CA2003572A1 - Use of benzomorphanes for cytoprotection - Google Patents
Use of benzomorphanes for cytoprotectionInfo
- Publication number
- CA2003572A1 CA2003572A1 CA002003572A CA2003572A CA2003572A1 CA 2003572 A1 CA2003572 A1 CA 2003572A1 CA 002003572 A CA002003572 A CA 002003572A CA 2003572 A CA2003572 A CA 2003572A CA 2003572 A1 CA2003572 A1 CA 2003572A1
- Authority
- CA
- Canada
- Prior art keywords
- benzomorphane
- compound
- methyl
- pharmacologically acceptable
- group
- 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.)
- Abandoned
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
- A61K31/33—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Neurology (AREA)
- Cardiology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Neurosurgery (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Abstract The invention relates to the use of benzomorphane derivatives and pharmacologically acceptable acid addition salts thereof for cytoprotection.
Description
~0(~3572 S010978.05 Use of benzomorPhanes for cytoProtection This invention relates to the use of benzomorphanes and to isomers and salts thereof having cytoprotective activity.
According to one aspect of the invention, we provide compounds of general formula I
1 o ~ R (I) HO
wherein R1 represents a methyl or ethyl group;
R2 represents a methyl or ethyl group;
R3 represents a 2-methoxyethyl, 2-methoxypropyl, 2-furylmethyl (furfuryl), 2-tetrahydrofurylmethyl 20(tetrahydrofurfuryl), or CH2-C-0-R6 group;
Rs R4 represents a hydrogen atom or a methyl group;
R5 represents a hydrogen atom OL a methyl group;
R6 represents a methyl, ethyl, propyl, isopropyl or phenyl group;
the ~ and ~ forms thereof, the enantiomeric forms thereof and the corresponding pharmacologically accepta~le acid addition salts thereof, all for cyto-protection.
;:003572 The benzomorphane derivatives of general formula (I) have at least 3 carbon atoms with a centre of asymmetry and depending on the nature of substitution of R3 they may also have other centres of asymmetry and may therefore occur in various stereochemical forms. The following may be mentioned by way of example:
(-)-(lR,5R,9R)-N-(2-furylmethyl)-5,9-dimethyl-2'-hydroxy-6,7-benzomorphane (~ form), (+)-(lS,5S,9S)-N-(2-furylmethyl)-5,9-dimethyl-2'-hydroxy-6,7-benzomorphane (~ form), (-)-(lR,5R,9S)-N-(2-furylmethyl)-5,9-dimethyl-2'-hydroxy-6,7-benzomorphane (~ form), (+)-(lS,5S,9R3-N-(2-furylmethyl)-5,9-dimethyl-2'-hydroxy-6,7-benzomorphane (~ form).
The invention therefore relates to the use of benzomorphanes of general formula I in the form either of their individual stereoisomers or mixtures thereof and the corresponding physiologically acceptable acid addition salts for cytoprotection.
It i5 known that after the systemic administration of glutamate, neurones are destroyed in the brains of mice [S.M. Rothman and T.W. Olney, Trends in Neurosciences 10 (1987) 299]. This finding leads one to conclude that glutamate plays a part in neuro-degenerative diseases [R. Schwarcz and B. Meldrum, The Lancet 11 (1985) 140].
In addition, substances such as quisqualic acid, kainic acid, ibotenic acid, glutamic acid and N-methyl-D-aspartate (NMDA) are known as exogenous or endogenous neurotoxins. With respect to their neurotoxicity these substances have a selective effect on different cell types, which means that loss of function may be induced in animals by specific brain lesions. These are comparable with those which occur in connection with epilepsy and other neurodegenerative diseases such as Huntington's disease and Alzheimer's disease.
Moreover, experiments carried out in ~1~ and ln vitro have shown that the cell damage and loss of function occurring in the brain as a result of hypoglycaemia, hypoxia, anoxia and ischaemia are partly due to increased synaptic activity, the glutamatergic synapse being of particular significance. Substances and ions which inhibit the activity of the glutamate receptor and the ion channel connected to this receptor, such as competitive and non-competitive antagonists of excitatory amino acids and magnesium ions (Mg2~) protect brain cells from hypoxic and ischaemic damage. These findings show that the glutamate receptor plays an important part in bringing about ischaemic damage.
Biochemical and electrophysiological studies teach that the receptor ion channel is highly sensitive to variations in the magnesium concentration. If the magnesium concentration falls, spontaneous epileptic after-discharges may occur in the Hlppocampus which can be inhibited by antagonists of excitatory amino acids.
Surprisingly, we have found that benzomorphanes of general formula I have a cytoprotective activity.
The preparation of these benzomorphane derivatives is known from DE-PS 21 05 743 and DE-OS 28 28 039 and from the literature [H. Merz and K. Stockhaus, J. Med.
25 Chem. 22 (1979) 1475]. Similarly, it is already known that compounds of this kind have an analgesic activity and can be used therapeutically as non-addictive analgesics and as antitussive agents (DE-PS 21 05 743).
According to another aspect of the invention, we provide a method of treatment of neuro-degenerative diseases, brain ischaemia and epilepsy in a human or animal subject which comprises administering to said sub3ect an effective amount of a benzomorphane of formula (I) or a pharmacologically acceptable acid addition salt as hereinbefore described.
The Hippocampal sllce is used as a test system for demonstrating the cytoprotective properties of 20035~72 benzomorphane derivatives. The Schaf~er collaterals of the Hippocampal slice located in a perfusion chamber are stimulated through microelectrodes and the ~um potential produced i9 derived extracellularly at the pyramid cells of the CA 1 region [H.L. Haas, B. Schaerer and M. Vosmansky, J. Neuroscience Meth. 1 (1979) 323].
The activity of the compounds may be understoo~
with reference to the accompanying drawings. Typical stimulation in a magnesium-containing medium is shown in Fig. la. Fig. lb shows multiple epileptic discharges in a magnesium-free medium. In Fig. lc, these discharges are shown to be inhibited for example by the addition of IOO mmol of (-)-(lR,5R,9R)-N-(2-furylmethyl)-5,9-dimethyl-2'-hydroxy-6,7-benzomorphane.
The cytoprotective activity of the benzomorphane derivatives which come under general formula I has also been demonstrated in relation to protein synthesis and the liberation of neurotransmitters in the Hippocampal slice.
Receptor binding tests also show that the benzomorphane derivatives disclosed are non-competitive glutamate receptor antagonists.
The cytoprotective activity of the benzomorphane derivatives of general formula I was a]so demonstrated on a mouse in vivo by inhibiting the lethality induced by N-methyl-D-aspartic acid [J.D. Leander et al., Brain Research 448 (1988) 115~.
These results show that the benzomorphane derivatives of general formula I can be used in neuro-degenerative diseases and brain ischaemia of variousorigins. These include, for example: epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, hypotonia, cardiac infarction, stroke and perinatal asphyxia.
Pharmaceutical preparations containing a benzomorphane derivative of general formula I or Z003S"~2 pharmacologically acceptable acid addition salts thereof in association with a pharmaceutically acceptable carrier, diluent or excipient may be prepared in a known manner into conventional formulations such as plain or coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions using inert pharmaceutically acceptable carriers or solvents. The amount of pharmaceutically active compound or compounds should always be in the range from 0.5 to 90% by weight of the total composition, i.e. in amounts which are sufficient to achieve the dosage range specified hereinafter.
The formulations may be produced for example by diluting the active substances with solvents and/or carriers, optionally using emulsifiers and/or dispersants whilst when water is used as the diluent it is possible for example to use organic solvents such as solubilisers or auxiliary solvents.
Examples of excipients include water, pharmaceutically acceptable organic solvents such as paraffin, (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silica and silicates), sugar (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, sulphite waste liquors, methyl cellulose, starch and polyvinyl-pyrrolidone) and lubricants, e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate.
The substances may be administered in the usual way, for example by oral or parenteral route, for example on the tongue or intravenously. In the case of oral administration, the table~s may obviously also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various added substances such as starch, preferably potato starch, gelatin and the like, as well as the carriers mentioned above. It is also possible to use lubricants such as magnesium stearate, sodium laurylsulphate and talc to produce the tablets. In the case of aqueous suspensions, the active substances may be combined with various flavour enhancers or dyes in addition to the excipients mentioned above.
For parenteral use, solutions of the active substances may be used with suitable liquid carrier materials.
The dosage for oral use ranges from 1 to 300 mg, preferably from 5 to 150 mg.
It may nevertheless be necessary to deviate from these amounts depending on body weight or the method of administration, individual response to the drug, the nature of the formulation and the time or interval at which the drug is administered. Thus, in some cases, it may be sufficient to use less than the minimum quantity specified, whereas in other cases it may be necessary to exceed the upper limit. If larger quantities are administered, it may be advisable to divide them into several individual doses to be administered over the course of the day.
The compounds of general formula I or the acid addition salts thereof may also be combined with active substances of other kinds.
Non-limitinq examples of formulations Tablets 1. The tablet contains the following constituents:
Active substance according to formula I 0.020 parts ~tearic acid 0.010 parts Dextrose 1.890 Parts Total 1.920 parts 200357~
Preparation The substances are mixed together in known manner and the mixture is compressed to form tablets, each weighing 1.92 g and containing 20 mg of active 5 substance.
Am~oule solution Composition 10 Active substance according to formula I 1.0 mg Sodium chloride 45.0 mg Water for injections ad 5.0 mg Preparation The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make the solution isotonic. The resulting solution is filtered to remove pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and heat-sealed.
The ampoules contain 1 mg, 5 mg and 10 mg of active substance.
Suppositories Each suppository contains:
Active substance according to formula I 1.0 parts Cocoa butter (melting point: 36-37C) 1200.0 parts Carnauba wax 5.0 parts Preparation The cocoa butter and carnauba wax are melted together. At 45C the active substance is added and stirred until a complete dispersion has formed. The mixture is poured into moulds of suitable size and the suppositories are appropriately packaged.
According to one aspect of the invention, we provide compounds of general formula I
1 o ~ R (I) HO
wherein R1 represents a methyl or ethyl group;
R2 represents a methyl or ethyl group;
R3 represents a 2-methoxyethyl, 2-methoxypropyl, 2-furylmethyl (furfuryl), 2-tetrahydrofurylmethyl 20(tetrahydrofurfuryl), or CH2-C-0-R6 group;
Rs R4 represents a hydrogen atom or a methyl group;
R5 represents a hydrogen atom OL a methyl group;
R6 represents a methyl, ethyl, propyl, isopropyl or phenyl group;
the ~ and ~ forms thereof, the enantiomeric forms thereof and the corresponding pharmacologically accepta~le acid addition salts thereof, all for cyto-protection.
;:003572 The benzomorphane derivatives of general formula (I) have at least 3 carbon atoms with a centre of asymmetry and depending on the nature of substitution of R3 they may also have other centres of asymmetry and may therefore occur in various stereochemical forms. The following may be mentioned by way of example:
(-)-(lR,5R,9R)-N-(2-furylmethyl)-5,9-dimethyl-2'-hydroxy-6,7-benzomorphane (~ form), (+)-(lS,5S,9S)-N-(2-furylmethyl)-5,9-dimethyl-2'-hydroxy-6,7-benzomorphane (~ form), (-)-(lR,5R,9S)-N-(2-furylmethyl)-5,9-dimethyl-2'-hydroxy-6,7-benzomorphane (~ form), (+)-(lS,5S,9R3-N-(2-furylmethyl)-5,9-dimethyl-2'-hydroxy-6,7-benzomorphane (~ form).
The invention therefore relates to the use of benzomorphanes of general formula I in the form either of their individual stereoisomers or mixtures thereof and the corresponding physiologically acceptable acid addition salts for cytoprotection.
It i5 known that after the systemic administration of glutamate, neurones are destroyed in the brains of mice [S.M. Rothman and T.W. Olney, Trends in Neurosciences 10 (1987) 299]. This finding leads one to conclude that glutamate plays a part in neuro-degenerative diseases [R. Schwarcz and B. Meldrum, The Lancet 11 (1985) 140].
In addition, substances such as quisqualic acid, kainic acid, ibotenic acid, glutamic acid and N-methyl-D-aspartate (NMDA) are known as exogenous or endogenous neurotoxins. With respect to their neurotoxicity these substances have a selective effect on different cell types, which means that loss of function may be induced in animals by specific brain lesions. These are comparable with those which occur in connection with epilepsy and other neurodegenerative diseases such as Huntington's disease and Alzheimer's disease.
Moreover, experiments carried out in ~1~ and ln vitro have shown that the cell damage and loss of function occurring in the brain as a result of hypoglycaemia, hypoxia, anoxia and ischaemia are partly due to increased synaptic activity, the glutamatergic synapse being of particular significance. Substances and ions which inhibit the activity of the glutamate receptor and the ion channel connected to this receptor, such as competitive and non-competitive antagonists of excitatory amino acids and magnesium ions (Mg2~) protect brain cells from hypoxic and ischaemic damage. These findings show that the glutamate receptor plays an important part in bringing about ischaemic damage.
Biochemical and electrophysiological studies teach that the receptor ion channel is highly sensitive to variations in the magnesium concentration. If the magnesium concentration falls, spontaneous epileptic after-discharges may occur in the Hlppocampus which can be inhibited by antagonists of excitatory amino acids.
Surprisingly, we have found that benzomorphanes of general formula I have a cytoprotective activity.
The preparation of these benzomorphane derivatives is known from DE-PS 21 05 743 and DE-OS 28 28 039 and from the literature [H. Merz and K. Stockhaus, J. Med.
25 Chem. 22 (1979) 1475]. Similarly, it is already known that compounds of this kind have an analgesic activity and can be used therapeutically as non-addictive analgesics and as antitussive agents (DE-PS 21 05 743).
According to another aspect of the invention, we provide a method of treatment of neuro-degenerative diseases, brain ischaemia and epilepsy in a human or animal subject which comprises administering to said sub3ect an effective amount of a benzomorphane of formula (I) or a pharmacologically acceptable acid addition salt as hereinbefore described.
The Hippocampal sllce is used as a test system for demonstrating the cytoprotective properties of 20035~72 benzomorphane derivatives. The Schaf~er collaterals of the Hippocampal slice located in a perfusion chamber are stimulated through microelectrodes and the ~um potential produced i9 derived extracellularly at the pyramid cells of the CA 1 region [H.L. Haas, B. Schaerer and M. Vosmansky, J. Neuroscience Meth. 1 (1979) 323].
The activity of the compounds may be understoo~
with reference to the accompanying drawings. Typical stimulation in a magnesium-containing medium is shown in Fig. la. Fig. lb shows multiple epileptic discharges in a magnesium-free medium. In Fig. lc, these discharges are shown to be inhibited for example by the addition of IOO mmol of (-)-(lR,5R,9R)-N-(2-furylmethyl)-5,9-dimethyl-2'-hydroxy-6,7-benzomorphane.
The cytoprotective activity of the benzomorphane derivatives which come under general formula I has also been demonstrated in relation to protein synthesis and the liberation of neurotransmitters in the Hippocampal slice.
Receptor binding tests also show that the benzomorphane derivatives disclosed are non-competitive glutamate receptor antagonists.
The cytoprotective activity of the benzomorphane derivatives of general formula I was a]so demonstrated on a mouse in vivo by inhibiting the lethality induced by N-methyl-D-aspartic acid [J.D. Leander et al., Brain Research 448 (1988) 115~.
These results show that the benzomorphane derivatives of general formula I can be used in neuro-degenerative diseases and brain ischaemia of variousorigins. These include, for example: epilepsy, hypoglycaemia, hypoxia, anoxia, brain trauma, brain oedema, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, hypotonia, cardiac infarction, stroke and perinatal asphyxia.
Pharmaceutical preparations containing a benzomorphane derivative of general formula I or Z003S"~2 pharmacologically acceptable acid addition salts thereof in association with a pharmaceutically acceptable carrier, diluent or excipient may be prepared in a known manner into conventional formulations such as plain or coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions using inert pharmaceutically acceptable carriers or solvents. The amount of pharmaceutically active compound or compounds should always be in the range from 0.5 to 90% by weight of the total composition, i.e. in amounts which are sufficient to achieve the dosage range specified hereinafter.
The formulations may be produced for example by diluting the active substances with solvents and/or carriers, optionally using emulsifiers and/or dispersants whilst when water is used as the diluent it is possible for example to use organic solvents such as solubilisers or auxiliary solvents.
Examples of excipients include water, pharmaceutically acceptable organic solvents such as paraffin, (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silica and silicates), sugar (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, sulphite waste liquors, methyl cellulose, starch and polyvinyl-pyrrolidone) and lubricants, e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate.
The substances may be administered in the usual way, for example by oral or parenteral route, for example on the tongue or intravenously. In the case of oral administration, the table~s may obviously also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various added substances such as starch, preferably potato starch, gelatin and the like, as well as the carriers mentioned above. It is also possible to use lubricants such as magnesium stearate, sodium laurylsulphate and talc to produce the tablets. In the case of aqueous suspensions, the active substances may be combined with various flavour enhancers or dyes in addition to the excipients mentioned above.
For parenteral use, solutions of the active substances may be used with suitable liquid carrier materials.
The dosage for oral use ranges from 1 to 300 mg, preferably from 5 to 150 mg.
It may nevertheless be necessary to deviate from these amounts depending on body weight or the method of administration, individual response to the drug, the nature of the formulation and the time or interval at which the drug is administered. Thus, in some cases, it may be sufficient to use less than the minimum quantity specified, whereas in other cases it may be necessary to exceed the upper limit. If larger quantities are administered, it may be advisable to divide them into several individual doses to be administered over the course of the day.
The compounds of general formula I or the acid addition salts thereof may also be combined with active substances of other kinds.
Non-limitinq examples of formulations Tablets 1. The tablet contains the following constituents:
Active substance according to formula I 0.020 parts ~tearic acid 0.010 parts Dextrose 1.890 Parts Total 1.920 parts 200357~
Preparation The substances are mixed together in known manner and the mixture is compressed to form tablets, each weighing 1.92 g and containing 20 mg of active 5 substance.
Am~oule solution Composition 10 Active substance according to formula I 1.0 mg Sodium chloride 45.0 mg Water for injections ad 5.0 mg Preparation The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make the solution isotonic. The resulting solution is filtered to remove pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and heat-sealed.
The ampoules contain 1 mg, 5 mg and 10 mg of active substance.
Suppositories Each suppository contains:
Active substance according to formula I 1.0 parts Cocoa butter (melting point: 36-37C) 1200.0 parts Carnauba wax 5.0 parts Preparation The cocoa butter and carnauba wax are melted together. At 45C the active substance is added and stirred until a complete dispersion has formed. The mixture is poured into moulds of suitable size and the suppositories are appropriately packaged.
Claims (8)
1. Use of a benzomorphane derivative of general formula I
(I) wherein R1 represents a methyl or ethyl group;
R2 represents a methyl or ethyl group;
R3 represents a 2-methoxyethyl, 2-methoxypropyl, 2-furylmethyl (furfuryl), 2-tetrahydrofurylmethyl (tetrahydrofurfuryl), or group;
R4 represents a hydrogen atom or a methyl group;
R5 represents a hydrogen atom or a methyl group;
R6 represents a methyl, ethyl, propyl, isopropyl or phenyl group;
the .alpha. and .beta. forms thereof, the enantiomeric forms thereof and the corresponding pharmacologically acceptable acid addition salts thereof in the preparation of a medicament for cytoprotection.
(I) wherein R1 represents a methyl or ethyl group;
R2 represents a methyl or ethyl group;
R3 represents a 2-methoxyethyl, 2-methoxypropyl, 2-furylmethyl (furfuryl), 2-tetrahydrofurylmethyl (tetrahydrofurfuryl), or group;
R4 represents a hydrogen atom or a methyl group;
R5 represents a hydrogen atom or a methyl group;
R6 represents a methyl, ethyl, propyl, isopropyl or phenyl group;
the .alpha. and .beta. forms thereof, the enantiomeric forms thereof and the corresponding pharmacologically acceptable acid addition salts thereof in the preparation of a medicament for cytoprotection.
2. Use of a benzomorphane compound as defined in claim 1 in the preparation of a medicament for the treatment of brain ischaemia of various origins, epilepsy and neuro-degenerative diseases.
3. A method of treatment of a neuro-degenerative disease, epilepsy or brain ischaemia in a human or non-human subject which comprises administering to said subject an effective amount of a compound of formula I
as defined in claim 1 or a pharmacologically acceptable acid-addition salt thereof.
as defined in claim 1 or a pharmacologically acceptable acid-addition salt thereof.
4. A use or method as claimed in any of claims 1 to 3 wherein the compound of formula (I) is (-)-(1R,5R,9R)-N-(2-furylmethyl)-5,9-dimethyl-2'-hydroxy-6,7-benzomorphane or a pharmacologically acceptable acid addition salt thereof.
5. The use of a benzomorphane compound as defined in claim 1 or an acid-addition salt thereof for cytoprotection.
6. The use as claimed in claim 5 wherein the benzomorphane compound is for the treatment of brain ischaemia, epilepsy or neuro-degenerative diseases.
7. The use as claimed in claim 5 or claim 6 wherein the compound of formula (I) is (-)-(1R,5R,9R)-N-(2-furylmethyl)-5,9-dimethyl-2'-hydroxy-6,7-benzomorphane or a pharmacologically acceptable salt thereof.
8. Each and every novel use, method and composition herein disclosed.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3839659A DE3839659A1 (en) | 1988-11-24 | 1988-11-24 | USE OF BENZOMORPHANES FOR CYTOPROTECTION |
| DEP3839659.9 | 1988-11-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2003572A1 true CA2003572A1 (en) | 1990-05-24 |
Family
ID=6367798
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002003572A Abandoned CA2003572A1 (en) | 1988-11-24 | 1989-11-22 | Use of benzomorphanes for cytoprotection |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0370499A3 (en) |
| JP (1) | JPH02193922A (en) |
| CA (1) | CA2003572A1 (en) |
| DE (1) | DE3839659A1 (en) |
| DK (1) | DK589089A (en) |
| HU (1) | HUT55231A (en) |
| ZA (1) | ZA898936B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4222092A1 (en) * | 1992-07-06 | 1994-01-13 | Miele & Cie | Oven with a cooling air blower and / or with a hot air blower |
| US5824662A (en) | 1996-09-27 | 1998-10-20 | Guilford Pharmaceuticals Inc. | Treatment of global and focal ischemia using naaladase inhibitors |
| US6017903A (en) | 1996-09-27 | 2000-01-25 | Guilford Pharmaceuticals Inc. | Pharmaceutical compositions and methods of treating a glutamate abnormality and effecting a neuronal activity in an animal using NAALADase inhibitors |
| EP1005348A1 (en) | 1996-09-27 | 2000-06-07 | Guilford Pharmaceuticals Inc. | Naaladase compositions and methods for treating glutamate abnormality and effecting neuronal activity in animals |
| DE19907874A1 (en) * | 1999-02-23 | 2000-08-24 | Boehringer Ingelheim Pharma | New N-substituted hexahydro-2,6-methano-3-benzazocin-10-ol derivatives, as tension-dependent sodium channel blockers useful for treating e.g. arrhythmia, spasms, pain or neurodegenerative diseases |
| TW201431842A (en) * | 2012-11-09 | 2014-08-16 | Purdue Pharma Lp | Benzomorphan analogs and the use thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CS166803B2 (en) * | 1971-02-08 | 1976-03-29 | Boehringer Sohn Ingelheim | |
| GB8600783D0 (en) * | 1986-01-14 | 1986-02-19 | Merck Sharp & Dohme | N-methyl-d-aspartate receptor antagonists |
-
1988
- 1988-11-24 DE DE3839659A patent/DE3839659A1/en not_active Withdrawn
-
1989
- 1989-11-22 CA CA002003572A patent/CA2003572A1/en not_active Abandoned
- 1989-11-22 JP JP1304573A patent/JPH02193922A/en active Pending
- 1989-11-23 EP EP19890121593 patent/EP0370499A3/en not_active Withdrawn
- 1989-11-23 HU HU896152A patent/HUT55231A/en unknown
- 1989-11-23 DK DK589089A patent/DK589089A/en not_active Application Discontinuation
- 1989-11-23 ZA ZA898936A patent/ZA898936B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK589089A (en) | 1990-05-25 |
| HUT55231A (en) | 1991-05-28 |
| JPH02193922A (en) | 1990-07-31 |
| DK589089D0 (en) | 1989-11-23 |
| EP0370499A2 (en) | 1990-05-30 |
| DE3839659A1 (en) | 1990-05-31 |
| ZA898936B (en) | 1991-07-31 |
| HU896152D0 (en) | 1990-02-28 |
| EP0370499A3 (en) | 1991-06-05 |
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