US3787324A - 4-hydroxy-3-(3-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,dioxides and process for their production - Google Patents

4-hydroxy-3-(3-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,dioxides and process for their production Download PDF

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Publication number
US3787324A
US3787324A US00119967A US3787324DA US3787324A US 3787324 A US3787324 A US 3787324A US 00119967 A US00119967 A US 00119967A US 3787324D A US3787324D A US 3787324DA US 3787324 A US3787324 A US 3787324A
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US
United States
Prior art keywords
benzothiazine
hydroxy
isoxazolocarbamyl
compounds
dioxides
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Expired - Lifetime
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US00119967A
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English (en)
Inventor
H Zinnes
M Schwartz
J Shavel
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Warner Lambert Co LLC
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Warner Lambert Co LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms

Definitions

  • R is hydrogen or methyl and R and R are hydrogen or alkyl. These compounds are useful as antiinflammatory agents, antipyretics, analgesics.
  • R is hydrogen or methyland R and R are hydrogen or alkyl having from one to seven carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like.
  • the compounds of this invention are useful as antiinflammatory agents, antipyretics, and analgesics in several mammalian species. When administeredorally to rats at a dose of -200 mg./kg., they are able to cause reduction in swelling of the paw induced by injection into the footpads of an irritant such as carrageenin.
  • the compounds inhibit adjuvant induced polyarthritis in the rat.
  • Oral doses of -100 mg./kg. are sufficient to inhibit yeast induced hyperthermia in the rat.
  • these compounds are indicated in conditions such as pain resultingfrom arthritis, bursitis and the like.
  • a daily dosage regimen of about 0.5 grams to about 2 grams in several divided doses is recommended for a mammal weighing about 70 kg. body weight to relieve the pain and swelling associated with these conditions.
  • These compounds are administered either orally or by injection.
  • these compounds are formulated into dosage forms such as tablets or syrups by blending with an inert pharmaceutical carrier such as lactose-or simple syrup by methods well known to the pharmacists art.
  • an inert pharmaceutical carrier such as lactose-or simple syrup
  • vehicles such as water, peanut oil, sesame
  • starting compound is refluxed with 3-aminoisoxazole ill in an inert solvent such as xylene.
  • the reactants are refluxed in the presence of a molecular sieve which promote the desired reaction by removing the alcohol which is formed as a by-product.
  • the use of molecular sieves results in a more convenient and practical process in that lengthy distillation to remove the alcohol is no longer required.
  • the reaction is carried out in a Soxhlet apparatus with the molecular sieves contained in the thimble.
  • molecular sieves which can be used in this process, are commercially available molecular sieves under the trade name Linde type 4A molecular sieve from Matheson Coleman & Bell Company. See also Fieser & Fieser, Reagents for Organic Synthesis, Vol. 1.
  • the starting material II are known compounds and they are prepared in accordance with the description in' US. Pat; No. 3,501,466.
  • the corresponding salts with metal or with amine are prepared by treating the above compounds with the desiredbase e.g., sodium alkoxide, potassium alkoxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, pyrrolidine and the like by conventional procedures.
  • desiredbase e.g., sodium alkoxide, potassium alkoxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, pyrrolidine and the like by conventional procedures.
  • the corresponding sodium salt was prepared by treating the above compound with sodium hydroxide which has the following structural formula:
  • EXAMPLE 111 4-1-1ydroxy-3-(5-methyl-3-isoxazolocarbamyl)-2H-1 ,2- benzothiazine 1 ,1 -Dioxide
  • R is liydrog en or rnethyl and R and R are benzothiazine 1 ,1 -Dioxide.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US00119967A 1971-03-01 1971-03-01 4-hydroxy-3-(3-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,dioxides and process for their production Expired - Lifetime US3787324A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US11996771A 1971-03-01 1971-03-01
US00333821A US3816628A (en) 1971-03-01 1973-02-20 4-hydroxy-3-(3-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,1-dioxides to treat inflammatory fever and pain conditions
US00356026A US3822258A (en) 1971-03-01 1973-04-30 4-hydroxy-3-(3-isoxazolylcarbamoyl)-2h-1,2-benzothiazine 1,1-dioxides and process for their production

Publications (1)

Publication Number Publication Date
US3787324A true US3787324A (en) 1974-01-22

Family

ID=27382407

Family Applications (4)

Application Number Title Priority Date Filing Date
US00119967A Expired - Lifetime US3787324A (en) 1971-03-01 1971-03-01 4-hydroxy-3-(3-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,dioxides and process for their production
US00333821A Expired - Lifetime US3816628A (en) 1971-03-01 1973-02-20 4-hydroxy-3-(3-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,1-dioxides to treat inflammatory fever and pain conditions
US00356026A Expired - Lifetime US3822258A (en) 1971-03-01 1973-04-30 4-hydroxy-3-(3-isoxazolylcarbamoyl)-2h-1,2-benzothiazine 1,1-dioxides and process for their production
US05/840,929 Expired - Lifetime USRE29836E (en) 1971-03-01 1977-10-11 4-Hydroxy-3-(3-isoxazolylcarbamoyl)-2H-1,2-benzothiazine 1,1-dioxides and process for their production

Family Applications After (3)

Application Number Title Priority Date Filing Date
US00333821A Expired - Lifetime US3816628A (en) 1971-03-01 1973-02-20 4-hydroxy-3-(3-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,1-dioxides to treat inflammatory fever and pain conditions
US00356026A Expired - Lifetime US3822258A (en) 1971-03-01 1973-04-30 4-hydroxy-3-(3-isoxazolylcarbamoyl)-2h-1,2-benzothiazine 1,1-dioxides and process for their production
US05/840,929 Expired - Lifetime USRE29836E (en) 1971-03-01 1977-10-11 4-Hydroxy-3-(3-isoxazolylcarbamoyl)-2H-1,2-benzothiazine 1,1-dioxides and process for their production

Country Status (5)

Country Link
US (4) US3787324A (enrdf_load_stackoverflow)
AU (1) AU456075B2 (enrdf_load_stackoverflow)
CA (1) CA978187A (enrdf_load_stackoverflow)
FR (1) FR2128371B1 (enrdf_load_stackoverflow)
GB (1) GB1323283A (enrdf_load_stackoverflow)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3957772A (en) * 1975-05-21 1976-05-18 Warner-Lambert Company Process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2h-1,2-benzothiazine 1,1-dioxide
US3987038A (en) * 1975-05-21 1976-10-19 Warner-Lambert Company Process for the preparation of {1-[5-(4-hydroxy-2H-1,2-benzothiazin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}ethanone S,S-dioxide
GB2154585A (en) * 1984-02-23 1985-09-11 Pfizer Prodrugs of antiinflammatory oxicams
US4551452A (en) * 1983-12-21 1985-11-05 Pfizer Inc. Anti-inflammatory 2-methyl-2H-1,2-benzo-(or -thieno-)thiazine-3-carboxamide 1,1-dioxide derivatives, compositions, and method of use therefor
EP0208404A2 (en) 1985-05-29 1987-01-14 Pfizer Inc. Benzothiazine dioxide derivatives
US4656265A (en) * 1984-06-21 1987-04-07 Pfizer Inc. Cyclic prodrugs of antiinflammatory oxicams
US4829062A (en) * 1986-05-16 1989-05-09 Pfizer Inc. Benzothiazine dioxide derivatives
US5308839A (en) * 1989-12-04 1994-05-03 The Research Foundation Of State University Of New York Composition comprising non-steroidal anti-inflammatory agent tenidap and effectively non-antibacterial tetracycline
US5321017A (en) * 1989-12-04 1994-06-14 The Research Foundation Of State University Of New York Composition comprising fluriprofen and effectively non-antibacterial tetracycline to reduce bone loss
WO2008044095A1 (en) 2006-10-11 2008-04-17 Techfields Biochem Co. Ltd Positively charged water-soluble prodrugs of oxicams and related compounds with very high skin penetration rate
US20090238763A1 (en) * 2006-07-09 2009-09-24 Chongxi Yu High penetration compositions and uses thereof
US20100172960A1 (en) * 2007-06-04 2010-07-08 Chongxi Yu Pro-drugs of nsaias with very high skin and membranes penetration rates and their new medicinal uses
US11135153B2 (en) 2006-07-09 2021-10-05 Techfields Pharma Co., Ltd. High penetration composition and uses thereof
US11541029B2 (en) 2008-12-04 2023-01-03 Techfields Pharma Co., Ltd. High penetration compositions and their applications

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3868367A (en) * 1974-04-11 1975-02-25 Warner Lambert Co 4-Hydroxy-3-(5-isoxazolylcarbamoyl)-2H-1,2-benzothiazine 1,1-dioxides
US4024136A (en) * 1975-06-20 1977-05-17 Warner-Lambert Company Process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine 1,1-dioxide
LU78009A1 (de) 1977-08-22 1979-05-23 Hoffmann La Roche Verfahren zur herstellung von thiazinderivaten
AU518216B2 (en) 1977-09-06 1981-09-17 Hafslund Nycomed Pharma Aktiengesellschaft Thienothiazine derivatives
US4289879A (en) * 1980-09-29 1981-09-15 Pfizer Inc. Synthetic method and intermediate for piroxicam
US4474955A (en) * 1981-06-17 1984-10-02 Vincenzo Iannella Process for preparing 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-[N-(2-pyridinyl)carboxamide]-1,1-dioxide, and its phosphoric ester
EP0082217A1 (de) * 1981-12-23 1983-06-29 Ciba-Geigy Ag Neue Ammoniumsalze, Verfahren zu ihrer Herstellung, diese enthaltende pharmazeutische Präparate und ihre Verwendung
DE3212485A1 (de) * 1982-04-03 1983-10-13 Gödecke AG, 1000 Berlin Verfahren zur herstellung von 4-hydroxy-3-(heterocyclocarbamoyl)-2h-1,2-benzothiazin-1,1-dioxiden
CA1197244A (en) * 1982-04-16 1985-11-26 Medichem, S.A. Process for the preparation of 4-hydroxy-2-methyl-2h- 1,2-benzothiazine-3-carboxamide-1,1-dioxides
IT1153293B (it) 1982-10-22 1987-01-14 Francia Famaceutici S R L Derivati del 4-idrossi-2-metil-2h-1, 2-benzotiazina-3-carbossamide 1, 1-biossido e procedimento per la loro preparazione
US4489077A (en) * 1983-03-23 1984-12-18 Warner-Lambert Company 3-Isoxa-zolyl-2H-1,2-benzothiazine-3-carboxamide, 1,1-dioxides
DE3346526C2 (de) * 1983-12-22 1986-12-11 A. Nattermann & Cie GmbH, 5000 Köln Pharmazeutisches Präparat zur therapeutischen Behandlung von rheumatischen Erkrankungen
US4610982A (en) * 1985-06-03 1986-09-09 Pfizer Inc. Anti-inflammatory benzo- and thieno-1,2-thiazine-3-carboxamide 1,1-dioxide derivatives, compositions, and method of use therefor
AU3961197A (en) 1996-07-16 1998-02-09 Richard J. Casull Extractor, cartridge, and receiver for a firearm, system for extracting a cartridge, and method of manufacturing a cartridge

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3501466A (en) * 1967-11-30 1970-03-17 Mcneilab Inc 3-carbamoyl and 3-alkoxycarbonyl benzothiazine-1,1-dioxides
US3591584A (en) * 1968-08-27 1971-07-06 Pfizer Benzothiazine dioxides
US3646021A (en) * 1970-07-16 1972-02-29 Warner Lambert Pharmaceutical 4 - hydroxy - 3 - furylcarbamyl - 2h - 1 2-benzothiazine 1 1-dioxides and process thereof
US3704298A (en) * 1971-06-22 1972-11-28 Warner Lambert Co 4-acyloxy-3-(2-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,1-dioxides
US3714155A (en) * 1971-09-27 1973-01-30 Warner Lambert Co 4-hydroxy-2,n-dimethyl-2h-1,2-benzothiazine-3-carboxanilide1,1-dioxide and process therefor

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3957772A (en) * 1975-05-21 1976-05-18 Warner-Lambert Company Process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2h-1,2-benzothiazine 1,1-dioxide
US3987038A (en) * 1975-05-21 1976-10-19 Warner-Lambert Company Process for the preparation of {1-[5-(4-hydroxy-2H-1,2-benzothiazin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}ethanone S,S-dioxide
US4551452A (en) * 1983-12-21 1985-11-05 Pfizer Inc. Anti-inflammatory 2-methyl-2H-1,2-benzo-(or -thieno-)thiazine-3-carboxamide 1,1-dioxide derivatives, compositions, and method of use therefor
GB2154585A (en) * 1984-02-23 1985-09-11 Pfizer Prodrugs of antiinflammatory oxicams
US4656265A (en) * 1984-06-21 1987-04-07 Pfizer Inc. Cyclic prodrugs of antiinflammatory oxicams
EP0208404A2 (en) 1985-05-29 1987-01-14 Pfizer Inc. Benzothiazine dioxide derivatives
US4829062A (en) * 1986-05-16 1989-05-09 Pfizer Inc. Benzothiazine dioxide derivatives
US5321017A (en) * 1989-12-04 1994-06-14 The Research Foundation Of State University Of New York Composition comprising fluriprofen and effectively non-antibacterial tetracycline to reduce bone loss
US5308839A (en) * 1989-12-04 1994-05-03 The Research Foundation Of State University Of New York Composition comprising non-steroidal anti-inflammatory agent tenidap and effectively non-antibacterial tetracycline
US5459135A (en) * 1989-12-04 1995-10-17 The Research Foundation Of State University Of New York Composition comprising indomethacin [non-steroidal anti-inflammatory agent] and effectively non-antibacterial tetracycline to reduce bone loss
US20090238763A1 (en) * 2006-07-09 2009-09-24 Chongxi Yu High penetration compositions and uses thereof
US9872846B2 (en) 2006-07-09 2018-01-23 Techfields Pharma Co., Ltd. High penetration compositions and uses thereof
US11135153B2 (en) 2006-07-09 2021-10-05 Techfields Pharma Co., Ltd. High penetration composition and uses thereof
WO2008044095A1 (en) 2006-10-11 2008-04-17 Techfields Biochem Co. Ltd Positively charged water-soluble prodrugs of oxicams and related compounds with very high skin penetration rate
US20100172960A1 (en) * 2007-06-04 2010-07-08 Chongxi Yu Pro-drugs of nsaias with very high skin and membranes penetration rates and their new medicinal uses
US9371284B2 (en) 2007-06-04 2016-06-21 Techfields Pharma Co., Ltd. Pro-drugs of NSAIAS with very high skin and membranes penetration rates and their new medicinal uses
US10233198B2 (en) 2007-06-04 2019-03-19 Techfields Pharma Co., Ltd. Pro-drugs of NSAIAs with very high skin and membranes penetration rates and their new medicinal uses
US11541029B2 (en) 2008-12-04 2023-01-03 Techfields Pharma Co., Ltd. High penetration compositions and their applications

Also Published As

Publication number Publication date
AU456075B2 (en) 1972-11-21
GB1323283A (en) 1973-07-11
CA978187A (en) 1975-11-18
FR2128371B1 (enrdf_load_stackoverflow) 1975-10-10
DE2208351A1 (de) 1972-09-14
USRE29836E (en) 1978-11-14
DE2208351B2 (de) 1976-09-16
US3816628A (en) 1974-06-11
AU3903872A (en) 1973-08-23
FR2128371A1 (enrdf_load_stackoverflow) 1972-10-20
US3822258A (en) 1974-07-02

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