US2848448A - Nu1-acyl-nu1-(5-ethyl-1, 3, 4-thiadiazole-2-yl)-sulfanilamides - Google Patents
Nu1-acyl-nu1-(5-ethyl-1, 3, 4-thiadiazole-2-yl)-sulfanilamides Download PDFInfo
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- US2848448A US2848448A US605706A US60570656A US2848448A US 2848448 A US2848448 A US 2848448A US 605706 A US605706 A US 605706A US 60570656 A US60570656 A US 60570656A US 2848448 A US2848448 A US 2848448A
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- Prior art keywords
- ethyl
- thiadiazole
- sulfanilamide
- acyl
- compounds
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- 150000001875 compounds Chemical class 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 23
- 229940124530 sulfonamide Drugs 0.000 description 18
- -1 S-ethyl- 1 ,3,4-thiadiazole-2-yl Chemical group 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 230000036765 blood level Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- SVYBEBLNQGDRHF-UHFFFAOYSA-N 4-amino-N-(5-ethyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide Chemical class S1C(CC)=NN=C1NS(=O)(=O)C1=CC=C(N)C=C1 SVYBEBLNQGDRHF-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001266 acyl halides Chemical class 0.000 description 3
- 125000001589 carboacyl group Chemical group 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- NHVHYFAWHCJELN-UHFFFAOYSA-N benzene;n,n-dimethylformamide Chemical compound CN(C)C=O.C1=CC=CC=C1 NHVHYFAWHCJELN-UHFFFAOYSA-N 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 2
- 150000003456 sulfonamides Chemical class 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- JAUFWTSSYRTLLB-UHFFFAOYSA-N (2-phenylacetyl) 2-phenylacetate Chemical compound C=1C=CC=CC=1CC(=O)OC(=O)CC1=CC=CC=C1 JAUFWTSSYRTLLB-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
- 241000588915 Klebsiella aerogenes Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000588767 Proteus vulgaris Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- HJJNNRNPEWJNSR-UHFFFAOYSA-N benzyl n-(2-chloro-2-oxoethyl)carbamate Chemical compound ClC(=O)CNC(=O)OCC1=CC=CC=C1 HJJNNRNPEWJNSR-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- BCUJNAKCLZNDSE-UHFFFAOYSA-N n-(5-ethyl-1,3,4-thiadiazol-2-yl)-4-nitrobenzenesulfonamide Chemical compound S1C(CC)=NN=C1NS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 BCUJNAKCLZNDSE-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- TVUUVVWHDOVWKJ-UHFFFAOYSA-N propan-2-one;2,2,4-trimethylpentane Chemical compound CC(C)=O.CC(C)CC(C)(C)C TVUUVVWHDOVWKJ-UHFFFAOYSA-N 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940007042 proteus vulgaris Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
Definitions
- this invention relates to N -acyl- N S-ethyl- 1 ,3,4-thiadiazole-2-yl) -su1fanilamides .represented by the general structural formula:
- I R C 0 represents an alkanoyl group.
- N -acyl group must be the acyl portion of a nontoxic acid.
- the lower saturated alkanoyl (preferably of from 2 to 6 carbon atoms) derivatives are of particular advantage.
- the alkyl group (R) is advantageously chosen of low molecular Weight so that the proportion of active N -(5-ethyl-l ,3,4-thiadiazole-2-yl) -sulfanilamide released per dosage unit of drug is high, thereby enabling administration of large amounts of active medicament in a dosage form of convenient size for the patient.
- R represents methyl is the compound of choice.
- the compounds of this invention have utility as chemotherapeutic agents, particularly as antibacterial agents active against both Gram negative and Gram positive organisms.
- chemotherapeutic agents particularly as antibacterial agents active against both Gram negative and Gram positive organisms.
- Exemplary of such organisms are Micrococcus pyogenes var. aureus, Micrococcus pyogenes var. albus, Streptococcus pyogenes, Diplococcus pneumoniae, Escherichia coli, Aerobacter aerogenes, Proteus vulgaris, and Salmonella typhosa.
- these compounds have particularly favorable characteristics which make them valuable in medical practice.
- N -(5-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide is excreted rapidly from the body. This necessitates repeated doses of the drug to provide adequate therapeutic effect.
- the compounds of this invention have been found to give prolonged blood and urine levels of active medicament upon oral administration.
- the sulfa family of chemotherapeutic agents is generally accepted to be detoxified in vivo by acetylation on the N atom. These N compounds are inactive biologically. Contrariwise, the synthetic N -acyl derivatives which are the object of this invention are antibacterially active on ingestion and give sustained therapeutic blood levels of N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide.
- the drug may be administered by preparing suitable pharmaceutical forms, such as tablets or suspensions for oral use.
- the compounds of this invention are prepared by reacting N -(S-ethyl-l,3,4-thiadiazole-2-yl)-sulfa.nilamide with an acylating agent, preferably an acid anhydride, in the presence of an inorganic or a tertiary organic base such as pyridine, collidine, tributylamine 'or sodium carbonate in .an inert organic solvent for the sulfanilamide such as dimethylformamide, water, acetone or a water-acetone mixture, preferably at relatively low temperatures, for instance from 030 C. It is apparent that the base may be present in equimolar quantities or in excess. In the latter case, the base may serve as the reaction medium as well. Since the N -acyl derivatives in solution tend to rearrange to the N atom under the influence of heat, the use of hot solvents during the preparation of the N -acyl derivatives should be avoided.
- an acylating agent preferably an acid anhydride
- the compounds of this invention are also prepared by acylating the N-(S-ethyl-1,3,4-thiadiazole-2-yl)-4-nitrobenzenesulfonamide with an acyl halide or acyl anhydride in an inert organic solvent for the sulfonamide, for example, acetone or dimethylformamide, with conditions which may be more forcing than those described previously, such as at higher temperatures, for example, room temperatures to C.
- the base may be present in equimolar quantities or in excess. In the latter case the base may serve as the reaction medium as well.
- N-acyl-N- (S-ethyl- 1,3 ,4-thiadiazole-2-yD-4-nitrobenzenesulfonamide is reduced under mild reduction conditions to the desired N -acyl-N -(5-ethyl-1,3,4- thiadiazole-Z-yl)-sulfanilamide, for example, by catalytic reduction using Adams catalyst or palladium-on-charcoal in an alcoholic medium, such as in ethanol or methanol at low pressures and temperatures.
- the N -acyl compounds of this invention can be prepared from the sodium, potassium or silver salt of N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide by reaction with an appropriate acyl halide in an inert organic solvent for the sulfanilamide such as acetone, acetonitrile or dimethylacetamide.
- Example I A suspension of 113.6 g. of N -(5-ethyl-1,3,4-thiadiazole-2-y1)-sulfanilamide in a mixture of 1 l. of acetone and l 1. of water is stirred with 26 ml. of strong ammonia water until a complete solution is attained. The solution is cooled to ()--10 C. and 51 g. of acetic anhydride is added rapidly dropwise. After thirty minutes in the cold, the desired product crystallizes from solution.
- the product is separated by filtration, washed with Water and cold ethanol to give white crystals of N -acetyl-N -(5-ethyl- 1,3,4-thiadiazole-2-y])-sulfanilamide; M. P. 220-221 C. after preliminary gathering at 137l38 C.
- the product may be recrystallized from aqueous acetone if desired.
- Example II A suspension of 31.6 g. of the sodium salt of N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide (prepared by reacting the sulfonamide with one equivalent of sodium hydroxide solution, evaporating the water by freeze-drying and using the salt at once) in 200 ml. of acetone with 12 ml. of tributylamine is stirred vigorously while 14.0 g. of benzoyl chloride is added dropwise over a two-hour period. The crystalline product is obtained by quenching in water and then Washing the precipitate with water to remove the admixed sodium chloride.
- the crude product N -benzoyl-N -(S-ethyl-1,3,4-thiadiazole-2-yl)- sulfanilamide, is purified by recrystallization from a benzene dimethylformamide mixture.
- Example III A suspension of 32 g. of N-(5-ethyl-1,3,4-thiadiazole- 2yl)-4-nitrobenzenesulfonamide in 150 ml. of pyridine is swirled as 13 g. of pivalyl chloride is added dropwise. After standing at room temperature for twelve hours, the reaction mixture is quenched in a large excess of water. The crude solid, N-trimethylacetyl-N-(S-ethyl- 1,3,4-thiadiazole-2-yl)-4-nitrobenzenesulfonarnide, is then suspended in 200 ml. of ethanol with 5% palladium-oncharcoal and hydrogenated at room temperature and 50 p. s. i.
- Example IV A suspension of 14.2 g. of N -(5-ethyl-1,3,4-thiadiazole- 2-yl)-sulfanilamide in 50 ml. of acetone is acylated with 6.5 g. of propionic anhydride in dimethylformamide with 6 ml. of pyridine at -5 C.
- the crystalline product, N -propionyl-N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide is obtained by quenching the reaction mixture in water and recrystallizing the precipitate from aqueous acetone; M. P. 2l9221 C. after preliminary melting at 9910l C.
- Example V A suspension of 26.4 g. of crude oleoyl anhydride (prepared by reacting 29 g. of oleic acid with 15 g. of acetic anhydride and removing the volatiles in vacuo) and 14.2 g. of N -(-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide is reacted according to the process of Example I-t0 give N -oleoyl-N (S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide after trituration With isooctane in the cold.
- crude oleoyl anhydride prepared by reacting 29 g. of oleic acid with 15 g. of acetic anhydride and removing the volatiles in vacuo
- N -(-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide is reacted according to the process of Example
- Example VI -butyryl-N 5 -ethyll ,3 ,4-thiadiazole-2-yl) -sulfanilamide is prepared from 14.2 g. of N -(5-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide and 7.9 g. of butyric anhydride as in Example I to give white crystals; M. P. 219-221 C. after preliminary melting at 120-122 C.
- N -phenylacetyl-N -(S-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide is prepared from 28.4 g. of N -(5-ethyll,3,4-thiadiazole-Z-yD-sulfanilamide and 25.4 g. of phenylacetic anhydride as in Example I, but using 4 ml. of pyridine as a base. The crude product is recrystallized from a benzene-dimethylformamide mixture.
- Example VIII A solution of 21.4 g. of carbobenzoxyglycyl chloride in dry ethyl ether is added dropwise to a stirred suspension of 31.4 g. of N-(S-ethyl-l,3,4-thiadiaZole-2-yl)-4-nitrobenzenesulfonamide in ml. of dried ethyl acetate with 9 ml. of pyridine. The reaction mixture is concentrated in vacuo and cooled. The resulting precipitate is then separated, washed with water and dried in vacuo.
- the crude N-carbobenzoxyglycyl-N-(5-ethyl-l,3,4-thiadiazole-Z-yl)-4-nitrobenzenesulfonamide is suspended in 350 m1. of ethanol and hydrogenated at low pressure and temperature in the presence of palladium black catalyst. The catalyst is separated by filtration. Concentrating the filtrate and cooling yields a white solid, N -glycyl-N -(5-ethyl-l,3,4-thiadiazolc-2-yl)-sulfanilamide by fractional crystallization.
- Example IX N -isobutyryl-N -(5-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide is prepared from 14.2 g. of N -(5-ethy1-l,3,4- thiadiazole-Z-yl)-sulfanilamide and 7.9 g. of isobutyryl anhydride as in Example I to give white crystals from aqueous acetone, M. P. 21922l C. after preliminary melting at l24125 C.
- Example X N -stearoyl-N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide is prepared from 14.2 g. of N -(5-ethyl-l,3,4-thiadiazole-Z-yl)-sulfanilamide and 27.5 g. of crude stcaric anhydride as in Example V to give white crystals from an isooctane-acetone mixture.
- Example XI N -caproyl-N -(5-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide is prepared from 28.4 g. of N -(5-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide and 21.4 g. of n-caproyl anhydride as in Example I but using tributyl amine as the basic reactant to give white crystals from aqueous acetone.
- alkanoyl having from 2 to 6 carbon atoms
- benzoyl oleoyl
- phcnylacetyl glycyl
- stearoyl a member selected from the group consisting of saturated alkanoyl having from 2 to 6 carbon atoms, benzoyl, oleoyl, phcnylacetyl, glycyl and stearoyl.
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Description
Patented Aug. 19, 1958 Free N -ACYL-N -(S-ETHYL-1,3,4-THIADIAZOLE-2-YL)- SULFANILAIVIIDES Russell E. Rhodes, Glenside, and Blaine M. Sutton, Philadelphia, Pa., assignors to Smith, Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania N Drawing. Application August 23, 1956 Serial No. 605,706
7 Claims. (Cl. 260-23935) This invention relates to a new class of N -(5-ethyl- 1,3,4-thiadiazole-2-yl)-sulfanilamide derivatives of unusual therapeutic properties.
More particularly, this invention relates to N -acyl- N S-ethyl- 1 ,3,4-thiadiazole-2-yl) -su1fanilamides .represented by the general structural formula:
where I R C 0 represents an alkanoyl group. As a practical matter the N -acyl group must be the acyl portion of a nontoxic acid.
The lower saturated alkanoyl (preferably of from 2 to 6 carbon atoms) derivatives are of particular advantage. The alkyl group (R) is advantageously chosen of low molecular Weight so that the proportion of active N -(5-ethyl-l ,3,4-thiadiazole-2-yl) -sulfanilamide released per dosage unit of drug is high, thereby enabling administration of large amounts of active medicament in a dosage form of convenient size for the patient. In this regard the compound where R represents methyl is the compound of choice.
The compounds of this invention have utility as chemotherapeutic agents, particularly as antibacterial agents active against both Gram negative and Gram positive organisms. Exemplary of such organisms are Micrococcus pyogenes var. aureus, Micrococcus pyogenes var. albus, Streptococcus pyogenes, Diplococcus pneumoniae, Escherichia coli, Aerobacter aerogenes, Proteus vulgaris, and Salmonella typhosa. Further, these compounds have particularly favorable characteristics which make them valuable in medical practice.
N -(5-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide is excreted rapidly from the body. This necessitates repeated doses of the drug to provide adequate therapeutic effect. The compounds of this invention have been found to give prolonged blood and urine levels of active medicament upon oral administration.
The sulfa family of chemotherapeutic agents is generally accepted to be detoxified in vivo by acetylation on the N atom. These N compounds are inactive biologically. Contrariwise, the synthetic N -acyl derivatives which are the object of this invention are antibacterially active on ingestion and give sustained therapeutic blood levels of N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide.
It is readily apparent to one skilled in the art that a drug form that gives prolonged therapeutic blood levels is of great advantage in medical practice. This unexpected property of the compounds of this invention enables the doctor to administer the drug, for example, twice a day rather than at four or six-hour intervals. The great advantage of such a dosage regimen is the security of therapeutic blood levels twenty-four hours a day with two doses. Another important advantage is convenience to the patient. A sustained blood level of active medicament is maintained rather than the peak and valley etfect of the multiple daily administration of current medical practice.
Further, these compounds are quite palatable when compared with the disagreeable taste of the parent compound, N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide. Therefore, the drug may be administered by preparing suitable pharmaceutical forms, such as tablets or suspensions for oral use.
The compounds of this invention are prepared by reacting N -(S-ethyl-l,3,4-thiadiazole-2-yl)-sulfa.nilamide with an acylating agent, preferably an acid anhydride, in the presence of an inorganic or a tertiary organic base such as pyridine, collidine, tributylamine 'or sodium carbonate in .an inert organic solvent for the sulfanilamide such as dimethylformamide, water, acetone or a water-acetone mixture, preferably at relatively low temperatures, for instance from 030 C. It is apparent that the base may be present in equimolar quantities or in excess. In the latter case, the base may serve as the reaction medium as well. Since the N -acyl derivatives in solution tend to rearrange to the N atom under the influence of heat, the use of hot solvents during the preparation of the N -acyl derivatives should be avoided.
The compounds of this invention are also prepared by acylating the N-(S-ethyl-1,3,4-thiadiazole-2-yl)-4-nitrobenzenesulfonamide with an acyl halide or acyl anhydride in an inert organic solvent for the sulfonamide, for example, acetone or dimethylformamide, with conditions which may be more forcing than those described previously, such as at higher temperatures, for example, room temperatures to C. Of course this wider range of reaction conditions, namely using higher temperature and the more reactive acyl halides, are applicable since the possibility of N -acylation is not present. The base may be present in equimolar quantities or in excess. In the latter case the base may serve as the reaction medium as well. The resulting N-acyl-N- (S-ethyl- 1,3 ,4-thiadiazole-2-yD-4-nitrobenzenesulfonamide is reduced under mild reduction conditions to the desired N -acyl-N -(5-ethyl-1,3,4- thiadiazole-Z-yl)-sulfanilamide, for example, by catalytic reduction using Adams catalyst or palladium-on-charcoal in an alcoholic medium, such as in ethanol or methanol at low pressures and temperatures. This method is particularly advantageous where acylation at the N position of, N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide is more diflicult due to RC=O in the foregoing structural formula being a particularly bulky group, such as a tertiary butyryl or benzoyl moiety.
Alternatively, the N -acyl compounds of this invention can be prepared from the sodium, potassium or silver salt of N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide by reaction with an appropriate acyl halide in an inert organic solvent for the sulfanilamide such as acetone, acetonitrile or dimethylacetamide.
The methods of preparing the compounds of this invention will be readily apparent from the following examples:
Example I A suspension of 113.6 g. of N -(5-ethyl-1,3,4-thiadiazole-2-y1)-sulfanilamide in a mixture of 1 l. of acetone and l 1. of water is stirred with 26 ml. of strong ammonia water until a complete solution is attained. The solution is cooled to ()--10 C. and 51 g. of acetic anhydride is added rapidly dropwise. After thirty minutes in the cold, the desired product crystallizes from solution. The product is separated by filtration, washed with Water and cold ethanol to give white crystals of N -acetyl-N -(5-ethyl- 1,3,4-thiadiazole-2-y])-sulfanilamide; M. P. 220-221 C. after preliminary gathering at 137l38 C. The product may be recrystallized from aqueous acetone if desired.
Example II A suspension of 31.6 g. of the sodium salt of N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide (prepared by reacting the sulfonamide with one equivalent of sodium hydroxide solution, evaporating the water by freeze-drying and using the salt at once) in 200 ml. of acetone with 12 ml. of tributylamine is stirred vigorously while 14.0 g. of benzoyl chloride is added dropwise over a two-hour period. The crystalline product is obtained by quenching in water and then Washing the precipitate with water to remove the admixed sodium chloride. The crude product, N -benzoyl-N -(S-ethyl-1,3,4-thiadiazole-2-yl)- sulfanilamide, is purified by recrystallization from a benzene dimethylformamide mixture.
Example III A suspension of 32 g. of N-(5-ethyl-1,3,4-thiadiazole- 2yl)-4-nitrobenzenesulfonamide in 150 ml. of pyridine is swirled as 13 g. of pivalyl chloride is added dropwise. After standing at room temperature for twelve hours, the reaction mixture is quenched in a large excess of water. The crude solid, N-trimethylacetyl-N-(S-ethyl- 1,3,4-thiadiazole-2-yl)-4-nitrobenzenesulfonarnide, is then suspended in 200 ml. of ethanol with 5% palladium-oncharcoal and hydrogenated at room temperature and 50 p. s. i. The resulting solution is then filtered. The solid thusly obtained is extracted with acetone. After concentrating the combined alcohol-acetone filtrates by evaporation under reduced pressure, a crystalline solid, N -trimethylacetyl-N -(S-ethyl-l ,3,4-thiadiazole2-yl sulfanilam de, is obtained.
Example IV A suspension of 14.2 g. of N -(5-ethyl-1,3,4-thiadiazole- 2-yl)-sulfanilamide in 50 ml. of acetone is acylated with 6.5 g. of propionic anhydride in dimethylformamide with 6 ml. of pyridine at -5 C. The crystalline product, N -propionyl-N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide, is obtained by quenching the reaction mixture in water and recrystallizing the precipitate from aqueous acetone; M. P. 2l9221 C. after preliminary melting at 9910l C.
Example V A suspension of 26.4 g. of crude oleoyl anhydride (prepared by reacting 29 g. of oleic acid with 15 g. of acetic anhydride and removing the volatiles in vacuo) and 14.2 g. of N -(-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide is reacted according to the process of Example I-t0 give N -oleoyl-N (S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide after trituration With isooctane in the cold.
Example VI -butyryl-N 5 -ethyll ,3 ,4-thiadiazole-2-yl) -sulfanilamide is prepared from 14.2 g. of N -(5-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide and 7.9 g. of butyric anhydride as in Example I to give white crystals; M. P. 219-221 C. after preliminary melting at 120-122 C.
4 Example VII N -phenylacetyl-N -(S-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide is prepared from 28.4 g. of N -(5-ethyll,3,4-thiadiazole-Z-yD-sulfanilamide and 25.4 g. of phenylacetic anhydride as in Example I, but using 4 ml. of pyridine as a base. The crude product is recrystallized from a benzene-dimethylformamide mixture.
Example VIII A solution of 21.4 g. of carbobenzoxyglycyl chloride in dry ethyl ether is added dropwise to a stirred suspension of 31.4 g. of N-(S-ethyl-l,3,4-thiadiaZole-2-yl)-4-nitrobenzenesulfonamide in ml. of dried ethyl acetate with 9 ml. of pyridine. The reaction mixture is concentrated in vacuo and cooled. The resulting precipitate is then separated, washed with water and dried in vacuo.
The crude N-carbobenzoxyglycyl-N-(5-ethyl-l,3,4-thiadiazole-Z-yl)-4-nitrobenzenesulfonamide is suspended in 350 m1. of ethanol and hydrogenated at low pressure and temperature in the presence of palladium black catalyst. The catalyst is separated by filtration. Concentrating the filtrate and cooling yields a white solid, N -glycyl-N -(5-ethyl-l,3,4-thiadiazolc-2-yl)-sulfanilamide by fractional crystallization.
Example IX N -isobutyryl-N -(5-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide is prepared from 14.2 g. of N -(5-ethy1-l,3,4- thiadiazole-Z-yl)-sulfanilamide and 7.9 g. of isobutyryl anhydride as in Example I to give white crystals from aqueous acetone, M. P. 21922l C. after preliminary melting at l24125 C.
Example X N -stearoyl-N -(S-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide is prepared from 14.2 g. of N -(5-ethyl-l,3,4-thiadiazole-Z-yl)-sulfanilamide and 27.5 g. of crude stcaric anhydride as in Example V to give white crystals from an isooctane-acetone mixture.
Example XI N -caproyl-N -(5-ethyl-1,3,4-thiadiazole-2-yl)-sulfanilamide is prepared from 28.4 g. of N -(5-ethyl-l,3,4-thiadiazole-2-yl)-sulfanilamide and 21.4 g. of n-caproyl anhydride as in Example I but using tributyl amine as the basic reactant to give white crystals from aqueous acetone.
What is claimed is:
is a member selected from the group consisting of saturated alkanoyl having from 2 to 6 carbon atoms, benzoyl, oleoyl, phcnylacetyl, glycyl and stearoyl.
2. Compounds in accordance with claim l characterized in that is acetyl.
3. Compounds in accordance with claim 1 characterized in that is propionyl.
4. Compounds in accordance with claim 1 characterized in that is butyryl.
5. Compounds in accordance with claim 1 charactcrized in that RC=O is isobutyryl.
6. Compounds in accordance with claim 1 character- 10 ized in that m -0 is caproyl.
7. Compounds in accordance With claim 1 characterized in that R(J=O is saturated alkanoyl having from 2 to 6 carbon atoms.
References Cited in the file of this patent UNITED STATES PATENTS
Claims (1)
1. COMPOUNDS REPRESENTED BY THE FOLLOWING FORMULA:
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US3332942A (en) * | 1962-11-02 | 1967-07-25 | White Lab Inc | Substituted thiadiazoles |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB638534A (en) * | 1946-12-19 | 1950-06-07 | Ciba Ltd | Manufacture of new condensation products of sulphanilamidothiodiazoles |
US2721200A (en) * | 1953-07-13 | 1955-10-18 | Hoffmann La Roche | Sulfisoxazole compounds |
-
1956
- 1956-08-23 US US605706A patent/US2848448A/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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GB638534A (en) * | 1946-12-19 | 1950-06-07 | Ciba Ltd | Manufacture of new condensation products of sulphanilamidothiodiazoles |
US2721200A (en) * | 1953-07-13 | 1955-10-18 | Hoffmann La Roche | Sulfisoxazole compounds |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3332942A (en) * | 1962-11-02 | 1967-07-25 | White Lab Inc | Substituted thiadiazoles |
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