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Publication numberUS2888455 A
Publication typeGrant
Publication dateMay 26, 1959
Filing dateSep 3, 1957
Priority dateSep 4, 1956
Publication numberUS 2888455 A, US 2888455A, US-A-2888455, US2888455 A, US2888455A
InventorsNishimura Haruo, Kano Hideo, Ogata Kazuko, Nakajima Kiyoshi
Original AssigneeShionogi & Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
New sulfonamide and process for producing the same
US 2888455 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

United States PatentQ ce 2,888,455

a en ed May 26, 195.52

In, contrast to the foregoing results, the in vivo testing 2,888,455 of the same compounds demonstrated a clear superiority for the unique compound of the invention. That is to NEW E say, by administering our sulfonamide derivative to 5 groups consisting of ten mice each weighing 17-18 HideqKano, Kamikyo-ku, Kyotorshi, liaruo Nishimura, grams, via the oral route at 2, 24, 48, 72 and 96 hours, Ashlya'shl Kiyoshl N l N y d g l, respectively, following intraperitoneal injection of Osaka, f Kazllko 8 Nasano-shi, Japan, assign l-OOMLD of the microorganism Diplococcus pneumoniae toshwnogla (type 1), 80 and 10 survival percentages at the dosage No Drawing. Application September 3,1957 10 level of 1 and gr pe gram o y i t Serial No. 681,468 re bserved, whereas sulfisoxazole gave 50 and 0 percent at the dosage level of 2 and; 1 milligrams in analogous Claims priority, application Japan September 4, 1956 experiments. The infections were fatal to all untreated 2 Claim (CL 2 39 9 animals; the ST-100 being two days. As a result of these experiments, it was shown that the sulfonamide Th present i ti l t t th provision of a of the invention is more than two times more effective new. sulfonamide derivative, and to a process for prothan sulfisoxazole when administered via the oral route.

ducing; the same. 3-sulfanilamido-5-methylisoxazole may be represented S-sulfanilamido isoxazoles and methods for producing y the following Structural formula! such compoundshave been described in US. Patent No.

2,43Q,09,4. The synthesis of 3-sulfanilamidoisoxazoles, HC -CNH'.S 0,NH,

however, in which the sulfanilamido group is bonded i,

tothe third position of the isoxazole nucleus has not been reported heretofore in the literature. The principal 0 object of the, present invention is to provide such a Thenovel compound of the invention may be produced compound possessing chemotherapeutic utility equivalent by condensing 3-amino-5'-methylisoxazole with a corn. to that normally possessed by known sulfa derivatives pound carrying a p-amino-or a p-substituted benzene of the general. class described. In particular, the invensulfonyl group, and thereafter changing the Nf -subtion contemplates the provision of the compound 3-sulstituent into a N -amino group in the latter condensation. fanilamido-S-methylisoxazole. This reaction may be illustrated by the following During the course of a systematic search for new structural equations:

sulfonamide compounds structurally related to sulwherein R is the residue of an easily reactive p-subfisoxazole, and' evaluation of the antibacterial activity stituted benzene sulfonic acid derivative; and R repof such compounds, we have succeeded in synthesizing resents a group which is convertible to an amino group. 3.-sul-fanilarnido-5-methylisoxazole, and have found that In the foregoing reaction, the condensation steps A this compound exhibits a high degree of antibacterial and A may be effected without the use of a solvent, activity in both in vitro and invivo tests. That is to but an inert solvent medium generally insures the promosay, the antibacterial activity of the unique compound tionof uniform reactions. In general, the type of solvent of the invention in vitro is similar to that of sulfisoxazole, employed is determined by its non-reactivity, but if whereas the antitubercular activity in vitro of said comsulfonyl halides are used as the easily reactive derivapound is found to be superior to that of sulfisoxazole. tives of benzene sulfonic acid, basic or basiiied solvents The in vitro data for the novel compound of the invensuch as pyridine, picoline or acetone with sodium tion as compared with sulfisoxazole are as follows: bicarbonate are preferably employed. We prefer to employ benzene sulfonyl halides, and particularly the m chloride, as the easily reactive derivative of benzene Test organisms fig sulfonic acid, but other functional derivatives of benzene (11101) sulfonlc ac1d, for example, the acid ester, may also be (11101) employed.

Step B in the foregoing synthesis is eifected subsequent are; ta s 8888888 F the step 2 which emerge-benzene sulfonamido Shigella flEITLGTiZ, 2(Z 1:500, 000 1:500, 000 isoxazole, bearing a substitutent convertible to an ammo iiggg ggg figgg ggg group at the fourth position of the benzene nucleus, is Shigella flezneri l, 4a.- 1=500,000 1:500, 000 produced. The aforementioned substituent at the 4-pos1- 5255335221 3 8 383 iiggg'ggg tion of the reactive benzene sulfonic acid derivatives sI mp Mp: 1:200: 000 1:200: 000 may include any of the nitro-acylamino or carbalkox-yms {E588 88g iiggg ggg amino groups. The type of reaction employed in step B Pseudomonas aeruginosa... 10, 000 10,000 is determined largely by the nature of substituent R. F ,-fff s $881888 ii88888 That is to say, when R is an acylamino radical such as $232 8% 338:838 the acetamino group or a carbalkoxyamino radical such Mycobac. tuberculosis nsmvm 1=10,000 1:2,000 as the carbethoxy amino group, the intermediate should be saponified, whereas when R, is a m'tro group, the intere 3 mediate should be reduced. These reactions may be effected in accordance with standard techniques, for example, by heating with aqueous sodium hydroxide solution for the hydrolysis reaction, or by treating with zinc dust and hydrochloric acid for the reduction reaction.

It should be noted that the starting material 3-arnino- S-methylisoxazole utilized in the foregoing reaction is also a new compound. It may be obtained by hydrolysis of ethyl 5-methylisoxa2ole-3-carbamate succeeding to the Curtius degradation of 5-methylisoxazole-3-carboxylic acid according to Freiris method (cf. CA-26, 5953, 1932). The compound is prismatic and melts at 6l-62 C.

It is believed that our invention may be best understood by reference to the following specific examples showing the application of the foregoing techniques to the production of the unique sulfonamide of the invention:

Example (a) Preparation of 3-amin0-5-methylisoxazole.1.7 g. of ethyl 5-methylisoxazole-3-carbamate was heated on a boiling water-bath with 5 cc. of a 10% aqueous sodium hydroxide solution for 8 hours, then the reaction mixture was extracted several times with ether or benzene and the extract was cooled succeeding to the removal of the solvent and drying. The residue was solidified after a while and gave prismatic crystals, melting point 6l-62 C., of 3-amino-5-methylisoxazole by recrystallization from benzene.

Elemental analysis for empirical formula C H ON Calculated-C, 48.97; H, 6.16; N, 28.57. FoundC, 49.42; H, 6.50; N, 28.28.

This substance is a new compound and is also obtained by a similar hydrolysis of benzyl 5-methylisox azole-3-carbamate, melting point 80-81 C.

(b) Preparation of 3 acetylsitlfanilamido 5 methylisoxazole.0.9 g. of 3-amino-5-methylisoxazole in 5 cc. of pyridine was allowed to react with 2.0 g. of acetylsulfanil chloride accompanied with the generation of heat. After about one hour, water was added to the reaction mixture and the crystal precipitated out was recrystallized from alcohol to give 2.5 g. of 3-acetylsulfanilamido-S-methylisoxazole, melting point (decomposition) 220221 C.

Elemental analysis for empirical formula C H O N S: CalculatedC. 48.81; H, 4.40; N, 14.33. Found-C, 49.08; H, 4.63; N, 14.05.

A similar result was obtained by the condensation in a sodium bicarbonate-acetone medium.

I (6) Preparation of .i-sulfanilamido -5 -methylisoxaz0le.2 g. of 3-acetylsulfanilamido-5-methylisoxazole was heated with 10 cc. of an aqueous sodium hydroxide aesaaee 6L solution on a Water-bath for one hour and after cooling the reactant was acidified by addition of acetic acid. The precipitate thus formed was recrystallized from dilute alcohol to give 15 g. of colorless prisms of 3-sulfanilamido-S-methylisoxazole, melting point 167 C.

Elemental analysis for empirical formula C H O N S: Calcula'tedC, 47.43; H, 4.35; N, 16.60. FoundC, 47.96; H, 4.49; N, 16.52.

This compound is bitterish and by acetylation in pyridine base gave the corresponding N ,N -diacetyl compound, melting point 209210 C.

Having thus described the subject matter of our inventioi, what it is desired to secure by Letters Patent is:

1. The chemical compound 3-sulfanilamido5-methylisoxazole, as represented by the formula:

wherein R represents a substituent member selected from the group consisting of amino, acylamino, nitro and carbo alkoxyarnino radicals, and treating said reaction product for the separation and recovery of the desired 3-sulfanilamido-S-methylisoxazole.

References Cited in the file of this patent UNITED STATES PATENTS Wuest Nov. 4, 1947 OTHER REFERENCES Backer et al.: Rec. Trav. Chin1., vol. 61, pp. 461-466 (1942).

Musante: Gazz. Chim. Ital., vol. 71, pp. 565-573 (1941).

Anderson: Iourn. of the American Chemical Society, vol. 64, pp. 2902-5 (1942).

Patent Citations
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Referenced by
Citing PatentFiling datePublication dateApplicantTitle
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US3138524 *Jun 6, 1962Jun 23, 1964Hoffmann La RochePharmaceutical suspensions
US3144448 *Dec 6, 1962Aug 11, 1964 Isoxazole derivatives of sulfanilamide
US3157669 *Jul 17, 1962Nov 17, 1964Hoffmann La RochePreparation of isoxazole compounds
US3227613 *Apr 24, 1963Jan 4, 1966Shionogi & CoMethod of producing prolonged sulfonamide level in blood
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Classifications
U.S. Classification548/246
International ClassificationC07D261/16, C07D261/14
Cooperative ClassificationC07D261/14, C07D261/16
European ClassificationC07D261/14, C07D261/16