|Publication number||US3825591 A|
|Publication date||Jul 23, 1974|
|Filing date||Jun 1, 1972|
|Priority date||Jun 23, 1971|
|Also published as||CA957371A, CA957371A1, DE2212741A1, DE2212741B2, DE2212741C3|
|Publication number||US 3825591 A, US 3825591A, US-A-3825591, US3825591 A, US3825591A|
|Inventors||Ernst Felder, Davide Pitre|
|Original Assignee||Bracco Ind Chimica Spa|
|Export Citation||BiBTeX, EndNote, RefMan|
|Referenced by (19), Classifications (11)|
|External Links: USPTO, USPTO Assignment, Espacenet|
United States Patent 3 825 591 ORALLY APPLICAIBLE CONTRAST AGENTS FOR CHOLECYSTOGRAPHY Ernst Felder and Davide Pitre, Milan, Italy, assignors to Bracco Industria Chimica Societe per Azioni, Milan,
Italy No Drawing. Filed June 1, 1972, Ser. No. 258,777 Claims priority, application 7S/v;i1tzerland, June 23, 1971,
Int. Cl. C07c 101/72 US. Cl. 260-519 4 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula wherein R is methyl or ethyl when R is hydrogen, or R and R jointly are ethyleneoxyethylene, and R is methyl or ethyl, and their physiologically tolerated alkali metal, alkaline earth metal, and alkanolamine salts produce superior X-ray images of the gall bladder and of the bile ducts after oral ingestion and are well tolerated and quickly eliminated in effective doses.
This invention relates to iodine-bearing X-ray contrast agents, and particularly to compounds and compositions which preferentially make the gall bladder and bile ducts radiopaque after oral ingestion.
Because of the hazards inherent in the intravenous administration of organic iodine compounds prior to cholecystography, which hazards are not readily dealt with outside of a Well-equipped hospital, private practitioners prefer to prepare patients for cholecystography with oral medication. The radiopaque compounds and compositions available heretofore for this purpose are not entirely satisfactory, particularly when it is important to visualize the bile ducts.
It has now been found that compound of the formula l C O and their physiologically tolerated salts with metals and amines, particularly alkali metals, alkaline earth metals, and alkanolamines compare favorably with the best cliniclly tested, orally administered contrast media for cholecystography in their toxicity and their ability of making the gall bladder visible, and are superior to the known contrast media suitable for oral ingestion in preferentially accumulating in the gall bladder and there-by reliably producing X-ray images of the bile ducts when R in the formula is methyl or ethyl, R being hydrogen, or R and R jointly are ethyleneoxyethylene in a morpholine ring, and R is methyl or ethyl. Under otherwise identical conditions, the compounds in which R is ethyl are preferred over those in which R is methyl.
In the following Table, pertinent data on four compounds A to D of the invention are compared with corresponding data obtained under closely controlled identical conditions on eight compounds E to M. Compounds E, F, G, and H are similar to the compounds of the invention in their chemical structure, the rather different compounds I and K are representative of the most favorable combination of features found in orally administered cholecystographic agents in current clinical use, and compounds L and M are homologs of compounds A and C respectively. The compounds identified by letters A to M are:
A: 3- [2- 3-N-ethylcarbamoyl-Z,4,6-triiodophenoxy ethoxy] -2-ethylpropionic acid B: 3- [2- 3-N-methylqarbamoyl-2,4,6-triiodophenoxy ethoxy]-2-ethylpropionic acid C: 3- [2- 3-N-methylcarbamoyl-2,4,6-triiodophenoxy) ethoxy]-2-methylpropionic acid D: 3- 2- 3-N-morpholino-oarbonyl-2,4,6-triiodophenoxy)-ethoxy]-2-methylpropionic acid E: 3-N-morpholino-carbonyl-2,4,6-triiodophenoxybutyric acid (US. Pat. N0. 3,452,134)
F: 2- 3-N-propylcarbamoyl-2,4,6-triiodophenoxy butyric acid (East German Pat. No. 48,210)
G: 2- [2-( 3-N-ethylacetylamino-2,4,6-triiodophenoxy ethoxy]propionic acid (Swiss Pat. No. 483,262)
H: 2- 2- 3-acetylamino-2,4,6-triiodopl1enoxy) -ethoxy] propionic acid I: 3-(3-amino-2,4,6-triiodophenyl)-2-ethylpropionic acid (iodopanoic acid) K: 3-(3-dimethylaminomethylenamino-2,4,6-triiodophenyl)-propionic acid (iopodate) L: 2- [2- 3-N-ethylcarbamoyl-2,4,6-triiodophenoxy) ethoxyJbutyric acid M: 2- 2- 3-N-methylcarbamoyl-2,4,6-triiodophenoxy) ethoxyJpropionic acid The toxicity values in the Table are LD in mg./-kg. mouse and were determined by oral ingestion and by intravenous injection (i.v.), the latter method being considered more reliable because it is not affected by variations in resorption through the intestinal wall.
The cholecystographic properties of the compounds were determined by the method of J. O. Hoppe (J. Amer. Pharm. Assoc., Sci. Ed. 48, 368-379, 1959) and were evaluated in the Hoppe Index scale on which 0 indicates no X-ray image, 1 a weak, 2 an adequate, 3 a good, and and 4 an excellent opacity and contrast quality of the image.
The visibility of the bile ducts is indicated in the Table on an arbitrary, but reproducible scale on which indicates no image or only an occasion image, indicates visibility in all instances, and indicates an image of superior detail.
The cholecystographic tests were performed on dogs (1) or on cats (2) at a dosage rate (a) of mg./kg. body weight or (b) of 200 mg./kg. body weight, all test compounds being administered orally. Hoppe Index values were determined 2, 4, 6, 8, and 24 hours after ingestion.
20% Suspensions of the free acids were prepared with gum arabic and were administered to the test animals by means of a stomach tube in the determination of Hoppes Index and of oral toxicity. Salts with sodium or N-methylglucamine, which are physiologically equivalent, were employed in determining toxicity by intravenous injection.
TABLE Toxicity Animal Hoppe Index after- Bn e Compound Oral LV. Dosage 2hrs. 4hrs. fihrs. 8hrs. 24 hrs. ducts A 2,800 1,400 llb 2.5 3.5 3.5 2/b 2 3 a B 1,400 lla 1 2 2 2 llb 1 2 2.5 2/a 2 2 3 2/b 2 2.5 a
C 4,000+ 1,050 Ill) 2 2 2.5 3 2/b 2.5 3.5 3.5
D 3,700 550 lla 2.5 3 3 3 llb 0.5 s 4 a5 2/b 2.5 3.5 3.5
F -1..- 5,000 1,100 l/a 1.5 2 2 2 1/b 1 2 2 2 425 1/a 1 2.25 2.75 llb 2. 75 3 3.25 2. 75
1,480 l/a 0 0 0.25 0.25 0 1/b 0 0.5 0.5 0.5 0
24o llb 1.5 1.5 2 0.5
2,100 1/a 0 0 0 0 Ill: 0 0 0 0 0 Nora-The toxicity values for Compound D are only approximate. Compound L left Compound M produced oligouria.
As is evident from the Table, the compounds of the invention are significantly better tolerated than Compounds I and K which are now in Wide clinical use. Their Hoppe Index values are better than or at least as good as those of all other tested compounds, and they are unique in their ability of precisely and reliably visualizing the bile ducts in a manner not possible heretofore except after intravenous injection of the contrast agents.
Because of their low toxicities, the compounds of the invention may be employed at higher dosage rates than conventional X-ray contrast agents which are administered orally. Because of the rapid excreation of the contrast agents of this invention and because of the absence of residues in the intestine, frequently observed with known orally applied radiopaque materials, such higher dosage rates are permissible with the compounds of the invention without causing disturbing side effects.
Many advantages of the invention apparently are due to the 3-oxy-2-alkylpropionic acid radicals present in all the compounds of the invention. It will be noted from the Hoppe Index values in the Table that Compounds L and M have little or no value in producing an X-ray image of the gall bladder whereas their next adjacent homologs, Compounds A and C, are among the best examples of this invention.
The compounds of the invention may be employed in the form of the free carboxylic acids or as salts with metals and amines which are physiologically tolerated when orally administered in amounts suificient for cholecystography. The alkali metal salts, such as the sodium and lithium salts, the alkaline earth metal salts, particularly the magnesium and calcium salts, and salts of alkanolamines are preferred. Suitable alkanolamines include N- methylglucamine, N-methylxylamine (l-methylamino-ldesoxy- [D] -xylite) 1-methylamino-2, 3-propanediol, ethanolamine, and diethanolamine. Other suitable alkanolamines will readily suggest themselves to the pharmaceutical chemist. The free acids and their salts may be compounded individually or as mixtures in radiopaque compositions.
The compounds of the invention may be prepared by reacting a 3-carbamoyl-2,4,6-triiodophenol of the formula with a reactive derivative of 3-alkoxy-Z-alkylpropionic acid of the formula nol may be employed in the form of the corresponding alkali metal phenolate. The preferred reactive derivatives are the 3-haloethoxy-Z-alkylpropionic acid esters and the 3-alkylsulfonyloxy-or 3-arylsulfonyloxyethoxy-2-alkylpropionic acid esters, and the condensation products are saponified after ether formation to obtain the free acid or the salt to be employed as an X-ray contrast agent.
The following Examples are further representative of the methods of preparing and using the compounds of this invention.
EXAMPLE 1 27.5 g. Sodium 3-N-methylcarbamoyl-2,4,6 triiodophenolate (0.05 mole) was dissolved in 50 ml. dimethylformamide, and 16.5 g. 3-(2-iodoethoxy)-2-ethylpropionic acid ethyl ester (0.055 mole) was added with stirring at 70 C. over a period of to 20 minutes. The reaction mixture was heated to NW C., and stirring was continued for 16 hours at that temperature. The mixture was then cooled to ambient temperature and poured into 500 ml. water. An oily product precipitated and gradually solidified. It was separated from the supernatant liquid and dissolved in ethyl acetate. The solution was washed sequentially with water, sodium carbonate solution, water, sodium hydrogen sul fite solution, and again with water, dried over desiccated sodium sulfate, and evaporated to dryness. The crystalline residue Was suspended in isopropyl ether, filtered oil with suction, and washed with isopropyl ether. IIt weighed 27.45 g. (78.5% yield), melted at 8-889 C., and gave an R value of 0.70 in a thin layer chromatogram on silica gel with benzene/chloroform/glacial acetic acid 7:3:2. It was identified as the ethyl ester of Compound B by elementary analysis:
Calculated for C17H22I3NO5: -29. 12% c; 54.31% I Found: 29.27% C; 54.55% I 36 g. Ethyl ester prepared as described above was dissolved in 140 ml. ethanol, and 170 ml. 0.3 N sodium hydroxide solution was added gradually with stirring at 50 C. over a period of three hours to saponify the ester. The ethanol was distilled 01f in a vacuum, and the residue was diluted with water and extracted with ethyl acetate. The aqueous phase was exposed to a vacuum to remove traces of dissolved ethyl acetate and acidified with 18% hydrochloric acid to precipitate Compound B in an amount of 26.9 g. (78% yield). It melted at 77-7 8 C.
After being suspended in 40 ml. boiling ethyl acetate, it was converted to the more stable crystal form melting at 138 C., and having an R; value of 0.65 in a thin layer chromatogram prepared by means of the above solvent system. It was identified by its elementary analysis:
Calculated for C H 'I NO 26.77% C; 56.57% I Found: 26.77% C; 56.31% I The free acid is practically insoluble in water, soluble in the lower alkanols, readily soluble in aqueous solutions of bases such as sodium hydroxide, ethanolamine, N-methylglucamine, etc. from which the corresponding salts can be recovered by evaporation of the water or by other conventional methods.
The 3-'(.2-iodoethoxy)-2-ethylpropionic acid ethylester employed as a starting material was prepared as follows:
0.8 Mole ethylmalonic acid diethyl ester was reacted in ethyl ether with 0.84 mole sodium hydride and thereafter with 0.8 mole '2-chloroethoxy-methyl chloride, and the 2-(2-chloroethoxymethyl)-2-ethylmalonic acid diethyl ester was recovered. B.P. 136144 C. at 4 mm. Hg. 0.47 Mole of the diestcr were partially saponified in 500 ml. 60% aqueous methanol with 0.5 mole sodium hydroxide at '6065 C. in two hours. The methanol Was then evaporated, and the residue was acidified and extracted with ethyl ether to recover 2-(2-chloroethoxymethyl)-2- ethylmalonic acid monoethyl ester which was decarboxylated by heating at 140-150 C. The resulting 3-(2- chloroethoxy)-2-ethylpropionic acid ethyl ester boiled at 11'91M C. at 14 mm. Hg. 0.325 Mole of the lastmentioned ester was reacted with 0.65 mole sodium iodide in 300 ml. ethanol by refluxing for -16 hours, whereupon the 3-(2-iodoethoxy)-2-ethylpropionic acid ethyl ester was recovered. B.P. 125-1128 C. at 3-4 mm. Hg n ='1.482.
EXAMPLE 2 11.3 g. Sodium 3-N ethylcar-bamoyl 2,4,6 triiodophenolate (the sodium salt of 3-hydroxy-2,4,6-triiodo- N-ethylbenzamide, 0.02 mole) Was dissolved in 200 ml. dimethylformamide, and the solution was heated at 90 C. for 15 hours with 6.6 g. 3--(2-iodoethoxy)-2-ethylpropionic acid ethyl ester (0.022 mole). The ethyl ester of Compound A was obtained in an amount of "10.5 g. (73.5% yield) and melted at -8 2 C. when recrystallized from aqueous ethanol. The same result was achieved by using 4.6 g. of the less costly 3-(2-chloroethoxy)-2- ethylpropionic acid ethyl ester with 3-4 g. sodium iodide.
The thin layer chromatogram of the ester on silica gel gave an R value of 0.65 with chloroform/ glacial acetic acid 19:1. The compound was identified by elementary analysis:
Calculated for C H 1 'NO 30.23% C; 53.24% I Found: 30.04% C; 53.01% I The ester was saponified as in Example 1 to produce the free acid in a yield of 52%. When recrystallized from ethyl acetate, Compound A melted at 1'1'4 1l6 C.-
and gave an R value of 0.415 in a thin layer chromatogram on silica gel (ethyl acetateisopropanol/conc. ammonium hydroxide 55 :35 :20). It was identified by elementary analysis:
Calculated for C H I NO 27.97% C; 55.42% I Found: 27.89% C; 55.52% 1 Compound A is practically insoluble in water, but soluble in the lower alkanols and in the aqueous bases mentioned in Example 1.
EXAMPLE 3 22 g. 3-N-Methylcarbamoyl-2,4,6-triiodophenol sodium salt was dissolved in 40 ml. dimethylformamide. 7.9 g. 3-(2-Chloroethoxy)-2-methy1propionic acid methyl ester was added, and the mixture was stirred at C. for 20 hours to form the methyl ester of Compound C. When recrystallized from a small amount of ethyl acetate, the ester melted at 7475 C. and had an R value of 0.56 in a thin layer chromatogram on silica gel (chloroform/ glacial acetic acid 19:?1).
Calculated for C H -I NO 26.77% C; 56.57% I Found: 26.73% C; 56.43% I The ester was saponified in the manner of Example 1 to Compound C with a yield of 75.5%. The free acid melted at 1-10112 C. R =0.-26 (chloroform/glacial acetic acid 19:1).
Calculated for C H I NO 25.51% C; 57.77% I Found: 25.47% C; 57.73% I The free acid is practically insoluble in Water, soluble in 10 parts (by weight) cold ethanol or 2 parts boiling ethanol, in 50 parts cold chloroform or 10 parts boiling chloroform. The solubility in water at 20 is 50 g./ 100 ml. for the sodium salt and for the N-mehylglucamine salt.
The 3-(2-chloroethoxy)-2-methylpropionic acid methyl ester employed as a starting material is prepared in a manner analogous to the preparation of the homologus ethyl ester described in Example 1.
g. Methylmalonic acid diethyl ester was reacted with 20 g. sodium hydride and 103.2 g. 2-chloroethoxymethyl chloride to 118.7 g. 2-(2-chloroethoxymethyl)-2- methylmalonic acid diethyl ester boiling at 132139 C./ 4 mm. Hg. The ester was saponified with 42 g. sodium hydroxide to 2-(2-chloroethoxymethyl) 2 methylmalonic acid which was partly decarboxylated to form 3-(2- chloroethoxy)-2-methylpropionic acid. The free acid was converted by means of diazomethane to the desired methyl ester which boiled at 103 105 C./ 16 mm. Hg.
EXAMPLE 4 13.4 g. Sodium 3-N-ethylcarbamoyl-2,4,6-triiodophenolate was dissolved in 30 ml. dimethylformamide and reacted with 7.65 g. 3-(2-iodoethoxy)-2-methylpropionic acid ethyl ester or with 5.16 g. 3-(2-chloroethoxy)-2-methylpropionic acid ethyl ester in the presence of 4.5 g. so-
7 dium iodide in hours at 90 C. to the ethyl ester of 3- [2-(3-N-ethylcarbamoyl-2,4,6-triiodophenoxy) ethoxy]- 2-methylpropionic acid ethyl ester melting at 99100 C. Thin layer chromatogram on silica gel with chloroform/ glacial acetic acid 19:1 R =O.69.
Calculated for C H I NO 29.12% C; 54.31% I Found: 29.17% C; 54.33% I The free acid was obtained in a yield of 89% by saponifying the ester with sodium hydroxide in ethanol and by acidfying the resulting solution of the sodium salt. It melted at 142143 C. Thin layer chromatogram on silica gel with ethyl acetate/isopropanol/conc. ammonium hydroxide solution 55:35:20. R =0.41.
The acid is practically insoluble in water, but dissolves readily in aqueous solutions of the afore-mentioned bases to form the corresponding salts which were readily obtained in solid form by evaporating the solutions in a vacuum.
The 3-(2-iodoethoxy)-2-methylpropionic acid ethyl ester employed as a starting material was prepared as follows:
267 g. 2-(2-Chloroethoxymethyl)-2-methylmalonic acid diethyl ester was partially saponified to the monoethyl ester by means of 42 g. sodium hydroxide. The monoester was decarboxylated to the 3-(2-chloroethoxy)-2-rnethylpropionic acid ethyl ester (B.P. 102103 C./l4 mm. Hg). The last-mentioned compound was reacted in an amount of 93 g. with 144 g. sodium iodide to produce 98 g. 3-(2-iodoethoxy)-2-methylpr0pionic acid ethyl ester (B.P. 119 C. at 3-5 mm. Hg).
EXAMPLE 5 30.15 g. 3-N-Morpholino-carbonyl 2,4,6-triiodophenol sodium salt was dissolved in 50 ml. dimethylformamide and heated for hours at 110 C. with 9.9 g. 3-(2-chloroethoxy)-2-methylpropionic acid mehyl ester to produce the methyl ester of Compound D which was saponified to 28.7 g. of the free acid as described in Example 1.
The crude acid was dissolved in isopropanol containing 4 ml. cyclohexylamine, whereby the cyclohexylamine salt of Compound D was gradually precipitated. The mixture was left standing overnight, and was then filtered with suction. The salt on the filter was washed with isopropanol and was then dissolved in about 300 ml. warm water. The solution was gradually stirred into 3% hydrochloric acid, whereby pure Compound D was precipitated. It was recovered in an amount of 23.9 g. (66.7% yield) and melted at 7578 C. Thin layer chromatogram on silica gel with chloroform/ glacial acetic acid 19:1: R =0.51.
Calculated for C17H2QI3NOG: I Found: 28.54% C; 53.22% I The free acid is practically insoluble in water, but dissolves readily in methanol, ethanol, or chloroform. The sodium and N-mehylglucamine salts dissolve in approximately equal weights of water at 20 C.
3 [2 (3 N morpholinocarbonyl-2,4,6-triiodophenoxy)-ethoxy]-2-ethylpropionic acid was prepared in an analogous manner.
The synthesis methods outlined above start with the methyl or ethyl esters of the 3-(2-haloethoxy)-2-methylor 2-ehylpropionic acids which are reacted with alkali metal triiodophenolates, but the same results were obtained by using the other lower alkyl esters, more specifically the propyl, isopropyl, and butyl esters, and there is no reason to assume that other alkyl esters, less readily available, would not be equally operative.
The 3-(2-alkylor -arylsulfonyloxyethoxy)-2-methylor -ethylpropionic acid esters generally give better yields than the analogous 3-(2-haloethoxy)-2-methylor -ethylpropionic acid alkyl esters, the highest yields being generally produced by means of the 3-(2-benzenesulfonyloxyethoxy)-2-ethylpropionic acid ethyl ester.
The condensation reactions may also be performed in ethanol, methoxyethanol, methylethylketone and other alochols and ketones in which the alkali metal phenolates are not readily soluble. The phenols are reacted in the alcohls in the presence of an alkali metal alcoholate corresponding to the alcohol employed as a solvent medium (for example, NaO-C H and NaOC H OCH with the afore-mentioned alcohols). An alkali metal carbonate, such as potassium carbonate, is preferably employed as a basic condensation agent when the solvent is a ketone.
The compounds of the invention are compounded with excipient in the manner conventional in galenic pharmacy for convenient oral administration. The free acids and the metal or amine salts may be combined with suitable carriers, diluents, coatings, or ingestible containers to produce dosage units which are capsules, granulates, tablets, drages, globuli, suspensions or solutions. The liquid compositions may also be administered rectally, but oral administration is preferred. The compounds of the invention are perferably micronized before being combined with other solid ingredients transparent to X-rays. Quicker absorption and denser shadows are normally obtained by the micronized compounds than by other forms, while no intestinal residues interfering with observation of the gall bladder or the bile ducts are formed.
The following additional Examples illustrate methods of combining the compounds of the invention with inert ingredients for convenient oral administration, but these procedures, conventional in themselves, will readily be modified by a skilled pharmacist to satisfy particular requirements.
EXAMPLE 6 Compound A was micronized to a particle size of less than 4 2, and the fine powder was mixed intimately with 20.4 g. Pluronic F68, a surface active material obtained by subjecting polypropyleneglycol to condensation with ethylene oxide, which is a solid at normal ambient temperature and prevents aggregation of the fine particles. The mixture was driven through a stainless steel screen having 324 openings per square centimeter, and 20.4 g. microcrystalline starch were admixed.
The resulting mixture was moistened with enough distilled water to permit the mass to be granulated by passage through a screen having 56 openings per square centimeter. The granulate was dried in an air stream at 40 C., mixed with 7.2 g. magnesium stearate as a lubricant, and distributed uniformly in 600 soft gelatin capsules containing each 500 mg. of the active compound.
EXAMPLE 7 3 kg. Compound B was kneaded mechanically into a dough-like mass with 2 liters starch paste containing g. corn starch. When the moist mass was tacky, a little dry starch was added. The mixture was then granulated on a granulating dish, and the granulate was dried in a vacuum. The dry granules were further mixed with 0.5 kg. corn starch and 25 g. magnesium stearate, and compressed to tablets containing each 500 mg. of the active ingredient.
EXAMPLE 8 The sodium salt of Compound D in an amount of 5 kg. was mixed intimately with 0.75 kg. granulated sugar, and 0.75 kg. corn starch. The mixture was moistened with one liter 50% aqueous ethanol and then granulated. The granulate was dried, screened, mixed with 0.65 kg. corn starch, 0.05 kg. talcum, and 0.05 kg. magnesium stearate and pressed to make 10,000 tablets.
EXAMPLE 9 Granules containing Compound A as the active ingredient were prepared as described in Example 1. They were coated in a kettle with sugar syrup in a weight ratio of 3:1, and the pills so formed were waxed whan dry.
9 10 What is claimed is: 3. A compound as set forth in claim 1, wherein R is '1. A compound which is an acid of the formula ethyl.
I 4. A compound as set forth in claim 3, which is a carboxylic acid. 5 References Cited 1;, UNITED STATES PATENTS I I 3,452,134 6/1969 Tilly 260-519 I 3,553,259 1/1971 Felder et al. 260-619 A 1o FOREIGN PATENTS or a salt of said acid with a metal or an amine, said salt 772,035 2/1972 Belgium 2605 19 being physiologically tolerated when administered orally in an amount suflicient for cholecystography, in said for- LORRAINE WEINBERGER Pnmary Exammer mula R being methyl or ethyl, R being hydrogen, R 15 P. J. HAGAN, Assistant Examiner being methyl or ethyl. 1
2. A compound as set forth in claim 1, wherein said US. Cl. X.R. metal is an alkali metal, calcium, OI magnesium, and said 2 0 247 2 R 501 11. 424 5 amine is an alkanolamine.
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|U.S. Classification||562/451, 544/173, 424/9.45, 544/171|
|International Classification||C07C235/84, C07D295/192, A61K49/04|
|Cooperative Classification||A61K49/0495, C07D295/192|
|European Classification||A61K49/04H8T, C07D295/192|