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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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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benzothiazine
hydroxy
isoxazolocarbamyl
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dioxides
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US00119967A
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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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  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Dentistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Plant Pathology (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (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)

Abstract

COMPOUNDS HAVING THE FOLLOWING STRUCTURAL FORMULA ARE DISCLOSED:

3-((4-R2,5-R3-2-ISOXAZOLIN-3-YL)-NH-CO-),1,1-DI(O=),2-R1,

4-(HO-)-2H-1,2-BENZOTHIAZINE

WHEREIN R1 IS HYDROGEN OR METHYL AND R2, AND R3 ARE HYDROGEN OR ALKYL. THESE COMPOUNDS ARE USEFUL AS ANTI-INFLAMMATORY AGENTS, ANTIPYRETICS, ANALGESICS.

Description

nited States Patent [191 Zinnes et a].
[ Jan. 22, 1974 Inventors: Harold Zinnes, Rocka Martin L. Schwartz, Gillette; John Shave], Jr., Mendham,
all of NJ.
[73] Assignee: Warner-Lambert Company,
lxl orris Plains, NJ. i
Mar. 1, 1971 [21] Appl. No.: 119,967
[52] 11.8. CI. 260/243 R, 424/246 [51] Int. Cl C07d 93/02 [58] Field of Search 260/243 R [56] References Cited UNITED STATES PATENTS 1/1970 Rasmussen 260/243 3/1970 Rasmussen 260/243 Primary Examiner-John M. Ford Attorney-Albert H. Graddis, Frank S. Chow, Neil D. Edwards, and Anne M. Kelly [5 7] ABSTRACT Compounds having the following structural formula are disclosed:
wherein R is hydrogen or methyl and R and R are hydrogen or alkyl. These compounds are useful as antiinflammatory agents, antipyretics, analgesics.
4 Claims, No Drawings 1 n 4-HYDROXY-3-(3-ISOXAZOLOCARBAMYL)-2H- 1,2-BENZOTHIAZINE l, DIOXIDES AND PROCESS FOR THEIR PRODUCTION The present invention relates to 4-Hydroxy-3-(.3-.
isoxazolocarbamyl)-2l-l-1 ,Z-benzothiazine 1 1- Dioxides having the following structural formula:
wherein 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.
'Therapeutically orprophylactically administered orally at a dose of -200 mg./kg., 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. At oral doses of 25-200 mg./kg. they exhibit a significant analgesic effect as determined by the phenylquinone writhing procedure in mice.
Generally speaking, 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.
In order to use these compounds, they 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. For injectionable dosage forms, they are formulated with vehicles such as water, peanut oil, sesame Generally speaking, starting compound is refluxed with 3-aminoisoxazole ill in an inert solvent such as xylene. In a preferred embodiment of the present invention, 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. Typically the reaction is carried out in a Soxhlet apparatus with the molecular sieves contained in the thimble.
Examples of the 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.
Starting compound 3-aminoisoxazole is prepared in accordance with the description in Chem. Pharm. Bull. 14, 1277 (1966); The starting compound 3-amino-5- methylisoxazole is commercially available from Hoffmann-La Roche. It is prepared in accordance with the description set forth in the Netherlands Pat; No. 6,511,924, issued Mar. 15, 1966.
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.
In order to further illustrate the practice of this invention, the following examples are included. All temperatures are givenin degrees centigrade.
EXAMPLE 1 4-Hydroxy-3-(5-methyl-3-isoxazolocarbamyl)-2- methyl-21L l ,2-benzothiazine l l -Dioxide A mixture of 40.5 g (0.15 3-carbethoxy-4-hydroxy- 2-methyl-2H-l,2-ben2othiazine 1,1-dioxide, 20.6 g (0.21 mole) of 3-amino-5-methylisoxazole, and 2500 ml of xylene was refluxed for 24 hr in a Soxholet apparatus, the thimble of which contained 60 g of Linde type 4A molecular sieve. The mixture was cooled to 25 and the resulting crystalline precipitate was collected and washed. with ether to give 44 g of crude product. Re-crystallization from 1600 ml of 1,4-dioxan gave 34.7 of material, mp 265271 dec.
Al'lal. Calcd for C14H13N305S: C, H, N, 12.53; S, 9.56. Found: C, 50.33; H, 3.88; N, 12.30; S, 9.49.
The corresponding sodium salt was prepared by treating the above compound with sodium hydroxide which has the following structural formula:
mole) of its 0 ENE-3* NCH! \OL ELAMPLE ll CONH NCH:
4-Hydroxy-3-( 3-isoxazo1ocarbamy1)-2-methyl-2H- 1 ,2- benzothiazine 1 1 -Dioxide A mixture of 4.15 g (0.0155 mole) of 3-carbethoxy- 4-hydroxy-2-methy1-2H-l ,2-benzothiazine 1 1 -dioxide, 1.3 g. (0.0155 mole) of 3-aminoisoxazole, and 500 ml of xylene was refluxed for 24 hr in a Soxholet apparatus, the thimble of which contained g of Linde 4A molecular sieve. The mixture was cooled to 25 and the resulting crystalline precipitate was collected and washed with ether to give 3.2 g of product, mp. 235-240 dec. Recrystallization from 175 ml of ethyl acetate gave 1.6 g of material, mp. 237-240 dec.
Anal. Calcd for C H N O S: C, 48.60; H, 3.45; N, 13.08; S, 9.98. Found: C, 48.77; H, 3.44; N, 12.86; S, 9.85.
. EXAMPLE 111 4-1-1ydroxy-3-(5-methyl-3-isoxazolocarbamyl)-2H-1 ,2- benzothiazine 1 ,1 -Dioxide A mixture of 15.3 g (0.06 mole) of 3-carbethoxy-4- hydroxy-2-methyl-2H-l ,2-benzothiazine 1 1 -dioxide, 5.9 g (0.06 mole) of 3-amino-5-methy1isoxazole, and 800 ml of xylene was refluxed for 24 hr. in a Soxholet apparatus, the thimble of which contained 20 g of Linde type 4A molecular sieve. The mixture was cooled to 25 and the resulting precipitate was collected and washed with ether to give 11.5 g of crude product, mp. 242248 dec. Recrystallization from 300 m1 of 1,4-dioxan gave 1 1.2 g of crystalline product, mp. 254257 dec.
Anal. Calcd for C H N O Sf C, 48.60; H, 3.45; N, 13.08; S, 9.98. Found: C, 48.67; H, 3.44; N, 12.91; S, 10.23.
We claim:
1. A compound of the formula:
SO; I
wherein R is liydrog en or rnethyl and R and R are benzothiazine 1 ,1 -Dioxide.
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)

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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

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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

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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

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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 (13)

* 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 (en) 1977-08-22 1979-05-23 Hoffmann La Roche METHOD FOR PRODUCING THIAZINE DERIVATIVES
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 (en) * 1981-12-23 1983-06-29 Ciba-Geigy Ag Ammonium salts, process for their preparation, pharmaceutical preparations containing them and their use
DE3212485A1 (en) * 1982-04-03 1983-10-13 Gödecke AG, 1000 Berlin METHOD FOR PRODUCING 4-HYDROXY-3- (HETEROCYCLOCARBAMOYL) -2H-1,2-BENZOTHIAZINE-1,1-DIOXIDES
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
US4489077A (en) * 1983-03-23 1984-12-18 Warner-Lambert Company 3-Isoxa-zolyl-2H-1,2-benzothiazine-3-carboxamide, 1,1-dioxides
DE3346526C2 (en) * 1983-12-22 1986-12-11 A. Nattermann & Cie GmbH, 5000 Köln Pharmaceutical preparation for the therapeutic treatment of rheumatic diseases
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

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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

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

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