WO1994009790A1 - The use of inositoltrisphosphate for the preparation of medicaments - Google Patents

The use of inositoltrisphosphate for the preparation of medicaments Download PDF

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Publication number
WO1994009790A1
WO1994009790A1 PCT/SE1993/000872 SE9300872W WO9409790A1 WO 1994009790 A1 WO1994009790 A1 WO 1994009790A1 SE 9300872 W SE9300872 W SE 9300872W WO 9409790 A1 WO9409790 A1 WO 9409790A1
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WO
WIPO (PCT)
Prior art keywords
hydrogen
phosphate
hydroxyl
pain
inositol
Prior art date
Application number
PCT/SE1993/000872
Other languages
English (en)
French (fr)
Inventor
Matti Sirén
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
Priority to JP6510956A priority Critical patent/JPH08503454A/ja
Priority to AU54359/94A priority patent/AU5435994A/en
Priority to KR1019950701801A priority patent/KR950703973A/ko
Priority to EP93924853A priority patent/EP0666748A1/en
Publication of WO1994009790A1 publication Critical patent/WO1994009790A1/en

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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
    • A61K31/66—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 at least one isomer of inositoltrisphosphate (IP 3 ) for the preparing of a medicament effective as an analgesic.
  • IP 3 inositoltrisphosphate
  • morphine are used for reducing severe pain related to surgical operations.
  • 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.
  • 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.
  • it has surprisingly become possible to reduce pain without, sedative effects by the use of at least one isomer of inositoltrisphosphate (IP 3 ) for the preparing of a medicament effective as an analgesic.
  • IP 3 inositoltrisphosphate
  • the medicament is intended to be used for preventing, alleviating and
  • 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 without showing any side-effects and without any sedative effects which is very beneficial for the patient.
  • IP 3 The production of IP 3 and the isolation of the different isomers thereof are disclosed in the US patent No 4.777.134.
  • the IP isomers can also be produced by synthetic methods, chemically or enzymatically, starting with e.g. inositol and a phosphorus source.
  • microbiological production methods including hybrid DNA-techniques of IP 3 are also suitable.
  • IP 3 The structure of IP 3 and the different isomers thereof are disclosed in the US patent No 4.735.936 and the US patent No 4.797.390.
  • the medicament used according to the invention exists in unit dosage form.
  • Tablets, granules or capsules are suitable administration forms for such unit dosage. Futhermore, 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 transdermal administration.
  • a usual pharmaceutically acceptable additive, excipient and/or carrier can be included 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. In certain cases, especially in acute situations, it is
  • the unit dosage in the form of a solution for intravenous administration. In other situations,
  • suspensions comprising the compound can be preferably used as administration form.
  • the medicament can also consist as such of IP 3 solely without any additive, excipient or carrier.
  • the medicament can be free of other inositol phosphates, IP 1 , IP 2 , IP 4 , IP 5 and IP 6 . Accordingly, the mixture of IP 3 isomers can have a purity of 90-100 % or preferably 95-100 %.
  • the medicament can consist of or comprise one or more specific IP 3 isomers, 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.
  • the medicament can consist of IP 3 , wherein said IP is provided by at least one of IP 6 , IP 5 or IP 4 and a degradative substance such as an enzyme suitable to form IP 3 .
  • IP 3 -isomer or isomers 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, zinc or magnesium salt or a micture 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
  • the preferred dosage for humans falls within the range of 0.1 to 1000 mg, especially 0.1-200 mg IP 3 /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 IP 3 per unit dosage.
  • composition used according to the present invention contains at least one, sometimes two or more of the following substances, which correspond to the essential IP 3 -isomer or isomers mentioned above:
  • X is hydrogen, at least one univalent, divalent or multivalent cation, or a mixture thereof, n is the number of ions, and z is the charge of the respective ion;
  • L-myo-inositol-1.3.4-trisphosphate of the formula
  • n ranges between 6 to 1 inclusive and z ranges from 1 to 6 inclusive.
  • n is between 3 to 6 inclusive and z is 3, 2 or 1.
  • D-myo-inositol-1.2.6-trisphosphate is preferred.
  • Other inositol trisphoshate isomers that may be utilized in the present invention as the active IP ingredient in the composition have the structural formula
  • inositol trisphosphate compounds is defined by the structural formula (I) where three of R 1 , R 3 , R 5 , R 7 ,
  • R 10 and R 11 are hydroxyla and the remaining three are phosphate and R 2 , R 4 , R 6 , R 8 , R 9 and R 12 are hydrogen.
  • inositol trisphosphates is defined by the structural formula (I) where three of R 1 , R 3 , R 3 , R 7 , R 9 and R 12 are hydroxyl and the remaining three are phosphate and R 2 , R 4 , R 5 , R 8 , R 10 and R 11 are hydrogen.
  • Still another group of inositol trisphosphates is defined by the structural formula (I) where three of R 1 , R 3 , R 5 , R 8 , R 10 and R 12 are hydroxyl and the remaining three are phosphate and R 2 , R 4 , R 6 , R 7 , R 9 and R 11 are hydrogen.
  • inositol trisphosphates is defined by the structural formula (I) where three of R 1 , R 4 , R 5 R 8 R 9 and R 12 are hydroxyl and the remaining three are phosphate and R 2 , R 3 , R 6 , R 7 , R 10 and R 11 are hydrogen.
  • Still yet another group of inositol trisphosphates is defined by the structural formula (I) where three of R 1 , R 3 , R 6 , R 8 , R 9 and R 12 are hydroxyl and the remaining three are phosphate and R 2 , R 4 , R 5 , R 7 , R 10 and R 11 are hydrogen.
  • inositol trisphosphates is defined by the structural formula (I) where three of R 1 , R 3 , R 6 , R 7 , R 10 and R 1 2 are hydroxyl and the remaining three are phosphate and R 2 , R 4 , R 5 , R 8 , R 9 and R 11 are hydrogen.
  • inositol trisphosphates is defined by the structural formula (I) where three of R 1 , R 3 , R 5 , R 8 , R 10 and R 11 are hydroxyl and the remaining three are
  • R 2 , R 4 , R 6 , R 7 , R 9 and R 12 are hydrogen.
  • inositol trisphosphates is defined by the structural formula (I) where three of R 1 , R 3 , R 5 , R 7 ,
  • R 9 and R 11 are hydroxyl and the remaining three are phosphate and R 2 , R 4 , R 6 , R 8 , R 10 and R 12 are hydrogen.
  • Particular inositol trisphosphate compounds within the contemplation of the above formula include compounds having the structural formula (I) where
  • R 5 , R 7 and R 10 are phosphate, R 1 , R 3 and R 11 are hydroxyl and
  • R 2 , R 4 , R g , R 8 , R g and R 12 are hydrogen;
  • R 1 , R 10 and R 11 are phosphate, R 3 , R 5 and R 7 are hydroxyl and
  • R 2 , R 4 , R 6 , R 8 , R 9 and R 12 are hydrogen; R 1 , R 3 and R 11 are phosphate, R 5 , R 7 and R 10 are hydroxyl and
  • R 2 , R 4 , R 6 , R 8 , R g and R 12 are hydrogen;
  • R 3 , R 5 and R 7 are phosphate, R 1 , R 10 and R 11 are hydroxyl and
  • R 2 , R 4 , R 6 , R 8 , R 9 and R 12 are hydrogen;
  • R 3 , R 7 and R 10 are phosphate, R 1 , R 5 and R 11 are hydroxyl and
  • R 2 , R 4 , R 6 , R 8 , R 8 and R 12 are hydrogen;
  • R 3 , R 10 and R 11 are phosphate, R 1 , R 5 and R 7 are hydroxyl and
  • R 2 , R 4 , R 6 , R 8 , R 9 and R 12 are hydrogen;
  • R 1 , R 3 and R 6 are phosphate, R 7 , R 9 and R 12 are hydroxyl andR 2 , R 4 , R 5 , R 8 , R 10 and R 11 are hydrogen;
  • R 6 , R 7 and R 9 are phosphate, R 1 , R 3 and R 12 are hydroxyl and
  • R 2 , R 4 , R 5 , R 8 , R 10 and R 11 are hydrogen;
  • R 3 , R 5 and R 8 are phosphate, R 1 , R 10 and R 12 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 9 and R 11 are hydrogen;
  • R 1 , R 3 and R 12 are phosphate, R 5 , R 8 and R 10 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 9 and R 11 are hydrogen;
  • R 1 , R 3 and R 5 are phosphate, R 8 , R 10 and R 12 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 9 and R 11 are hydrogen;
  • R 1 , R 5 and R 8 are phosphate, R 3 , R 10 and R 12 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 9 and R 11 are hydrogen;
  • R 1 , R 5 and R 12 are phosphate,
  • R 3 , R 8 and R 10 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 9 and R 11 are hydrogen;
  • R 1 , R 3 and R 12 are phosphate,
  • R 6 , R 8 and R 9 are hydroxyl and
  • R 2 , R 4 , R 5 , R 7 , R 10 and R 11 are hydrogen;
  • R 1 , R 3 and R 6 are phosphate, R 7 , R 10 and R 12 are hydroxyl and
  • R 2 , R 4 , R 5 , R 8 , R 9 and R 11 are hydrogen;
  • R 4 , R 5 and R 8 are phosphate, R 1 , R 9 and R 12 are hydroxyl and
  • R 2 , R 3 , R 6 , R 7 , R 10 and R 11 are hydrogen;
  • R 3 , R 5 and R 8 are phosphate, R 1 , R 10 and R 11 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 9 and R 12 are hydrogen;
  • R 1 , R 3 and R 5 are phosphate, R 8 , R 10 and R 1 1 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 9 and R 12 are hydrogen;
  • R 1 , R 3 and R 5 are phosphate, R 7 , R 9 and R 11 are hydroxyl and
  • R 2 , R 4 , R 6 , R 8 , R 10 and R 12 are hydrogen;
  • R 1 , R 3 and R 12 are phosphate, R 5 , R 8 and R 9 are hydroxyl and
  • R 2 R 4 , R 6 , R 7 , R 10 and R 1 1 are hydrogen;
  • R 1 , R 3 and R are phosphate, R 5 , R 9 and R 12 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 10 and R 11 are hydrogen;
  • R 3 , R 5 and R 12 are phosphate, R 1 , R 8 and R 9 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 10 and R 11 are hydrogen;
  • R 1 , R 5 and R 9 are phosphate, R 3 , R 8 and R 12 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 10 and R 11 are hydrogen;
  • R 1 , R 5 and R 12 are phosphate,
  • R 3 , R 8 and R 9 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 10 and R 11 are hydrogen;
  • R 1 , R 3 and R 9 are phosphate, R 5 , R 8 and R 12 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 10 and R 11 are hydrogen;
  • R 3 , R 5 and R 9 are phosphate, R 1 , R 8 and R 12 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 10 and R 11 are hydrogen;
  • R 5 , R 9 and R 12 are phosphate, R 1 , R 3 and R 8 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 10 and R 11 are hydrogen;
  • R 1 , R 8 and R 9 are phosphate, R 3 , R 5 and R 12 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 10 and R 11 are hydrogen;
  • R 1 , R 8 and R 12 are phosphate, R 3 , R 5 and R 9 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 10 and R 11 are hydrogen;
  • R 5 , R 8 and R 12 are phosphate, R 1 , R 3 and R 9 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 10 and R 11 are hydrogen;
  • R 1 , R 9 and R 12 are phosphate, R 3 , R 5 and R 8 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 10 and R 11 are hydrogen;
  • R 5 , R 8 and R 9 are phosphate, R 1 , R 3 and R 12 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 10 and R 11 are hydrogen;
  • R 3 , R 8 and R 9 are phosphate, R 1 , R 5 and R 12 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 10 and R 11 are hydrogen;
  • R 3 , R 9 and R 12 are phosphate, R 1 , R 5 and R 8 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 10 and R 11 are hydrogen;
  • R 3 , R 8 and R 12 are phosphate,
  • R 1 , R 5 and R 9 are hydroxyl and
  • R 2 , R 4 , R 6 , R 7 , R 10 and R 11 are hydrogen;
  • R 8 , R and R 12 are phosphate, R 1 , R 3 and R 5 are hydroxyl and R 2 , R 4 , R 6 , R 7 , R 10 and R 11 are hydrogen.
  • inositol trisphosphate where the inositol is selected from the group myoinositol, cisinositol, epiinositol, alloinositol, neo- inositol, mucoinositol, chiroinositol and scylloinositol.
  • Example 1-3 demonstrate the effect of IP 3 to reduce pain in different conditions and where Example 4 shows the manufacturing of a solution of IP for intravenous administration.
  • IP 3 D-myo-inositol-1.2.6-trisphosphate
  • the pain-index was calculated for all the patients.
  • the three patients treated with penta- barbital had a pain index of 35 which is in full agreement with data from many other patients treated in a similar way.
  • the three patients treated with IP 3 had a pain index of 15 for the same period which demonstrates that IP 3 very
  • a total of six patients with rheumatoid arthritis were given an infusion of D-myo-inositol-1.2.6-trisphosphate (IP 3 ) for 48 hours (2 mg/kg/hr).
  • IP 3 D-myo-inositol-1.2.6-trisphosphate
  • the pain experienced by each patient was assessed with a pain score ranging from 0 to 10 where a high figure represents a high sense of pain.
  • the average value was 8.4 ⁇ 0.8 before the start of the infusion and after 24 hrs the value was determined to 2.8 ⁇ 0.9. This lower value remained not only during the infusion but also for another twelve days after the infusion was stopped.
  • results show a quick on-set of the reduction of pain and also a long duration of the analgetic properties after the termination of the administration of the compound.
  • each rat received an intraperitoneal injection of 1 ml of a 1 % (w/w) solution of acetic acid.
  • control group had an average of 48 writhes during the period while the group receiving IP 3 had an average of 18 writhes during the period.
  • IP 3 D-myo-inositol-1.2.6-trisphosphate

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Public Health (AREA)
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  • Pain & Pain Management (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/SE1993/000872 1992-11-05 1993-10-26 The use of inositoltrisphosphate for the preparation of medicaments WO1994009790A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP6510956A JPH08503454A (ja) 1992-11-05 1993-10-26 薬剤調製におけるイノシトール三燐酸の使用
AU54359/94A AU5435994A (en) 1992-11-05 1993-10-26 The use of inositoltrisphosphate for the preparation of medicaments
KR1019950701801A KR950703973A (ko) 1992-11-05 1993-10-26 약물 조제용 이노시톨 트리스포스페이트(inositoltrisphosphate)의 사용
EP93924853A EP0666748A1 (en) 1992-11-05 1993-10-26 The use of inositoltrisphosphate for the preparation of medicaments

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9203296-0 1992-11-05
SE9203296A SE470511B (sv) 1992-11-05 1992-11-05 Användning av inositolreisfosfat för beredning av läkemedel

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WO1994009790A1 true WO1994009790A1 (en) 1994-05-11

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PCT/SE1993/000872 WO1994009790A1 (en) 1992-11-05 1993-10-26 The use of inositoltrisphosphate for the preparation of medicaments

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EP (1) EP0666748A1 (sv)
JP (1) JPH08503454A (sv)
KR (1) KR950703973A (sv)
AU (1) AU5435994A (sv)
SE (1) SE470511B (sv)
WO (1) WO1994009790A1 (sv)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997049408A1 (en) * 1996-06-24 1997-12-31 Perstorp Ab The use of growth factor modulating compounds

Citations (1)

* 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

Patent Citations (1)

* 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

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997049408A1 (en) * 1996-06-24 1997-12-31 Perstorp Ab The use of growth factor modulating compounds

Also Published As

Publication number Publication date
JPH08503454A (ja) 1996-04-16
AU5435994A (en) 1994-05-24
KR950703973A (ko) 1995-11-17
EP0666748A1 (en) 1995-08-16
SE9203296D0 (sv) 1992-11-05
SE9203296L (sv) 1994-05-06
SE470511B (sv) 1994-06-27

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