WO1999008672A1 - Utilisateur d'un inhibiteur de cholinesterase pour traiter des maladies liees a l'activite de l'enzyme proteolytique - Google Patents

Utilisateur d'un inhibiteur de cholinesterase pour traiter des maladies liees a l'activite de l'enzyme proteolytique Download PDF

Info

Publication number
WO1999008672A1
WO1999008672A1 PCT/GB1998/002448 GB9802448W WO9908672A1 WO 1999008672 A1 WO1999008672 A1 WO 1999008672A1 GB 9802448 W GB9802448 W GB 9802448W WO 9908672 A1 WO9908672 A1 WO 9908672A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
hydrogen
alkyl
group
cholinesterase inhibitor
Prior art date
Application number
PCT/GB1998/002448
Other languages
English (en)
Inventor
Ernir Snorrason
James Robert Murray
Original Assignee
Shire International Licensing Bv
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
Priority claimed from GBGB9717399.1A external-priority patent/GB9717399D0/en
Priority claimed from GBGB9717401.5A external-priority patent/GB9717401D0/en
Application filed by Shire International Licensing Bv filed Critical Shire International Licensing Bv
Priority to AU87421/98A priority Critical patent/AU8742198A/en
Publication of WO1999008672A1 publication Critical patent/WO1999008672A1/fr

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
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • the present invention relates to a method of therapy.
  • the invention relates to a method of combatting diseases associated with elevated levels of proteolytic enzymes.
  • Proteolytic enzymes have been found to play a role in a variety of diseases. These include skin diseases such as psoriasis, osteoarthritis, rheumatoid arthritis, other forms of arthritis, inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, chronic obstructive pulmonary diseases, amyloidosis, emphysema and certain cancers such as cancer of the pancreas, breast and colon. Despite what might be perceived as an extremely diverse range of symptoms exhibited by patients suffering from these diseases, they are all characterised by the underlying involvement of proteolytic enzymes. We have developed a new therapeutic method capable of combatting any of these diseases.
  • cholinesterase inhibitors such as galantamine can effectively combat diseases associated with proteolytic enzymes at the affected body site.
  • the present invention provides a method of combatting diseases associated with proteolytic enzyme activity comprising administering to a subject a pharmaceutically acceptable cholinesterase inhibitor.
  • the invention provides the use of a pharmaceutically acceptable cholinesterase inhibitor in the manufacture of a medicament for combatting diseases associated with proteolytic enzyme activity.
  • the term 'combatting' includes both therapy and prophylaxis.
  • the acetylcholinesterase inhibitors act to block or inhibit the protease activity. This belief is based on our findings that in joint diseases such as osteoarthritis and rheumatoid arthritis, where increased protease activity in synovial fluid is well established, there is an increase in acetylcholinesterase levels, and that treatment with acetylcholinesterase inhibitors such as galantamine has been found useful in counteracting the symptoms associated with joint diseases.
  • proteolytic activity is associated with acetylcholinesterase and that the acetylcholinesterase inhibitor is acting to block or inhibit proteolytic activity. It is further believed that the proteolytic activity in other diseases is associated with acetylcholinesterase and that such acetylcholinesterase inhibitors will likewise act to block or inhibit proteolytic activity and thereby counteract the symptoms of other diseases associated with proteolytic enzyme activity.
  • proteolytic enzyme activity plays a role in diseases such as psoriasis, Crohn's disease and ulcerative colitis.
  • collagenase is known to be associated with the inflammatory bowel diseases ulcerative colitis and Crohn's disease
  • PMN protease is associated with psoriasis, elastase with psoriasis and ulcerative colitis, proteinase 3 and plasminogen activator with psoriasis.
  • Psoriasis is one example of a disease where proteolytic enzyme activity play a role.
  • Psoriasis is an inflammatory skin disease which can effect all age groups. It is characterised by redness and scaly patches over the skin surface. The disfiguration which results can cause considerable distress to the sufferer, with implications on all aspects of daily life.
  • Current therapeutic approaches aim to reduce epidermal cell turnover and thereby control the skin lesions without causing damage to the skin or to other organs. There is no known cure. Treatment by drugs generally involves topical application to the affected sites (s) . Topical steroids have been used extensively however long term use of steroids is limited by the skin atrophy which occurs and is not recommended.
  • the invention provides a method of combatting psoriasis comprising administering to a subject a pharmaceutically acceptable cholinesterase inhibitor.
  • the invention provides the use of a pharmaceutically acceptable cholinesterase inhibitor in the manufacture of a medicament for combatting psoriasis.
  • Arthritic diseases such as osteoarthritis and rheumatoid arthritis are also examples of diseases where proteolytic enzyme activity plays a role, as are other rheumatoid diseases such as Juvenile Arthritis, Systemic
  • the invention also relates to a novel method of treatment or prophylaxis of such diseases and manifestations.
  • the method comprises administering a pharmaceutically acceptable cholinesterase inhibitor.
  • Rheumatoid covers any of a variety of disorders marked by degeneration or metabolic derangement of the connective tissue structures of the body, especially the joints and related structures, including muscles, bursae (synovial membranes), tendons and fibrous tissue. They are attended by pain, stiffness, or limitation of motion of these parts.
  • Rheumatoid Arthritis is a chronic, recurrent systemic inflammatory disease primarily of the joints, usually polyarticular, marked by inflammatory changes in the synovial membranes and articular structures and by atrophy and rarefaction of the bones. In late stages deformity and ankylosis develop.
  • Extra- articular manifestations include vasculitis, atrophy of the skin and muscle, subcutaneous nodules, lymphadenopathy, splenomegaly, leukopaenia and often chronic anaemia.
  • the arthritic disorder is osteoarthritis.
  • Osteoarthritis is a chronic degenerative disease of skeletal joints, which affects specific joints, commonly knees, hips, hand joints and spine, in adults of all ages. Osteoarthritis is characterized by a number of the following manifestations including degeneration and thinning of the articular cartilage with associated development of "ulcers" or craters, osteophyte formation, hypertrophy of bone at the margins, and changes in the synovial membrane and enlargement of affected joints.
  • osteoarthritis is accompanied by pain and stiffness, particularly after prolonged activity.
  • the method of the invention results in the treatment or prevention of one or several of the following symptoms or signs associated with the above- mentioned diseases: muscle pain, muscle weakness, muscle stiffness, joint stiffness, joint pain, joint or tissue swelling, inflammation, and extra-articular manifestation as mentioned above, including anaemia.
  • the invention is based on discoveries made in connection with the treatment of patients for other conditions, e.g. chronic fatigue syndrome.
  • the present invention relates to the use of cholinesterase inhibitors for the preparation of a medicament for treatment or prophylaxis of anaemia associated with chronic disorders.
  • the present invention provides a method of treating or preventing arthritic disorders, including osteoarthritis, rheumatoid arthritis and other rheumatoid diseases such as Juvenile Arthritis, Systemic Lupus Erythematosis, Sj ⁇ gren's Syndrome, Progressive Systemic Sclerosis, Polymyositis, Dermatomyositis , Ankylosing Spondilitis, Reiter's Syndrome, Psoriatic
  • the invention encompasses the use of any cholinesterase inhibitor, provided of course that it is pharmaceutically acceptable.
  • cholinesterase inhibitors which may be used according to the invention include, but are not limited to, physostigmine, tacrine and tacrine analogues, fasiculin, metrifonate, heptyl -physostigmine, norpyridostigmine, norneostigmine, huperazine, donepezil and pro-drugs of any of these in which the inhibitor is modified in accordance with principles of pro-drug construction known in the art. Examples of such modifications include the introduction of hydrophilic or lipophilic groups to enhance solubility, or penetration through cell membranes, respectively.
  • Preferred cholinesterase inhibitors for use according to the invention are acetylcholinesterase inhibitors particularly those which are capable of crossing the blood brain barrier.
  • Galantamine was previously known as galantamine. It is a tertiary alkaloid which can be extracted from various snowdrop bulbs e.g. the Caucasian snowdrop galanthus woronowii (Amaryllidaceae) and related species and daffodil bulbs or made by chemical synthesis. It has a high selectivity for acetylcholinesterase as opposed to butyrylcholinesterase . It is active substantially selectively at nicotinic receptor sites with substantially little effect on muscarinic receptor sites.
  • cholinesterase inhibitors for use in the invention are galantamine and its derivatives of formula ( I )
  • each R x is independently selected from hydrogen, hydroxyl, straight or branched chain alkyl , hydroxyalkyl , carboxyalkyl amino, alkylamino, acyl, lower alkanoyl, cyano, sulfhydryl, C ⁇ alkoxy, alkylthio, aryloxy, arylthio, R 3 - substituted aryloxy, R 3 -substituted arylthio, aralkoxy, an optionally R 3 - substituted aliphatic or aryl carbamyl group, aralkylthio, R 3 -substituted aralkoxy, R 3 - substituted aralkylthio, aryloxymethyl , R 3 -substituted aryloxymethyl , alkanoyloxy, hydroxy-substituted alkanoyloxy, benzoyloxy, R
  • R 2 is selected from hydrogen, straight or branched chain , alkenyl or alkaryl group, optionally substituted by a halogen atom or a cycloalkyl, hydroxy, alkoxy, nitro, amino, aminoalkyl , acylamino, heteroaryl, heteroaryl-alkyl, aryl, arylalkyl, cyano, amyl , aroyl , cycloalkylmethyl , allyl, phenyl, R 3 -substituted phenyl, alkylphenyl, R 3 -substituted alkylphenyl, heterocyclyl selected from ⁇ - or ⁇ -furyl, ⁇ - or ⁇ -thienyl, thenyl , pyridyl, pyrazinyl, and pyrimidyl, alkyl -heterocyclyl or R' -substituted heterocyclyl, where R' is alkyl or
  • R 6 is hydrogen or or when R ⁇ at carbon atom 2 is hydroxyl, R 6 may be a moiety of formula I wherein R 6 is hydrogen and R ⁇ is a linking bond; or
  • R ⁇ at carbon atom 2 and R 6 may jointly form semicarbazone ,
  • X is oxygen or NR 3 ,
  • Y is nitrogen or phosphorus, and methylenedioxy derivatives thereof and pharmaceutically acceptable acid addition salts thereof.
  • alkyl moieties contain 1 to 8 carbon atoms
  • halogen atoms are preferably fluorine, bromine, chlorine
  • aryl moieties are preferably phenyl
  • cycloalkyl groups are preferably 3- to 7-membered rings, especially cyclopropyl or cyclobutyl
  • acyl groups are preferably lower alkanoyl groups
  • heteroaryl moieties are preferably 5- to 8-membered rings, e.g., thienyl, furyl , pyridyl, pyrrolyl , or pyrizanyl.
  • Preferred compounds of formula I are the compounds of formula II
  • R 1 and R 2 which may be the same or different each represents a hydrogen atom or an acyl group, such as a lower alkanoyl group, e.g. an acetyl group or a straight-chained or branched alkyl group, e.g. methyl, ethyl, propyl, or isopropyl;
  • R 3 is a straight or branched chain alkyl, alkenyl or alkaryl group which is optionally substituted by a halogen atom or a cycloalkyl, hydroxy, alkoxy, nitro, amino, aminoalkyl , acylamino, heteroaryl, heteroarylalkyl , aroyl , aroylalkyl or cyano group; and
  • R 4 represents a hydrogen or a halogen atom attached to at least one of the ring carbons of the tetracyclic skeleton, and pharmaceutically acceptable salts thereof, such as a hydrobromide , hydrochloride, methylsulphate or methiodide .
  • Formula II includes galantamine itself.
  • galantamine itself, and salts thereof such as halides for example galantamine hydrobromide and the use of these compounds in the manufacture of a medicament for combatting diseases associated with proteolytic entymes provides a further aspect of the invention.
  • Galantamine and its derivatives of formula I and II may be prepared by the methods described in these publications.
  • the cholinesterase inhibitors for use in the invention include compounds which are functionally similar to galantamine. These are defined herein as compounds which possess an at least 10-fold selectivity, preferably an at least 20-fold selectivity, more preferably an at least 40-fold selectivity, and most preferably an at least 50 fold selectivity, for acetylcholinesterase as opposed to butyryl- cholinesterase, when measured by the in vitro method of Thomsen and Kewitz: Selective Inhibition of Human Acetylcholinesterase by Galantamine in vitro and in vivo, Life Sciences, Vol 46, pp. 1553-1558 (1990), and T. Thomsen, H. Kewitz and O. Pleul, J. Clin. Chem. Clin. Biochem.
  • galantamine hydrobromide when tested under the conditions described, shows a 50-fold selectivity; this selectivity value is taken as the "fix-point" whenever in vitro selectivities are discussed herein and could be used, for the purpose of determining the selectivities for other cholinesterase inhibitors, as a calibration value which is the one to establish with galantamine hydrobromide in any repetition of the experiment described by Thomsen and Kewitz.
  • a preferred acetylcholinesterase inhibitor is one which in the in vitro method described has an at least 10 -fold selectivity for acetylcholinesterase as opposed to butyrylcholinesterase, such as an at least 20-fold selectivity for acetylcholinesterase as opposed to butyrylcholinesterase, e.g. an at least 40-fold selectivity for acetylcholinesterase as opposed to butyrylcholinesterase.
  • a selectivity test is commercially available (from Sigma Diagnostics) .
  • the cholinesterase inhibitor such as galantamine and derivatives and salts thereof may be formulated according to conventional methods of pharmacy, together where appropriate with one or more pharmaceutically acceptable carriers, excipients or diluents such as, for example, are described in Remingtons Pharmaceutical Sciences.
  • Such formulations may for example take the form of tablets, capsules, solutions, or lozenges, pessaries, creams, suppositories or transdermal formulations such as patches, creams, ointments or lotions, depending upon the administration route to be used, which may include enterally or parenterally, including orally or injection via the intravenous, intramuscular or subcutaneous routes, or intrathecally by means of an implanted device.
  • Oral and transdermal administration routes are preferred.
  • dosage rates and regimes will depend upon the individual patient and may be determined by the medical practitioner based on individual circumstances.
  • doses may be within the range of 5-100 mg per day, such as 2 to 70 mg per day eg. 10 to 30 mg.
  • galanthamine may be delivered in equivalent daily doses.
  • dosages may be in the range of 0.1 to 100 mg per day, such as 5 to 100 mg per day, e.g. 10 to 50 mg per day, including 5 to 30 mg per day; lower dosages are often preferred.
  • Galantamine and its acid addition salts form crystals. They are generally only sparingly soluble in water at room temperature; therefore, injectable compositions are normally in the form of an aqueous suspension. If necessary, pharmaceutically-acceptable suspension aids may be employed. Typically, such a suspension will be employed at a concentration of 0.1-50 mg/ml, such as 1-50 mg/ml, more commonly 5-40 mg/ml, for example, 5-30 mg/ml or 10-40 mg/ml, such as 10-30 mg/ml, especially 20-30 mg/ml of galantamine. Cholinesterase inhibitors such as galantamine and salts thereof may be used as the sole drug in the management of diseases associated with proteolytic enzyme activity, or may be used together with other agents useful in managing such diseases . The invention will now be described with reference to the following non-limiting examples.
  • Galantamine lOg Melt the Cetostearyl Alcohol and heat to approximately 95°C. Add the Sodium Lauryl Sulphate, mix, add approximately 1 ml Purified Water, heat to 115°C and maintain at this temperature, stirring vigorously, until frothing ceases and the product is translucent. Cool quickly while adding the White Soft Paraffin and Liquid Paraffin and stir until the product reaches room temperature .
  • SIGMA DIAGNOSTICS ® CHOLINESTERASE (PTC) kit available from Sigma Diagnostics, can be used for determining the activity and selectivity of cholinesterase inhibitors. In the following, it is illustrated how the kit is used for the determination of the activity and selectivity of galantamine hydrobromide.
  • 5-Thio-2-Nitrobenzoic Acid is assessed by measuring the absorbance at 405 nm.
  • the rate of change in absorbance at 405 nm is directly proportional to cholinesterase activity.
  • the activity of erythrocyte cholinesterase may be calculated on the basis of the measurement of butyrylcholinesterase (pseudocholinesterase) in serum and cholinesterase in haemolyzed whole blood (haemolysate) , both measured simultaneously by the method described above, and evaluated according to the haematocrit value according to the formula
  • HChE (EChE x Hct* ) + (PChE x ( 1 -Hct* .
  • EChE erythrocyte cholinesterase activity
  • PChE plasma cholinesterase activity
  • HChE haemolysate cholinesterase activity
  • Hct haematocrit value of the sample.
  • Another way of assessing the cholinesterase activity is to measure the plasma cholinesterase and the cholinesterase in purified haemolyzed erythrocytes . By doing this, the values are obtained directly. Blood samples from 3 patients were tested with the Sigma test. The tests were carried out with samples where no galantamine was added and with samples where 1.25 ⁇ g/ml galantamine and 2.5 ⁇ g/ml were added in vitro. The results are shown below in table 1.
  • results show a significant reduction of the haemolysate cholinesterase activity with increased concentration of galantamine hydrobromide, whereas the data for the serum activity do not show any statistically significant changes as a response to the addition of the galantamine hydrobromide, which is an indication of a high selectivity of the galantamine hydrobromide with respect to acetylcholinesterase as opposed to butyrylcholinesterase.
  • Selectivity for acetylcholinesterase in erythrocytes opposed to butyrylcholinesterase is contemplated to reflect the selectivity for acetylcholinesterase at nicotinic receptor sites opposed to the acetylcholinesterase at muscarinic receptor sites .
  • This test may be used as a screening for candidate cholinesterase inhibitors with respect to their selectivity. However, other tests may be used.
  • Acetylcholinesterase (AcChE) activity was determined in synovial fluid from 8 patients with osteoarthritis (OA) and 5 subjects with different Rheumatoid conditions. In each patient synovial fluid was taken from an affected joint by arthrocentesis . Table 2 shows mean values of up to six samples from individual subjects. A broad spectrum of values was seen between these patients, but with a high degree of correspondence between samples taken on different days from the same patient. Samples with high values show bands with AcChE activity on isoelectric focusing gels. It seems that this acetylcholinesterase activity is from free proteins rather than membrane bound simply because of the parsity of lymphocytes seen in the microliter samples.
  • Patients numbers 1, 3 and 11 are males, the remaining patients are females.
  • N number of measurements
  • the first volunteer who was already acknowledged by the General Practitioner to be suffering from osteoarthritis, received 10 mg galantamine hydrobromide per day (in the form of 2 x 5 mg doses orally) . After seven days, the patient spontaneously reported an improvement in osteoarthritis symptoms. This improvement was maintained over a 31 day period, during which the galantamine hydrobromide dose was raised to 30 mg per day. Symptoms were reported to recur when medication was discontinued.
  • the second patient who had been experiencing joint pain for several years, but had not had osteoarthritis diagnosed, also received 10 mg per day galantamine hydrobromide in 2 x 5 mg tablet doses. This patient spontaneously reported an improvement in symptoms after three days of treatment with galantamine.
  • Example 8 Treatment of a patient with anaemia of chronic disorder
  • Patient numbers 4 and 12 are males, the remaining patients are females. Age is measured in years, age in brackets reflect approximate age.
  • Stiffness Joint stiffness is a complaint covering sensations which range from slight resistance to all movements through the normal range, to blocking of certain movements due to fixed anatomical changes. Certain types of stiffness are highly characteristic, such as early morning stiffness.
  • osteoarthritis stiffness tends to come on later in the day and is preceded by activity.
  • rheumatoid patients on galantamine the parameters evaluated were tiredness, sleep, pain and stiffness.
  • RA patient patient number 1
  • VAS Visual Analogue Scale

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'un inhibiteur pharmaceutiquement acceptable de la cholinestérase, ou d'un promédicament conçu à cet effet, dans la fabrication d'un médicament destiné à lutter contre des maladies liées à l'activité de l'enzyme protéolytique telles que le psoriasis, l'arthrose, l'arthrite rhumatoïde, la maladie de Crohn et la colite ulcéreuse.
PCT/GB1998/002448 1997-08-15 1998-08-14 Utilisateur d'un inhibiteur de cholinesterase pour traiter des maladies liees a l'activite de l'enzyme proteolytique WO1999008672A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU87421/98A AU8742198A (en) 1997-08-15 1998-08-14 Use of cholinesterase inhibitor for treating diseases associated with pro teolytic enzyme activity

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GBGB9717399.1A GB9717399D0 (en) 1997-08-15 1997-08-15 Method of treatment
GBGB9717401.5A GB9717401D0 (en) 1997-08-15 1997-08-15 Treatment of psoriasis
GB9717399.1 1997-08-15
GB9717401.5 1997-08-15

Publications (1)

Publication Number Publication Date
WO1999008672A1 true WO1999008672A1 (fr) 1999-02-25

Family

ID=26312077

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1998/002448 WO1999008672A1 (fr) 1997-08-15 1998-08-14 Utilisateur d'un inhibiteur de cholinesterase pour traiter des maladies liees a l'activite de l'enzyme proteolytique

Country Status (2)

Country Link
AU (1) AU8742198A (fr)
WO (1) WO1999008672A1 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000015205A2 (fr) * 1998-09-11 2000-03-23 Eisai Co., Ltd. Utilisation d'inhibiteurs acetylcholinesterases pour la preparation de compositions pharmaceutiques destinees au traitement de syndromes de douleur fonctionnelle et/ou organique
US6509368B1 (en) * 1998-10-02 2003-01-21 Gruenenthal Gmbh Use of catechol derivatives as proteinase inhibitors
GB2419093A (en) * 2004-10-12 2006-04-19 Ernir Snorrason Acetylcholinesterase inhibitors for the treatment of skin
WO2006040688A2 (fr) * 2004-10-12 2006-04-20 Ernir Snorrason Procede pour traiter des maladies de peau
WO2007039138A1 (fr) 2005-09-22 2007-04-12 Galantos Pharma Gmbh Amplificateurs cholinergiques de perméabilité de la barrière sang-cerveau améliorée pour le traitement de maladies accompagnées d'une déficience cognitive
JP2007509186A (ja) * 2003-10-26 2007-04-12 イッサム リサーチ ディベロプメント カンパニー オブ ザ ヘブル ユニバーシティ オブ エルサレム 抗炎症薬としてのＡＣｈＥアンチセンスデオキシオリゴヌクレオチド
WO2011100373A1 (fr) 2010-02-09 2011-08-18 The Johns Hopkins University Procédés et compositions pour améliorer la fonction cognitive
US8003632B2 (en) 2004-01-27 2011-08-23 The Feinstein Institute For Medical Research Cholinesterase inhibitors for treating inflammation
WO2014144801A1 (fr) 2013-03-15 2014-09-18 Agenebio Inc. Procédés et compositions pour améliorer la fonction cognitive
US9763953B2 (en) 2005-09-22 2017-09-19 Neurodyn Life Sciences Inc. Cholinergic enhancers with improved blood-brain barrier permeability for the treatment of diseases accompanied by cognitive impairment
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
US10159648B2 (en) 2015-05-22 2018-12-25 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam
US10806717B2 (en) 2013-03-15 2020-10-20 The Johns Hopkins University Methods and compositions for improving cognitive function
WO2023070351A1 (fr) * 2021-10-27 2023-05-04 香港理工大学 Prévention et traitement de maladies ostéoarticulaires par inhibition de l'acétylcholinestérase

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1491679A (en) * 1975-01-09 1977-11-09 Gallardo Antonio Sa Pharmaceutical compositions
US4661509A (en) * 1982-09-28 1987-04-28 Gordon Arnold Z Methods for treating leukopenia
US5229401A (en) * 1991-09-23 1993-07-20 Hoechst-Roussel Pharmaceuticals Incorporated Substituted pyridinylamino benzo[b]thiophene compounds
WO1997029750A1 (fr) * 1996-02-19 1997-08-21 Ernir Snorrason Traitement des affections arthritiques, de la polyarthrite rhumatoide et des manifestations associees aux affections rhumatoides
WO1998000119A2 (fr) * 1996-07-02 1998-01-08 Boehringer Ingelheim Pharma Kg Utilisation nouvelle de principes actifs influant sur les fonctions d'acetylcholine non neuronale

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1491679A (en) * 1975-01-09 1977-11-09 Gallardo Antonio Sa Pharmaceutical compositions
US4661509A (en) * 1982-09-28 1987-04-28 Gordon Arnold Z Methods for treating leukopenia
US5229401A (en) * 1991-09-23 1993-07-20 Hoechst-Roussel Pharmaceuticals Incorporated Substituted pyridinylamino benzo[b]thiophene compounds
WO1997029750A1 (fr) * 1996-02-19 1997-08-21 Ernir Snorrason Traitement des affections arthritiques, de la polyarthrite rhumatoide et des manifestations associees aux affections rhumatoides
WO1998000119A2 (fr) * 1996-07-02 1998-01-08 Boehringer Ingelheim Pharma Kg Utilisation nouvelle de principes actifs influant sur les fonctions d'acetylcholine non neuronale

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"SHIRE PHARMACEUTICALS AND JANSSEN BUY OUT NIVALIN RIGHTS", DIALOG FILE SUPPLIER: FILE 129: PHIND (ARCHIVAL); AN=539896 & SCRIP 2240, 13 June 1997 (1997-06-13), pages 8, XP002086645 *
"SHIRE TO DOUBLE UK PRODUCT SALES", DIALOG FILE SUPPLIER: FILE 129:PHIND (ARCHIVAL); AN=537410 & SCRIP 2234, 23 May 1997 (1997-05-23), pages 10, XP002086644 *
DIALOG FILE SUPPLIER: FILE 187: F-D-C REPORTS; AN=154052 & THE TAN SHEET, vol. 4, no. 27, 1 July 1996 (1996-07-01), XP002086647 *
DIALOG FILE SUPPLIER: FILE 187: F-D-C REPORTS; AN=192079 & THE PINK SHEET, vol. 59, no. 32, 11 August 1997 (1997-08-11), XP002086646 *
T.G. DIMITROV: "EFFECT OF THE PSYCHOSTIMULANT MESOCARB ON THE ANTIINFLAMMATORY AND ANALGESIC ACTIVITY OF NIVALIN", DOKLADY BOLGARSKOI AKADEMII NAUK, vol. 42, no. 9, 1989, pages 115 - 118, XP002086648 *

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000015205A3 (fr) * 1998-09-11 2000-08-24 Eisai Co Ltd Utilisation d'inhibiteurs acetylcholinesterases pour la preparation de compositions pharmaceutiques destinees au traitement de syndromes de douleur fonctionnelle et/ou organique
US6608088B1 (en) 1998-09-11 2003-08-19 Eisai., Ltd. Use of donerezil for the treatment of functional and/or organic pain syndromes
WO2000015205A2 (fr) * 1998-09-11 2000-03-23 Eisai Co., Ltd. Utilisation d'inhibiteurs acetylcholinesterases pour la preparation de compositions pharmaceutiques destinees au traitement de syndromes de douleur fonctionnelle et/ou organique
US6509368B1 (en) * 1998-10-02 2003-01-21 Gruenenthal Gmbh Use of catechol derivatives as proteinase inhibitors
JP2007509186A (ja) * 2003-10-26 2007-04-12 イッサム リサーチ ディベロプメント カンパニー オブ ザ ヘブル ユニバーシティ オブ エルサレム 抗炎症薬としてのＡＣｈＥアンチセンスデオキシオリゴヌクレオチド
US8722876B2 (en) 2003-10-26 2014-05-13 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Antisense oligonucleotides against AChE in the treatment of gastrointestinal inflammation disorders
JP4753088B2 (ja) * 2003-10-26 2011-08-17 イッサム リサーチ ディベロプメント カンパニー オブ ザ ヘブル ユニバーシティ オブ エルサレム 抗炎症薬としてのＡＣｈＥアンチセンスデオキシオリゴヌクレオチド
US8003632B2 (en) 2004-01-27 2011-08-23 The Feinstein Institute For Medical Research Cholinesterase inhibitors for treating inflammation
WO2006040688A3 (fr) * 2004-10-12 2006-10-12 Ernir Snorrason Procede pour traiter des maladies de peau
US9730919B2 (en) * 2004-10-12 2017-08-15 Hakon Hakonarson Method of treating skin diseases
EP2008660A1 (fr) * 2004-10-12 2008-12-31 Ernir Snorrason Procédé de traitement de maladies de la peau
US20150297574A1 (en) * 2004-10-12 2015-10-22 I Ernir SNORRASON Method of treating skin diseases
US9186345B2 (en) 2004-10-12 2015-11-17 Hakon Hakonarson Method of treating skin diseases
WO2006040688A2 (fr) * 2004-10-12 2006-04-20 Ernir Snorrason Procede pour traiter des maladies de peau
GB2419093A (en) * 2004-10-12 2006-04-19 Ernir Snorrason Acetylcholinesterase inhibitors for the treatment of skin
WO2007039138A1 (fr) 2005-09-22 2007-04-12 Galantos Pharma Gmbh Amplificateurs cholinergiques de perméabilité de la barrière sang-cerveau améliorée pour le traitement de maladies accompagnées d'une déficience cognitive
EP1777222A1 (fr) * 2005-09-22 2007-04-25 Galantos Pharma GmbH Inhibiteurs de la cholinesterase avec une perméabilité améliorée de la barrière ématoencéphalique pour le traitement de troubles cognitifs
US9763953B2 (en) 2005-09-22 2017-09-19 Neurodyn Life Sciences Inc. Cholinergic enhancers with improved blood-brain barrier permeability for the treatment of diseases accompanied by cognitive impairment
US10265325B2 (en) 2005-09-22 2019-04-23 Neurodyn Life Sciences Inc. Cholinergic enhancers with improved blood-brain barrier permeability for the treatment of diseases accompanied by cognitive impairment
WO2011100373A1 (fr) 2010-02-09 2011-08-18 The Johns Hopkins University Procédés et compositions pour améliorer la fonction cognitive
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
US10624875B2 (en) 2012-11-14 2020-04-21 The Johns Hopkins University Methods and compositions for treating schizophrenia
WO2014144801A1 (fr) 2013-03-15 2014-09-18 Agenebio Inc. Procédés et compositions pour améliorer la fonction cognitive
US10806717B2 (en) 2013-03-15 2020-10-20 The Johns Hopkins University Methods and compositions for improving cognitive function
US11160785B2 (en) 2013-03-15 2021-11-02 Agenebio Inc. Methods and compositions for improving cognitive function
US10159648B2 (en) 2015-05-22 2018-12-25 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam
US10925834B2 (en) 2015-05-22 2021-02-23 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam
WO2023070351A1 (fr) * 2021-10-27 2023-05-04 香港理工大学 Prévention et traitement de maladies ostéoarticulaires par inhibition de l'acétylcholinestérase

Also Published As

Publication number Publication date
AU8742198A (en) 1999-03-08

Similar Documents

Publication Publication Date Title
EP0918523B1 (fr) Traitement des affections arthritiques, de la polyarthrite rhumatoide et des manifestations associees aux affections rhumatoides
WO1999008672A1 (fr) Utilisateur d'un inhibiteur de cholinesterase pour traiter des maladies liees a l'activite de l'enzyme proteolytique
PT879596E (pt) Utilização de galantaminas para reduzir os efeitos secundários das benzodiazepinas
EP1001761B1 (fr) Utilisation d'inhibiteurs de cholinesterase dans le traitement des troubles deficitaires de l'attention
US5474991A (en) Lipid metabolism improving medicinal composition
NL8802634A (nl) Therapeutische preparaten.
Zemel et al. Metabolic and hemodynamic effects of magnesium supplementation in patients with essential hypertension
US5298522A (en) 6-chloro-5-fluoro-3-(2-thenoyl)-2-oxindole-1-carboxamide as an analgesic and anti-inflammatory agent while maintaining a normal urine protein/creatinine ratio
Feller et al. Dissociation of hypolipidemic and antiplatelet actions from adverse myotonic effects of clofibric acid related enantiomers
EP0774257B1 (fr) Dérivés de pipérazine et homopipérazine pour l'inhibition de l'adhésion et l'infiltration cellulaire
US4960765A (en) Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration
PT1392355E (pt) Utilização de inibidores do proteassoma para tratar distúrbios associados à secura ocular
KR20010015551A (ko) 알도스 환원 효소 억제제 및 안지오텐신 전환 효소억제제를 포함하는 약학 조성물
EP0399051B1 (fr) Agent anti-inflammatoire polyvalent
JPH02223521A (ja) 血清コレステロール低下剤
RU2250103C2 (ru) ПРИМЕНЕНИЕ (R)-АРИЛПРОПИОНОВЫХ КИСЛОТ ДЛЯ ПОЛУЧЕНИЯ ЛЕКАРСТВЕННЫХ СРЕДСТВ ДЛЯ ЛЕЧЕНИЯ ЗАБОЛЕВАНИЙ ЛЮДЕЙ И ЖИВОТНЫХ, НА КОТОРЫЕ МОЖНО ОКАЗЫВАТЬ ТЕРАПЕВТИЧЕСКОЕ ВОЗДЕЙСТВИЕ ПУТЕМ ИНГИБИРОВАНИЯ АКТИВАЦИИ NF-κВ
CA1120400A (fr) Traitement de l'hypertension et medicaments utilises a cette fin
US4559326A (en) Antiinflammatory compositions and methods
US6677319B1 (en) Phosphatidylcholine as medication with protective effect large intestinal mucosa
AU2004290925B2 (en) Pharmaceutical compositions for the treatment of renal dysfunction, disease or disorder, in particular in diabetic patients
US20050192245A1 (en) Medicinal composition for treating arteriosclerosis
US4847255A (en) Cyclopentyl ethers and their use in medicine
EP0429676B1 (fr) Medicament pour l'ameliorations des fonctions cerebrales
JPH11302178A (ja) 脂肪肝予防及び治療剤
JP2657614B2 (ja) アロマターゼ阻害剤

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
NENP Non-entry into the national phase

Ref country code: KR

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase