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GB1572035A - Therapeutically active glycerol ester containing clofibryl- and 2-acetylsalicylgroups - Google Patents

Therapeutically active glycerol ester containing clofibryl- and 2-acetylsalicylgroups Download PDF

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GB1572035A
GB1572035A GB49963/76A GB4996376A GB1572035A GB 1572035 A GB1572035 A GB 1572035A GB 49963/76 A GB49963/76 A GB 49963/76A GB 4996376 A GB4996376 A GB 4996376A GB 1572035 A GB1572035 A GB 1572035A
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asp
chlorophenoxy
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OM LAB SA
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Priority claimed from CH17376A external-priority patent/CH616911A5/fr
Priority claimed from CH979076A external-priority patent/CH617175A5/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C305/00—Esters of sulfuric acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/16—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by esterified hydroxyl radicals
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    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
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    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
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    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl

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Description

(54) THERAPEUTICALLY ACTIVE GLYCEROL ESTER CONTAINING CLOFIBRYL- AND 2-ACETYLSALICYL-GROUPS (71) We, LABORATOIRES OM SOCIETY ANONYME, a Body C or- porate organised under the Laws of Switzerland of Meyrin, Geneva, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention is directed to therapeutically active glycerol mixed esters having the general formula:
wherein R1 is -clof and R2 is asp, or R1 is -asp and R2 is -clof and wherein -clof represents the clofibryl residue of formula
and -asp represents the 2-acetylsalicyl residue of formula
The compounds of formula (I) have pharmacological and clinical properties characterized by an hypolipemient, and hypocholesterolemient action, and which inhibits the aggregation of blood platelets. Said compounds can be compounded in pharmaceutical compositions and administered in various ways in the various pharmaceutical forms, e.g. orally, in the form of tablets or capsules.
The methods of synthesis of compounds of formula (I) are based on the intro duction of the -asp and -clof residues on glycerol having free or partially protected functions. The protective functions can be removed by acid hydrolysis, hydrogenolysis or directly transformed into esters by the acylating function. The choice of introduction of the acylating residues depends on the ratio desired between the different kinds of acylating functions.
The synthetic methods comprise: 1) The introduction of one or two acyl residues of one kind onto glycerol, protecting the integrity of the other alcohol function(s) which will be- esterified by the acylating groups of the other kind.
2) The use of an alcohol protecting function such as a hydrolysable or hydro genolysable acetal or cyclic acetal, protecting one or two alcoholic functions which will be acylated by one or two acylating groups of one kind. The one or two alcohol function(s) set free after eliminating the protective function(s) will be acylated by the group(s) of the other kind.
3) The transformation of an alcohol protecting function, directly into an ester function by one or more acylating groups, for example: 3a) From a 1,2-epoxide By the action of an acid chloride or an acid anhydride according to the reaction scheme:
3b) From a 1,2-epoxide or by the reaction with a carboxylic function representing an acylating residue.
3c) From a dihalohydrin by reaction with one or more alkaline or alkaline-earth metal carboxylates representing an acylating residue(s):
hal being a halogen atom, and M an alkaline or alkaline-earth metal; then the acylation of the free alcohol residue:
or on the contrary the acylation of the alcohol function of the acylated dihalohydrin with an alkaline or alkaline-earth carboxylate:
3d) By the transformation of a cyclic or non-cyciic acetal by an acylating function such as an acid chloride or acid anhydride.
The above reactions take place in suitable organic solvents and can be catalysed by catalysts suitable for a specific type of reaction.
The following non-limiting examples illustrate various methods for obtaining the compounds according to the invention.
EXAMPLE I.
Compound (II) 1,3 - Di - (2 - p - chlorophenoxy - 2 - methylpropionyloxy) - 2 - (acetylsalicyloxy) propane Method I.
1.1.1. 1,3-Benzylidene-2-(acetylsalicyloxy) -glycerol To a solution of 19.8 g (0.11 mole) of I,3-benzylidene glycerol (b.p. 110 /0.1 Torr.) in dry ether containing 15.3 ml of TEA and 8.9 ml of pyridine, are added dropwise, with stirring, a solution of 21.8 g of acetylsalicylic acid chloride. After 24 hours, the ester is separated from the TEA hydrochloride and product 3 a) is crystal lized at 180 in ethylacetate.
C1,H18O6 (342.3) F. = 129-132 Ref=0.59 (n-hexane/ethylacetate 2/1 vol.) IR (characteristic frequencies) 1760, 1710, 1610, 1195 cm-1.
1.12. 2-(acetylsalicyloxy) -glycerol 1.1.1. is hydrolysed in the presence of palladised charcoal at 10 , after removing the air, and under hydrogen pressure at room temperature.
C12H1+O6 (254.2) Rf =without migration (n-hexane/ethylacetate 2/1 vol.) IR (characteristic frequencies) 3380, 1765, 1725 cm-1.
1.1.3. 1,3 - di - (2 - p - chlorophenoxy - 2 - methyl propionyloxy) - 2 - (acetyl salicyloxy) - propane To a solution in dry ether of 14.9 g (0.0585 mole) of 1.1.2., 16.3 ml of TEA and 9.4 ml of pyridine, is added, dropwise with stirring, a solution in dry ether of 27.3 g (0.117 mole) of p-chlorophenoxy-2-methylpropionic acid chloride. After 15 hours reaction, the product is separated from the TEA hydrochloride and the ether solution is washed with a solution of NaHCOa in water. After evaporating the solvent, a colourless product (II) is obtained.
C2HS2c12Olo (647.5) Analysis: Calc. % Found % C 59.36 59.38 H 4.98 5.02 Cl 10.95 11.11 e226era=29'730 (ethanol 95%) Rf= 0.67 (n-hexane/ethylacetate 2/1 vol.) IR Sh 1705, 1750, Sh 1735, 1605, 1595, 1580, 1485, 1465, 1380, 1370, 1285, 1240, 1170, 1160, 1125, 1095, 1080, 1010, 965, 920, 830, 760, 700, 670 cm-1.
Compound (II) 1,3 - Di - (2 - p - chlorophenoxy - 2 - methylpropionyloxy) - 2 - (acetylsalicyloxy) propane Method II.
1.2.1. 1 - (2 - p - chlorophenoxy - 2 - methylpropionyloxy) - 2,3 - epoxypropane To a solution of 7.4 g (0.1 mole) of 1,2-epoxy-3-propanol containing 13.93 ml of TEA, is added dropwise 23.3 g (0.1 mole) of 2-p-chlorophenoxy-2-methylpropionic acid chloride in dry ether. After 17 hours, the product is separated from the TEA hydrochloride and the ether solution is washed with an aqueous 5% solution of NaHCOs. The epoxy ester is distilled, then it is redistilled at 113116C/0.09 Tort.
C1sHl6Cl Os (270.7) Rf= 0.80 (n-hexane/ethylacetate 2/1 vol.) IR (characteristic frequencies) 1745, 1600, 1590, 1250, 840, 860 cm-1.
1.2.2. 1,3 - di - (2 - p - chlorophenoxy - 2 - methylpropionyloxy) - 2 - propanol The mixture of 5.4 g of 1.2.1. (0.02 mole) with 4.3 g of p-chlorophenoxy-iso butyric acid (0.02 mole) and 0.47 g of Na p-chlorophenoxy-2-methylpropionate is heated for 2 hours at 1200. After extracting the product with ether, the solution is treated with an aqueous 5% solution of NaHCOs. An oil is obtained which releases at 2000/0.07 Torr. a small fraction of the initial product.
C2sH26Cl2O7 (485.4) Rf=0.62 (n-hexane/ethylacetate 2/1 vol.) IR (characteristic frequencies) 3480, 1740, 1600 et 1590, 1150, 840 et 860 cm-1.
1.2.3. 1,3 - di - (2 - p - chlorophenoxy - 2 - methylpropionyloxy) - 2 - acetylsalicyl oxy) - propane To a solution of 10.4 g of 1.2.2. in dry ether containing 3 ml of TEA, and 1 ml of pyridine, is added dropwise, with stirring, 4.26 g of acetylsalicylic acid chloride.
After 24 hours reaction, the product is separated from the TEA hydrochloride, and the ether solution is washed with an aqueous 5% solution of NaHCO. A product (II) is obtained, identical to that obtained under 1.1.3.
Compound (11) 1,3 - Di - (2 - p - chIorophenoxy - 2 - methylpropionyloxy) - 2 - (acetylsalicyloxy) propane Method III.
1.3.1. 1,3-dichloro-2- (salicyloxy ) -propane To a solution of 138 g of salicylic acid (1 mole) in 645 g of 1,3-chloropropanol, is added 40 ml of concentrated sulfuric acid. After 16 hours at 105"C, the excess of alcohol is distilled at 60 /12 Torr. The residue is dissolved in ether and washed with an aqueous solution of NaHCO3. The ether phase is dried and the solvent removed.
The ester is distilled twice at 153--155"/12 Torr. and at 125--126"/0.5 Torr. It is crystallized in petroleum ether at 18o.
F=49-50" CloHloCl2Os (249.1) Rf = 0.65 (n-hexane/ethylacetate 2/1 vol.) IR=3240, 1685, 1610, 1580, 1480, 1460, 1400, 1395, 1370, 1305, 1295, 1250, 1180, 1150, 1130, 1085, 1035, 880, 780, 760, 710 cm-l.
1.3.2. 1,3 - di - (2 - p - chlorophenoxy - 2 - methylpropionyloxy) - 2 - (salicyloxy) propane The mixture of 124.5 g of 1.3.1. (0.5 mole) and 236.5 g (1.0 mole) of p-chlorophenoxy-2-methylpropionate of sodium is heated for 10 hours at 1800. It is taken up in ether and filtered. The residue after evaporation of the solvent gives the desired product.
C,0H10Cl2O9 (605.5) Rf=0.68 (n-hexane/ethylacetate 2/1 vol.) IR=3150, 1745, 1730, 1610, 1595-1580, 1485, 1385, 1360, 1310, 1300, 1285, 1250-1220, 1200, 1170--1145, 1120, 1090, 1010, 970, 830, 770, 730, 700, 670 cm-1.
1.3.3. 1,3 - di - (2 - p - chlorophenoxy - 2 - methylpropionyloxy) - 2 - (acetylsali cyloxy) - propane A solution of 280 g of 1.3.2. in 500 ml of acetic anhydride (d= 1.08) is refluxed for 1+ hours, then the excess of anhydride is distilled and a product (II) is obtained, identical to that obtained under 1.1.3.
Compound (II) 1,3 - Di - (2 - p - chlorophenoxy - 2 - methylpropionyloxy) - 2 - (acetylsalicyloxy) propane Method IV.
1.4.1. 1,3 - di - (2 - p - chlorophenoxy - 2- methylpropionyloxy) - 2 - propanol A suspension of 118.3 g (0.5 mole) of sodium p-chlorophenoxy-2-methylpropionate in a solution of 60 ml of anhydrous EtOH containing 7.5 g of NaI and 64.5 g of 1,3-dichloro-2-propanol (0.5 mole) is refluxed for 90 hours. The solvent is evaporated under reduced pressure and the liquid residue is distilled at 138--141"/0.07 Torr.
C23H26Cl2O (485.4) 1.4.2. 1,3 - di - (2 - p - chlorophenoxy - 2 - methylpropionyloxy) - 2 - (acetylsali cyloxy) - propane 24.2 g (0.05 mole) of 1,3 - di - (2 - p - chlorophenoxy - 2 - methyl propionyloxy) - 2 - propanol is taken up in 300 ml of dry ether containing 0.055 mole of triethylamine, 10.9 g (0.055 mole) of acetylsalicylic acid chloride and 4 ml of pyridine.
After 16 hours reaction with stirring, the organic suspension is filtered and the filtrate washed with a solution of 5% NaHCOS, then with 2 volumes of EloOs and dried with Na2SO4. The solvent is evaporated under reduced pressure; a product (II) is obtained identic ll to that obtained under 1.1 The 1,3 - di - (2 - p - chlorophenoxy - 2 - methylpropionyloxy) - 2 - propanol used as a starting material in step 1.4.2. above can also be prepared as follows: a suspension of 23.7 g (0.1 mole) of p-chlorophenoxy-2-methylpropionate of Na in 14 g (0.11 mole) of 1,3-dichloro-2-propanol is heated in a closed steel cylinder at 155 for 14 hours. After cooling, it is taken up in ether and the soluble fraction is distilled at 138--141"/0.07 Torr.
Compound (II) 2 - (acetylsalicyloxy) - 1,3 - di - (p - chlorophenoxy - 2 - methylpropionyloxy) propane Method V.
1.5.1. 2-acetylsalicyloxy-1 ,3 -dichioropropane To a solution in THF of 12.9 g (0.1 mole) of 1,3-dichloro-2-propanol, is added 10.1 g (0.1 mole) of TEA, then slowly with stirring, 19.9 g (0.1 mole) of acetyl salicylic acid chloride. After removing the TEA hydrochloride, acetvlsalicyloxy-1,3 dichloropropane is obtained quantitatively, and it crystallizes in petroleum ether.
Cl2Hl2OCl2O, (291.1) m.p. =67--69 Rf = 0.58 (ethylacetate/n-hexane 2/1 vol.) IR-1750, 1725, 1610, 1580, 1485, 1335, 1295, 1270, 1250, 1200, 1135, 1075, 1010, 915, 820, 760, 700 cm-l.
1.5.2. 2 - (acetylsalicyloxy) - 1,3 - di - (p - chlorophenoxy - 2 - methylpropionyl oxy) - propane To 29.1 g (0.1 mole) of 1.5.1 and 47.3 g of sodium p-chlorophenoxy-2-methylpropionate are admixed. The paste-like mixture is heated at 1600 for 5 hours. The product is taken up in ether and the solution is extracted with a solution of 5% NaHCOt in water, it is washed twice with water and dried with anhydrous Na2SO,.
The solvent is removed and a product (II) identical to that obtained under 1.1.3. is obtained quantitatively.
EXAMPLE 2.
Compound (III) 3 - (acetylsalicyloxy) - 1,2 - di - (2 - p - chlorophenoxy - 2 - methylpropionyloxy) propane Method l.
2.1.1. 1- ( acetylsalicyloxy) -2,3-epoxy-propane To a solution of 44.4 g (0.6 mole) of 1-hydroxy-2,3-epoxydopropane in dry ether, 84 ml of TEA are added, dropwise with stirring, 119.1 g (0.6 mole) 2-acetylsalicylic acid chloride are also added. After 24 hours, the product is separated from the TEA hydrochloride, and the ether solution is washed with aqueous solution of 5% NaHCO".
An oily product is isolated. B.p. 114--115 /0.02 Torr.
C,2HI20- (263.2) e22r ,,rn = 14'120 (methanol) Rf=0.52 (n-hexane/ethylacetate 2/1 vol.) IR (characteristic frequencies) 1760, 1735, 1610, 1265 cm-1.
2.1.2. 3 - (acetylsalicyloxy) - 1,2 - di(2 - p - chlorophenoxy - 2 - methylpropionyl oxy) - propane 23.0 g (0.1 mole) of 3.1.1. are mixed with 41.1 g (0.1 mole) of p-chlorophenoxy2-methylpropionic acid anhydride. at a temperature of 1000. The mixture becomes homogeneous, the temperature of the mixture is then brought to 1200 for 1i hour. The product is extracted with ether, washed with an aqueous solution of 5% NaHCO2, then decolored with active charcoal. A colourless oil (III) is obtained.
C32Hs2Cl2OIo (647.5) Analysis: Calc. /, Faund % C 59.35 59.32 H 4.94 5.22 Cl 10.97 11.11 e226 rn=30'900 (ethanol 95%) Ref= 0.67 (n-hexane/ethylacetate 2/1 vol.) Cc=homogeneous peak (Carbowax (Registered Trade Mark) 4%, temperature 1520, N2 30 ml/rnn IR (characteristic frequencies) 1760--1730, 1610, 1600 and 1595, 840 and 860 cm.
Note: For the 2.1.2. reaction, the temperature can be between 60 and 2200; in the pres ence of a Lewis acid such as BF (introduced in the form of BF,OC2H5 or BF(CsH N)), the reaction can be carried out at ordinary temperature. The reaction can also be effected in a solvent inert to the anhydride and the epoxide function.
Compound (III) 1,2 - Dl (2 - p - chlorophenoxy - 2 - methylpropionyloxy) - 3 - acetylsalicyloxy propane Method II.
2.2.1. 3 - chloro - 1,2 - di(p - chlorophenoxy - 2 - methylpropionyloxy) - propane 41.1 g (0.1 mole) of the p-chlorophenoxy-2-methylpropionic acid anhydride are added to 9.25 g (0.1 mole) of epichlorohydrin. It is heated to 1300, then the excess of unreacted anhydride is removed by hydrolysis with NaHCO,. An oil is obtained.
C23H2sCI30t; (503.8) 1R=1745, 1592, 1490, 1480, 1390, 1370, 1280, 1240, 1150, 1130, 1100, 1015, 970, 855, 845, 770, 725, 710, 680 cm-1.
2.2.2. 1,2 - di - (2 - p - chlorophenoxy - 2 - methylpropionyloxy) - 3 - (salicyloxy) propane 25 g (0.05 mole) of 2.2.1. are mixed with 12 g (0.075 mole) of sodium salicylate and heated to 1800 for 16 h. The sodium chloride is removed by desalting the product in ether. An oil is obtained.
C30H30Cl2O, (605.5) IR=1740, 1680, 1590, 1575, 1485, 1380, 1360, 1300, 1240, 1180, 1160, 1120, 1090, 1010, 965, 850, 825, 760, 695, 680 cm 2.2.3. 1,2 - di - (2 - p - chlorophenoxy - 2 - methylpropionyloxy) - 3 - acetylsalicyl oxy) - propane 28 g (0.04 mole) of 2.2.2. are dissolved in 50 ml of acetic anhydride, and heated to 105 . The excess of reagent is removed by washing the ether solution with an aqueous solution of 5% NaHCOs. The organic phase is dried with Na,SO4. An oil (III) is obtained identical to that obtained under 2.1.2.
PHARMACOLOGICAL PROPERITES A) Acute toxicity The acute toxicity of compounds II and III was determined on the male rat (Table 1).
Product Administration means LDso g /kg II P.O. > 7.5 g /kg III p.o. > 6.2 g/kg Both of these derivatives are therefore much less toxic than the clofibrate (LD,,:1.2 g/kg) and acetylsalicylic acid (LDs,:1.75 g/kg).
B) Pharmacokinetics The compounds this specification is directed to release clofibric acid and acetylsalicylic acid in the blood. The metabolites were determined by gas chromatography after transformation to silane derivatives. Two peaks are observed, one representing the sum of salicylated derivatives and the other clofibric acid. In Table II, the maximum plasma levels attained in the rat after a single administration are given.
TABLE II
Max. plasma levels g/ml After Dose p.o. Salcyl clofibric x Product mg /kg derivatives acid hours Test: clofibrate + acetylsal. ac. 300 + 100 180 280 1 Compound II 400 40 60 16 Compound III 400 45 58 16 It is seen that the release of two active metabolites can be infiuenced by modifying the steric hindrance of the compounds in question, indeed, when the steric hindrance is increased, the metabolisation thereof is slowed down.
C) Hypocholesterolemiating and hypolipemiating activity Groups of 10 normolipemiating rats were treated for 10 days, by gastric probe, with the equivalent of 75 mg/kg of clofibrate, administered every 12 hours. After 10 days, 12 hours after the last administration, they were sacrificed and the cholesterol and triglycerides analysed (Table III).
TABLE III
Triglycerides Decrease Cholesterol Decrease Product mm le/l. 9b mg/100 ml Test: without treatment 1.13 90.79 Test: clofibrate 0.83 27 65.24 28 Compound II 0.92 19 73.90 19 Compound III 0.91 19 75.63 17 D) Anti-aggregating and anti-adhesive activity The anti-aggregating and anti-adhesive activity of compounds II and III was tested ex vivo on the rabbit after an administration equivalent to 50 mg/kg of acetylsalicylic acid. All the compounds possess both anti-aggragating and anti-adhesive activity (ADP, collagen) identical to that of the blanks (50 mg/kg of acetyl salicylic acid). The blood was taken, under narcosis, 24 hours after administration of the dose (intubation).
THERAPEUTICAL APPLICATIONS Compounds II and III are intended for the treatment of mixed hypercholesterolemiae and hyperlipidemiae, hyperaggragability of the platelets, as well as atherosclerous erects connected with such disorders. The compounds are administered orally in one or stal doses daily at a dosage of 0.30 g to 4 g per day according to the gravity of the ilWs and the results of laboratory examinations. The compounds are given alone or the pharmaceutically acceptable vehicles, e.g. in the form of hard or soft capsules, plain or coated tablets, granulates or syrups.

Claims (4)

WHAT WE CLAIM IS:
1. A therapeutically active mixed glycerol ester of formula
wherein Rl is -clof and RZ is -asp, or Rl is -asp and R2 is -clof, and wherein clof represents the clofibryl residue of formula
and -asp represents the 2-acetylsalicyl residue of the formula
2. A compound according to Claim 1, of formula:
wherein-clof indicates the clofibryl residue and -asp the 2-acetylsalicyl residue.
3. A compound according to Claim 1, of formula:
wherein-clof indicates the clofibryl residue and asp- indicates the 2-acetylsalicyl residue.
4. A process for preparing the compound of formula
wherein-clof is the clofibryl residue of formula
and -asp is the 2-acetylsalicyl residue of formula
characterized in that the compound of formula
is first reacted with the acid asp-OH or with a halide, asp-hal, to give the compound of formula
whereafter this compound is reacted with a metal salt of formula clof-OM to give said compound of formula II, or characterized in that said compound of formula III above is first reacted with salicylic acid to give the compound of formula
whereafter this compound is reacted with a metal salt of formula clofOM to give the compound of formula
and wherein finally the phenolic hydroxyl group of this compound is acetylated.
GB49963/76A 1976-01-08 1976-11-30 Therapeutically active glycerol ester containing clofibryl- and 2-acetylsalicylgroups Expired GB1572035A (en)

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CH17376A CH616911A5 (en) 1976-01-08 1976-01-08
CH979076A CH617175A5 (en) 1976-07-30 1976-07-30 Processes for the preparation of mixed polyol esters

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GB1572035A true GB1572035A (en) 1980-07-23

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GB49963/76A Expired GB1572035A (en) 1976-01-08 1976-11-30 Therapeutically active glycerol ester containing clofibryl- and 2-acetylsalicylgroups

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JP (1) JPS5285139A (en)
BG (1) BG27537A3 (en)
CA (1) CA1075708A (en)
DD (1) DD128400A5 (en)
DE (1) DE2654951A1 (en)
EG (1) EG12290A (en)
ES (1) ES453795A1 (en)
FI (1) FI763529A (en)
FR (1) FR2337552A1 (en)
GB (1) GB1572035A (en)
GR (1) GR61818B (en)
IL (1) IL51039A0 (en)
NL (1) NL7613457A (en)
PL (1) PL117246B1 (en)
PT (1) PT65894B (en)
RO (1) RO70355A (en)
SE (1) SE7613426L (en)
YU (1) YU286476A (en)

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* Cited by examiner, † Cited by third party
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NL176551C (en) * 1979-04-25 1985-05-01 Shell Int Research PROCESS FOR PREPARING AN AROMATIC HYDROCARBON MIXTURE BY CATALYTIC CONVERSION OF A MIXTURE OF CARBON MONOXIDE AND HYDROGEN.

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JPS5285139A (en) 1977-07-15
DD128400A5 (en) 1977-11-16
EG12290A (en) 1979-06-30
NL7613457A (en) 1977-07-12
FR2337552A1 (en) 1977-08-05
PL117246B1 (en) 1981-07-31
PL194851A1 (en) 1979-05-07
FI763529A (en) 1977-07-09
BG27537A3 (en) 1979-11-12
YU286476A (en) 1982-08-31
PT65894B (en) 1978-05-18
IL51039A0 (en) 1977-02-28
GR61818B (en) 1979-01-22
DE2654951A1 (en) 1977-07-21
RO70355A (en) 1981-08-17
CA1075708A (en) 1980-04-15
SE7613426L (en) 1977-07-09
PT65894A (en) 1976-12-01
ES453795A1 (en) 1978-01-16

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