WO1987002891A1 - Composes et procede de traitement local des inflammations et des douleurs - Google Patents

Composes et procede de traitement local des inflammations et des douleurs Download PDF

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Publication number
WO1987002891A1
WO1987002891A1 PCT/US1985/002206 US8502206W WO8702891A1 WO 1987002891 A1 WO1987002891 A1 WO 1987002891A1 US 8502206 W US8502206 W US 8502206W WO 8702891 A1 WO8702891 A1 WO 8702891A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
methyl salicylate
ibuprofen
nsaid
compound
Prior art date
Application number
PCT/US1985/002206
Other languages
English (en)
Inventor
James Edward Mckie
George Mclean Milne
Original Assignee
Pfizer Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to PCT/US1985/002206 priority Critical patent/WO1987002891A1/fr
Publication of WO1987002891A1 publication Critical patent/WO1987002891A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • C07D209/28—1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof

Definitions

  • This invention relates to the treatment of inflammation and pain in mammalian subjects by topical administration of certain chemical substances.
  • Musculo-s eletal inflammation and pain are common afflictions of mammals. They often appear as a manifestation of a chronic, inflammatory disease state, such as one of the arthritides, but they also appear as acute conditions in which case they can be triggered by a variety of causative factors. Such factors include bacteria, radiation and hypersensitivity to one or more chemical agents. However, a common cause of acute inflammation and pain in humans is simple over-exertion, leading to sprains, strains, muscle spasms, muscle tension, and the like.
  • NSAID's consists of propionic acid derivatives (the so-called “profens,” e.g., ibuprofen)
  • another group of NSAID's consists of acetic acid derivatives (e.g., indomethacin) .
  • NSAID's and various salts thereof, are commonly administered orally, thereby achieving systemic levels of the drug entity.
  • in many situa ⁇ tions particularly when acute therapy is desired, a more convenient mode of treatment involves topical administration directly to the inflamed and/or painful situs.
  • NSAID's are often not well-absorbed when administered topically.
  • methyl salicylate which is often applied to the skin in the form of an ointment or cream and which elicits a soothing, mildly-analgesic effect.
  • methyl salicylate suffers from the disadvantage that it possesses an odor, which under certain circumstances, and to certain individuals, can be regarded as un- pleasant.
  • the grouping Z-CO- represents an acyl radical of a carboxylic acid of the formula Z-CO-OH, wherein Z-CO-OH is a carboxy group-containing, non-steroidal antunflammatory drug (NSAID) .
  • NSAID non-steroidal antunflammatory drug
  • This coherent therapy with two complementary drug entities provides fast, effective relief, and has advantages of use in that: (i) absorption of the two components is converged, thereby delivering both components to the site of action at the same time; (ii) the odor of methyl salicylate is not observed because it is liberated only beneath the surface of the skin; and (iii) improved levels of absorption of the NSAID are achieved, compared to conventional formulations.
  • this invention provides a pharmaceutical composition which comprises a topically-acceptable pharmaceutical carrier and an antunflammatory and analgesic response eliciting amount of a phenolic ester of methyl salicylate of the formula I, wherein Z is as defined above.
  • the compounds of the formula I above are novel compositions of matter, except in the case in which the NSAID component is derived from aspirin.
  • this invention also provides a new genus of chemical compounds which can be represented by the following chemical formula
  • grouping Z -CO- represents an acyl radical of a carboxylic acid of the formula Z -CO-OH, wherein Z -CO-OH is a carboxy group-containing NSAID other than aspirin.
  • NSAID's can be used as the NSAID component of a compound of the formula I.
  • various carboxy group-containing compounds of the formula Z-CO-OH which can be used, four' sub-classes of NSAID's are particularly effective. There are:
  • the preferred compounds of the formula I are those in which the acyl group Z-CO- is derived from aspirin, ibuprofen or indomethacin. Consequently, preferred groups for Z -CO- in compounds of the formula II are the acyl groups derived from ibuprofen and indomethacin.
  • the compounds of the formula I can be prepared directly from the appropriate NSAID and methyl salicylate, viz:
  • NSAID such as by acid chloride formation
  • the acid of the formula 3-CO-OH is reacted with from one to four molar equivalents of thionyl chloride, in an inert solvent such as carbon tetra- chloride or chloroform, at a temperature from about 40 to about 80°C.
  • the reaction proceeds quite quickly, and conversion into acid chloride is usually sub- stantially complete within about 12 hours. At that point, the volatile materials are removed by evaporation in vacuo to give the crude acid chloride.
  • the crude acid chloride can be purified if desired, it is usually pure enough in the crude state for conversion into a compound of the formula I.
  • a small amount of aluminum trichloride can be added if desired.
  • reaction-inert solvents are ethers, such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane, and chlorinated hydrocarbons, such as chloroform and dichloromethane.
  • tertiary amines are pyridine, triethylamine and N,N-dimethylaniline.
  • the reagents are usually combined at or about room temperature, but it is then common to heat the reaction mixture at a temperature from about 30 to about 80°C, preferably about 40°C, for several hours to complete the reaction.
  • the product can be isolated by standard procedures. For example, when a water-immiscible reaction solvent has been used, the reaction mixture can be washed with dilute hydrochloric acid, followed by dilute sodium bicarbonate solution. Evaporation of the dried organic solven € then affords the crude product of formula I.
  • the product can be purified by conventional methods, such as recrystallization and/or chromatograph .
  • the Z grouping of the NSAID of the formula Z-CO-OH contains a functional group which can react with an acid chloride (e.g., OH, NH-, etc) , it is usually advantageous to protect this functional group prior to acid chloride formation.
  • the protecting group is then removed after reaction with the methyl salicylate.
  • Conventional protecting groups can be used for this purpose. Selection of an appropriate group, and methods for its attachment and removal, will be achieved readily by one skilled in the art.
  • a compound of the formula I will be administered in combination with a topically- acceptable pharmaceutical carrier, in a pharmaceutical composition.
  • Said pharmaceutical composition will be prepared according to standard pharmaceutical practice for a composition intended for topical use.
  • the pharmaceutical composition will be in the form of an ointment, gel, lotion or cream.
  • a compound of the formula I can be formulated with waxes, such as white wax or lanolin, and paraffins such as petrolatum.
  • Emulsifying agents such as sodium lauryl sulfate and stearyl alcohol, can also be added.
  • a compound of the formula I can be formulated by adding a gelling agent to a solution or partial solution of the active ingredient in a suitable organic solvent, such as ethyl alcohol, propyl alcohol, propylene glycol, glycerol or mixtures thereof.
  • a gelling agent which can be used are polyoxyethylated amines (e.g., PEG-15 cocamine) and carboxymethyl celluloses.
  • a compound of the formula I can be formulated in aqueous propylene glycol containing various emulsifying agents and emollients.
  • Typical emulsifying agents are glyceryl stearate, sorbitan monostearate, sorbitan mono-oleate, and the like;
  • typical emollients are waxes and paraffins, such as lanolin or light mineral oil.
  • a pharmaceutical composition containing a compound of the formula I can also contain other additives conventionally used for topical pharmaceuticals, such as stabilizers, preservatives and antioxidants, and penetration enhancers, such as dimethyl sulfoxide and N-methylpyrrolidone. Conventional coloring and odor-enhancing substances can also be added.
  • a pharmaceutical composition comprising a compound of the formula I
  • the dosage to be used will vary according to factors such as the severity of the symptom's being treated, the response of the individual patient, the frequency of administration and the antunflammatory and/or analgesic potency of the NSAID component of the compound of the formula I.
  • administration of an antunflammatory and analgesic response eliciting amount of a compound of a formula I will require topical administration of a pharmaceutical composition containing a compound of the formula I such that the
  • flash chromato- graphy refers to the procedure described by Still et. al. , Journal of Organic Chemistry, 43, 2923 (1978) .
  • the infrared spectrum of the product ( Br disc) showed prominent absorptions at 3200-2950, 1770, 1725, 1610, 1220-1190 and 1165 cm -1 .
  • the mass spectrum of the product showed major peaks at mass-to-charge ratios (m/e) of 314.1, 282.9, 163.3, 151.9, 134.9 and 120.9.
  • the infrared spectrum of the product ( Br disc) showed prominent absorptions at 3100-2850, 1765, 1730, 1610, 1300, 1140 and 1080 cm “1 .
  • the mass spectrum of the product showed major peaks at mass-to-charge ratios (m/e) of 341.0, 309.0, 188.2, 161.0, 145.0, 118.0 and 57.0.
  • Mixtures A and B are adjusted to the same temperature, mixed, and blended until homogeneous. The resulting mixture is allowed to cool to room temperature with slow stirring.
  • Ingredients 1, 2, 3 and 4 are blended until " homogeneous at a temperature between 22 and 30°C, to produce a molten mixture.
  • Ingredient 5 is added slowly, with gentle mixing, until a gel forms. Mixing is continued until a uniform blend is obtained.
  • a cross-linked polyacrylic acid A cross-linked polyacrylic acid
  • Ingredient 7 is dispersed in ingredient 6 and heated to 60°C with agitation (Mixture B) .
  • Mixture A is blended into Mixture B at 60°C and stirred until uniform and then the mixture is cooled to 50°C (Mixture C) .
  • a solution of ingredient 9 in ingredient 8 is heated to 50°C. This solution is added to Mixture C with gentle stirring and gradual cooling during the addition.
  • a cross-linked polyacrylic acid A cross-linked polyacrylic acid
  • Ingredients 3 and 4 are blended until homogeneous, and then a mixture of ingredients 1 and 2 is added. Blending is continued until homogeneous. The PEG-15 cocamine is added and blending is continued until a gel forms.
  • Ingredients 1-6 are blended until homogeneous at a suitable temperature, not to exceed 60°C, such that a molten mixture is obtained (Mixture A) .
  • a solution of the triethanolamine in the water is heated to the same temperature as Mixture A.
  • Mixture A is added to the aqueous triethanolamine with vigorous agitation and cooling. As a cream forms, the rate of agitation is slowed, and a smooth, white product develops.
  • a cross-linked polyacrylic acid A cross-linked polyacrylic acid
  • Ingredient 6 is dispersed in ingredient 5 and heated to 60°C with agitation (Mixture B) .
  • Mixture A is blended into Mixture B at 60°C and stirred until uniform and then the mixture is cooled to 50°C (Mixture C) .
  • a solution of ingredient 8 in ingredient 7 is heated to 50°C. This solution is added to Mixture C with gentle stirring and gradual cooling during the addition.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des esters de salicylate de méthyle associés à certains médicaments anti-inflammatoires non stéroïdes (NSAID's) peuvent être administrés localement à des mammifères, afin de provoquer une réaction qui combine les effets anti-inflammatoires et analgésiques des NSAID et les effets de contre-irritation du salicylate de méthyle. Lesdits médicaments anti-inflammatoires non stéroïdes pouvant être utilisés sont l'aspirine (acide acétylsalicylique), l'ibuprofène et l'indométhacine. Ledit ester de salicylate de méthyle-NSAID peut être administré de manière avantageuse sous la forme d'une composition pharmaceutique telle qu'onguent, gel, lotion, crème ou substance analogue.
PCT/US1985/002206 1985-11-07 1985-11-07 Composes et procede de traitement local des inflammations et des douleurs WO1987002891A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/US1985/002206 WO1987002891A1 (fr) 1985-11-07 1985-11-07 Composes et procede de traitement local des inflammations et des douleurs

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1985/002206 WO1987002891A1 (fr) 1985-11-07 1985-11-07 Composes et procede de traitement local des inflammations et des douleurs

Publications (1)

Publication Number Publication Date
WO1987002891A1 true WO1987002891A1 (fr) 1987-05-21

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Country Status (1)

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5028431A (en) * 1987-10-29 1991-07-02 Hercon Laboratories Corporation Article for the delivery to animal tissue of a pharmacologically active agent
EP0510080A1 (fr) * 1989-12-26 1992-10-28 Nova Pharmaceutical Corporation Anhydrides sous forme de promedicaments d'aspirine, d'indomethacine et d'ibuprofene, leur preparation, leurs compositions, et leur mode anti-inflammatoire d'emploi
US6572871B1 (en) * 1999-01-06 2003-06-03 W. Edward Church Pain treatment method and apparatus using heating wrap and analgesic cream
WO2006096360A1 (fr) 2005-03-03 2006-09-14 Isw Group, Inc. Compositions de gels topiques
WO2006117516A2 (fr) * 2005-05-05 2006-11-09 Reckitt Benckiser Inc Compositions topiques
WO2008030359A2 (fr) * 2006-09-06 2008-03-13 Isw Group, Inc. Compositions topiques
US7871427B2 (en) 2005-02-08 2011-01-18 Carewave, Inc. Apparatus and method for using a portable thermal device to reduce accommodation of nerve receptors
EP2311454A2 (fr) * 2008-06-20 2011-04-20 Ignacio Umbert Millet Composition pharmaceutique dermatologique destinée au traitement de pathologies inflammatoires cutanées telles que la dermatite, la dermatite atopique, le vitiligo, l'alopécie areata, l'acné, le psoriasis et le prurit, et de combinaisons de ces dernières
US8579953B1 (en) 2007-12-07 2013-11-12 Peter J. Dunbar Devices and methods for therapeutic heat treatment
US10561627B2 (en) 2014-12-31 2020-02-18 Eric Morrison Ibuprofen nanoparticle carriers encapsulated with hermetic surfactant films
US10596117B1 (en) 2014-12-31 2020-03-24 Eric Morrison Lipoleosomes as carriers for aromatic amide anesthetic compounds
US10603208B2 (en) 2011-01-21 2020-03-31 Carewave Medical, Inc. Modular stimulus applicator system and method
US11007161B1 (en) 2014-12-31 2021-05-18 Eric Morrison Ibuprofen nanoparticle carriers encapsulated with hermatic surfactant films

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE236196C (fr) *
DE211403C (fr) * 1907-05-23

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE236196C (fr) *
DE211403C (fr) * 1907-05-23

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J. OF PHARM. SCI., 72, (1983), REEPMEYER et al., pages 322-323. *
MERCK INDEX, 9th Ed., (1976), MERCK & CO., USA, pages 1080-1081. *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5028431A (en) * 1987-10-29 1991-07-02 Hercon Laboratories Corporation Article for the delivery to animal tissue of a pharmacologically active agent
EP0510080A1 (fr) * 1989-12-26 1992-10-28 Nova Pharmaceutical Corporation Anhydrides sous forme de promedicaments d'aspirine, d'indomethacine et d'ibuprofene, leur preparation, leurs compositions, et leur mode anti-inflammatoire d'emploi
EP0510080A4 (en) * 1989-12-26 1992-12-02 Nova Pharmaceutical Corporation Prodrug anhydrides of asprin, indomethacin and ibuprofen, their preparation, compositions, and anti-inflammatory method of use
US5498729A (en) * 1989-12-26 1996-03-12 Domb; Abraham J. Prodrug compositions
US6572871B1 (en) * 1999-01-06 2003-06-03 W. Edward Church Pain treatment method and apparatus using heating wrap and analgesic cream
US7871427B2 (en) 2005-02-08 2011-01-18 Carewave, Inc. Apparatus and method for using a portable thermal device to reduce accommodation of nerve receptors
US10188547B2 (en) 2005-02-08 2019-01-29 Carewave Medical, Inc. Apparatus and method for using a portable thermal device to reduce accommodation of nerve receptors
US8702775B2 (en) 2005-02-08 2014-04-22 Carewave, Inc. Apparatus and method for using a portable thermal device to reduce accommodation of nerve receptors
WO2006096360A1 (fr) 2005-03-03 2006-09-14 Isw Group, Inc. Compositions de gels topiques
WO2006117516A3 (fr) * 2005-05-05 2007-01-25 Reckitt Benckiser Inc Compositions topiques
WO2006117516A2 (fr) * 2005-05-05 2006-11-09 Reckitt Benckiser Inc Compositions topiques
WO2008030359A3 (fr) * 2006-09-06 2008-07-31 Isw Group Inc Compositions topiques
WO2008030359A2 (fr) * 2006-09-06 2008-03-13 Isw Group, Inc. Compositions topiques
US8579953B1 (en) 2007-12-07 2013-11-12 Peter J. Dunbar Devices and methods for therapeutic heat treatment
US9937072B2 (en) 2007-12-07 2018-04-10 Carewave Medical, Inc. Devices and methods for therapeutic heat treatment
EP2311454A2 (fr) * 2008-06-20 2011-04-20 Ignacio Umbert Millet Composition pharmaceutique dermatologique destinée au traitement de pathologies inflammatoires cutanées telles que la dermatite, la dermatite atopique, le vitiligo, l'alopécie areata, l'acné, le psoriasis et le prurit, et de combinaisons de ces dernières
EP2311454A4 (fr) * 2008-06-20 2012-02-22 Millet Ignacio Umbert Composition pharmaceutique dermatologique destinée au traitement de pathologies inflammatoires cutanées telles que la dermatite, la dermatite atopique, le vitiligo, l'alopécie areata, l'acné, le psoriasis et le prurit, et de combinaisons de ces dernières
US10603208B2 (en) 2011-01-21 2020-03-31 Carewave Medical, Inc. Modular stimulus applicator system and method
US10561627B2 (en) 2014-12-31 2020-02-18 Eric Morrison Ibuprofen nanoparticle carriers encapsulated with hermetic surfactant films
US10596117B1 (en) 2014-12-31 2020-03-24 Eric Morrison Lipoleosomes as carriers for aromatic amide anesthetic compounds
US11007161B1 (en) 2014-12-31 2021-05-18 Eric Morrison Ibuprofen nanoparticle carriers encapsulated with hermatic surfactant films

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