EP0730461A1 - Emploi d'un ester d'inositoltriphosphate pour la preparation d'un analgesique - Google Patents

Emploi d'un ester d'inositoltriphosphate pour la preparation d'un analgesique

Info

Publication number
EP0730461A1
EP0730461A1 EP95902365A EP95902365A EP0730461A1 EP 0730461 A1 EP0730461 A1 EP 0730461A1 EP 95902365 A EP95902365 A EP 95902365A EP 95902365 A EP95902365 A EP 95902365A EP 0730461 A1 EP0730461 A1 EP 0730461A1
Authority
EP
European Patent Office
Prior art keywords
inositoltrisphosphate
ester
medicament
myo
inositol
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP95902365A
Other languages
German (de)
English (en)
Inventor
Lars Persson
Nicola Rehnberg
Torgny Gustafsson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Perstorp AB
Original Assignee
Perstorp AB
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 Perstorp AB filed Critical Perstorp AB
Publication of EP0730461A1 publication Critical patent/EP0730461A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/66—Phosphorus compounds
    • 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

Definitions

  • the present invention relates to the use of an ester of inositoltrisphosphate for the preparing of a medicament effective as an analgesic.
  • Another type of pharmaceuticals used to reduce pain are sedative agents such as barbiturates and benzodiazepines. Many of these drugs have side effects such as depressant action on respiration and circulation and are producing nausea and vomiting, which limit their use to many groups of patients. Furthermore many of the used drugs give hypnotic effects which are undesirable for the patient.
  • Nonsteroidal anti-inflammatory drugs are used to treat pain and inflammation. This class of compounds works by preventing the synthesis of prostaglandins and side- effects such as damage to the gastic mucosa often appear.
  • the medicament is intended to be used for preventing, alleviating and combatting pain.
  • the medicament can be used for example in the following conditions in order to reduce pain:
  • Tissue damage induced mechanically or chemically such as burns, trauma i.e. wounds or injuries caused by physical damage.
  • Inflammatory conditions such as joint inflammations.
  • the medicament can also be effective in other disorders or conditions where reduction of pain is desirable.
  • the medicament exerts significant analgesic effects with ⁇ out showing any side-effects and without any sedative effects which is very beneficial for the patient.
  • a pharmaceutical composition comprising as a pharmaceutically active in ⁇ gredient at least one isomer of inositoltrisphosphate is known.
  • the effect of this pharmaceutical composition is shown for different areas, such as plate ⁇ let aggregation.
  • esters of inositoltrisphosphate and the isolation of the different isomers thereof are disclosed in the European Patent Application No. 0269105.
  • esters of inositoltrisphos- phates differs from the profile of inositoltrisphosphates in many important aspects. Chemical properties such as lipophilicity, solubility and pF -values are changed which affect the potency and selectivity of the compound.
  • the medicament used according to the invention exists in unit dosage form.
  • Tablets, granules or capsules are suitable administration forms for such unit dosage.
  • tablets and granules can easily be surface treated such as to provide an enteric coating to prevent an uncontrolled hydrolysis in the stomach and to bring about a desired absorption in the intestine.
  • Other suitable administration forms are slow release and transder al administration.
  • a usual pharmaceutically acceptable additive, excipient and/or carrier can be in ⁇ cluded in the medicament.
  • the tablets or granules can also contain a disintegrant which causes the tablets or the granules, respectively, to disintegrate easily in the intestine.
  • suspensions comprising the compound can be preferably used as administration form.
  • the medicament can also consist as such of esters of ino ⁇ sitoltrisphosphate solely without any additive, excipient or carrier.
  • the medicament can consist of or comprise one or more specific isomers of esters of inositoltrisphosphate, each present in substantially pure form.
  • the different isomers can be isolated from each other in substantially pure form, which means that they have a purity of 80-100 %, such as 82-100 % or 85-100 %, preferably 90-100 %. Since the isomers can be produced in pure form they can be mixed in any proportion, of course.
  • ester of inositol ⁇ trisphosphate used for the preparing of the medicament according to the invention are present in salt form in order not to affect the mineral balance negatively.
  • the salt should preferably consist of a sodium, potassium, calcium or magnesium salt or a mixture of two or more of these salts.
  • the medicament contains a surplus or an extra addition of at least one pharmaceutically acceptable salt of calcium, zinc or magnesium with a mineral acid or organic acid. This is especially valuable for elderly persons who are often deficient in these minerals.
  • the preferred dosage for humans falls within the range of 0.1 to 1000 mg, especially 0.1-200 mg of the compound/day/kg body weight.
  • the medicament usually contains 0.01-1.5 g, such as 0.05-1.3 g or preferably 0.1-1 g of the compound per unit dosage.
  • composition used according to the present invention contains at least one, sometimes two or more of the following compounds which correspond to esters of inosi- toltrisphosphates with the structural formula:
  • (10) a heterocyclic ring containing at least one atom of oxygen, nitrogen or sulfur said meanings (1) to (10) being unsubstituted or substituted with hydroxy, oxo, alkoxy, aryloxy, halo, cyano, isocyano, carboxy, esterified carboxy, amino, substituted amino, formyl, acyl, acyloxy, acylamino, sulfinyl, sulfonyl, phosphino, phosphinyl, phosphonyl, mer- capto, alkylthio, arylthio, silyl, silyloxy, silyl- thio, nitro or azido
  • R_ / and RO Q are the same or different and are (1) hydrogen
  • X is a radical of myo-inositol or a configura ⁇ tion iso er thereof.
  • the substituent A could be the same for all R , R and R_ or could have different structures following the above definition.
  • R , R and R_ are vicinal and all are
  • n is an integer between 1 and 10; preferably n is between 2 and 4
  • n is an integer between 1 and 10 and where R Q y is a substituted or unsubstituted straight or branched alkyl, cycloalkyl, aryl or alkaryl; preferably n is between 2 and 4 and R n y is a lower alkyl such as methyl, ethyl or propyl.
  • n and m is an integ ⁇ er between 1 and 10 and where Y is oxygen or sulphur; preferably n is 1 and is between 2 and 4.
  • n and m is an integer between 1 and 10, where Y is oxygen or sulphur and where R g is a substituted or unsubstituted straight or branched alkyl, cycloalkyl, aryl or alkaryl; pre ⁇ ferably n is 1, m is between 2 and 4 and R_ is a lower alkyl such as methyl, ethyl or propyl. (5) nteger between 1 and
  • R 9_ is a substituted or unsubstituted, straight or branched alkyl, cycloalkyl, aryl or aralkyl; preferably n " is 1 or 2 and R g is a lower alkyl such as methyl, ethyl or propyl.
  • nCOOR,io_ where n is an integer between 1 and
  • R n is hydrogen or a substituted or un ⁇ substituted, straight or branched alkyl, cycloalkyl, aryl or aralkyl; preferably n is 2 or 3 and R is hydrogen or a lower alkyl such as methyl, ethyl or propyl.
  • n is an integer between 1 and
  • y is a substituted or unsubstituted, straight or branched alkyl, cycloalkyl, aryl or aralkyl; preferably n is 1 and R is a lower alkyl such as methyl, ethyl or propyl.
  • n is an integer between 1 and 10 and where R g is a substituted or unsubstitu ⁇ ted, straight or branched alkyl, cycloalkyl, aryl or aralkyl, and where R is hydrogen or substituted or unsubstituted, straight or branched alkyl, cyclo ⁇ alkyl, aryl or aralkyl; preferably n is 1, R Q y is lower alkyl such as methyl, ethyl or propyl and R. _ is hydrogen. O O O O
  • n is an integer between 1 and 10 and where R g is a substituted or unsubstitu ⁇ ted, straight or branched alkyl, cycloalkyl, aryl or aralkyl and where R is hydrogen or substituted or unsubstituted, straight or branched alkyl, cyclo ⁇ alkyl, aryl or aralkyl; preferably n is 1, Ry_ is lower alkyl such as methyl, ethyl or propyl and R_ 0 is hydrogen.
  • n is an integer between 1 and 10 and where R Q y is a substituted or unsubstituted, straight or branched alkyl, cycloalkyl, aryl or aralkyl; preferably n is 1 and R is a lower alkyl such as methyl, ethyl or propyl.
  • Z1 i.s substituted or unsubstituted cycloalkyl such as CH(CH 2 ) 2 , CH(CH 2 ) 3 , CH(CH 2 ) 4 , CH(CH 2 ) 5 , CH(CH 2 ) 6 or CH(CH 2 ) 2 (CH) 2 .
  • n ubstituted or unsubsti- tuted cycloalkyl such as CH(CH2) 2 , CH(CH 2 ) 3 , CH(CH 2 ) 4 , CH(CH 2 ) 5 , CH(CH 2 ) 6 or CH(CH 2 ) 2 (CH) 2 and where n is an integer between 1 and 10; preferably n is 1.
  • n and m is an integer between 1 and 10, where Ry_ is a substituted or unsubstituted, straight or branched alkyl, cyclo ⁇ alkyl, aryl, alkaryl and where R and R are hydrogen or substituted or unsubstituted straight or branched alkyl, cycloalkyl, aryl, alkaryl; pre ⁇ ferably n is 1 or 2, is 2 or 3, R is lower alkyl and R 10 and R are hydrogen.
  • the formula above discloses specific esters of inositol ⁇ trisphosphate where the inositol moiety is selected from the group of myoinositol, cisinositol, epiinositol, allo- inositol, neoinositol, mucoinositol, chiroinositol and scylloinositol.
  • (10) a heterocyclic ring containing at least one atom of oxygen, nitrogen or sulfur said meanings (1) to (10) being unsubstituted or substituted with hydroxy, oxo, alkoxy, aryloxy, halo, cyano, isocyano, carboxy, esterified carboxy, amino, substituted amino, for yl, acyl, acyloxy, acylamino, sulfinyl, sulfonyl, phosphino, phosphinyl, phosphonyl, mer- capto, alkylthio, arylthio, silyl, silyloxy,- silyl- thio, nitro or azido
  • R_ / and Ro 0 are the same or different and are
  • the compounds contemplated in this embodiment of the invention are esters of myo-inositoltrisphosphates and preferred compounds are esters of D-myo-inositol-1,2,6- trisphosphates.
  • Example 1 shows the manufacturing of a solution of an ester of myo-inositoltrisphosphate for in ⁇ travenous administration.
  • Example 2-6 demonstrate the manufacture of different esters of myo-inositoltrisphos ⁇ phate and Example 7 and 8 illustrate the effect of esters of myo-inositoltrisphosphate to reduce pain.
  • Example l shows the manufacturing of a solution of an ester of myo-inositoltrisphosphate for in ⁇ travenous administration.
  • Example 2-6 demonstrate the manufacture of different esters of myo-inositoltrisphos ⁇ phate
  • Example 7 and 8 illustrate the effect of esters of myo-inositoltrisphosphate to reduce pain.
  • Example l shows the manufacturing of a solution of an ester of myo-inositoltrisphosphate for in ⁇ travenous administration.
  • Example 2-6 demonstrate the manufacture of different esters of myo-inositoltrisphos ⁇
  • IP_ D-myo-inositol-1,2,6-tris- phosphate
  • the product was eluted with 200 ml of water and was treated with sodium hydrogen carbonate to reach pH 5.8. After filtration the supernatant was evaporated to dryness and analysed with NMR. The compound was identified as D-3 ,4,5-tri-O-phenylcarbamoyl-myo-inositol- -1,2,6-trisphosphate.
  • PP 10-202 Two groups of rats, 10 animals per group, were used in order to investigate the analgetic effect of D-3,4,5-tri- -0-hexanoyl-myo-inositol-l,2,6-trisphosphate (PP 10-202).
  • the control group was given an intravenous dose of saline while the other group was given a dose of 80 mg/kg of the sodium salt of PP 10-202.
  • each rat received an intraperifoneal injection of 1 ml of a 1 % (w/w) solution of acetic acid.
  • each animal was placed into individual observation chambers and the numbers of writhes elicited during the subsequent 25- minute period were recorded.
  • the number of writhes during the observation period is an expression of the pain experienced by the animal.
  • the control group had an average of 48 writhes during the period while the group receiving PP 10-202 had an average of 6 writhes during the period.

Landscapes

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

Abstract

L'invention porte sur l'emploi d'un ester d'inositoltriphosphate pour la préparation d'un médicament agissant efficacement comme analgésique.
EP95902365A 1993-11-22 1994-11-18 Emploi d'un ester d'inositoltriphosphate pour la preparation d'un analgesique Withdrawn EP0730461A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE9303855 1993-11-22
SE9303855A SE502990C2 (sv) 1993-11-22 1993-11-22 Användning av en inositoltrisfosfatester för beredning av ett smärtstillande läkemedel
PCT/SE1994/001092 WO1995014476A1 (fr) 1993-11-22 1994-11-18 Emploi d'un ester d'inositoltriphosphate pour la preparation d'un analgesique

Publications (1)

Publication Number Publication Date
EP0730461A1 true EP0730461A1 (fr) 1996-09-11

Family

ID=20391830

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95902365A Withdrawn EP0730461A1 (fr) 1993-11-22 1994-11-18 Emploi d'un ester d'inositoltriphosphate pour la preparation d'un analgesique

Country Status (5)

Country Link
EP (1) EP0730461A1 (fr)
JP (1) JPH09505580A (fr)
AU (1) AU1125595A (fr)
SE (1) SE502990C2 (fr)
WO (1) WO1995014476A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9602463D0 (sv) * 1996-06-24 1996-06-24 Perstorp Ab The use of growth factor modulating compounds
US7015200B2 (en) 2000-09-22 2006-03-21 Orphan Medical, Inc. Gamma-hydroxybutyrate compositions containing carbohydrate, lipid or amino acid carriers

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4515722A (en) * 1982-03-30 1985-05-07 Merck & Co., Inc. Phosphatidyl inositol analogs useful as anti-inflammatory/analgesic agents
SE8605063D0 (sv) * 1986-11-26 1986-11-26 Matti Siren Derivatives of cyclohexane

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9514476A1 *

Also Published As

Publication number Publication date
AU1125595A (en) 1995-06-13
SE502990C2 (sv) 1996-03-04
JPH09505580A (ja) 1997-06-03
SE9303855L (sv) 1995-05-23
SE9303855D0 (sv) 1993-11-22
WO1995014476A1 (fr) 1995-06-01

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