CA1051897A - Process for preparing mono- and di-esters of 2,5-dihydroxybenzene sulfonic acid - Google Patents
Process for preparing mono- and di-esters of 2,5-dihydroxybenzene sulfonic acidInfo
- Publication number
- CA1051897A CA1051897A CA218,959A CA218959A CA1051897A CA 1051897 A CA1051897 A CA 1051897A CA 218959 A CA218959 A CA 218959A CA 1051897 A CA1051897 A CA 1051897A
- Authority
- CA
- Canada
- Prior art keywords
- sulfonic acid
- salt
- isobutyroyl
- benzene sulfonic
- dihydroxy benzene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
- C07D213/18—Salts thereof
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Abstract
Abstract of the disclosure Compounds of the general formula:
wherein each R residue is hydrogen or the residue of p-chloro-phenoxy isobutyric acid having the formula:
wherein each R residue is hydrogen or the residue of p-chloro-phenoxy isobutyric acid having the formula:
Description
The main Canadian Pat~nt No. 1,009 ,238, issued April 26, 1977 to the assignee of this application, concerns mono- and di-esters oE Z,5-dihydroxy benzene sulfonic acid having one of the following general formulas O--R O--H O-R
3503.1: [~503.~ ~3,sol.8 O--H O--R O--R ' II III
wherein R and R' can be the same or different and represent an alkanoyl, arylal~canoyl, aryloxyalkanoyl, aroyl, alkanesulfonyl, arenesulfonyl, alkylarenesulfonyl or arylallcanesulfonyl radical, B represents a cation of an alkali metal, an alkaline earth metal, amrnonia, a substituted or unsubstituted amine or an N containing heterocyclic ring.
The proce s for preparing these compounds is characterized in that a cornpound having the formula: _ S03 a B
is reacted with a halide or anhydride of an acid having the formula R H
and possibly an acid hav~ng the formula R'-H wherein B and R' have the meaning given above.
YVe have ~ound that among these esters, tho~e having the general ~ormula:
~05~B97 ~R
OR
wherein each X residue is hydrogen or the residue of p-chloro-phenoxy isobutyric acid having the formula:
Cl ~ ~ O_ I _ C ~
with the proviso that both Rs are not hydroyen simultaneously, and B is hydrogen or the equivalent of an inorganic or organic cation, are particularly desirable.
The salts of magnesium, calcium and piperazine are preferred. The~ can be prepared simply by neutralizing sul-fonic acid, for instance with magnesium or calcium carbonate, or with piperazine which can neutralize one or two molecules of the acid. The latter can be prepared from the pyridine salt, by treating said salt with concentrated sulfuric acid, pre-ferably with approximately 1~ N sulfuric acid, in tne case of di-esters and mono-esters in the 5-position.
The pyridine salt of the mono-ester can be obtained according to Example 2 of the main Patent.
l1ono-esterification in 2-position is ~ffected start-ing fro-m the calcium salt of 2,5-dihydroxy benzene sulfonic acid, according to Example 12; thus the corresponding calci~n salt is obtained directly. The magnesium or piperazine salts are prepared by neutrali~ing the rnono-2-0-(p-chloro phenoxy isobutyroly)-
3503.1: [~503.~ ~3,sol.8 O--H O--R O--R ' II III
wherein R and R' can be the same or different and represent an alkanoyl, arylal~canoyl, aryloxyalkanoyl, aroyl, alkanesulfonyl, arenesulfonyl, alkylarenesulfonyl or arylallcanesulfonyl radical, B represents a cation of an alkali metal, an alkaline earth metal, amrnonia, a substituted or unsubstituted amine or an N containing heterocyclic ring.
The proce s for preparing these compounds is characterized in that a cornpound having the formula: _ S03 a B
is reacted with a halide or anhydride of an acid having the formula R H
and possibly an acid hav~ng the formula R'-H wherein B and R' have the meaning given above.
YVe have ~ound that among these esters, tho~e having the general ~ormula:
~05~B97 ~R
OR
wherein each X residue is hydrogen or the residue of p-chloro-phenoxy isobutyric acid having the formula:
Cl ~ ~ O_ I _ C ~
with the proviso that both Rs are not hydroyen simultaneously, and B is hydrogen or the equivalent of an inorganic or organic cation, are particularly desirable.
The salts of magnesium, calcium and piperazine are preferred. The~ can be prepared simply by neutralizing sul-fonic acid, for instance with magnesium or calcium carbonate, or with piperazine which can neutralize one or two molecules of the acid. The latter can be prepared from the pyridine salt, by treating said salt with concentrated sulfuric acid, pre-ferably with approximately 1~ N sulfuric acid, in tne case of di-esters and mono-esters in the 5-position.
The pyridine salt of the mono-ester can be obtained according to Example 2 of the main Patent.
l1ono-esterification in 2-position is ~ffected start-ing fro-m the calcium salt of 2,5-dihydroxy benzene sulfonic acid, according to Example 12; thus the corresponding calci~n salt is obtained directly. The magnesium or piperazine salts are prepared by neutrali~ing the rnono-2-0-(p-chloro phenoxy isobutyroly)-
2,5-dihydroxy benzene sulfonic acid, obtained by treating the calcium salt according to Example 12 with approxima.tely 2N sulfuric acid.
In one aspect of this invention there is provided a process for preparing the pyridine salt of a mono- or di- ester of p-dihydroxybenzene sulfonic acid of the formula:
OR
hr S03H
~
OR
wherein R is hydrogen or an acyl group of the formula:
C~
Cl~ O- I - C \
20 with the proviso that at least one R is the acyl group; or the calcium salt of a monoester of p-dihydroxyben~ene sulfonic acid of the formula:
~SO~~ ~' OE: 2 wherein R is the acyl group as defined above, which process comprises reacting the diethylamine salt of 2,5-dihydroxybenzene sulfonic acidw1th p-chlorophenoxy isobutyric acid chloride in the presence of pyridine; or reacting the calcium salt of 2,5-dihydroxybenzene sulfonic acid with the 30 anhydride of p-chlorophenoxy isobutyric acid and calcium oxide in the presence of an organic solvent.
,f j ~5~ 7 In an~the;r ~spect of th;s invention there is p~ovided a process for preparing the pyridine salt o~ mono-5~ (p-chlolo phenoxy isobutyroyl)-2,5-dihydroxy benzen~ sulfonic acid, comprising reacting the diethylamine salt ol Z,5-dihydroxy benzene sulfonic acid with p-chloro phenoxy isobutyric acid chloride in the presence of pyridine.
In a still another aspect of th;s invention there is pro~ided a process for preparing the pyridine salt of di-O~(p-chloro phenoxy isobutyroyl) -2,5-dihydroxy benzene sulfonic acid, corllprising reacting the diethylamine Z,5-dihydroxy benzene sulfonate with p-chloro phenoxy isobutylic acid chloride in the presence of pyridine.
In a further aspect of this invention there is provided a process for preparing the calcium salt of mono-2-O-(p-chloro phenoxy isobut~-royl)-2,5-dihydroxybenzene sulfonic acid, comprising reacting the calcium salt of 2,5-dihydroxy ben~ene sulfonic acid with p-chloro phenoxy isobutyric acid anhydride and calcium oxide in an organic solvent.
In a still further aspect of this invention there is provided a process as set out above, wherein the ~olvent is acetone, being a process for preparing the magnesium salt of mono-2-O-(p-chloro phenoxy isobutyroyl) -2,5-dihydroxy benzene sul~onic acid, wherein said process further com-prises: (a) reacting said calcium salt with sulfuric acid to form mono-2-O-(p-chloro phenoxy isobutyroyl)-2 ,5-dihydroxy benzene sulfonic acid; and (b) neutralizing said sulfonic acid with a magnesium base.
In a still further aspect of this invention there are provided the products of the preceding aspects.
The compounds according to this invention significantly inhibit the increase of plasma cholesterol, triglycerides, and total lipids contents in rats treated with Triton* WR-1339 according to the techniques described in the main patent. The acute toxicities for the mouse are also very low.
LD50 ~or the mouse was determined according to the modified method of Reed and Muench (Reecl L. J. & Muench H., Am, J. Hyg., 27, 493, 1938).
* Trademark.
- 4a - -The pharmacodynamical properties of the compounds according to the invention are illustrated herebelow by those of the piperazine salt with one mole of the di-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulEonic acid;
LD50 Percentage of diminution of lipids Proposed oral per administration per os of dose (mg/k~)2 millimole~kg of product (g / day) Cholesterol Triglycerides Total lipids . _ _ (p.o.) Example 1 In an erlenmeyer provided with stirring and refriger-ation are placed 50-60 ml of 18 N sulfuric acid, and 13.8 g of the pyridine salt of the mono-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulfonic acid are added, preferably the isomer esterified in 5-position, and this is left stirring - 4b -~S~ 37 at a low ter,peratuxe Lor 1J millU~e.~. l`nen 50 ml of ethyl etner are added, and stirriny is con-tlnued until the t~o layers are completely clear. The t,ro layers are separated by rneans of a dropping funnel, and the aqueous ~,hase is extracted ~itil 2 x 50 ml oE ethyl ether. The orcsanic phase is dried over anhydrous sodiulr, sulface, filterec1, and evaporated at reduced pressure at 35C. ~hus 10.1 y of mono-O-(p-chloro ~henoxy isobutyrate) of 2,5-dihydroxv benzene sulfonic acid are ob-tained in the form of an oil, ~hose infrared spectrum measurea on a KBr tablet ~ives maxima at the following frequencies:
3290; 1740, 1480, 1220, 1110, 1000, ~1~ and 700 cm 1.
_ample 2 To a solution of 1.0 g of piperazine hexahydrate in 10 ml of ethanol, a solution of 1.9 g of mono-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulfonic acid, obtained according to ~xample 1, in 10 ml of ethanol, is added. The precipitate formed is riltered, and 2.1 g of the mono-salt of piperazine of mono-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulfonic acid are obtained, in crys-talline forrn haviny a meltiny point of 202-205C.
Exarnple 3 To a solution of 1.9 y of piperazine hexahydrate in 20 ml of ethanol, a solution of 7.5 y of mono-O-(p-chloro phenoxy isobutyrate) of 2,5-dinydroxy benzene sulfonic acid, obtained accordiny to Example 1, in 20 ml of ethanol, is added.
The precipitate formed is filtered, and 9.2 ~ of the di-sait of piperazine of mono-O-(p-chloro phenoxy isobutyrate) of 1~5~89~
2,5-dihydroYy benzene sulfonic acid are obtained, in crystal-line form, havillg a ~eltiny ~oint of 245-246 C.
Ex~ le 4 .p To a solution or 3.~ g o mono-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulEonic acid, obtained according to ~xample 1, in 15 ml of a 5:1 mixture (v/v) of ethanol and water, a slight excess of calcium carbonate is added. This is filtered and evaporclted, and 3.8 g of the calcium salt of mono-O-(p-chloro phenoxy butyrate) of 2,5-dihydroxy benzene sulfonic acid are obtained in the form of a white powder whose infrared spectrum determined in a KBr tablet gives maxima at the following frequencies: 34~0, 31~0, 1770, 1750, 1490, 1220, 860 and 820 cm Example 5 To a solution of 3.8 g of mono-O-(p-chloro phenoxy butyrate) of 2,5-dihydroxy benzene sulfonic acid, obtained according to Example 1, in 15 ml of ethanol, a slight excess oE basic magnesium carbonate is added. This is filtered, evaporated and 3.0 g of the magnesium salt of mono-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulfonic acid are obtained in the form of a slightly hygroscopic white powder, having an infrared spectrum measured in a KBr tablet which has maxima at the following frequencies: 3390, 1750, 1480, 1230, 1170, 1020, 320 and 700 cm 1 Example 6 To a solution of 263 g of diethylamine 2,S-dihydroxy benzene sulfonate in 500 ml of pyridine, 470 g of the chloride of p-chloro phenoxy isobutyric acid are added with stirring.
~, _ The reaction is exothermic, but it is effected without refri-geration, letting it cool to ambient temperature. A coloured precipitate forms, which is filtered and washed with water, and then copio~lsly with ethanol. Thus 601 g of the pyridine salt of the di-O-(p-chloro phenoxy isobutyrate) of 2,5-di-hydroxy benzene sulfonic acid are obtained in the form of a white crystalline powder having a melting point of 186-188C.
Example 7 In an erlenmeyer provided with stirring and refriger-ation, 50-60 ml of 18 N sulfuric acid are placed, 19.8 g of the pyridine salt of di-O-(p-chloro phenoxy isobutyrate~ of 2,5-dihydroxy benzene sulfonic acid are added, and this is left stirring, at a low temperature, for 20 minutes. Then 50 ml of ethyl ether are added, and stirring is continued until the two layers are completely transparent. The two layers are separated in a dropping funnel, and the aqueous phase is ex-tracted with 2 x 50 ml of ethyl ether. The organic phase is dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure, and 17.5 g of di-O-(p-chloro phenoxy isobu-tyrate) of 2,5-dihydroxy benzene sulfonic acid are obtained in the form of a viscous oil whose infrared spectra give maxima at at the following frequencies: 3285, 2990, 1750, 1480, 1220, 1080, 1000, 820, and 705 cm 1.
Example 8 To a solution of 1.9 g of piperazine hexahydrate in 20 ml of ethanol, a solution of 6.0 g of di-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulfonic acid in 10 ml of ethanol is added. The mix-ture is left in a refrigerator for 2 hrs., it is filtered, the product formed is recrystal-lized, and 4.3 g of the piperazine mono-salt of di-O-(p-~0~11!3~7 chloro phenoxy isobutyrate of 2,5-dihydroxy benzene sulfonic acid is obtained in the form of whit.e crystals having a melt-ing point of 168C.
Example 9 To a solution of 1.9 g of piperazine hexahydrate in 20 ml of ethanol, a solution of 12 g of di-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulfonic acid in 20 ml of ethanol is added. The precipitate formed is fil-tered, re-crystallized and 9.8 g of the piperazine di-salt of di-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulfonic acid is obtained in the form of white crystals having a melt-ing point of 197-200C.
Example 10 To a solution of 6.0 g of di-O-(p-ehloro phenoxy iso-butyrate) of 2,5-dihydroxy benzene sulfonie aeid in 20 ml of ethanol, an exeess of ealeium carbonate is added, this is fil-tered, evaporated and 5.9 g of the caleium salt of di-O-(p-ehloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulfonic aeid is obtained in the form of white erystals whose infrared speetrum, measured on a KBr tablet, gives maxima at the following frequeneies: 3520, 3400, 1750, 1480, 1230, 1080, 820, and 700 em 1.
Example 11 To a solution of 6.0 g of di-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulfonic aeid in 20 ml ~5~
o e-thanol, a s~ nt eY~cess of basic magnesiurn carbonate is added, this is filtered, evapora-ted and 5~0 y of magnesium salt OL di-~-(p-crlloro phenoxy isobutyrat~) of ~,5-diny~roxy benzene sulfonic acià is obtained in the form of a white powder whose infrared spectrw~, measured in a KBr tablet, gives maxima at the follo~ling frequencies: 3400, 1760, 1050 1480, 1230, 1090, 1020, ~40, 820, and 705 cm 1.
~xam le 12 p To a solution of 10.70 g ~0.02~ mole) of calcium hydroquinone sulfonate ~containing 0.63 equivalen-ts of H~O) in 100 ml of acetone containing 4.5 rnl of water, 20.~5 g (0.050 mole) of p-chloro phenoxy isobutyric acid anhydride are added, and ~Jith stirring for 4 hours, 1.4 g (0.025 mole) of CaO are added portions~ise (Ca content determined previous-ly). A precipitate of calcium p-chloro phenoxy isobutyrate dihydrate forms gradually. After 5 hours reaction at room temperature, this is concentrated to dryness under reduced pressure, the amorphous residue is taken up in 200 ml of water at 2C, it is left at this temperature for 2 hours, and then 12~0 g of calcium p-chloro phenoxy isobutyrate dihydrate is filtered off. llhe mother liquors are concentrated to dryness, under reduced pressure, and the amorphous crystalline residue is crystallized with ether. The fraction thus obtained is soluble in tetrahydrofuran (THF), ethyl acetate, acetone. It is recrystallized in the THF solution with ether.
lne product crys~allizes with one molecule of the solvent, e.g. THF, acetone, ethyl acetate. The crystallization _ g _ L8~7 sol~ent is removed at 100C, 17 hours. Yield: 15.5 g (74~).
The product, whic;l e~hibits polymorphism, is calcium 2-O-(p-chloro phenoxy isobutyryl)-hydroquinone sulfonate. Coefficien-ts of molecular ~xtinction ir, W:
223 nrn = 39,500 ~ 2~0 nm = 8,j00 3 2 The infrared spectrum, measured with nujol, gives maxima at 3340, 1750, 1~00, 1230, 1200, 1130, 1090, 1030, ~70, 830 and 720 cm ~
To an aqueous solution of 93.4~ g (0.11 mole) of calcium 2-O-(p-chloro phenoxy isobutyryl) hydroquinone sulfonate dinydrate, 110 ml of 2N sulfuric acid are added dropwise, with stirring; the suspension is cooled to 2C for 120 minutes~
SO4Ca is removed by filtering. To the clear filtrate 4.76 c (0.11 mole) of MgO are added with stirring. After a few minutes, the whole of the oxide was consumed. The solvent is removed under reduced pressure, and the amorphous residue is taken up in acetone. The remaining SO~Ca is filtered, the ~0 solvent is removed under reduced pressure, the evaporation residue is taken up in ether, wherefrom 91.0 g of mayresium 2-O-(p-chloro phPnoxy isobutyryl)hydroquinone sulfonate crystallizes. This product is kept at 98C for 17 hours. At room temperature, the ester re-equilibrates its H~O content.
83.8 g of magnesium 2-O-(p-chloro phenoxy isobutyryl)hydro-quinone sulfonate dihydrate are obtained.
The infrared spec-trum, measured with nujol, gives Maxima at 3450, 1750, 1600, 1200, 1090, 1040, 1030, 970, ~70, 840 and 720 cm 1.
1 C95~8~7 Example 14 To a solution of 1.69~ g (2 mmoles) of calcium 2-O-(p-chloro phenoxy isobutyrylj-hydroquinone sulfonate in water, 2 ml of 2N sulfuric acid are added, the SO4Ca formed is re-moved by filtration, 172.2 mg (2 mmoles) of piperazine areadded to the filtrate. This is evaporated to dryness under re-duced pressure; the residue is taken up in acetone, a small amount of residual SO4Ca is removed by filtration, the filtrate is evaporated to dryness, and the piperazine salt is crystal-lized in ethyl acetate, and recrystallized in a mixture of te-trahydrofuran and ether~ Bis-2-O-(p-chloro phenoxy iso-butyryl)-hydroquinone sulfonate of piperazine having a melting point of 226-229C is obtained.
Because of the low toxicity of these compounds, and hence their high therapeutical index, their clinical perform-ance is shown to be extremely interesting for the treatment of various types of hyperlipemia and dislipemia.
The pharmacodynamical properties of the compounds according to the invention are illustrated in the Table here-below e.g. the medium lethal dose ~LD50~, and the percent in-hibition with respect to Triton*WE-1339 of total cholesterol, triglycerides and total lipids. In this Triton*WR-1339 method, all the compounds are administered at a dose of 2 mmoles/kg orally excepted those compounds in which R is the residue of p-chloro phenoxy isobutyric acid, which are administered orally at a dose corresponding to 2 mmoles of R per kg, i.e.
the amount used is calculated on the basis of the residue R
only.
*Trademark.
89~
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EYample of formulation fGr a takl~
piperazine 2,5-~ihyaroxybenzenesulfonate monosylate 0-500 Y
rice starcn 0.100 y lactose 0.100 g polyvinyl~yrrolidone 0.020 y maynesium stearate 0.003 g weight of tablet 0.723 g Example of formulation for a capsule piperazine 2,5-dihydroxybenzenesulfonate monotosylate 0.250 g lactose 0.050 g aerosil 0.001 y magnesium stearate 0.002 g weight of capsule 0.303 y
In one aspect of this invention there is provided a process for preparing the pyridine salt of a mono- or di- ester of p-dihydroxybenzene sulfonic acid of the formula:
OR
hr S03H
~
OR
wherein R is hydrogen or an acyl group of the formula:
C~
Cl~ O- I - C \
20 with the proviso that at least one R is the acyl group; or the calcium salt of a monoester of p-dihydroxyben~ene sulfonic acid of the formula:
~SO~~ ~' OE: 2 wherein R is the acyl group as defined above, which process comprises reacting the diethylamine salt of 2,5-dihydroxybenzene sulfonic acidw1th p-chlorophenoxy isobutyric acid chloride in the presence of pyridine; or reacting the calcium salt of 2,5-dihydroxybenzene sulfonic acid with the 30 anhydride of p-chlorophenoxy isobutyric acid and calcium oxide in the presence of an organic solvent.
,f j ~5~ 7 In an~the;r ~spect of th;s invention there is p~ovided a process for preparing the pyridine salt o~ mono-5~ (p-chlolo phenoxy isobutyroyl)-2,5-dihydroxy benzen~ sulfonic acid, comprising reacting the diethylamine salt ol Z,5-dihydroxy benzene sulfonic acid with p-chloro phenoxy isobutyric acid chloride in the presence of pyridine.
In a still another aspect of th;s invention there is pro~ided a process for preparing the pyridine salt of di-O~(p-chloro phenoxy isobutyroyl) -2,5-dihydroxy benzene sulfonic acid, corllprising reacting the diethylamine Z,5-dihydroxy benzene sulfonate with p-chloro phenoxy isobutylic acid chloride in the presence of pyridine.
In a further aspect of this invention there is provided a process for preparing the calcium salt of mono-2-O-(p-chloro phenoxy isobut~-royl)-2,5-dihydroxybenzene sulfonic acid, comprising reacting the calcium salt of 2,5-dihydroxy ben~ene sulfonic acid with p-chloro phenoxy isobutyric acid anhydride and calcium oxide in an organic solvent.
In a still further aspect of this invention there is provided a process as set out above, wherein the ~olvent is acetone, being a process for preparing the magnesium salt of mono-2-O-(p-chloro phenoxy isobutyroyl) -2,5-dihydroxy benzene sul~onic acid, wherein said process further com-prises: (a) reacting said calcium salt with sulfuric acid to form mono-2-O-(p-chloro phenoxy isobutyroyl)-2 ,5-dihydroxy benzene sulfonic acid; and (b) neutralizing said sulfonic acid with a magnesium base.
In a still further aspect of this invention there are provided the products of the preceding aspects.
The compounds according to this invention significantly inhibit the increase of plasma cholesterol, triglycerides, and total lipids contents in rats treated with Triton* WR-1339 according to the techniques described in the main patent. The acute toxicities for the mouse are also very low.
LD50 ~or the mouse was determined according to the modified method of Reed and Muench (Reecl L. J. & Muench H., Am, J. Hyg., 27, 493, 1938).
* Trademark.
- 4a - -The pharmacodynamical properties of the compounds according to the invention are illustrated herebelow by those of the piperazine salt with one mole of the di-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulEonic acid;
LD50 Percentage of diminution of lipids Proposed oral per administration per os of dose (mg/k~)2 millimole~kg of product (g / day) Cholesterol Triglycerides Total lipids . _ _ (p.o.) Example 1 In an erlenmeyer provided with stirring and refriger-ation are placed 50-60 ml of 18 N sulfuric acid, and 13.8 g of the pyridine salt of the mono-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulfonic acid are added, preferably the isomer esterified in 5-position, and this is left stirring - 4b -~S~ 37 at a low ter,peratuxe Lor 1J millU~e.~. l`nen 50 ml of ethyl etner are added, and stirriny is con-tlnued until the t~o layers are completely clear. The t,ro layers are separated by rneans of a dropping funnel, and the aqueous ~,hase is extracted ~itil 2 x 50 ml oE ethyl ether. The orcsanic phase is dried over anhydrous sodiulr, sulface, filterec1, and evaporated at reduced pressure at 35C. ~hus 10.1 y of mono-O-(p-chloro ~henoxy isobutyrate) of 2,5-dihydroxv benzene sulfonic acid are ob-tained in the form of an oil, ~hose infrared spectrum measurea on a KBr tablet ~ives maxima at the following frequencies:
3290; 1740, 1480, 1220, 1110, 1000, ~1~ and 700 cm 1.
_ample 2 To a solution of 1.0 g of piperazine hexahydrate in 10 ml of ethanol, a solution of 1.9 g of mono-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulfonic acid, obtained according to ~xample 1, in 10 ml of ethanol, is added. The precipitate formed is riltered, and 2.1 g of the mono-salt of piperazine of mono-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulfonic acid are obtained, in crys-talline forrn haviny a meltiny point of 202-205C.
Exarnple 3 To a solution of 1.9 y of piperazine hexahydrate in 20 ml of ethanol, a solution of 7.5 y of mono-O-(p-chloro phenoxy isobutyrate) of 2,5-dinydroxy benzene sulfonic acid, obtained accordiny to Example 1, in 20 ml of ethanol, is added.
The precipitate formed is filtered, and 9.2 ~ of the di-sait of piperazine of mono-O-(p-chloro phenoxy isobutyrate) of 1~5~89~
2,5-dihydroYy benzene sulfonic acid are obtained, in crystal-line form, havillg a ~eltiny ~oint of 245-246 C.
Ex~ le 4 .p To a solution or 3.~ g o mono-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulEonic acid, obtained according to ~xample 1, in 15 ml of a 5:1 mixture (v/v) of ethanol and water, a slight excess of calcium carbonate is added. This is filtered and evaporclted, and 3.8 g of the calcium salt of mono-O-(p-chloro phenoxy butyrate) of 2,5-dihydroxy benzene sulfonic acid are obtained in the form of a white powder whose infrared spectrum determined in a KBr tablet gives maxima at the following frequencies: 34~0, 31~0, 1770, 1750, 1490, 1220, 860 and 820 cm Example 5 To a solution of 3.8 g of mono-O-(p-chloro phenoxy butyrate) of 2,5-dihydroxy benzene sulfonic acid, obtained according to Example 1, in 15 ml of ethanol, a slight excess oE basic magnesium carbonate is added. This is filtered, evaporated and 3.0 g of the magnesium salt of mono-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulfonic acid are obtained in the form of a slightly hygroscopic white powder, having an infrared spectrum measured in a KBr tablet which has maxima at the following frequencies: 3390, 1750, 1480, 1230, 1170, 1020, 320 and 700 cm 1 Example 6 To a solution of 263 g of diethylamine 2,S-dihydroxy benzene sulfonate in 500 ml of pyridine, 470 g of the chloride of p-chloro phenoxy isobutyric acid are added with stirring.
~, _ The reaction is exothermic, but it is effected without refri-geration, letting it cool to ambient temperature. A coloured precipitate forms, which is filtered and washed with water, and then copio~lsly with ethanol. Thus 601 g of the pyridine salt of the di-O-(p-chloro phenoxy isobutyrate) of 2,5-di-hydroxy benzene sulfonic acid are obtained in the form of a white crystalline powder having a melting point of 186-188C.
Example 7 In an erlenmeyer provided with stirring and refriger-ation, 50-60 ml of 18 N sulfuric acid are placed, 19.8 g of the pyridine salt of di-O-(p-chloro phenoxy isobutyrate~ of 2,5-dihydroxy benzene sulfonic acid are added, and this is left stirring, at a low temperature, for 20 minutes. Then 50 ml of ethyl ether are added, and stirring is continued until the two layers are completely transparent. The two layers are separated in a dropping funnel, and the aqueous phase is ex-tracted with 2 x 50 ml of ethyl ether. The organic phase is dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure, and 17.5 g of di-O-(p-chloro phenoxy isobu-tyrate) of 2,5-dihydroxy benzene sulfonic acid are obtained in the form of a viscous oil whose infrared spectra give maxima at at the following frequencies: 3285, 2990, 1750, 1480, 1220, 1080, 1000, 820, and 705 cm 1.
Example 8 To a solution of 1.9 g of piperazine hexahydrate in 20 ml of ethanol, a solution of 6.0 g of di-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulfonic acid in 10 ml of ethanol is added. The mix-ture is left in a refrigerator for 2 hrs., it is filtered, the product formed is recrystal-lized, and 4.3 g of the piperazine mono-salt of di-O-(p-~0~11!3~7 chloro phenoxy isobutyrate of 2,5-dihydroxy benzene sulfonic acid is obtained in the form of whit.e crystals having a melt-ing point of 168C.
Example 9 To a solution of 1.9 g of piperazine hexahydrate in 20 ml of ethanol, a solution of 12 g of di-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulfonic acid in 20 ml of ethanol is added. The precipitate formed is fil-tered, re-crystallized and 9.8 g of the piperazine di-salt of di-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulfonic acid is obtained in the form of white crystals having a melt-ing point of 197-200C.
Example 10 To a solution of 6.0 g of di-O-(p-ehloro phenoxy iso-butyrate) of 2,5-dihydroxy benzene sulfonie aeid in 20 ml of ethanol, an exeess of ealeium carbonate is added, this is fil-tered, evaporated and 5.9 g of the caleium salt of di-O-(p-ehloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulfonic aeid is obtained in the form of white erystals whose infrared speetrum, measured on a KBr tablet, gives maxima at the following frequeneies: 3520, 3400, 1750, 1480, 1230, 1080, 820, and 700 em 1.
Example 11 To a solution of 6.0 g of di-O-(p-chloro phenoxy isobutyrate) of 2,5-dihydroxy benzene sulfonic aeid in 20 ml ~5~
o e-thanol, a s~ nt eY~cess of basic magnesiurn carbonate is added, this is filtered, evapora-ted and 5~0 y of magnesium salt OL di-~-(p-crlloro phenoxy isobutyrat~) of ~,5-diny~roxy benzene sulfonic acià is obtained in the form of a white powder whose infrared spectrw~, measured in a KBr tablet, gives maxima at the follo~ling frequencies: 3400, 1760, 1050 1480, 1230, 1090, 1020, ~40, 820, and 705 cm 1.
~xam le 12 p To a solution of 10.70 g ~0.02~ mole) of calcium hydroquinone sulfonate ~containing 0.63 equivalen-ts of H~O) in 100 ml of acetone containing 4.5 rnl of water, 20.~5 g (0.050 mole) of p-chloro phenoxy isobutyric acid anhydride are added, and ~Jith stirring for 4 hours, 1.4 g (0.025 mole) of CaO are added portions~ise (Ca content determined previous-ly). A precipitate of calcium p-chloro phenoxy isobutyrate dihydrate forms gradually. After 5 hours reaction at room temperature, this is concentrated to dryness under reduced pressure, the amorphous residue is taken up in 200 ml of water at 2C, it is left at this temperature for 2 hours, and then 12~0 g of calcium p-chloro phenoxy isobutyrate dihydrate is filtered off. llhe mother liquors are concentrated to dryness, under reduced pressure, and the amorphous crystalline residue is crystallized with ether. The fraction thus obtained is soluble in tetrahydrofuran (THF), ethyl acetate, acetone. It is recrystallized in the THF solution with ether.
lne product crys~allizes with one molecule of the solvent, e.g. THF, acetone, ethyl acetate. The crystallization _ g _ L8~7 sol~ent is removed at 100C, 17 hours. Yield: 15.5 g (74~).
The product, whic;l e~hibits polymorphism, is calcium 2-O-(p-chloro phenoxy isobutyryl)-hydroquinone sulfonate. Coefficien-ts of molecular ~xtinction ir, W:
223 nrn = 39,500 ~ 2~0 nm = 8,j00 3 2 The infrared spectrum, measured with nujol, gives maxima at 3340, 1750, 1~00, 1230, 1200, 1130, 1090, 1030, ~70, 830 and 720 cm ~
To an aqueous solution of 93.4~ g (0.11 mole) of calcium 2-O-(p-chloro phenoxy isobutyryl) hydroquinone sulfonate dinydrate, 110 ml of 2N sulfuric acid are added dropwise, with stirring; the suspension is cooled to 2C for 120 minutes~
SO4Ca is removed by filtering. To the clear filtrate 4.76 c (0.11 mole) of MgO are added with stirring. After a few minutes, the whole of the oxide was consumed. The solvent is removed under reduced pressure, and the amorphous residue is taken up in acetone. The remaining SO~Ca is filtered, the ~0 solvent is removed under reduced pressure, the evaporation residue is taken up in ether, wherefrom 91.0 g of mayresium 2-O-(p-chloro phPnoxy isobutyryl)hydroquinone sulfonate crystallizes. This product is kept at 98C for 17 hours. At room temperature, the ester re-equilibrates its H~O content.
83.8 g of magnesium 2-O-(p-chloro phenoxy isobutyryl)hydro-quinone sulfonate dihydrate are obtained.
The infrared spec-trum, measured with nujol, gives Maxima at 3450, 1750, 1600, 1200, 1090, 1040, 1030, 970, ~70, 840 and 720 cm 1.
1 C95~8~7 Example 14 To a solution of 1.69~ g (2 mmoles) of calcium 2-O-(p-chloro phenoxy isobutyrylj-hydroquinone sulfonate in water, 2 ml of 2N sulfuric acid are added, the SO4Ca formed is re-moved by filtration, 172.2 mg (2 mmoles) of piperazine areadded to the filtrate. This is evaporated to dryness under re-duced pressure; the residue is taken up in acetone, a small amount of residual SO4Ca is removed by filtration, the filtrate is evaporated to dryness, and the piperazine salt is crystal-lized in ethyl acetate, and recrystallized in a mixture of te-trahydrofuran and ether~ Bis-2-O-(p-chloro phenoxy iso-butyryl)-hydroquinone sulfonate of piperazine having a melting point of 226-229C is obtained.
Because of the low toxicity of these compounds, and hence their high therapeutical index, their clinical perform-ance is shown to be extremely interesting for the treatment of various types of hyperlipemia and dislipemia.
The pharmacodynamical properties of the compounds according to the invention are illustrated in the Table here-below e.g. the medium lethal dose ~LD50~, and the percent in-hibition with respect to Triton*WE-1339 of total cholesterol, triglycerides and total lipids. In this Triton*WR-1339 method, all the compounds are administered at a dose of 2 mmoles/kg orally excepted those compounds in which R is the residue of p-chloro phenoxy isobutyric acid, which are administered orally at a dose corresponding to 2 mmoles of R per kg, i.e.
the amount used is calculated on the basis of the residue R
only.
*Trademark.
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EYample of formulation fGr a takl~
piperazine 2,5-~ihyaroxybenzenesulfonate monosylate 0-500 Y
rice starcn 0.100 y lactose 0.100 g polyvinyl~yrrolidone 0.020 y maynesium stearate 0.003 g weight of tablet 0.723 g Example of formulation for a capsule piperazine 2,5-dihydroxybenzenesulfonate monotosylate 0.250 g lactose 0.050 g aerosil 0.001 y magnesium stearate 0.002 g weight of capsule 0.303 y
Claims (35)
1. A process for preparing the pyridine salt of a mono- or di-ester of p-dihydroxybenzene sulfonic acid of the formula:
wherein R is hydrogen or an acyl group of the formula:
with the proviso that at least one R is the acyl group; or the calcium salt of a monoester of p-dihydroxybenzene sulfonic acid of the formula:
wherein R is the acyl group as defined above, which process comprises reacting the diethylamine salt of 2,5-dihydroxybenzene sulfonic acid with p-chlorophenoxy isobutyric acid chloride in the presence of pyridine; or reacting the calcium salt of 2,5-dihydroxybenzene sulfonic acid with the anhydride of p-chlorophenoxy isobutyric acid and calcium oxide in the presence of an organic solvent.
wherein R is hydrogen or an acyl group of the formula:
with the proviso that at least one R is the acyl group; or the calcium salt of a monoester of p-dihydroxybenzene sulfonic acid of the formula:
wherein R is the acyl group as defined above, which process comprises reacting the diethylamine salt of 2,5-dihydroxybenzene sulfonic acid with p-chlorophenoxy isobutyric acid chloride in the presence of pyridine; or reacting the calcium salt of 2,5-dihydroxybenzene sulfonic acid with the anhydride of p-chlorophenoxy isobutyric acid and calcium oxide in the presence of an organic solvent.
2. A process for preparing the pyridine salt of mono-5-0-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, com-prising reacting the diethylamine salt of 2,5-dihydroxy benzene sulfonic acid with p-chloro phenoxy isobutyric acid chloride in the presence of pyridine.
3. The process, according to Claim 2, for preparing mono-5-0-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, wherein said process further comprises reacting the pyridine salt with concentrated sulfuric acid.
4. The process according to Claim 3 wherein approximately 18 N sulfuric acid is used.
5. The process, according to Claim 3, for preparing the calcium or magnesium salt of the sulfonic acid, wherein said process further comprises neutralizing said sulfonic acid with a corresponding base.
6. The process according to Claim 5 wherein the corresponding base is calcium carbonate or magnesium carbonate.
7. The process according to Claim 3 for preparing the piperazine salt of one or two moles of the sulfonic acid wherein said process comprises neutralizing said sulfonic acid with piperazine.
8. The process according to Claim 7 wherein said piperazine is piperazine hexahydrate.
9. A process for preparing the pyridine salt of di-O-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, comprising reacting the diethylamine 2,5-dihydroxy benzene sulfonate with p-chloro phenoxy isobutyric acid chloride in the presence of pyridine.
10. The process, according to Claim 9, for preparing di-O-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, wherein said process further comprises reacting the pyridine salt with concentrated sulfuric acid.
11. The process according to Claim 10 wherein approximately 18 N sulfuric acid is used.
12. The process according to Claim 9 for preparing the calcium or magnesium salt of the sulfonic acid wherein said process further comprises neutralizing said sulfonic acid -with a corresponding base.
13. The process according to Claim 12 wherein the corres-ponding base is calcium carbonate or magnesium carbonate.
14. The process according to Claim 9 for preparing the piperazine salt of one or two moles of the sulfonic acid, wherein said process further comprises neutralizing said sulfonic acid with piperazine.
15. A process for preparing the calcium salt of mono-2-0-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, comprising reacting the calcium salt of 2,5-dihydroxy benzene sulfonic acid with p-chloro phenoxy isobutyric acid anhydride and calcium oxide in an organic solvent .
16. The process according to Claim 15 wherein said organic solvent is acetone.
17. The process according to Claim 16 for preparing the magnesium salt of mono-2-0-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, wherein said process further comprises:
(a) reacting said calcium salt with sulfuric acid to form mono-2-0-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid; and (b) neutralizing said sulfonic acid with a magnesium base.
(a) reacting said calcium salt with sulfuric acid to form mono-2-0-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid; and (b) neutralizing said sulfonic acid with a magnesium base.
18. The process according to Claim 17 wherein in the step (a) approximately 2N sulfuric acid is used.
19. The process according to Claim 17 wherein said magnesium base is MgO.
20. The process according to Claim 16 for preparing the piperazine salt of two moles of mono-2-0-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid wherein said process further comprises:
(a) reacting said calcium salt with sulfuric acid to form mono-2-0-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, and (b) neutralizing said sulfonic acid with piperazine.
(a) reacting said calcium salt with sulfuric acid to form mono-2-0-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, and (b) neutralizing said sulfonic acid with piperazine.
21, The process according to Claim 20 wherein in the step (a) approximately 2 N sulfuric acid is used.
22. The pyridine salt of a mono- or di-ester of p-dihydroxy-benzene sulfonic acid of the formula:
wherein R is hydrogen or an acyl group of the formula:
with the proviso that at least one R is the acyl group; or the calcium salt of a monoester of p-dihydroxybenzene sulfonic acid of the formula:
wherein R is the acyl group as defined above, whenever prepared by the process of Claim 1 or by an obvious chemical equivalent thereof.
wherein R is hydrogen or an acyl group of the formula:
with the proviso that at least one R is the acyl group; or the calcium salt of a monoester of p-dihydroxybenzene sulfonic acid of the formula:
wherein R is the acyl group as defined above, whenever prepared by the process of Claim 1 or by an obvious chemical equivalent thereof.
23. The pyridine salt of mono-5-O-(p-chloro phenyl isobutyroyl) -2,5-dihydroxy benzene sulfonic acid, whenever prepared by the process of Claim 2 or by an obvious chemical equivalent thereof.
24. Mono-5-O-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, whenever prepared by the process of Claim 3 or 4 or by an obvious chemical equivalent thereof.
25. The calcium or magnesium salt of mono-5-O-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, whenever prepared by the process of Claim 5 or 6 or by an obvious chemical equivalent thereof .
26. The piperazine salt of one or two moles of mono-5-O-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, whenever prepared by the process of Claim 7 or 8 or by an obvious chemical equivalent thereof.
27. The pyridine salt of di-O-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, whenever prepared by the process of Claim 9 or by an obvious chernical equivalent thereof.
28. Di-O-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, whenever prepared by the process of Claim 10 or 11 or by an obvious chemical equivalent thereof.
29. The calcium or magnesium salt of di-O-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, whenever prepared by the process of Claim 12 or 13 or by an obvious chemical equivalent thereof.
30. The piperazine salt of one or two moles of di-O-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, whenever prepared by the process of Claim 14 or by an obvious chemical equivalent thereof.
31. The calcium salt of mono-2-O-(p-chloro phenoxy iso-butyroyl)-2,5-dihydroxy benzene sulfonic acid, whenever prepared by the process of Claim 15 or 16 or by an obvious chemical equivalent thereof.
32. The magnesium salt of mono-2-O-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, whenever prepared by the process of Claim 17, 18 or 19 or by an obvious chemical equivalent thereof.
33. The piperazine salt of two moles of mono-2-O-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, whenever pre-pared by the process of Claim 20 or 21 or by an obvious chemical equivalent thereof.
34. The process according to Claim 16 for preparing mono-2-O-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, wherein said process further comprises reacting said calcium salt with approximately 2 N sulfuric acid.
35. Mono-2-O-(p-chloro phenoxy isobutyroyl)-2,5-dihydroxy benzene sulfonic acid, whenever prepared by the process of Claim 34 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| CH628874A CH591437A5 (en) | 1974-05-08 | 1974-05-08 |
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| JP (1) | JPS50148518A (en) |
| BE (1) | BE825369R (en) |
| CA (1) | CA1051897A (en) |
| CH (1) | CH591437A5 (en) |
| DD (1) | DD119782A6 (en) |
| DE (1) | DE2459614A1 (en) |
| DK (1) | DK671274A (en) |
| FR (1) | FR2269931B2 (en) |
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| ES2015433A6 (en) * | 1989-08-03 | 1990-08-16 | Esteve Quimica Sa | Process for preparing the piperazine salt of 2,5-dihydroxybenzenesulphonic acid monotosylate. |
| US5214191A (en) * | 1990-05-22 | 1993-05-25 | Cortech, Inc. | Oxidant sensitive and insensitive aromatic esters as inhibitors of human neutrophil elastase |
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| CH563356A5 (en) * | 1972-05-17 | 1975-06-30 | Esteve Dr Lab Del Sa | |
| CH551956A (en) * | 1972-05-17 | 1974-07-31 | Esteve Lab Del Dr Sa | PROCESS FOR THE PREPARATION OF SULPHONES SALTS DERIVED FROM 2,5-DIHYDROXYBENZENEMONOSULPHONIC AND 2,5DIHYDROXYBENZENEDISULPHONIC ACIDS. |
| AR204506A1 (en) * | 1972-05-17 | 1976-02-12 | Esteve Labor Dr | PROCEDURE FOR THE PREPARATION OF SALTS OF P-DIHYDROXYBENE DISULPHONIC ACIDS |
-
1974
- 1974-05-08 CH CH628874A patent/CH591437A5/xx not_active IP Right Cessation
- 1974-12-17 DE DE19742459614 patent/DE2459614A1/en not_active Ceased
- 1974-12-20 DK DK671274A patent/DK671274A/en unknown
- 1974-12-27 NL NL7416909A patent/NL7416909A/en not_active Application Discontinuation
-
1975
- 1975-01-06 RO RO7581049A patent/RO72515A/en unknown
- 1975-01-28 GB GB3752/75A patent/GB1490247A/en not_active Expired
- 1975-01-29 CA CA218,959A patent/CA1051897A/en not_active Expired
- 1975-02-10 BE BE153219A patent/BE825369R/en not_active IP Right Cessation
- 1975-02-10 ZA ZA00750833A patent/ZA75833B/en unknown
- 1975-02-14 FR FR7504673A patent/FR2269931B2/fr not_active Expired
- 1975-03-26 JP JP50036643A patent/JPS50148518A/ja active Pending
- 1975-05-07 DD DD185898A patent/DD119782A6/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK671274A (en) | 1975-11-09 |
| FR2269931B2 (en) | 1978-07-21 |
| ZA75833B (en) | 1976-01-28 |
| RO72515A (en) | 1982-05-10 |
| FR2269931A2 (en) | 1975-12-05 |
| AU7824775A (en) | 1976-08-19 |
| DD119782A6 (en) | 1976-05-12 |
| JPS50148518A (en) | 1975-11-28 |
| BE825369R (en) | 1975-05-29 |
| GB1490247A (en) | 1977-10-26 |
| CH591437A5 (en) | 1977-09-15 |
| DE2459614A1 (en) | 1975-11-20 |
| NL7416909A (en) | 1975-11-11 |
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