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Número de publicaciónUS2888455 A
Tipo de publicaciónConcesión
Fecha de publicación26 May 1959
Fecha de presentación3 Sep 1957
Fecha de prioridad4 Sep 1956
Número de publicaciónUS 2888455 A, US 2888455A, US-A-2888455, US2888455 A, US2888455A
InventoresNishimura Haruo, Kano Hideo, Ogata Kazuko, Nakajima Kiyoshi
Cesionario originalShionogi & Co
Exportar citaBiBTeX, EndNote, RefMan
Enlaces externos: USPTO, Cesión de USPTO, Espacenet
New sulfonamide and process for producing the same
US 2888455 A
Resumen  disponible en
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Descripción  (El texto procesado por OCR puede contener errores)

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).

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Patente citada Fecha de presentación Fecha de publicación Solicitante Título
US2430094 *11 Jul 19444 Nov 1947 Isoxazole derivatives of
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Patente citante Fecha de presentación Fecha de publicación Solicitante Título
US3085937 *6 Feb 196116 Abr 1963Shionogi & CoMethod of combating coccidiosis with sulfonamide compositions
US3138524 *6 Jun 196223 Jun 1964Hoffmann La RochePharmaceutical suspensions
US3144448 *6 Dic 196211 Ago 1964 Isoxazole derivatives of sulfanilamide
US3157669 *17 Jul 196217 Nov 1964Hoffmann La RochePreparation of isoxazole compounds
US3227613 *24 Abr 19634 Ene 1966Shionogi & CoMethod of producing prolonged sulfonamide level in blood
US3251840 *14 Jun 196217 May 1966Acraf3-sulfamyl phenyl-5-aminoalkyl-1, 2, 4-oxadiazoles
US4062861 *15 Mar 197613 Dic 1977Shionogi & Co., Ltd.3-Isoxazolylurea derivatives
US5378715 *15 Jul 19933 Ene 1995Bristol-Myers Squibb Co.Hypotensive agents
US5514696 *29 Oct 19937 May 1996Bristol-Myers Squibb Co.Isoxazole moiety attached to n; used to treat hypertension, cell disorders and growth, endotoxemia and ischemia
US5594021 *6 Jun 199514 Ene 1997Texas Biotechnology CorporationThienyl-, furyl- and pyrrolyl sulfonamides and derivatives thereof that modulate the activity of endothelin
US5612359 *7 Jun 199518 Mar 1997Bristol-Myers Squibb CompanySubstituted biphenyl isoxazole sulfonamides
US5760038 *6 Feb 19952 Jun 1998Bristol-Myers Squibb CompanySubstituted biphenyl sulfonamide endothelin antagonists
US5780473 *25 Jul 199614 Jul 1998Bristol-Myers Squibb CompanySubstituted biphenyl sulfonamide endothelin antagonists
US5804585 *15 Abr 19968 Sep 1998Texas Biotechnology CorporationThieno-pyridine sulfonamides derivatives thereof and related compounds that modulate the activity of endothelin
US5827869 *9 Dic 199627 Oct 1998Bristol-Myers Squibb CompanySubstituted biphenyl isoxazole sulfonamides
US5846990 *13 Feb 19978 Dic 1998Bristol-Myers Squibb Co.Substituted biphenyl isoxazole sulfonamides
US5856507 *21 Ene 19975 Ene 1999Bristol-Myers Squibb Co.Methods for the preparation of biphenyl isoxazole sulfonamides
US5916907 *27 Ene 199829 Jun 1999Bristol-Myers Squibb CompanyAdministering an effective amount of n-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)(1,1-biphenyl)-2-sufonamide or a salt as an endothelin antagonist
US5939446 *21 Mar 199717 Ago 1999Bristol-Myers Squibb Co.Heteroaryl substituted phenyl isoxazole sulfonamide endothelin antagonists
US5958905 *26 Mar 199628 Sep 1999Texas Biotechnology CorporationPhosphoramidates, phosphinic amides and related compounds and the use thereof to modulate the activity of endothelin
US5962490 *27 Sep 19965 Oct 1999Texas Biotechnology CorporationThienyl-, furyl- and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin
US5965732 *30 Ago 199312 Oct 1999Bristol-Myers Squibb Co.Sulfonamide endothelin antagonists
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US6013655 *4 Sep 199811 Ene 2000Texas Biotechnology CorporationHypotensive agents; respiratory system diisorders
US6030991 *6 Dic 199629 Feb 2000Texas Biotechnology Corp.Adjusting the binding of an endothelin peptide to endothelin a or, particularly, endothelin b receptors, i.e. inhibiting or stimulating; antiinflammatory agent; asthma; kidneys; gastrointestinal, cardioascular disorders; hypotensive agents
US6043265 *27 Ene 199828 Mar 2000Bristol-Myers Squibb Co.Isoxazolyl endothelin antagonists
US6080774 *8 Oct 199627 Jun 2000Bristol-Myers Squibb CompanySubstituted biphenylsulfonamide endothelin antagonists
US6107320 *11 Ene 199622 Ago 2000Bristol-Myers Squibb Co.Hypotensive agents
US624876726 Sep 199719 Jun 2001Texas Biotechnology Corp.Formulation of sulfonamides for treatment of endothelin-mediated disorders
US62654288 Jun 199924 Jul 2001Texas Biotechnology CorporationVasodilation
US627124820 Ene 20007 Ago 2001Bristol-Myers Squibb CompanySubstituted biphenysulfonamide endothelin antagonists
US631330820 Mar 20006 Nov 2001Bristol-Myers Squibb CompanyMethods for the preparation of biphenyl isoxazole sulfonamides
US632938717 Nov 199911 Dic 2001Texas Biotechnology Corporation.Use of thieno-pyridine sulfonamides derivatives thereof and related compounds that modulate the activity of endothelin
US633163722 Mar 199918 Dic 2001Texas Biotechnology CorporationN-Alkyl, N-Alkenyl, N-Alkynyl, N-Aryl and N-fused bicyclo or tricyclo thienyl-, furyl-,and Pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin
US63842613 Sep 19987 May 2002Texas Biotechnology CorporationTreating endothelin-mediated disorders; inhibitory binding of endothilin peptides to eta and/or etb receptors; elucidating the physiological and pathophysiological roles and isolating endothelin receptors; antagonists
US642056726 Sep 199716 Jul 2002Texas Biotechnology CorporationProdrugs
US64329942 Abr 199813 Ago 2002Texas Biotechnology CorporationCardiovascular disorders, glaucoma; antiinflammatory, wound healing, hypotensive, antiasthmatic, and antianaphylactic agents
US645880523 Feb 20011 Oct 2002Texas Biotechnology CorporationAntagonists; especially sodium salts
US651513627 Ago 19984 Feb 2003Bristol-Myers Squibb CompanyTo the novel intermediates prepared by these methods. The biphenyl isoxazole sulfonamides prepared by the present methods are endothelin antagonists useful, inter alia, for the treatment of hypertension.
US654501415 Jun 20018 Abr 2003Texas Biotechnology CorporationGlaucoma; adjusting concentration of nitric oxide; hypotensive, antispasmodic, antiischemic, cardiotonic agents; bronchodilators; urogentital disorders; agonists, antagonists for endothelin receptors
US65732543 Feb 19993 Jun 2003University Of MarylandAdministering to avian species amount of sulfonamide which inhibits production of thyroid hormone and stimulates gonadotropins, exposing avian species to long photoperiod for time sufficient to stimulate production of sperm
US66138044 Dic 20012 Sep 2003Encysive Pharmaceuticals, Inc.Biphenylsulfonamides and derivatives thereof that modulate the activity of endothelin
US66328295 Nov 200114 Oct 2003Texas Biotechnology Corp.Thienyl, furyl and pyrrolyl-sulfonamides, useful for treating hypertension, cardiovascular disease, asthma, pulmonary hypertension, inflammatory diseases, vision defects, menstrual disorders, renal failure and other diseases
US663908228 Sep 200128 Oct 2003Bristol-Myers Squibb CompanyCycloboronate intermediates; endothelin antagonists useful, inter alia, for the treatment of hypertension.
US668310320 Dic 200127 Ene 2004Texas Biotechnology CorporationSulfonamides containing oxazole and substituted thiophene rings, useful for treating hypertension, cardiovascular disease, asthma, pulmonary hypertension, inflammatory diseases, vision defects, menstrual disorders, renal failure
DE1263771B *18 Jul 196321 Mar 1968Shionogi & CoVerfahren zur Herstellung von 3-Sulfanilamido-4-jod-5-methylisoxazol
EP0558258A1 *23 Feb 19931 Sep 1993E.R. SQUIBB & SONS, INC.N-isoxazole-naphthylsulfonamide derivatives and their use as endothelin antagonists
Clasificación de EE.UU.548/246
Clasificación internacionalC07D261/16, C07D261/14
Clasificación cooperativaC07D261/14, C07D261/16
Clasificación europeaC07D261/14, C07D261/16