EP1667769A2 - Verwendung von galanthamin und seinen derivaten zum herstellen von arzneimitteln - Google Patents
Verwendung von galanthamin und seinen derivaten zum herstellen von arzneimittelnInfo
- Publication number
- EP1667769A2 EP1667769A2 EP04737381A EP04737381A EP1667769A2 EP 1667769 A2 EP1667769 A2 EP 1667769A2 EP 04737381 A EP04737381 A EP 04737381A EP 04737381 A EP04737381 A EP 04737381A EP 1667769 A2 EP1667769 A2 EP 1667769A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- branched
- straight
- chain
- galanthamine
- 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- Withdrawn
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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
Definitions
- the invention relates to the use of galanthamine and its derivatives for the manufacture of medicaments for the treatment of postoperative delirium.
- delirium A state of disturbed consciousness characterized by general confusion, a decrease in cognitive functions (attention, concentration and memory), hallucinations and unstable emotions. This means that the delirium exhibits elements of dementia as well as psychotic state images, but is mainly due to its acute nature and the mostly spontaneous, though often incomplete and delayed, reversibility delimited. Unlike degenerative dementia syndromes, postoperative delirium is exclusively a functional disturbance of the central nervous system Clinical picture generated by psychiatric symptoms can fluctuate very quickly - occasionally within seconds. Acute or subacute delirium (according to the World Health Organization classifications ICD 293.0 and 293.1) is often induced by taking pharmacologically active substances.
- drugs with an anticholinergic effect which partially block the nervous system based on the neurotransmitter acetylcholine, can induce delirium, but also sedatives, such as benzodiazepines, and antimanics, such as lithium salts.
- Intoxicants or their acute withdrawal after chronic use can also cause delirium. This is very often the case with massive acute alcohol abuse or alcohol withdrawal (ICD 291.0), but cannabis products, amphetamines, cocaine etc. can also cause delirious conditions.
- Postoperative delirium is now regarded as a multifunctional syndrome i 1 ), whereby the age and general health of the patient play a role as well as any preoperative cognitive disorders, undefined influences of the anesthetics administered, and possibly also certain intraoperative ones physiological changes ().
- a POD can be present immediately after waking from anesthesia, it is not the same as the rapidly passing benign disorientation after anesthesia.
- a POD can only be used on the second postoperative day or even later after the actual awakening from the anesthesia has been clinically normal. In this case, a direct effect of the perioperatively administered anesthetics or analgesics can be excluded.
- Antipsychotics and / or sedatives treated ( 7 ).
- Therapy of the so-called subsyndromal POD (which does not meet all the required psycho-etrical criteria of a POD) would be extremely important, since its existence is a risk factor for
- Performance is associated with later check-ups ( 8 ); in the case of the latter late effects, one also speaks of the condition of the
- WO 00/032185 A discloses effectors of the cholinergic system for treating delirium, including the POD, which is referred to as “non-cholinergic delirium”. In WO 00/032185 A, this is understood to mean a delirium that arises without within during the previous 48 to 72 hours, treatment or intoxication with substances that block the cholinergic conduction system has taken place.
- the in WO 00/032185 A disclosed use of choline sterase inhibitors for
- WO 00/32185 A does not contain examples of the use of galanthamine and its derivatives for treating PODs. WO
- 00/32185 A contains as the only example the case of a patient who had suffered a lithium intoxication in the course of drug therapy for her longstanding bipolar disorder and the delirium that followed with the
- galanthamine and its cholinergic derivatives for the manufacture of medicaments for the treatment of postoperative delirium and / or subsyndronal postoperative delirium. Furthermore, the use of galanthamine and its derivatives having cholinergic activity for the production of medicaments for the preventive treatment of postoperative delirium and / or subsyndronal postoperative delirium is proposed according to the invention.
- Galantha are preferably derivatives with the general formula Ia
- R x is H, branched or straight-chain (CACg) alkyl, Br, N0 2 , NR 5 R 6 ,
- R 5 and R ⁇ are identical or different and denote H, branched or straight-chain (C x -C 6 ) alkyl,
- R 2 is OH, branched or straight-chain (CC 6 ) alkyl, methoxy, phenyloxy or the following group
- Pol is a polymer, preferably one according to WO-Al-01/174820, and wherein
- R 3 and R 4 are either simultaneously or alternately H, D, CN, straight-chain or branched (Cj-Cg) alkyl or together are a carbonyl group,
- R 8 and R 9 are the same or different and H, branched or straight-chain (C ⁇ -Cg) alkyl, - (CH 2 ) 2 -OH, CHO, CONH 2 , tBOC (terc. Butoxycarbonyl), or -COCOOH mean, Rio is H or CH 3 , and where Yi is -0- (CH2) 2 ⁇ OH Y 2 is OH, and wherein
- Zi is H, branched or straight-chain [C ⁇ ⁇ C 6 ) alkyl, (C 2 -C) alkenyl (C 2 -C ⁇ ) alkynyl, trifluoroacetyl, formyl, phenyl or a group selected from:
- R a is H, straight-chain (C] -C 6 ) alkyl, branched (-C-C 6 ) alkyl or (C 2 -Cj) alkenyl, Rj 2 and R13 are identical or different and H, straight-chain or branched (-C-C 3 ) alkyl, phenyl, chlorophenyl, (trifluoromethyl) phenyl or 1-naphthyl, where R 14 is H, F, CH 3 , N0 2 , Cl, Br, J, CF 3 , n the above has the meaning given, is 0 or 1, and W has the meaning H or 0,
- R 15 and R 16 alternately mean H, COOCH 3 , COOCH 2 CH 3 , CN, COCH 3 .
- Y 3 and Y 4 alternately denote H and OH
- X is Cl, Br or I
- Z 2 is oxygen (N-oxide and no counterion), branched or straight-chain (C ⁇ -C 6 ) alkyl, or (C 2 -C 7 ) alkenyl or (C 2 -C 7 ) alkynyl or a group selected from:
- Y 3 and Y 4 have the meanings given above, and Z 3 is oxygen (N-oxide and no counterion) or a methyl group.
- Galanthamine derivatives used according to the invention are furthermore compounds with the general formula Id id
- Y 5 and Y 6 alternately denote H or OH or together form a keto group
- R ⁇ 7 , Ri8 / R 19 alternately denote two substituents H, the third substituent being NH 2 or CONH 2 .
- Z 4 is a straight-chain or branched (-CC 6 ) alkyl or 4-bromobenzyl.
- benzazepinium advantageously halides, preferably bromide, and carboxylic acids with 1-3 carboxyl functions, tartrates, malonates, fumarates and succinates being particularly preferred, and sulfonic acids, preferably methanesulfonic acid, being selected.
- the galanthamine used according to the invention and the galanthamine derivatives used according to the invention can be prepared by the processes as disclosed in WO 96/12692 A, WO 97/40049 and WO 01/74820.
- the cholinergic activity of galanthamine and its derivatives is essential for the invention, and this property must be specified to the extent that the compounds used according to the invention inhibit the cholinolytic action of choline esterases. This property can - as shown in the following table - be demonstrated by the concentration values for acetyl- or butyrylcholinesterase, which have been reduced to 50% by inhibition.
- the drugs obtainable using galanthamine and its derivatives can also contain an active ingredient or a combination of active ingredients.
- a combination is also understood to mean combinations of the compounds considered according to the invention with other pharmaceutically active substances. It has now been established and confirmed by an extensive clinical study that oral administration of galanthamine (in the form of the commercially available hydrobromide under the brand name Reminyl® for the treatment of mild to moderate Alzheimer's disease) to preoperatively non-demented or cognitively impaired patients with acute POD an unexpectedly rapid and extensive improvement in symptoms that has not been described so far.
- Example 1 The administration of galanthamine or its pharmacologically acceptable salts and solvates for the therapy or prophylaxis of postoperative delirium can be administered orally (in the form of tablets, capsules, drinking solutions or buccal tablets), intravenously, rectally ( in the form of suppositories) or transdermally (in the form of passive or active galanthamine through the skin-releasing systems).
- a preferred form of administration is oral, an exemplary administration scheme for the prophylaxis of the postoperative delirium being that 8 mg galanthamine hydrobromide in the form of tablets or drinking solutions which directly release the active ingredient are administered in the evening after the surgical intervention. On the four days following the day of surgery, 4 mg each in the morning and at noon, then 8 mg in the evening administered. On the fifth postoperative day, 4 mg are administered in the morning and at noon, and the prophylaxis is then ended. It goes without saying for the person skilled in the art that these dosages can be adapted to the body weight of the patient, his general condition, etc.
- Tablets containing galanthamine hydrobromide with direct release of the active ingredient, which according to the invention are suitable for this type of administration, are approved under the trade name Reinyl® for the therapy of Alzheimer's disease.
- Drinking solutions containing galanthamine, which according to the invention are suitable for this type of administration are described in WO-0130318, such a drinking solution being composed, for example, as follows:
- Another oral administration regimen uses capsules with delayed release of active ingredient, 8 mg galanthamine hydrobromide being administered in the evening after the surgery and 8 mg each in the afternoon or evening for the following four days.
- capsules with delayed release of active ingredient which can be used according to the invention are described in document WO 0038686, to which reference is made here in their entirety.
- Another preferred dosage form according to the invention is transdermal, the passive transdermal systems described in WO-9416707 being particularly suitable. In this case, such a transdermal patch, which releases about 10 mg of galanthamine base in the course of 24 hours, is applied immediately after waking up from anesthesia and is replaced on the next four days with a new patch; on the fifth day there is no more application.
- combinations of different administration routes described here are possible. In particular, it has proven useful to speed up transdermal delivery
- Example 2 The administration of (4aS, 6R, 8aS) -6-hydroxy-3-methoxy-ll-methyl-4a, 5, 9, 10-tetrahydro-6H-benzofuro [3a, 3, 2-ef] [2 ] benzazepinium compounds were made, for example, with bromide as the counter ion. It is a galanthamine derivative with the following structural formula:
- the therapy or prophylaxis of the postoperative delirium can be oral (in the form of tablets, capsules, drinking solutions or buccal tablets), intravenously, rectally (in the form of suppositories) or transdermally (in the form of passively or actively the aforementioned connection through the skin-delivering systems). respectively.
- a preferred form of administration is oral, with an exemplary regimen for prophylaxis of postoperative delirium being that in the evening after surgery, 2-6 mg (4aS, 6R, 8aS) -6-hydroxy-3-methoxy-ll-methyl -4a, 5, 9, 10-tetrahydro-6H-benzofuro [3a, 3, 2-ef] [2] benzazepinium bromide in the form of tablets or drinking solutions that directly release the active ingredient.
- 1-3 mg are administered in the morning and at noon, then 2-6 mg in the evening.
- On the fifth postoperative day 1-3 mg in the morning and at noon administered and the prophylaxis then ended.
- Trzepacz PT Update on the neuropathogenesis of delirium. Dement Geriatr Cogn Disord. 1999; 10: 330-334.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Psychology (AREA)
- Pain & Pain Management (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT15382003 | 2003-09-29 | ||
PCT/AT2004/000251 WO2005030332A2 (de) | 2003-09-29 | 2004-07-12 | Verwendung von galanthamin und seinen derivaten zum herstellen von arzneimitteln |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1667769A2 true EP1667769A2 (de) | 2006-06-14 |
Family
ID=34382391
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP04737381A Withdrawn EP1667769A2 (de) | 2003-09-29 | 2004-07-12 | Verwendung von galanthamin und seinen derivaten zum herstellen von arzneimitteln |
Country Status (7)
Country | Link |
---|---|
US (1) | US20060111341A1 (de) |
EP (1) | EP1667769A2 (de) |
CN (1) | CN1859949A (de) |
CA (1) | CA2506282A1 (de) |
MX (1) | MXPA05005570A (de) |
NO (1) | NO20052177L (de) |
WO (1) | WO2005030332A2 (de) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090253654A1 (en) | 2005-09-22 | 2009-10-08 | Galantos Pharma Gmbh | Cholinergic enhancers with improved blood-brain barrier permeability for the treatment of diseases accompanied by cognitive impairment |
WO2008022365A2 (de) * | 2006-08-24 | 2008-02-28 | Sanochemia Ltd. | Mittel zum beeinflussen der wirkungen von organophosphorverbindungen und verwendung von galanthamin, dessen derivaten und analoga zum herstellen solcher mittel |
WO2013160728A1 (en) | 2012-04-26 | 2013-10-31 | Alma Mater Studiorum - Universita' Di Bologna | Dual targeting compounds for the treatment of alzheimer's disease |
CN104860955B (zh) * | 2015-04-22 | 2017-07-14 | 华东理工大学 | 加兰他敏类似物及其用途 |
US10414778B2 (en) * | 2016-04-29 | 2019-09-17 | New Mexico Tech University Research Park Corporation | Methods for treatment of resistant cancer |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6150354A (en) * | 1987-01-15 | 2000-11-21 | Bonnie Davis | Compounds for the treatment of Alzheimer's disease |
US6407229B1 (en) * | 1994-10-21 | 2002-06-18 | Sanochemia Pharmazeutika Ag | Processes for the preparation of derivatives of 4a,5,9,10,11,12-hexahydro-6H-benzofuro-[3a,3,2-ef][2] benzazapine |
JP4187786B2 (ja) * | 1994-10-21 | 2008-11-26 | ザノヒェミア・ファルマツォイティカ・アー・ゲー | 4a,5,9,10,11,12−ヘキサヒドロ−6H−ベンゾフロ[3a,3,2−ef][2]ベンズアゼピン誘導体の製造方法 |
GB9514821D0 (en) * | 1995-07-19 | 1995-09-20 | Sod Conseils Rech Applic | Galanthamine derivatives |
JP4422342B2 (ja) * | 1998-11-27 | 2010-02-24 | ザノヒェミア・ファルマツォイティカ・アー・ゲー | せん妄の治療へのコリン作動性中枢神経系エフェクターの使用 |
-
2004
- 2004-07-12 CA CA002506282A patent/CA2506282A1/en not_active Abandoned
- 2004-07-12 WO PCT/AT2004/000251 patent/WO2005030332A2/de not_active Application Discontinuation
- 2004-07-12 US US10/537,568 patent/US20060111341A1/en not_active Abandoned
- 2004-07-12 MX MXPA05005570A patent/MXPA05005570A/es not_active Application Discontinuation
- 2004-07-12 EP EP04737381A patent/EP1667769A2/de not_active Withdrawn
- 2004-09-09 CN CNA2004800283471A patent/CN1859949A/zh active Pending
-
2005
- 2005-05-03 NO NO20052177A patent/NO20052177L/no not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO2005030332A3 * |
Also Published As
Publication number | Publication date |
---|---|
MXPA05005570A (es) | 2005-10-18 |
CN1859949A (zh) | 2006-11-08 |
CA2506282A1 (en) | 2005-04-07 |
NO20052177D0 (no) | 2005-05-03 |
WO2005030332A2 (de) | 2005-04-07 |
US20060111341A1 (en) | 2006-05-25 |
NO20052177L (no) | 2005-06-24 |
WO2005030332A3 (de) | 2005-06-02 |
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