WO1995016443A1 - Agents anti-inflammatoires a base de composes de di-tert-butylphenol - Google Patents

Agents anti-inflammatoires a base de composes de di-tert-butylphenol Download PDF

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Publication number
WO1995016443A1
WO1995016443A1 PCT/US1994/014405 US9414405W WO9516443A1 WO 1995016443 A1 WO1995016443 A1 WO 1995016443A1 US 9414405 W US9414405 W US 9414405W WO 9516443 A1 WO9516443 A1 WO 9516443A1
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WO
WIPO (PCT)
Prior art keywords
compound
integer
hydrogen
tert
compounds
Prior art date
Application number
PCT/US1994/014405
Other languages
English (en)
Inventor
Thomas Tod Hudec
Maurice Edward Loomans
Joel Ira Shulman
Original Assignee
The Procter & Gamble Company
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 The Procter & Gamble Company filed Critical The Procter & Gamble Company
Priority to SK769-96A priority Critical patent/SK76996A3/sk
Priority to CZ961755A priority patent/CZ285436B6/cs
Priority to JP7516940A priority patent/JPH09506624A/ja
Priority to AU13722/95A priority patent/AU702254B2/en
Priority to BR9408334A priority patent/BR9408334A/pt
Priority to EP95904909A priority patent/EP0734256A1/fr
Priority to NZ277986A priority patent/NZ277986A/en
Publication of WO1995016443A1 publication Critical patent/WO1995016443A1/fr
Priority to NO962535A priority patent/NO962535L/no

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the subject invention relates to nonsteroidal anti-inflammatory drugs, particularly to substituted di-tert-butylphenol compounds.
  • Di-tert-butylphenol compounds are a class of compounds known for their use as stabilizers for plastics, oils and fats; see, e.g., U.S. Patent No. 3,711,544 issued to Engelhardt, Fruhstorfer, Hesse, Dennler & Baumer on January 16, 1973.
  • compositions comprising compounds having the structure:
  • n is an integer from 1 to about 5
  • m is an integer from 0 to about 3
  • -R is hydrogen or straight or branched chain C1-C3 alkanyl; and a pharmaceutically-acceptable carrier.
  • the subject invention also involves methods for treating diseases characterized by inflammation and/or pain, such as rheumatoid arthritis and osteoarthritis, in humans or lower animals by administration of a safe and effective amount of these compounds to the human or lower animal in need of such treatment.
  • the subject invention involves particular di-tert-butylphenol com ⁇ pounds having the following structure:
  • n is an integer of from 1 to about 5, pre ⁇ ferably from 1 to 4, more preferably 1 or 2 or 3, most preferably 2.
  • m is an integer of from 0 to about 3, preferably from 0 to 2, more preferably 0 or 1, most preferably 0.
  • -R is hydrogen or straight or br nched chain alkanyl having from 1 to about 3 carbon atoms.
  • -R is preferably hydrogen, methyl or ethyl, most preferably hydrogen.
  • Preferred compounds useful in the subject invention include:
  • testing of the subject compounds in animals is carried out using various assays known to those skilled in the art.
  • the anti-inflammatory activity of the subject compounds can be conveniently demonstrated using an assay designed to test the ability of the subject compounds to antagonize the local edema which is characteristic of the inflammatory response. Examples of such known tests include the rat carrageenan edema test, the oxazolone-induced inflamed mouse ear test, and the mouse arachadonic acid-induced inflamed ear test.
  • Analgesic activity may be tested in art-known models such as the phenylbenzoquinone- induced writhing test in mice, and the Randall & Selitto test in rats.
  • rat adjuvant arthritis test which is a useful model for assessing anti-inflammatory activity, anti-arthritic and anti-resorptive activity in a chronic, rather than an acute, model.
  • rat adjuvant arthritis test is a useful model for assessing anti-inflammatory activity, anti-arthritic and anti-resorptive activity in a chronic, rather than an acute, model.
  • These and other appropriate tests for pharmacological activity are disclosed and/or referred to in U.S. Patent No. 4,130,666 issued to Moore on December 19, 1978; U.S. Patent No. 4,431,656 issued February 14, 1984 to Katsumi, et al.; U.S. Patent No. 4,440,784 issued to Katsumi, et al. on April 3, 1984; Japanese Patent Application
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAIDs non-steroidal anti- inflammatory drugs
  • gastrointestinal side effects especially when dosed perorally; such side effects may include ulcers and erosions.
  • These side effects which are often asymptomatic, can become serious enough to require hospitalization and can even be lethal.
  • Compounds of the subject invention generally cause fewer such gastrointestinal side effects compared to other NSAIDs, even compared to many other di-tert-butylphenol derivatives.
  • Certain NSAIDs including certain di-tert-butylphenol derivatives, when dosed systemicaliy, cause an undesirable increase in systemic levels of certain liver enzymes.
  • Compounds of the subject invention generally cause less of such liver enzyme side effects compared to other di-tert-butylphenol compounds.
  • compositions of the subject invention comprise a safe and effective amount of the subject compounds, and a pharmaceutically- acceptable carrier.
  • safe and effective amount means an amount of a compound sufficient to significantly induce a positive modification in the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgement.
  • a safe and effective amount of a compound will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.
  • Compositions of the subject invention preferably comprise from about 0.1% to about 99.9% by weight of a compound, more preferably from about 20% to about 80%, and most preferably from about 40% to about 70%.
  • compositions of the subject invention contain a pharmaceutically-acceptable carrier.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or lower animal.
  • compatible means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations.
  • Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or lower animal being treated.
  • substances which can serve as pharmaceutically-acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as comstarch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid, magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the
  • Tweens® wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents, excipients; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.
  • the subject compound is to be injected, it is preferably injected non-intravenously;
  • the preferred pharmaceutically-acceptable carrier is sterile, physiological saline, with blood compatible suspending agent, the pH of which has been adjusted to about 7.4.
  • injectable compositions preferably comprise from about 1 % to about 50% of the subject compound, more preferably from about 5% to about 25%, also preferably from about 10 mg to about 600 mg of the subject compound per dose.
  • Topical compositions preferably contain from about 1% to about 50% of an emollient, more preferably from about 5% to about 25% of an emollient. Such topical compositions preferably comprise from about 0.1% to about 50%, of the subject compound, more preferably from about 0.5% to about 10%, also preferably from about 5 mg to about 3500 mg per dose.
  • the preferred mode of administering the subject compound is perorally.
  • the preferred unit dosage form is therefore tablets, capsules and the like, comprising a safe and effective amount of the compound, which is preferably from about 5 mg to about 3500 mg, more preferably from about 10 mg to about 1000 mg, and most preferably from about 25 mg to about 600 mg.
  • the pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well-known in the art. Their selection will depend on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be made without difficulty by a person skilled in the art.
  • a solubilizing agent may be included in the composition.
  • solubilizing agents include polyethylene glycol, propylene glycol, ethanol, and polyoxyethylene (35) castor oil.
  • compositions of the subject invention are disclosed in pending U.S.
  • Another aspect of the subject invention is methods for treating or preventing diseases characterized by inflammation by administering a safe and effective amount of a subject compound to a human or lower animal in need of such treatment.
  • diseases characterized by inflammation means conditions which are known to involve inflammation, and may include conditions such as arthritis (e.g., rheumatoid arthritis, osteoarthritis, psoriatic arthritis, juvenile arthritis,
  • inflammation in the oral cavity e.g., inflammation associated with gingivitis or periodontal disease
  • inflammation in the gastrointestinal tract e.g., inflammation associated with ulcers and irritable bowel disease
  • inflammation associated with dermatological diseases e.g., psoriasis, acne, and other skin inflammation
  • inflammation associated with the respiratory tract e.g., asthma, bronchitis, and allergies.
  • Another aspect of the subject invention is methods for treating or preventing pain by administering a safe and effective amount of a subject compound to a human or lower animal in need of such treatment.
  • Pain which can be treated or prevented by administering the subject compounds may include peripheral pain, menstrual pain, dental pain, and lower back pain.
  • Another aspect of the subject invention is methods for protecting against free radical damage resulting from oxidative stress and ischemic conditions by administering a safe and effective amount of a subject compound to a human or lower animal in need of such treatment.
  • Such treatment may include protecting against ischemic heart disease, atherosclerosis, stroke, and ischemic cell damage of heart.
  • the preferred mode of administration of the subject compounds is peroral, but other known methods of administration are contemplated as well, e.g., denmatomucosally (for example, dermally, rectally and the like), and parenterally (for example, by subcutaneous injection, intramuscular injection, intraarticular injection, intravenous injection and the like). Ocular administration and inhalation are also included.
  • compositions include, without limitation, peroral, transdermal, mucosal, sublingual, intranasal, intramuscular, intravenous, intraperitoneal, subcutaneous, and topical administration.
  • Preferred doses of the subject compounds range from about 0.2 mg/kg to about 70 mg/kg, more preferably from about 0.5 mg/kg to about 12 mg kg.
  • Preferred injectable doses comprise from about
  • Preferred topical doses comprise from about 1 mg cm 2 to about 200 mg/crn 2 of the subject compound applied to the skin surface.
  • Preferred peroral doses comprise from about 0.5 mg/kg to about 25 mg/kg of the subject compound. Such doses are preferably administered from about once to about six times daily, more preferably from about twice to about four times daily.
  • Example 2 illustrates the subject invention.
  • compositions in the form of tablets are prepared by conventional methods, such as mixing and direct compaction, formulated as follows: Ingredient Quantity (mg per tablet) 4-(1 ,5-dioxohexyl)-
  • Magnesium Stearate 3 When administered orally two times daily, the above composition significantly reduces the inflammation in a patient suffering from rheumatoid arthritis. A significant benefit is also achieved by twice daily administration of this composition to a patient suffering from osteoarthritis.
  • Example 3
  • a pharmaceutical composition in capsule form is prepared by conventional methods, formulated as follows:
  • Lactose To fill to volume of capsule The above capsule administered orally once a day substantially reduces the symptomology of a patient afflicted with rheumatoid arthritis or osteoarthritis.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention porte sur des compositions comprenant: (a) une quantité inoffensive et efficace d'un composé de formule (i) où n est un entier allant de 1 à 5 environ, m est un entier allant de 0 à 3 environ et -R un hydrogène ou un alcanyle C1-C3 à chaîne droite ou ramifiée; et (b) un excipient pharmacocompatible. L'invention porte également sur des méthodes de traitement de maladies caractérisées par les inflammations ou douleurs causées par l'arthrite rhumatoïde ou l'ostéoarthrite, par administration à l'homme et à l'animal qui le nécessitent de doses inoffensives et efficaces dudit composé.
PCT/US1994/014405 1993-12-17 1994-12-16 Agents anti-inflammatoires a base de composes de di-tert-butylphenol WO1995016443A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
SK769-96A SK76996A3 (en) 1993-12-17 1994-12-16 Di-tert-butylphenol compounds useful as anti-inflammatory agents
CZ961755A CZ285436B6 (cs) 1993-12-17 1994-12-16 Di-tert.-butylfenolové sloučeniny použitelné jako protizánětlivá činidla
JP7516940A JPH09506624A (ja) 1993-12-17 1994-12-16 抗炎症剤として有用なジ−ｔｅｒｔ−ブチルフェノール化合物
AU13722/95A AU702254B2 (en) 1993-12-17 1994-12-16 Di-tert-butylphenol compounds useful as anti-inflammatory agents
BR9408334A BR9408334A (pt) 1993-12-17 1994-12-16 Compostos de di-ter-butilfenol úteis como agentes antiinflamatórios
EP95904909A EP0734256A1 (fr) 1993-12-17 1994-12-16 Agents anti-inflammatoires a base de composes de di-tert-butylphenol
NZ277986A NZ277986A (en) 1993-12-17 1994-12-16 Di-tertiary-butylphenol ketone derivatives as anti-inflammatory agents
NO962535A NO962535L (no) 1993-12-17 1996-06-14 Di-tert-butylfenolforbindelser anvendbare som antiflammatoriske midler

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US16934793A 1993-12-17 1993-12-17
US08/169,347 1993-12-17

Publications (1)

Publication Number Publication Date
WO1995016443A1 true WO1995016443A1 (fr) 1995-06-22

Family

ID=22615292

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/014405 WO1995016443A1 (fr) 1993-12-17 1994-12-16 Agents anti-inflammatoires a base de composes de di-tert-butylphenol

Country Status (13)

Country Link
EP (1) EP0734256A1 (fr)
JP (1) JPH09506624A (fr)
CN (1) CN1137752A (fr)
AU (1) AU702254B2 (fr)
BR (1) BR9408334A (fr)
CA (1) CA2179009A1 (fr)
CZ (1) CZ285436B6 (fr)
HU (1) HUT74507A (fr)
NO (1) NO962535L (fr)
NZ (1) NZ277986A (fr)
PL (1) PL315061A1 (fr)
SK (1) SK76996A3 (fr)
WO (1) WO1995016443A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4130666A (en) * 1977-05-16 1978-12-19 Riker Laboratories, Inc. Anti-inflammatory method
WO1993007865A1 (fr) * 1991-10-16 1993-04-29 The Procter & Gamble Company Composes de di-tert-butylphenol utiles comme agents anti-inflammatoires

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4130666A (en) * 1977-05-16 1978-12-19 Riker Laboratories, Inc. Anti-inflammatory method
WO1993007865A1 (fr) * 1991-10-16 1993-04-29 The Procter & Gamble Company Composes de di-tert-butylphenol utiles comme agents anti-inflammatoires

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Determination of tebufelone (a new antiinflammatory drug) strength and stability in bulk drug, dosage formulations and feed admixtures by reversed phase high performance liquid chromatography", J.CHROMATOGR., vol. 505, no. 2, pages 349 - 56 *

Also Published As

Publication number Publication date
HU9601656D0 (en) 1996-08-28
AU1372295A (en) 1995-07-03
AU702254B2 (en) 1999-02-18
NZ277986A (en) 1998-03-25
JPH09506624A (ja) 1997-06-30
BR9408334A (pt) 1997-08-19
NO962535L (no) 1996-08-15
CZ285436B6 (cs) 1999-08-11
CA2179009A1 (fr) 1995-06-22
CN1137752A (zh) 1996-12-11
EP0734256A1 (fr) 1996-10-02
CZ175596A3 (en) 1996-11-13
NO962535D0 (no) 1996-06-14
SK76996A3 (en) 1997-05-07
PL315061A1 (en) 1996-09-30
HUT74507A (en) 1997-01-28

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