pentyl, n-hexyl, ~2,3-dihydroxypropyl, 2,2-dimethyl--1,3-dioxolan-4-yl-methyl, pivaloyloxymethyl, benzyl or phenyl, or -CO-~RiVRV
where either RiV=Rv and each is hydrogen, methyl or ethyl or one of RiV and Rv is hydrogen and the other is methyl or ethylO
The invention further provides processes for - the manufacture of the new 1,3-diphénoxypropan-2-ol derivatives of the general formula (2).
According to a first process a glycidyl ether of the ge~eral fo~mula , . .
~ - 3 -Rl ~ -O-CH2-CH - CH2 (3) \0/
in which Rl is as hereinbefore defined, is reacted with a phenol of the general formula HO ~ A-R4 (4) in which A is as hereinbefore defined and R4 represents n-alkoxycarbonyl in which the n-alkyl radical contains 4 to 6 carbon atoms or benzyl, in the presencelof a base, advantageously an alkali metal hydroxide or Lewis acids, for example boron trifluoride ethyl etherate.
In a second process, a ph0nol of the formula R1 ~ OH . (5) in which Rl is as hereinbefore defined is reacted, as described above, with a glycidyl ether of the formula H2C - CH-CH2-0 ~ A-R4 (&) in which -A-R4 has the meaning indicated in formula (4).
The manufacture of the esters of formula
In our Canadian Patbnt No. 1,065,870, we have described and cIaimed compounds of the general formula .
Rl_ ~ 1 2 ~ (1) O-R
and their therapeutically acceptable salts, in which X
and Y are both -0-, or one of them is -~H-, and the other is -0-, or Y is -O- and X is -S-; Rl = -Cl or C(CH3)3; R2 = -H, or if X and Y denote -O- or Y is -O-: and X is -S-, nicotinoyl; A is a valence bond,. vinylene or ethylene; and R3 = COOH; -COOMe, (wherein M~ is sodium, potassium, magnesium, alwminium or a therapeutically ; acceptable ammonium cation); -COOR' (wherein R' is a ~traight or branched, saturated or unsaturated alkyl radical of l to 3 carbon atoms unsubstituted or bearing a terminal hydroxy, methoxy, chlorine, dimethylamino, or piperidyl-l radical, or R' is pyridyl-3-methyl); -CO~HOH, if X and Y are both -O- or Y iB -O- ~ and X is -S-:
O-R"
-CH , (wherein R" is methyl or ethyl when A
O-R"
;is a ~alente bond, X and Y are both -O or ~ is -0- and X
is -S-); or -CH l . , (where A is a valence bond, X and Y are both -O-, or Y is -O- and X is -S-.
.
3V~
The compounds of the general formula (1) have a good lipid-lowering actionl coupled with go~d tolerance.
They are thus suitable for the therapeutic treatment of hyperlipaemias.
- It Xas now been fow,~d that compoundsof the general formula (2) below also possess a strong lipid-lowering action, coupled with good tolerance.
, The present invention thus provides compounds of the formula R~ o-CH2-CH-cH2-o~
OH
in which Rl and A are as hereinbefore defined, and R4 is -COOR"', wherein Ri" is n-butyl, n-pentyl, n-hexyl, ~2,3-dihydroxypropyl, 2,2-dimethyl--1,3-dioxolan-4-yl-methyl, pivaloyloxymethyl, benzyl or phenyl, or -CO-~RiVRV
where either RiV=Rv and each is hydrogen, methyl or ethyl or one of RiV and Rv is hydrogen and the other is methyl or ethylO
The invention further provides processes for - the manufacture of the new 1,3-diphénoxypropan-2-ol derivatives of the general formula (2).
According to a first process a glycidyl ether of the ge~eral fo~mula , . .
~ - 3 -Rl ~ -O-CH2-CH - CH2 (3) \0/
in which Rl is as hereinbefore defined, is reacted with a phenol of the general formula HO ~ A-R4 (4) in which A is as hereinbefore defined and R4 represents n-alkoxycarbonyl in which the n-alkyl radical contains 4 to 6 carbon atoms or benzyl, in the presencelof a base, advantageously an alkali metal hydroxide or Lewis acids, for example boron trifluoride ethyl etherate.
In a second process, a ph0nol of the formula R1 ~ OH . (5) in which Rl is as hereinbefore defined is reacted, as described above, with a glycidyl ether of the formula H2C - CH-CH2-0 ~ A-R4 (&) in which -A-R4 has the meaning indicated in formula (4).
The manufacture of the esters of formula
(2) by transesterification is preferred. In this procedure, a compound of the general formula Rl ~ 0-CH2 CH-CH2-o ~ A-COOCH3 (7) OH
in which Rl and A are as hereinbefore defined, is reacted with an excess of the alcohol of formula R4-oH required for transesterification, in the presence of an acid or alkaline catalyst.
A further method of manufacturing esters of formula (2) consists in reacting a compound of the general formula Rl ~ O-CH2-CH-CH2-O ~ A-COOZ (8) OH
~ in which Rl and A are as hereinbefore defined and Z is an alkali'metal, for example sodium, or an alkylammonium group, with a halogeno compound of the general formula . 4 Hal-R (9) wherein Hal denotes chlorine or bromine and R4 is alkyl of 4 to 6 carbon atoms, 2,3-dihydroxypropyl, pivaloyloxy-methyl or benzyl in a dipolar aprotic solvent, such as, for example, hexamethylphosphoric acid triamide or dimethyl-formamide.
Esters according to formula (2) can also bemanufactured by reacting a compound of the general formula Rl_ ~ ~O~CH2~CH~CH2~0 ~ 3 A-CO-Hal (10) O--Z
in which Rl and ~ have the meaning indicated in formula (2), Z denotes an acetyl or benzyl group, and Hal represents chlorine or bromine, with n-b'utanol, n-pentanol, n-hexanol, benzyl'alcohol or phenol and subsequently, depending on its nature, selectively splitting off the protective group by hydrolysis or hydrogenolysis, without other irreversible changes in the molecule taking place simultaneously.
Amides of the general formula (11) Rl ~ ~H ~ -A-C0-~RiVRv (11) in which Rl, A, RiV, and Rv have the meanings - indicated in formula (2) can be manufaqtured by reacting a compound of the formula R ~3 f ~A-CO-Hal ( 12 ) 0-Ac in which Rl and A have the meaning indicated.in formula (2) 10 AC denotes an a-cetyl group, and Hal represents chlorine or bromine, with a~monia, methylamine, dimethylamine, ethylamine, or die!thylamine in excess and subsequently selectively splitting off the acetyl group by hydrolysis, without other . irreversible changes.in the molecule.taking place simultaneously.
~ Compounds acc~rding-to formula (2) in which Rl has the meaning indicated in formula (2), A represents an ethylene group and R2 is a hydrogenolytically inert ester - or amide radical can be easily manufactured, above all, by subjecting thé readily accessible compounds according to formula (2), in which-A represents a vinylene group and Rl and~R2 have the abovementioned meaning, to a catalytic hydro-genation, Raney nlckel preferably being used as the catalyst.
Glyci~yl ethers of the general formula (3) are formed in the reaction of compounds of the general formula (5), in which Rl has the meaning indicated in formula (2), with epi-halogenohydrins, preferably epichlorohydrin, in the presence , 39~
of bases, preferably alkali metal hydroxides, the halogeno-hydrins formed as intermediates, of the general formula (13) Rl ~ O-CH2-CH-~H2~Hal (13) OH
in which Rl has the meaning given above and ~al can be chlorine or bromine, not having to be isolated Glycidyl ethers of the general formula (6~ can be obtained by reacting compounds of the general formula (4), in which A and R2 have the meaning indicated in formula (4), with epihalogenohydrins in the presence of bases, preferably alkali metal hydroxides, it being possible to dispense with an isolation of the halogenohydrins first formed, of the general formula (14~
Hal-CH2-CH~CH2-O ~ A-R2 (14) -OH
in which~A and R2~have the meaning given above.
The compounds of the general formula (2) are prefer-ably administered orally. The oral daily dose for adults is usually 0.1 to 10 g, preferably 0.5 to 3 g.
The active compounds can be galenically compounded in the customary manner for oral administration.
Suitable pharmaceutical excipients are customary auxiliaries, such as lactose, sucrose, sorbitol, mannitol, potato starch or maize starch, cellulose derivatives ox gelatine, optionally with the addition of lubricants, such as, for example, magnesium stearate or calcium stearate, Carbowax(R) or polyethylene glycols.
Preferred administration forms are push-fit capsules of hard gelatine or sealed capsules of soft gelatine with a plasticizer, such as, for example, glycerol. The push-fit capsules optionally contain the pure pulverulent active compound, if appropriate with the addition of a lubricant. In the case of appropriate physical properties of the active compound, processing to granules is p~eferred, potato starch, maize starch, amylopectin, cellulose deriva-tives, gelatine or also highly disperse silicas being con-jointly used as auxiliaries. Oily ac~ive compounds are made up in the pure form, preferably in soft gelatine capsules. The pure active compound is optionally dissolved - ln suitable liquids, that is to say, 'or example, in liquid polyethylene glycols or in vegeta~le oils.
In the following text, the invention is explained in ~ore detail with the aid of illustrative embodiments.
Example 1
in which Rl and A are as hereinbefore defined, is reacted with an excess of the alcohol of formula R4-oH required for transesterification, in the presence of an acid or alkaline catalyst.
A further method of manufacturing esters of formula (2) consists in reacting a compound of the general formula Rl ~ O-CH2-CH-CH2-O ~ A-COOZ (8) OH
~ in which Rl and A are as hereinbefore defined and Z is an alkali'metal, for example sodium, or an alkylammonium group, with a halogeno compound of the general formula . 4 Hal-R (9) wherein Hal denotes chlorine or bromine and R4 is alkyl of 4 to 6 carbon atoms, 2,3-dihydroxypropyl, pivaloyloxy-methyl or benzyl in a dipolar aprotic solvent, such as, for example, hexamethylphosphoric acid triamide or dimethyl-formamide.
Esters according to formula (2) can also bemanufactured by reacting a compound of the general formula Rl_ ~ ~O~CH2~CH~CH2~0 ~ 3 A-CO-Hal (10) O--Z
in which Rl and ~ have the meaning indicated in formula (2), Z denotes an acetyl or benzyl group, and Hal represents chlorine or bromine, with n-b'utanol, n-pentanol, n-hexanol, benzyl'alcohol or phenol and subsequently, depending on its nature, selectively splitting off the protective group by hydrolysis or hydrogenolysis, without other irreversible changes in the molecule taking place simultaneously.
Amides of the general formula (11) Rl ~ ~H ~ -A-C0-~RiVRv (11) in which Rl, A, RiV, and Rv have the meanings - indicated in formula (2) can be manufaqtured by reacting a compound of the formula R ~3 f ~A-CO-Hal ( 12 ) 0-Ac in which Rl and A have the meaning indicated.in formula (2) 10 AC denotes an a-cetyl group, and Hal represents chlorine or bromine, with a~monia, methylamine, dimethylamine, ethylamine, or die!thylamine in excess and subsequently selectively splitting off the acetyl group by hydrolysis, without other . irreversible changes.in the molecule.taking place simultaneously.
~ Compounds acc~rding-to formula (2) in which Rl has the meaning indicated in formula (2), A represents an ethylene group and R2 is a hydrogenolytically inert ester - or amide radical can be easily manufactured, above all, by subjecting thé readily accessible compounds according to formula (2), in which-A represents a vinylene group and Rl and~R2 have the abovementioned meaning, to a catalytic hydro-genation, Raney nlckel preferably being used as the catalyst.
Glyci~yl ethers of the general formula (3) are formed in the reaction of compounds of the general formula (5), in which Rl has the meaning indicated in formula (2), with epi-halogenohydrins, preferably epichlorohydrin, in the presence , 39~
of bases, preferably alkali metal hydroxides, the halogeno-hydrins formed as intermediates, of the general formula (13) Rl ~ O-CH2-CH-~H2~Hal (13) OH
in which Rl has the meaning given above and ~al can be chlorine or bromine, not having to be isolated Glycidyl ethers of the general formula (6~ can be obtained by reacting compounds of the general formula (4), in which A and R2 have the meaning indicated in formula (4), with epihalogenohydrins in the presence of bases, preferably alkali metal hydroxides, it being possible to dispense with an isolation of the halogenohydrins first formed, of the general formula (14~
Hal-CH2-CH~CH2-O ~ A-R2 (14) -OH
in which~A and R2~have the meaning given above.
The compounds of the general formula (2) are prefer-ably administered orally. The oral daily dose for adults is usually 0.1 to 10 g, preferably 0.5 to 3 g.
The active compounds can be galenically compounded in the customary manner for oral administration.
Suitable pharmaceutical excipients are customary auxiliaries, such as lactose, sucrose, sorbitol, mannitol, potato starch or maize starch, cellulose derivatives ox gelatine, optionally with the addition of lubricants, such as, for example, magnesium stearate or calcium stearate, Carbowax(R) or polyethylene glycols.
Preferred administration forms are push-fit capsules of hard gelatine or sealed capsules of soft gelatine with a plasticizer, such as, for example, glycerol. The push-fit capsules optionally contain the pure pulverulent active compound, if appropriate with the addition of a lubricant. In the case of appropriate physical properties of the active compound, processing to granules is p~eferred, potato starch, maize starch, amylopectin, cellulose deriva-tives, gelatine or also highly disperse silicas being con-jointly used as auxiliaries. Oily ac~ive compounds are made up in the pure form, preferably in soft gelatine capsules. The pure active compound is optionally dissolved - ln suitable liquids, that is to say, 'or example, in liquid polyethylene glycols or in vegeta~le oils.
In the following text, the invention is explained in ~ore detail with the aid of illustrative embodiments.
Example 1
3-~4'-Phenylmethoxycarbonylphenoxy~ C4'-chloro~henoxy) propan-2~ol 25.10 g (0.11 mol~ o~ 4'-hydroxybenzoic acid benzyl ester and 18.46 g C0.1 mol~ of 3-(4'-chlorophenoxy)-1,2-epoxypropane are added to a solution of 0.56 g (~.01 mol) of' potassium hydroxide in 150 ml of anhydrous isopropanol ana the mixture is stirred f'or 9 hours under reflux. It is then concentrated in vacuo, the residue is taken up in ether and the solution is extracted with 2 N potassium hydroxide solution, washed until it gives a neutral reaction and dried over sodium sulphate. After removing the solvent , in vacuo, the residue is recrystallized; colourless crystals of melting point 80-82C (petroleum ether), yield 26.3 g C63.7~1.
C23H21ClO5 (412.87~ Calculated: C 67.25 H 4.67 Cl 8.58 Found : C 66.86 H 5.18 Cl 8.52 - 8 ~
.
IR spectrum (KBr)~ (OH~: 3,520 om l,v(C-O): 1,700 om 1.
1H-NMR spectrum (CDC13)2): 2.8 s (1) OH, 4.0-4.5 m (5) CH2CHCH2~ 5.3 ~ (2) COOC~2 6.7-8.1 (131 aromatic Example 2 3-~4'-(2-Pentoxycarbonylvinyl)-phenoxy]-1-(4'-chlorophenoxy)-propan-2-ol 36.28 g (0.1 mol~ of 3-[4'-(2-methoxycarbonylvinyl)-phenoxy]-l-(4'-chlorophenoxy)-propan~2-ol are introduaed into a solution of 1.3 g of potassium hydroxide in 300 ml of n-pentanol and the mixture is heated to reflux. The reaction mixture is stirred, whilst continuously distilling o~ methanol, until no further methyl ester can be detected by NMR spectroscopy. The mixture is then concentrated in vacuo, the residue is taken up in ether and the ethér solution is washed with water and dried over sodium sulphate. After -removing the ether in vacuo, an oil remains which slowly crystallizes; for purification, it is first recrystallized from methylcyclohexane and then from ~ g ~
1) The IR spectra were recorded with a Perkin-Elmer Type 257 instrument.
2~ The lH~NMR spectra were recorded with an EM-360 Varian spectrometer, the chemical shifts are indicated in ppm relative to TMS (6 = 0.0~ and the relative intensities are added in bracketsO Singlet=s, dou~let=d, triplet=t and multiplet-m.
'L~", chloroform/petroleum ether, Colourless crystals of melting point 79-80C, yi.eld :L9.6 g (46,8%), .. C23H27C105 (418.93) Calculated; C 65,94 H 6.50 Found, C 65.89 H 6,42 IR spectrum (KBr): v(OH): 3,500 cm 1, v(C=O): 1,700 cm 1 v(C=C): 1,630 cm~l.
H-NMR spectrum (CDC13): 1,0 -t (3) CH2CH3, 1,1-2,0 m (6) (CH2)3CH3~ 3.1 s (1) OH, 4 0-4 5 m (7) COOCH2~ CH2CHC_2, 6,3 d (1) CHCO t lo 6,7-7,5 m (8) aromatic, 7.6 d (1) CH-C6H4 .
Example 3 - 3-~4'-(2-Phen~lmethoxycarbonylethyl)-~henoxyl-1-(4'-ter-t.=
butyl~henoxy)-propan-2-ol .
15 11.45 ml (0.1 mol) of benzyl chloride are added dropwise to ~ solution o~ 39,44 g (0.1 mol) of the sodium - salt of 3-[4~-(2-carboxyethyl)-phenoxy~-1-(4'--ter-t.-butyl-phenoxy)-propan-2-ol in 100 ml of hexamethylphosphoric acid - triamide at 60C and the mixture is stirred for a further 8 hours at 80C, After cooling, water is added and the 'oil which has separated out is taken up in e-ther, The . organic phase is washed with dilute potassium hydroxide solu-tion and then with wa-ter, dried over sodium sulphate and concentrated in vacuo, On molecular distillation, . 25 the residue gives ~ colourless oil of boiling point 220C/
2 x 10 2 mm Hg; yield 26.7 g (57.7%), 2~H345 (46~,59) Calculated. C 75.30 H 7.41 Found C 75.05 H 7.30 .. ..
... .. .
~0~
IR spectrum (film): ~OH): 3,450 cm 1, v(C=O): 1,725 cm 1 ~, , lH-NMR spectrum (CC14): 1.2 s (9) C(CH3)3, 2,2-3.0 m (4) CH2CH2, 3.1 d (1) OH, 3.8-4.3 m (5) CH2CHCH2, 5.0 s (2) COOCH2, 6.5-7.3 m , (13) aromatic.
~ ` Example 4 1 3-(4'-Phenox~carbonylphenoxy)=1-(4'-chlor_phenox~-propan-2-ol !
g.41 g (0.1 mol) of phenol are added to a solution o~
38.42 g (0.1 mol) of 3-(4'-chlorocarbonylphenoxy)-1-(4'-chlorophenoxy)-prop-2-yl acetate in 100 ml of anhydrous I pyridine and the mixture is stirred for 8 hours under reflux;
I it is then concentrated in vacuo, t,he residue is taken up in I ether and the ether solution is washed with water, several times with 2 N po-tassium hydroxide solution and again with i 15 - water. After drying over sodium sulphate, the ether is removed in vacuo, whereupon an oil remains ~hich slowly cry~tallises, Colourless crystals of melting point 88-90C (ethyl acetate/petroleum ether), yield 34.7 g (78.7%).
IR spectrum (CHC13): v(C=O): 1,730 cm~l, 1,740 cm~l, H-MMR spectrum (CDC13~: 2.1 s (3) COCH3, 4,2 d (2) OCH2,
C23H21ClO5 (412.87~ Calculated: C 67.25 H 4.67 Cl 8.58 Found : C 66.86 H 5.18 Cl 8.52 - 8 ~
.
IR spectrum (KBr)~ (OH~: 3,520 om l,v(C-O): 1,700 om 1.
1H-NMR spectrum (CDC13)2): 2.8 s (1) OH, 4.0-4.5 m (5) CH2CHCH2~ 5.3 ~ (2) COOC~2 6.7-8.1 (131 aromatic Example 2 3-~4'-(2-Pentoxycarbonylvinyl)-phenoxy]-1-(4'-chlorophenoxy)-propan-2-ol 36.28 g (0.1 mol~ of 3-[4'-(2-methoxycarbonylvinyl)-phenoxy]-l-(4'-chlorophenoxy)-propan~2-ol are introduaed into a solution of 1.3 g of potassium hydroxide in 300 ml of n-pentanol and the mixture is heated to reflux. The reaction mixture is stirred, whilst continuously distilling o~ methanol, until no further methyl ester can be detected by NMR spectroscopy. The mixture is then concentrated in vacuo, the residue is taken up in ether and the ethér solution is washed with water and dried over sodium sulphate. After -removing the ether in vacuo, an oil remains which slowly crystallizes; for purification, it is first recrystallized from methylcyclohexane and then from ~ g ~
1) The IR spectra were recorded with a Perkin-Elmer Type 257 instrument.
2~ The lH~NMR spectra were recorded with an EM-360 Varian spectrometer, the chemical shifts are indicated in ppm relative to TMS (6 = 0.0~ and the relative intensities are added in bracketsO Singlet=s, dou~let=d, triplet=t and multiplet-m.
'L~", chloroform/petroleum ether, Colourless crystals of melting point 79-80C, yi.eld :L9.6 g (46,8%), .. C23H27C105 (418.93) Calculated; C 65,94 H 6.50 Found, C 65.89 H 6,42 IR spectrum (KBr): v(OH): 3,500 cm 1, v(C=O): 1,700 cm 1 v(C=C): 1,630 cm~l.
H-NMR spectrum (CDC13): 1,0 -t (3) CH2CH3, 1,1-2,0 m (6) (CH2)3CH3~ 3.1 s (1) OH, 4 0-4 5 m (7) COOCH2~ CH2CHC_2, 6,3 d (1) CHCO t lo 6,7-7,5 m (8) aromatic, 7.6 d (1) CH-C6H4 .
Example 3 - 3-~4'-(2-Phen~lmethoxycarbonylethyl)-~henoxyl-1-(4'-ter-t.=
butyl~henoxy)-propan-2-ol .
15 11.45 ml (0.1 mol) of benzyl chloride are added dropwise to ~ solution o~ 39,44 g (0.1 mol) of the sodium - salt of 3-[4~-(2-carboxyethyl)-phenoxy~-1-(4'--ter-t.-butyl-phenoxy)-propan-2-ol in 100 ml of hexamethylphosphoric acid - triamide at 60C and the mixture is stirred for a further 8 hours at 80C, After cooling, water is added and the 'oil which has separated out is taken up in e-ther, The . organic phase is washed with dilute potassium hydroxide solu-tion and then with wa-ter, dried over sodium sulphate and concentrated in vacuo, On molecular distillation, . 25 the residue gives ~ colourless oil of boiling point 220C/
2 x 10 2 mm Hg; yield 26.7 g (57.7%), 2~H345 (46~,59) Calculated. C 75.30 H 7.41 Found C 75.05 H 7.30 .. ..
... .. .
~0~
IR spectrum (film): ~OH): 3,450 cm 1, v(C=O): 1,725 cm 1 ~, , lH-NMR spectrum (CC14): 1.2 s (9) C(CH3)3, 2,2-3.0 m (4) CH2CH2, 3.1 d (1) OH, 3.8-4.3 m (5) CH2CHCH2, 5.0 s (2) COOCH2, 6.5-7.3 m , (13) aromatic.
~ ` Example 4 1 3-(4'-Phenox~carbonylphenoxy)=1-(4'-chlor_phenox~-propan-2-ol !
g.41 g (0.1 mol) of phenol are added to a solution o~
38.42 g (0.1 mol) of 3-(4'-chlorocarbonylphenoxy)-1-(4'-chlorophenoxy)-prop-2-yl acetate in 100 ml of anhydrous I pyridine and the mixture is stirred for 8 hours under reflux;
I it is then concentrated in vacuo, t,he residue is taken up in I ether and the ether solution is washed with water, several times with 2 N po-tassium hydroxide solution and again with i 15 - water. After drying over sodium sulphate, the ether is removed in vacuo, whereupon an oil remains ~hich slowly cry~tallises, Colourless crystals of melting point 88-90C (ethyl acetate/petroleum ether), yield 34.7 g (78.7%).
IR spectrum (CHC13): v(C=O): 1,730 cm~l, 1,740 cm~l, H-MMR spectrum (CDC13~: 2.1 s (3) COCH3, 4,2 d (2) OCH2,
4,3 d (2) OCH2, 5,5 q (1) Il CH2CHCH2, 6.6-8.2 m (13) aromatic.¦ In order to remove the acetyl pro-tective group, lO`ml of concentrated ammonia are added -to a solution of 44,1 g , (0,1 mol) of 3-(4'-phenoxycarbonylphenoxy)-1-(4'~chloro-phenoxy)-prop-2-yl acetate in 2 1 of methanol ~t 40C and the mixture is stirred for 3 hours at room temperature, Af-ter concentrating in vacuo, -the residue is dissolved in . . .
. .
l.
ether, the ether solution is washed with water until neutral and dried over sodium sulpha-te and the sol~en-t is removed in . vacuo Colourless crystals o~ melting point 119-120C
(ethyl acetate/petroleum ether), yield 12.1 g (30 4%) C22HlgC105 (398 85) Calculated C 66.25 H 4.80 - Found C 66.15 H 4.80 IR spectrum (KBr): v(OH): 39500 cm~l; ~(C=O): 1,720 cm~
H-NMR spectrum (CDC13): 2 7 d (1) OH9 4.0-4.6 m (5) CH2CHCH2, 6.7-8.3 m (13) aromatic.
; 10 Further compounds of the general formula (2) were manufactured, using the processes described in Examples 1--4, and are listed, with their physical characteristics, in Table 1 which follows.i For reasons o~ completeness, the compounds dealt with in -the examples are given again in Table 1, arranged according to structural characteristics.
Table 1 ~1 ~ 2 OH 2 ~ -A-R2 (2) - 1 2 Melting point (C)l) ~r boiling No. R A-~ poin-t (C/mm Hg)2) _ . .v _ ... _ . _ . _ . ......... .. .. ~_,_ _ 1 Cl COC~(CH2)3-C~ 71-2 (et~ acetate/pe-troleum 2 Cl CCC~(C~)5-CH3 . 80-1 (methy ethyl ke-tone/
petroleum ether) .Cl COOCH~ ~ 80-2 (petroleum ether) 4 Cl GCCC~120COC(C1~3)3 84-6 (e-thyl acetate/petroleum . ether)
. .
l.
ether, the ether solution is washed with water until neutral and dried over sodium sulpha-te and the sol~en-t is removed in . vacuo Colourless crystals o~ melting point 119-120C
(ethyl acetate/petroleum ether), yield 12.1 g (30 4%) C22HlgC105 (398 85) Calculated C 66.25 H 4.80 - Found C 66.15 H 4.80 IR spectrum (KBr): v(OH): 39500 cm~l; ~(C=O): 1,720 cm~
H-NMR spectrum (CDC13): 2 7 d (1) OH9 4.0-4.6 m (5) CH2CHCH2, 6.7-8.3 m (13) aromatic.
; 10 Further compounds of the general formula (2) were manufactured, using the processes described in Examples 1--4, and are listed, with their physical characteristics, in Table 1 which follows.i For reasons o~ completeness, the compounds dealt with in -the examples are given again in Table 1, arranged according to structural characteristics.
Table 1 ~1 ~ 2 OH 2 ~ -A-R2 (2) - 1 2 Melting point (C)l) ~r boiling No. R A-~ poin-t (C/mm Hg)2) _ . .v _ ... _ . _ . _ . ......... .. .. ~_,_ _ 1 Cl COC~(CH2)3-C~ 71-2 (et~ acetate/pe-troleum 2 Cl CCC~(C~)5-CH3 . 80-1 (methy ethyl ke-tone/
petroleum ether) .Cl COOCH~ ~ 80-2 (petroleum ether) 4 Cl GCCC~120COC(C1~3)3 84-6 (e-thyl acetate/petroleum . ether)
5 Cl Coo ~ 119-20 (ethy1 acetate/petroleu~
. ether)
. ether)
6 Cl COOcH2~0 C`~3 (x) .
1~0~
Table 1 (continuation) Mel-tin~ poin-t (o~l) or boiling No, Rl A_R2 point ~C/mm Hg)~ _ -- -. . ~ _
1~0~
Table 1 (continuation) Mel-tin~ poin-t (o~l) or boiling No, Rl A_R2 point ~C/mm Hg)~ _ -- -. . ~ _
7 Cl COOC~I2Cl~OHCH2CH (x)
8 Cl CH-CH-COO(CH2)3-CH3 83~5 (acetone/petroleum ether) ( H2)4-CH~ 79-80 (chloroform/petroleum 10 C~ C~I=CH-C00(CH2) -CH3 67-8 (methylcyclohexane) 11 Cl CH-C~~COOC~2- ~ 117-9 (ethanol) 12 Cl CH=CH-COOC~20CoCtCH3) 389-90 (methanol) ~3 Cl CH=CH-C00~ ether) i4 Cl CH=CH-COOCH2~r ~ CH3 205/1 x 10 3 Cl CH=C~I-COOCH2CHOHCH2C~ (~) ` 16 Cl CH2CH2COOCH2 ~ 220/3 x lO
17 (CH3)3C COO(CH2)3-CH3 45-8 ( methylcyclohexane) 18 - (CH3)3C C00(CH2)~-CH3 5,~-3 (petroleum ether) 1519 (C~3)3C ~OO(CH2) ~ H3 .37-8 (petroleum ether) 3)3 2 ~ 81-2 (petroleum ether) 21 (CH3)3C COoc~2o5oc(c~3)3 80-2 (methylcyclchexane).
( ) ~ 6~ (ethyl acetate/petroleum ether~
23 (CH3)3C COOCH2- ~,CH3 (X) 24 (CH3)3C CH=CH-C00(CH2~5-CH3 73-4 (metha)nol/diisopropyl (CH3)3C C~2C~12COOC~I2 ~ 220/2 X 10 - - - - ...... ~--.,.. ___ ._ _ _ . ............... ........ _ .. .. _ (x) = viscous oil, purified by column chromatography.
1) The me~ting points were determined with a Kcfler heated stage microscope and are not corrected, 2) Liquid products were purified with a laboratory molecular distillation lnstalla-tion (Leybold-Heraeus KDl i); the boiling points indicated relate to -the hea-ting jacket tempera-tures.
j ., . - 13 Example 5 3=(4'-Carbamoylphenox~ (4'~chlorophenox~-propan-2-ol Dry ammonia gas is passed into a solution of 38.32 g (0.1 mol) o~ 3-(4'-chlorocarbonylphenoxy)-1-(4'-chloro-phenoxy~-prop-2-yl acetate in 300 ml of anhydrous dioxane at 0C until the solution is satura~éd; after 2 hours, the mixture is concentrated in vacuo, the residue is digested with hot water and d~ied over phosphorus pentoxide and a small amount is recrystallised for analysis. Melting point 138-40 (acetone).
IR spectrum (KBr): v(NH): 3,420 cm 1, 3,160 cm 1, v(C=O):
1,745 cm~l, 1,640 cm~l.
H-NMR spectrum (d6-acetone): 2.1 s (3) COCH3, 4 2 d (2) OCH2, 4.3 d (2) OCH2, 5.5 q (1) CH2CHCH2, 6.8-8.5 m (10) aromatic, NH2 In order to remove the acetyl protective group, the solid is dissolved in 300 ml of methanol, whilst warming, and 50 ml of concentrated ammonia are added. The mix-ture is then stirred for 5 hou~s at room -temperature, con~
centrated to dryness in vacuo and the residue is recrystal-lised. Colourless crystals of melting point 168-9C
- (ethyl ace~a-te), yield 20 3 g (63.1%), C16H16ClN04 (321.77) Calculated. C 59.74 H 5.01 N 4.35 Found. C 60.09 H 5.25 N 4.35 IR spectrum (KBr): v(NH, OH) 3,480-3,100 cm 1, ~(c=oj:
1,640 cm~ .
-lH-NMR spectrum (d6-acetone~: 4.1 m (5) CH2CHCH2, 5.2 d (1) OH, 6.8-8.0 m (10) aromatic, NH2.
Example 6 .
3- ~4'-(N-Ethylcarbamoyl~-phenoxy]-1-(4'-tert.-butylphenoxy)-propan-2-ol 17.5 ml (0.2 mol) of a 70% strength ethylamine solution are added to a solution of 40.49 g (0.1 mol) of 3- (4'-chlorocarbonyiphenoxy)-1-(4'-tert.-butylphenoxy)-prop-2-yl acetate in 300 ml of anhydrous dioxane at room temperature and the mixture is then stirred for 8 hours ~nder reflux. The salt which is formed is separated off, the filtrate is concentrated in vacuo, the residue is taken up in chloroform and the chloroform solution is extracted with 2 N potassium hydroxide solution. The organic phase is washed until it gives a neutral reaction, dried over sodium sulphate and concentrated in vacuo, the solid which remains is used, without further purification, for the removal of the acetyl protective group.
The solid is dissolved in 200 ml of methanol, 50 ml of concentrated ammonia are added and the mixture is left for 5 hours at room temperature. It is then concentrated to dryr~ess in vacuo and the residue is purified by recrystal-lization; colourless crystals of melting point 120-122C
(ethyl acetate/petroleum ether~, yield 19.1 g (51.496).
C22H29NO4 (371.48) Calculated: C 71.13 H 7.87 N 3.77 Found : C 70.66 H 7.86 N 3.32 IR spectrum (RBrl: v (NH, OH): 3,300 cm (main absorption), v (C=OI: 1.630 cm 1.
H~NMR spectrum (CDC13]: 1.2 t (3~ CH2CH3, 1.3 s (9~ (CH3]3C~
3.2-3.7 m (31 C~2CH3, OH, 3.9-4.6 m~(5 CH2C_CH2, 6.4 t (1) NH, 6.7~7.8 m (8) aromatic.
. Further carboxylic acid amides according to ~ormula (2) were manu~ac-tured, using the process illustr~ted in Examples 5 and 6, and are listed in Table 2. For reasons of completeness, the compounds dealt with in the examples - 5 are given again in Table 2, arranged according to structural characteristics. -Table 2 R ~ F 2 ~H ~ A-R~ (2) No. R1 A_R2 Melting poin-t (C) 26 Cl C0~2 168-9 (ethyl acetate) 27 Cl CONHC2H5 118-9 (chloroform) Cl CON(C2H5~2 96-7 (chloroform/petroleum ether) 29 Cl cH=cH-coI~n~2 154-5 (ethyl acetate/pe-troleum e-ther) Cl CH2C~2C0~2 90-1 (acetone/petroleum ether).
31 (CH3)3c CONH2 150-2 ~chloroform) 32 (CH3)3c CONHCH3 (x) 3~ (cH3)3c C~C2H5 120-2 (ethyl)acetate/petroleum ( 3)3 ( 2H5)2 68-70 (etthyl)aceta-te/petroleum . (x.) = viscous oil purified by column chromatography.
Example 7 Medicament containin~ ~-L4~-(2-hexox~carbonylv n~ phenoxyl-__ 1-(4~-chloro ~
100 g of 3 [4'-(2-hexoxycarbonylvinyl)-phenoxy~-1-(4'-chlorophenoxy) propan-2-ol are mixed -thoroughly with . _ 16 -.. . .
16 g of maize starch and 6 g o~ highly disperse silica and the mixture is then moistened with a solution o~ 2 g of stearic acid, 6 g o~ acetylcellulose and 6 g o~
stearin in 70 ml of isopropanol and granulated, The dried granules are forced th~ough a sieve and, after mixin~
with 16 g of maize starch, 16 g of ~alc and 2 g of magne,sium stearate, are pressed into 1,000 dragee cores. After coating with a syrup of 2 g o~ lacca, 7.5 g of gum arabic 9 - 0.15 g of dyestu~f, 2 g of colloidal silica, 25 mg of talc and 53.35 g of sucrose, and drying, one thousand dragées weighing 260 mg and each containing 100 mg of active compound are obtained.
Exam~]e 8 Medicament containin 3-r4'-(2- henvlmethoxYcarbonylethyl)-g ~ - ~ P ~
~
250 g of 3_~4 t _ ( 2-phenylmethoxycarbonylethyl)-phenoxy]-1-(4'-chlorophenoxy)-propan-2-ol are mixed with 250 g of polyethylene glycol and filled in-to one thousand oval capsules, which each contain 250 mg of active compound by the Scherer process.
Example 9 3l92~ r rL__2 ol , A finely powdered mixture of 250 g of 3-[4'-(N-ethylcarbamoyl)-phenoxy~ (4'-chlorophenoxy)-propan-2-ol, 133 g of maize starch? 12 g o~ magnesium stearate and 5 g of gelatine is pressed through a fine-meshed sieve ana then filled, in the dry state, into one -thousand hard gela-tine - 17 ~
.. ~ .
capsules, which each contain 250 mg of active compound.
Example 10 Pharmacological testing 1. Oral tolerance After oral administration of the test compounds to mice of the strain NMR-I, weighing 15-20 g, the acute toxicity was determined. The LDSo values were calculated according to Litchfield-Wilcoxon [~. Pharmacol. Exp. Ther.
96, 99 (19492] and relate to the ~ighth day of the treatment. In this series of experiments the LD50 for Clofibrat was 1~900 mg/kg. The substances according to the invention were consi~tently better tolerated and superior to Clofibrat.
2. Lipid-lowerin~ action The lipid-lowering action was tested on grou~s of, in each case, 10 normolipaemic, male Spraque-Dawley rats (Ivanovas, Kisslegg~, weiyhing 190-230 g, on normal rations ("ssniff" complete feed~O
The test compounds were taken up in an aqueous solu-tion of 0.25% of agar and 0.85~ of NaCl and a~ministered o~ally. After administration of 4 x 100 mg/kg o~er a period of 3 days, the animals were bled by cardiac puncture, after being deprived of food for four hoursl).
Serum lipids were determi~ed with a Technicon auto-analyzer. The total cholesterol (TC) was tested by the enzymatic colour test ). The quantitative analysis of triglycerides (TG2 was carried out enzymatically according to Eggstein and Kreutz [Klin. Wschr. 44, 262 (1966)], modified for the autoanalyzer.
1) H. Enomoto and R. Zschocke, 3rd Int. Symp. Atherosol., Berlin, 1973, A~stract 238.
2) P. Roschlau, E. Burnt and W. Gruber, Z. Klin. Chem.
Klin. Biochem 12 403 (lq742.
The lipid-lowering action is expressed as the per-centage reduction of total cholesterol and triglycerides compared with the control, Under the experimental con-ditions given above, an average lowering of total cholesterol by 19.5 + 13.3% and of triglycerides by 54.8 + 20.1% (X ~ Sx in each case) could be achieved with Clofibrat in this series . of experiments. All the compounds tested were superio.r to Clofibrat at Ieast in one value, Table 3 Percentage lowerin of the triglyceride (TG) and total cholesterol ~TC) levels in the rat.serum after oral administra-tion of the tes-t substances . , . , , . . ~ .
C o~ nb~r ~
. . TG TC
. X ~ Sx ' X ~ x 1 57.0 ~ 12.4 25.2 ~19,6 V . . . . . . . ..... _ _ , 2 61~4 ~ 8.4 24.3 ~ 15.~
- - -3 80,0 ~ 7.2 19.4 ~ 15.1 4 69.3 ~ 5.2 49'7 + 11.6 .
6 81.1 ~ 11.0 22.0 ~ 17.6 7 60.0 ~ 6.7 30.7 ~ 10.4 8 69.9 + 8.9 29.1 f6.3 - 10 78.8 ~ 6.2 32.2 ~12.9 _ j4 80.0 + 7~4 23.3 +1302 ~ -- _ _. .
69J7 ~ 8.4 44~ ~12,2 .. .. . . . . . . .
, .. .. . . . . _ . . _ , ~ . _ . . . . . . .. _ . .. _ ... _ .. . _ .. .... .... . . ..
:~C~ ?
Coml~und _umber % _ owerin~
TG TC
,+ Sx X ~ Sx - 16 79.5 ;~ 7.4 34.5 ~ 12.4 17 47.8 ~14.0 29.6 + 9.9 18 69.7 + 5.6 31~5 + 12.2 _. _ , .
19 76.9 + 9.9 -0.2 + 14.0 . . . .
73.9 ~ 4.6 18.2 + 8.8 ` - 21 62.8 + 12.0 21.6 + 9.8 . .. _ . . .. _ _ . _ _ _ _ _ .
; 23 84.5 ~ 9.2 18,1 + 12.6 ... . .. . . _ _ _ _ 24 50.9 ~ 9.1 15.6 + 10.6 .. . . .. .
77.3 + 3.3 14.8~ 11.2 .
- 26 59.3 +10.3 19,6+ 17,4 27 ~ 67.7 ~ 8.6 40.4~ 17.2 28 67.5 + ?.6 18.3+ 1S-4 ~1 82.5 + 9.3 51.0 + 9.7 _ 33 75.9 ~ 4.9 18.8 ~ 8.3 .
' 34 77.2 + 5.8 17.2 + 8.3 .
. .
17 (CH3)3C COO(CH2)3-CH3 45-8 ( methylcyclohexane) 18 - (CH3)3C C00(CH2)~-CH3 5,~-3 (petroleum ether) 1519 (C~3)3C ~OO(CH2) ~ H3 .37-8 (petroleum ether) 3)3 2 ~ 81-2 (petroleum ether) 21 (CH3)3C COoc~2o5oc(c~3)3 80-2 (methylcyclchexane).
( ) ~ 6~ (ethyl acetate/petroleum ether~
23 (CH3)3C COOCH2- ~,CH3 (X) 24 (CH3)3C CH=CH-C00(CH2~5-CH3 73-4 (metha)nol/diisopropyl (CH3)3C C~2C~12COOC~I2 ~ 220/2 X 10 - - - - ...... ~--.,.. ___ ._ _ _ . ............... ........ _ .. .. _ (x) = viscous oil, purified by column chromatography.
1) The me~ting points were determined with a Kcfler heated stage microscope and are not corrected, 2) Liquid products were purified with a laboratory molecular distillation lnstalla-tion (Leybold-Heraeus KDl i); the boiling points indicated relate to -the hea-ting jacket tempera-tures.
j ., . - 13 Example 5 3=(4'-Carbamoylphenox~ (4'~chlorophenox~-propan-2-ol Dry ammonia gas is passed into a solution of 38.32 g (0.1 mol) o~ 3-(4'-chlorocarbonylphenoxy)-1-(4'-chloro-phenoxy~-prop-2-yl acetate in 300 ml of anhydrous dioxane at 0C until the solution is satura~éd; after 2 hours, the mixture is concentrated in vacuo, the residue is digested with hot water and d~ied over phosphorus pentoxide and a small amount is recrystallised for analysis. Melting point 138-40 (acetone).
IR spectrum (KBr): v(NH): 3,420 cm 1, 3,160 cm 1, v(C=O):
1,745 cm~l, 1,640 cm~l.
H-NMR spectrum (d6-acetone): 2.1 s (3) COCH3, 4 2 d (2) OCH2, 4.3 d (2) OCH2, 5.5 q (1) CH2CHCH2, 6.8-8.5 m (10) aromatic, NH2 In order to remove the acetyl protective group, the solid is dissolved in 300 ml of methanol, whilst warming, and 50 ml of concentrated ammonia are added. The mix-ture is then stirred for 5 hou~s at room -temperature, con~
centrated to dryness in vacuo and the residue is recrystal-lised. Colourless crystals of melting point 168-9C
- (ethyl ace~a-te), yield 20 3 g (63.1%), C16H16ClN04 (321.77) Calculated. C 59.74 H 5.01 N 4.35 Found. C 60.09 H 5.25 N 4.35 IR spectrum (KBr): v(NH, OH) 3,480-3,100 cm 1, ~(c=oj:
1,640 cm~ .
-lH-NMR spectrum (d6-acetone~: 4.1 m (5) CH2CHCH2, 5.2 d (1) OH, 6.8-8.0 m (10) aromatic, NH2.
Example 6 .
3- ~4'-(N-Ethylcarbamoyl~-phenoxy]-1-(4'-tert.-butylphenoxy)-propan-2-ol 17.5 ml (0.2 mol) of a 70% strength ethylamine solution are added to a solution of 40.49 g (0.1 mol) of 3- (4'-chlorocarbonyiphenoxy)-1-(4'-tert.-butylphenoxy)-prop-2-yl acetate in 300 ml of anhydrous dioxane at room temperature and the mixture is then stirred for 8 hours ~nder reflux. The salt which is formed is separated off, the filtrate is concentrated in vacuo, the residue is taken up in chloroform and the chloroform solution is extracted with 2 N potassium hydroxide solution. The organic phase is washed until it gives a neutral reaction, dried over sodium sulphate and concentrated in vacuo, the solid which remains is used, without further purification, for the removal of the acetyl protective group.
The solid is dissolved in 200 ml of methanol, 50 ml of concentrated ammonia are added and the mixture is left for 5 hours at room temperature. It is then concentrated to dryr~ess in vacuo and the residue is purified by recrystal-lization; colourless crystals of melting point 120-122C
(ethyl acetate/petroleum ether~, yield 19.1 g (51.496).
C22H29NO4 (371.48) Calculated: C 71.13 H 7.87 N 3.77 Found : C 70.66 H 7.86 N 3.32 IR spectrum (RBrl: v (NH, OH): 3,300 cm (main absorption), v (C=OI: 1.630 cm 1.
H~NMR spectrum (CDC13]: 1.2 t (3~ CH2CH3, 1.3 s (9~ (CH3]3C~
3.2-3.7 m (31 C~2CH3, OH, 3.9-4.6 m~(5 CH2C_CH2, 6.4 t (1) NH, 6.7~7.8 m (8) aromatic.
. Further carboxylic acid amides according to ~ormula (2) were manu~ac-tured, using the process illustr~ted in Examples 5 and 6, and are listed in Table 2. For reasons of completeness, the compounds dealt with in the examples - 5 are given again in Table 2, arranged according to structural characteristics. -Table 2 R ~ F 2 ~H ~ A-R~ (2) No. R1 A_R2 Melting poin-t (C) 26 Cl C0~2 168-9 (ethyl acetate) 27 Cl CONHC2H5 118-9 (chloroform) Cl CON(C2H5~2 96-7 (chloroform/petroleum ether) 29 Cl cH=cH-coI~n~2 154-5 (ethyl acetate/pe-troleum e-ther) Cl CH2C~2C0~2 90-1 (acetone/petroleum ether).
31 (CH3)3c CONH2 150-2 ~chloroform) 32 (CH3)3c CONHCH3 (x) 3~ (cH3)3c C~C2H5 120-2 (ethyl)acetate/petroleum ( 3)3 ( 2H5)2 68-70 (etthyl)aceta-te/petroleum . (x.) = viscous oil purified by column chromatography.
Example 7 Medicament containin~ ~-L4~-(2-hexox~carbonylv n~ phenoxyl-__ 1-(4~-chloro ~
100 g of 3 [4'-(2-hexoxycarbonylvinyl)-phenoxy~-1-(4'-chlorophenoxy) propan-2-ol are mixed -thoroughly with . _ 16 -.. . .
16 g of maize starch and 6 g o~ highly disperse silica and the mixture is then moistened with a solution o~ 2 g of stearic acid, 6 g o~ acetylcellulose and 6 g o~
stearin in 70 ml of isopropanol and granulated, The dried granules are forced th~ough a sieve and, after mixin~
with 16 g of maize starch, 16 g of ~alc and 2 g of magne,sium stearate, are pressed into 1,000 dragee cores. After coating with a syrup of 2 g o~ lacca, 7.5 g of gum arabic 9 - 0.15 g of dyestu~f, 2 g of colloidal silica, 25 mg of talc and 53.35 g of sucrose, and drying, one thousand dragées weighing 260 mg and each containing 100 mg of active compound are obtained.
Exam~]e 8 Medicament containin 3-r4'-(2- henvlmethoxYcarbonylethyl)-g ~ - ~ P ~
~
250 g of 3_~4 t _ ( 2-phenylmethoxycarbonylethyl)-phenoxy]-1-(4'-chlorophenoxy)-propan-2-ol are mixed with 250 g of polyethylene glycol and filled in-to one thousand oval capsules, which each contain 250 mg of active compound by the Scherer process.
Example 9 3l92~ r rL__2 ol , A finely powdered mixture of 250 g of 3-[4'-(N-ethylcarbamoyl)-phenoxy~ (4'-chlorophenoxy)-propan-2-ol, 133 g of maize starch? 12 g o~ magnesium stearate and 5 g of gelatine is pressed through a fine-meshed sieve ana then filled, in the dry state, into one -thousand hard gela-tine - 17 ~
.. ~ .
capsules, which each contain 250 mg of active compound.
Example 10 Pharmacological testing 1. Oral tolerance After oral administration of the test compounds to mice of the strain NMR-I, weighing 15-20 g, the acute toxicity was determined. The LDSo values were calculated according to Litchfield-Wilcoxon [~. Pharmacol. Exp. Ther.
96, 99 (19492] and relate to the ~ighth day of the treatment. In this series of experiments the LD50 for Clofibrat was 1~900 mg/kg. The substances according to the invention were consi~tently better tolerated and superior to Clofibrat.
2. Lipid-lowerin~ action The lipid-lowering action was tested on grou~s of, in each case, 10 normolipaemic, male Spraque-Dawley rats (Ivanovas, Kisslegg~, weiyhing 190-230 g, on normal rations ("ssniff" complete feed~O
The test compounds were taken up in an aqueous solu-tion of 0.25% of agar and 0.85~ of NaCl and a~ministered o~ally. After administration of 4 x 100 mg/kg o~er a period of 3 days, the animals were bled by cardiac puncture, after being deprived of food for four hoursl).
Serum lipids were determi~ed with a Technicon auto-analyzer. The total cholesterol (TC) was tested by the enzymatic colour test ). The quantitative analysis of triglycerides (TG2 was carried out enzymatically according to Eggstein and Kreutz [Klin. Wschr. 44, 262 (1966)], modified for the autoanalyzer.
1) H. Enomoto and R. Zschocke, 3rd Int. Symp. Atherosol., Berlin, 1973, A~stract 238.
2) P. Roschlau, E. Burnt and W. Gruber, Z. Klin. Chem.
Klin. Biochem 12 403 (lq742.
The lipid-lowering action is expressed as the per-centage reduction of total cholesterol and triglycerides compared with the control, Under the experimental con-ditions given above, an average lowering of total cholesterol by 19.5 + 13.3% and of triglycerides by 54.8 + 20.1% (X ~ Sx in each case) could be achieved with Clofibrat in this series . of experiments. All the compounds tested were superio.r to Clofibrat at Ieast in one value, Table 3 Percentage lowerin of the triglyceride (TG) and total cholesterol ~TC) levels in the rat.serum after oral administra-tion of the tes-t substances . , . , , . . ~ .
C o~ nb~r ~
. . TG TC
. X ~ Sx ' X ~ x 1 57.0 ~ 12.4 25.2 ~19,6 V . . . . . . . ..... _ _ , 2 61~4 ~ 8.4 24.3 ~ 15.~
- - -3 80,0 ~ 7.2 19.4 ~ 15.1 4 69.3 ~ 5.2 49'7 + 11.6 .
6 81.1 ~ 11.0 22.0 ~ 17.6 7 60.0 ~ 6.7 30.7 ~ 10.4 8 69.9 + 8.9 29.1 f6.3 - 10 78.8 ~ 6.2 32.2 ~12.9 _ j4 80.0 + 7~4 23.3 +1302 ~ -- _ _. .
69J7 ~ 8.4 44~ ~12,2 .. .. . . . . . . .
, .. .. . . . . _ . . _ , ~ . _ . . . . . . .. _ . .. _ ... _ .. . _ .. .... .... . . ..
:~C~ ?
Coml~und _umber % _ owerin~
TG TC
,+ Sx X ~ Sx - 16 79.5 ;~ 7.4 34.5 ~ 12.4 17 47.8 ~14.0 29.6 + 9.9 18 69.7 + 5.6 31~5 + 12.2 _. _ , .
19 76.9 + 9.9 -0.2 + 14.0 . . . .
73.9 ~ 4.6 18.2 + 8.8 ` - 21 62.8 + 12.0 21.6 + 9.8 . .. _ . . .. _ _ . _ _ _ _ _ .
; 23 84.5 ~ 9.2 18,1 + 12.6 ... . .. . . _ _ _ _ 24 50.9 ~ 9.1 15.6 + 10.6 .. . . .. .
77.3 + 3.3 14.8~ 11.2 .
- 26 59.3 +10.3 19,6+ 17,4 27 ~ 67.7 ~ 8.6 40.4~ 17.2 28 67.5 + ?.6 18.3+ 1S-4 ~1 82.5 + 9.3 51.0 + 9.7 _ 33 75.9 ~ 4.9 18.8 ~ 8.3 .
' 34 77.2 + 5.8 17.2 + 8.3 .
. .
Claims
The embodiments of the invention, in which an exclusive privilege or property is claimed, are defined as follows:
1. Process for the preparation of a 1,3-diphenoxy-propan-2-ol derivative of the general formula (2) in which R1 is C1 or -C(CH3)3; A is a single bond, vinylene or ethylene, and R4 = -COOR"', wherein R"' is n-butyl, n-pentyl, n-hexyl, 2,3-dihydroxypropyl, 2,2-dimethyl-1,3-dioxolan-4-yl-methyl, pivaloyloxymethyl, benzyl or phenyl, or -CO-NRivRv, where either Riv = Rv, and each is hydrogen, methyl or ethyl or one of Riv and Rv is hydrogen and the other is methyl or ethyl, which comprises a) reacting a compound of the general formula (3) in which R1 is as hereinbefore defined with a phenol of the general formula (4) in which A is as hereinbefore defined and R4 represents n-alkoxycarbonyl in which the n-alkyl radical contains 4 to 6 carbon atoms, or benzyl;
b) reacting a compound of the general formula (5) in which R1 is as hereinbefore defined with a glycidyl ether of the general formula (6) in which A,and R4 are as hereinbefore defined;
c) reacting a compound of the general formula (7) in which R1 and A are as hereinbefore defined by transesterification with an excess of a less volatile alcohol of formula R4-OH, in the presence of an acid or alkaline catalyst, d) reacting a compound of the general formula (8) in which R1 and A are as hereinbefore defined and Z represents an alkali metal or an alkylammonium group, with a halogeno compound of the general formula Hal-R4 (9) in which Hal denotes chlorine or bromine and R4 is an alkyl of 4 to 6 carbon atoms, 2.3-dihydroxypropyl, pivaloyloxymethyl or benzyl. in a dipolar aprotic solvent;
e) reacting a compound of the general formula (10) in which R1 and A are as hereinbefore defined, Z represents acetyl or benzyl and Hal denotes chlorine or bromine, with n-butanol, n-pentanol, n-hexanol, benzyl alocohol or phenol and subsequently selectively splitting off the protective group;
f) reacting a compound of the general formula (12) in which R1 and A are as hereinbefore defined, Ac denotes acetyl and Hal is chlorine or bromine, with ammonia, methyl-amine, dimethylamine, ethylamine or diethylamine and subsequently splitting off the acetyl group; or g) hydrogenating a compound of the general formula (15) in which R1 is as hereinbefore defined and R4 is n-butoxy, n-pentoxy, n-hexoxy, 2,3-dihydroxypropoxy, 2,2-dimethyl-1,3-dioxolan-4-yl-methoxy, pivaloyloxymethoxy, phenoxy, amino, methylamino, dimethylamino, ethylamino or diethylamino.
2. The process of claim 1 wherein a compound of the formula:
is reacted with a phenol of the formula:
to form 3-[4'-(2-hexoxycarbonylvinyl)-phenoxy]-1-(4'-chlorophenoxy)-propan-2-ol.
The process of claim 1 wherein a compound of the formula:
is reacted with a phenol of the formula:
to form 3-[4'-(2-phenylmethoxycarbonylethyl)-phenoxy]-1-(4'-chlorophenoxy)-propan-2-ol.
The process of claim 1 wherein a compound of the formula:
where Z represents an alkali metal or an alkyl-ammonium group, is reacted with a halogeno com-pound of the formula:
Cl-CH2-OOC-C(CH3)3 to form 3-(4'-pivaloyloxymethoxycarbonylphenoxy)-1-(4'-tert.butylphenoxy)-propan-2-ol.
5. The process of claim 1 wherein a compound of the formula:
where Hal is chlorine or bromine, is reacted with ammonia, and subsequently the acetyl group is split off to form 3-(4'-carbamoyl-phenoxy)-1-(4'-tert butylphenoxy)-propan-2-ol.
6. The process of claim 1 wherein a compound of the formula:
where Hal is chlorine or bromine, is reacted with ethylamine, and subsequently the acetyl group is split off to form 3-[4'-(N-ethyl-carbamoyl)-phenoxy]-1-(4'-chlorophenoxy)-propan-2-ol.
7. Substituted 1,3-diphenoxypropan-2-ol derivatives of the general formula (2) in which R1 is C1 or -C(CH3)3; A is a single bond, vinylene or ethylene; and R4 = -COOR"', wherein R"' is n-butyl, n-pentyl, n-hexyl, 2,3-dihydroxypropyl, 2,2-dimethyl-1,3-dioxolon-4-yl-methyl, pivaloyloxymethy, benzyl or phenyl; or -CO-NRivRv, where either Riv = Rv, and each is hydrogen, methyl or ethyl or one of Riv and Rv is hydrogen and the other is methyl or ethyl, when prepared by the process claimed in claim 1 or any obvious chemical equivalent thereof.
8. 3-[4'-(2-Hexoxycarbonylvinyl)-phenoxy]-1-(4'-chlorophenoxy)-propan-2-ol, when prepared by the process claimed in claim 2 or any obvious chemical equivalent thereof.
9. 3-[4'-(2-Phenylmethoxycarbonylethyl)-phenoxy]-1-(4'-chlorophenoxy)-propan-2-ol,when prepared by the process claimed in claim 3 or any obvious chemical equivalent thereof.
10. 3-(4'-Pivaloyloxymethoxycarbonylphenoxy)-1-(4'-tert.-butylphenoxy)propan-2-ol, when prepared by the process claimed in claim 4 or any obvious chemical equivalent thereof.
11. 3-(4'-Carbarnoylphenoxy)-1-(4'-tert.-butylphenoxy)-propan-2-ol, when prepared by the process claimed in claim 5 or any obvious chemical equivalent thereof.
12. 3-[4'-(N-Ethylcarbamoyl)-phenoxy]-1-(4'-chlorophenoxy)-propan-2-ol, when prepared by the process claimed in claim 6 or any obvious chemical equivalent thereof.
1. Process for the preparation of a 1,3-diphenoxy-propan-2-ol derivative of the general formula (2) in which R1 is C1 or -C(CH3)3; A is a single bond, vinylene or ethylene, and R4 = -COOR"', wherein R"' is n-butyl, n-pentyl, n-hexyl, 2,3-dihydroxypropyl, 2,2-dimethyl-1,3-dioxolan-4-yl-methyl, pivaloyloxymethyl, benzyl or phenyl, or -CO-NRivRv, where either Riv = Rv, and each is hydrogen, methyl or ethyl or one of Riv and Rv is hydrogen and the other is methyl or ethyl, which comprises a) reacting a compound of the general formula (3) in which R1 is as hereinbefore defined with a phenol of the general formula (4) in which A is as hereinbefore defined and R4 represents n-alkoxycarbonyl in which the n-alkyl radical contains 4 to 6 carbon atoms, or benzyl;
b) reacting a compound of the general formula (5) in which R1 is as hereinbefore defined with a glycidyl ether of the general formula (6) in which A,and R4 are as hereinbefore defined;
c) reacting a compound of the general formula (7) in which R1 and A are as hereinbefore defined by transesterification with an excess of a less volatile alcohol of formula R4-OH, in the presence of an acid or alkaline catalyst, d) reacting a compound of the general formula (8) in which R1 and A are as hereinbefore defined and Z represents an alkali metal or an alkylammonium group, with a halogeno compound of the general formula Hal-R4 (9) in which Hal denotes chlorine or bromine and R4 is an alkyl of 4 to 6 carbon atoms, 2.3-dihydroxypropyl, pivaloyloxymethyl or benzyl. in a dipolar aprotic solvent;
e) reacting a compound of the general formula (10) in which R1 and A are as hereinbefore defined, Z represents acetyl or benzyl and Hal denotes chlorine or bromine, with n-butanol, n-pentanol, n-hexanol, benzyl alocohol or phenol and subsequently selectively splitting off the protective group;
f) reacting a compound of the general formula (12) in which R1 and A are as hereinbefore defined, Ac denotes acetyl and Hal is chlorine or bromine, with ammonia, methyl-amine, dimethylamine, ethylamine or diethylamine and subsequently splitting off the acetyl group; or g) hydrogenating a compound of the general formula (15) in which R1 is as hereinbefore defined and R4 is n-butoxy, n-pentoxy, n-hexoxy, 2,3-dihydroxypropoxy, 2,2-dimethyl-1,3-dioxolan-4-yl-methoxy, pivaloyloxymethoxy, phenoxy, amino, methylamino, dimethylamino, ethylamino or diethylamino.
2. The process of claim 1 wherein a compound of the formula:
is reacted with a phenol of the formula:
to form 3-[4'-(2-hexoxycarbonylvinyl)-phenoxy]-1-(4'-chlorophenoxy)-propan-2-ol.
The process of claim 1 wherein a compound of the formula:
is reacted with a phenol of the formula:
to form 3-[4'-(2-phenylmethoxycarbonylethyl)-phenoxy]-1-(4'-chlorophenoxy)-propan-2-ol.
The process of claim 1 wherein a compound of the formula:
where Z represents an alkali metal or an alkyl-ammonium group, is reacted with a halogeno com-pound of the formula:
Cl-CH2-OOC-C(CH3)3 to form 3-(4'-pivaloyloxymethoxycarbonylphenoxy)-1-(4'-tert.butylphenoxy)-propan-2-ol.
5. The process of claim 1 wherein a compound of the formula:
where Hal is chlorine or bromine, is reacted with ammonia, and subsequently the acetyl group is split off to form 3-(4'-carbamoyl-phenoxy)-1-(4'-tert butylphenoxy)-propan-2-ol.
6. The process of claim 1 wherein a compound of the formula:
where Hal is chlorine or bromine, is reacted with ethylamine, and subsequently the acetyl group is split off to form 3-[4'-(N-ethyl-carbamoyl)-phenoxy]-1-(4'-chlorophenoxy)-propan-2-ol.
7. Substituted 1,3-diphenoxypropan-2-ol derivatives of the general formula (2) in which R1 is C1 or -C(CH3)3; A is a single bond, vinylene or ethylene; and R4 = -COOR"', wherein R"' is n-butyl, n-pentyl, n-hexyl, 2,3-dihydroxypropyl, 2,2-dimethyl-1,3-dioxolon-4-yl-methyl, pivaloyloxymethy, benzyl or phenyl; or -CO-NRivRv, where either Riv = Rv, and each is hydrogen, methyl or ethyl or one of Riv and Rv is hydrogen and the other is methyl or ethyl, when prepared by the process claimed in claim 1 or any obvious chemical equivalent thereof.
8. 3-[4'-(2-Hexoxycarbonylvinyl)-phenoxy]-1-(4'-chlorophenoxy)-propan-2-ol, when prepared by the process claimed in claim 2 or any obvious chemical equivalent thereof.
9. 3-[4'-(2-Phenylmethoxycarbonylethyl)-phenoxy]-1-(4'-chlorophenoxy)-propan-2-ol,when prepared by the process claimed in claim 3 or any obvious chemical equivalent thereof.
10. 3-(4'-Pivaloyloxymethoxycarbonylphenoxy)-1-(4'-tert.-butylphenoxy)propan-2-ol, when prepared by the process claimed in claim 4 or any obvious chemical equivalent thereof.
11. 3-(4'-Carbarnoylphenoxy)-1-(4'-tert.-butylphenoxy)-propan-2-ol, when prepared by the process claimed in claim 5 or any obvious chemical equivalent thereof.
12. 3-[4'-(N-Ethylcarbamoyl)-phenoxy]-1-(4'-chlorophenoxy)-propan-2-ol, when prepared by the process claimed in claim 6 or any obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP2625688.2 | 1976-06-08 | ||
| DE2625688A DE2625688C3 (en) | 1976-06-08 | 1976-06-08 | 1,3-Diphenoxypropanol- (2) derivatives and processes for their preparation and their use as pharmaceuticals |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1090812A true CA1090812A (en) | 1980-12-02 |
Family
ID=5980082
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA280,051A Expired CA1090812A (en) | 1976-06-08 | 1977-06-07 | Substituted 1,3-diphenoxypropan-2-o1 derivatives and their manufacture and use |
Country Status (7)
| Country | Link |
|---|---|
| JP (2) | JPS537638A (en) |
| BE (1) | BE855464R (en) |
| CA (1) | CA1090812A (en) |
| DE (1) | DE2625688C3 (en) |
| FR (1) | FR2354312A2 (en) |
| GB (1) | GB1533820A (en) |
| ZA (1) | ZA773426B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4567201A (en) * | 1981-11-25 | 1986-01-28 | Takeda Chemical Industries, Ltd. | Diphenoxypropane derivatives and compositions of antiasthmatic and antiinflammatory agents thereof |
| US5135940A (en) * | 1982-09-23 | 1992-08-04 | Merck Frosst Canada, Inc. | Leukotriene antagonists |
| JPS6020430U (en) * | 1983-07-20 | 1985-02-13 | 三菱自動車工業株式会社 | Sliding seat rail structure |
| JPS6043436U (en) * | 1983-08-29 | 1985-03-27 | 三菱自動車工業株式会社 | Rail mounting structure of sliding seat |
| US6124495A (en) * | 1997-03-11 | 2000-09-26 | Beacon Laboratories, Inc. | Unsaturated oxyalkylene esters and uses thereof |
| US5939455A (en) * | 1997-03-11 | 1999-08-17 | Beacon Laboratories, Inc. | Therapeutic augmentation of oxyalkylene diesters and butyric acid derivatives |
-
1976
- 1976-06-08 DE DE2625688A patent/DE2625688C3/en not_active Expired
-
1977
- 1977-06-06 FR FR7717280A patent/FR2354312A2/en active Granted
- 1977-06-07 JP JP6637877A patent/JPS537638A/en active Pending
- 1977-06-07 ZA ZA00773426A patent/ZA773426B/en unknown
- 1977-06-07 CA CA280,051A patent/CA1090812A/en not_active Expired
- 1977-06-07 BE BE178260A patent/BE855464R/en active
- 1977-06-08 GB GB24010/77A patent/GB1533820A/en not_active Expired
-
1980
- 1980-10-31 JP JP15238180A patent/JPS5677244A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| BE855464R (en) | 1977-10-03 |
| JPS537638A (en) | 1978-01-24 |
| JPS5677244A (en) | 1981-06-25 |
| JPS5748136B2 (en) | 1982-10-14 |
| DE2625688C3 (en) | 1982-01-28 |
| FR2354312B2 (en) | 1981-02-13 |
| ZA773426B (en) | 1978-05-30 |
| DE2625688B2 (en) | 1981-01-15 |
| GB1533820A (en) | 1978-11-29 |
| FR2354312A2 (en) | 1978-01-06 |
| DE2625688A1 (en) | 1977-12-22 |
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