WO2002007714A2 - Use of anellated dihydropyridines for the preparation of pharmaceutical compositions for the treatment of chronic pain - Google Patents
Use of anellated dihydropyridines for the preparation of pharmaceutical compositions for the treatment of chronic pain Download PDFInfo
- Publication number
- WO2002007714A2 WO2002007714A2 PCT/EP2001/008453 EP0108453W WO0207714A2 WO 2002007714 A2 WO2002007714 A2 WO 2002007714A2 EP 0108453 W EP0108453 W EP 0108453W WO 0207714 A2 WO0207714 A2 WO 0207714A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- denotes
- group
- compound according
- formula
- methyl
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
-
- 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
- A61K31/47—Quinolines; Isoquinolines
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4747—Quinolines; Isoquinolines spiro-condensed
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
Definitions
- the invention relates to the use of aneliated dihydropyridines and the salts thereof with physiologically acceptable acids for preparing agents for the treatment of chronic pain.
- A is benzo or thieno, and if A is benzo R , R 2 and R 3 independently of one another denote
- R 1 , R 2 and R 3 denote hydrogen; R 4 and R 5 independently of one another denote
- R 6 denotes C1-C12 alkyl or a phenyl or benzyl group substituted by the groups R 7 and R 8 , - 2
- R 7 and R 8 independently of one another denote hydrogen, halogen (F, Cl, Br, I), C 1 -C 5 alkyl, C1-C5 alkoxy or C1-C5 fluoroalkyl group.
- Z denotes O, S or an NHCO- group or, if at least one of the groups R 4 and R 5 is other than hydrogen, Z may also denote a single bond.
- EP 0 491 441 A1 describes the compound of Formula
- Chronic or chronically recurring pain include, inter alia, migraine, neuralgia, muscle pain and inflammatory pain. They have mechanisms in common with chronically recurring pain [Dray, A. Urban L. and Dickenson, A. Trends in Pharmacological Sciences 1994; 15:190-197].
- the chronic neuronal pains include inter alia postoperative pain, shingles, phantom pain, diabetic neuropathy, pain after chronic nerve compression as well as AIDS and cancer in their final stages.
- the aim of the present invention is to provide an active substance for treating chronic pain, particularly chronic neuronal pain, with good bioavailability and a powerful antinociceptive activity.
- the compounds according to the present invention exhibit a powerful antinociceptive activity based on the blockade of voltage-dependent N-type Ca +2 - channels.
- the invention therefore relates to the use of the compounds of Formula I or the salts thereof with physiologically acceptable acids for the preparation of a pharmaceutical composition for treating chronic pain :
- A is benzo or thieno, and if A is benzo
- R 1 , R 2 and R 3 independently of one another denote H, OH,C ⁇ -C 5 alkyl, C1-C5 alkoxy, -O-(CH 2 ) ⁇ -5-OCH3 or R 2 and R 3 in positions 6 and 7 together form the group
- R 1 , R 2 and R 3 denote hydrogen
- R 4 and R 5 independently of one another denote H, C 1 -C5 alkyl or together with the central atom to which they are bonded form a C 3 -C ring.
- R 6 denotes C 1 -C 12 alkyl or a phenyl or benzyl group substituted by the groups R 7 and R 8 , wherein R 7 and R 8 independently of one another denote hydrogen, halogen (F, Cl, Br, I), C1-C5 alkyl, C1-C5 alkoxy or C 1 -C5 fluoroalkyl group.
- Z denotes O, S or an NHCO- group or, if at least one of the groups R 4 and R 5 is other than hydrogen, Z may also denote a single bond.
- the invention further relates to the compounds of Formula I, with the proviso that the compound of Formula
- Preferred compounds are the compounds of general Formula IA and their use as described above,
- R 1 , R 2 and R 3 preferably independently of one another denote hydrogen, methyl or methoxy, particularly wherein R 2 and R 3 denote methoxy and R 1 is methoxy or hydrogen.
- R 4 and R 5 independently of each other denote hydrogen or a methyl group.
- Acids suitable for forming the salts of the compounds according to the invention include, for example, hydrochloric acid hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, oxalic acid, malonic acid, fumaric acid, maleic acid, tartaric acid, citric acid, ascorbic acid and methanesulphonic acid.
- alkyl groups denotes branched and unbrahched alkyl groups having 1 to 12, preferably 2 to 10, most preferably 5 to 6 carbon atoms, including, for example: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec. butyl, tert. -butyl, n-pentyl, iso-pentyl, neo-pentyl and n-hexyl, but also n-decyl.
- alkoxy groups denotes branched and unbranched alkoxy groups having 1 to 5 carbon atoms, including for example: methyloxy, ethyloxy, n-propyloxy, iso- propyloxy, n-butyloxy, iso-butyloxy, sec. butyloxy, tert.-butyloxy, n-pentyloxy, iso- pentyloxy and neo-pentyloxy.
- cycloalkyl groups having 3 to 7 carbon atom denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
- fluoroalkyl groups denotes branched and unbranched fluoroalkyl groups having 1 to 5 carbon atoms and 1 to the maximum possible number of fluorine atoms, preferably 1 ,1,1-trifluoroethyl, most preferably trifluoromethyl.
- the compounds according to this invention exhibit an antinociceptive activity which is based on the blockade of voltage-dependent N-type Ca +2 -channels.
- the blocking action on voltage-dependent N-type calcium channels was demonstrated on primary cell cultures of FLUO-3 charged recombinant HEK-cells expressing N-type Ca +2 -channels, by fluorescent recording to the cytosolic calcium kinetics after potassium depolarisation (80mM K + ) (Test A).
- the concentration of the half-maximum inhibition (ICso-values) for the selected substances is in the submicro- to micromolar range.
- the principle of the method is producing hyperalgesia and allodynia in the plantar region (the sole of the hind paw).
- Sprague-Dawley rats Harian weighing 250-350 grams are used.
- four loose ligatures are placed on the sciatic nerve of the left hind paw at intervals of 2.5 mm in such a way that the perinervai circulation is affected but not prevented. This leads to extravasation and oedema, resulting in neuropathy of the nerves which innervate the planter region.
- the right hind paw is treated in the same way without the ligatures.
- Control tests for allodynia and/or hyperalgesia are carried out without the administration of any substance before and 8-10 days after the operation. Then substance tests are carried out at intervals of 2-3 days.
- the animals are placed on a glass platform through which an increasingly powerful heat producing radiant source is directed onto the sole of the hind paws
- the animals are placed in cages with a wire mesh base.
- a blunt needle e.g. a large safety pin
- the skin of the sole of the paw Plant-region
- the sole of the paw is pinched gently with forceps. Normal animals react to this stimulus only slightly or not at all. Animals with CCI withdraw their paws very much more quickly (away from the pin) and hold them in the air for longer (holding away). The number and duration of positive reactions of the operated and control paws are measured.
- Mechano-Allodynia The animals are put in cages with a wire mesh base. The skin (Plantar-region) of the hind paw is touched with fibres of varying flexibility (von Frey hairs) until the fibre bends. The tester examines which thickness of fibre causes the animals to raise their operated or control paws.
- the animals are placed in cages with a wire mesh base. Using a small spray, acetone is carefully applied to the sole of the hind paw (Plantar-region) from below. The healthy animals reacts to this cold stimulus only slightly by raising the paw. Animals with CCI react more frequently and distinctly with their affected paw. The latency period until the operated or control paw is raised and the duration are observed and measured over an observation period of 5 minutes.
- Test C Formalin-Paw Test (Rat)
- Test D Benett (CCD-Model (Rat)
- Measuring parameter mechanohyperalgesia (ED50 values in mg/kg; p.o.)
- the compounds may be administered both enterally and parenterally.
- a proposed dose for oral administration is 0.1 to 500 mg of active of active substance per dose, whilst for intravenous administration a dose of 0.05 to 150 mg per dose is suggested.
- the desired therapeutic dose depends on the preparation and can be determined experimentally.
- 1 tablet core contains:
- the mixture of the active substance with lactose and maize starch is granulated with a 10% aqueous gelatine solution through a screen with a 1 mm mesh, dried at 40°C and passed through a screen again.
- the granules thus obtained are mixed with magnesium stearate and compressed.
- the resulting cores are coated in the usual way with a coating applied using an aqueous suspension of sugar, titanium dioxide, talc and gum arabic.
- the finished coated tablets are polished with beeswax.
- the active substance and magnesium stearate are granulated with an aqueous solution of the soluble starch, the granules are dried and intimately mixed with lactose and maize starch. The mixture is then compressed to form tablets weighing 210 mg.
- the active substance, lactose and maize starch are first combined in a mixer and then in a grinder.
- the mixture is returned to the grinder, thoroughly mixed with the talc and mechanically packed into hard gelatine capsules.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2001289719A AU2001289719A1 (en) | 2000-07-25 | 2001-07-21 | Use of anellated dihydropyridines for the preparation of pharmaceutical compositions for the treatment of chronic pain |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10035997.3 | 2000-07-25 | ||
DE10035997A DE10035997A1 (de) | 2000-07-25 | 2000-07-25 | Verwendung von anellierten Dihydropyridinen zur Herstellung von Mitteln für die Behandlung von chronischen Schmerzen |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2002007714A2 true WO2002007714A2 (en) | 2002-01-31 |
WO2002007714A3 WO2002007714A3 (en) | 2002-09-06 |
Family
ID=7650021
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2001/008453 WO2002007714A2 (en) | 2000-07-25 | 2001-07-21 | Use of anellated dihydropyridines for the preparation of pharmaceutical compositions for the treatment of chronic pain |
Country Status (5)
Country | Link |
---|---|
AR (1) | AR029981A1 (es) |
AU (1) | AU2001289719A1 (es) |
DE (1) | DE10035997A1 (es) |
UY (1) | UY26852A1 (es) |
WO (1) | WO2002007714A2 (es) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003014089A1 (en) * | 2001-07-31 | 2003-02-20 | Virginia Commonwealth University | Aminotetrahydroisoquinoline derivatives as analgesics |
RU2711646C1 (ru) * | 2019-04-08 | 2020-01-17 | Федеральное государственное бюджетное учреждение науки Институт молекулярной генетики Российской академии наук | Синтез меченного тритием 6,7-диметокси-4,4-диметил-1-[4-(4-трифторметилфенокси)фенил]-3Н-изохинолина |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3823148A (en) * | 1971-06-03 | 1974-07-09 | A Jansen | 4-biphenylyl isoquinoline derivatives |
EP0251361A1 (en) * | 1986-05-21 | 1988-01-07 | Duphar International Research B.V | New di- and tetrahydroisoquinoline derivatives |
GB2236674A (en) * | 1989-09-20 | 1991-04-17 | Wyeth John & Brother Ltd | Pharmaceutical composition containing gaba autoreceptor antagonists |
EP0491441A1 (en) * | 1990-12-17 | 1992-06-24 | Shell Internationale Researchmaatschappij B.V. | Fungicidal isoquinoline derivatives |
WO2000044725A1 (de) * | 1999-01-28 | 2000-08-03 | Boehringer Ingelheim Pharma Kg | Anellierte dihydropyridine und verwendung von anellierten dihydropyridinen für die herstellung von mitteln für die behandlung von epilepsie |
-
2000
- 2000-07-25 DE DE10035997A patent/DE10035997A1/de not_active Withdrawn
-
2001
- 2001-07-21 AU AU2001289719A patent/AU2001289719A1/en not_active Abandoned
- 2001-07-21 WO PCT/EP2001/008453 patent/WO2002007714A2/en active Application Filing
- 2001-07-25 AR ARP010103543A patent/AR029981A1/es not_active Suspension/Interruption
- 2001-07-25 UY UY26852A patent/UY26852A1/es not_active Application Discontinuation
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3823148A (en) * | 1971-06-03 | 1974-07-09 | A Jansen | 4-biphenylyl isoquinoline derivatives |
EP0251361A1 (en) * | 1986-05-21 | 1988-01-07 | Duphar International Research B.V | New di- and tetrahydroisoquinoline derivatives |
GB2236674A (en) * | 1989-09-20 | 1991-04-17 | Wyeth John & Brother Ltd | Pharmaceutical composition containing gaba autoreceptor antagonists |
EP0491441A1 (en) * | 1990-12-17 | 1992-06-24 | Shell Internationale Researchmaatschappij B.V. | Fungicidal isoquinoline derivatives |
WO2000044725A1 (de) * | 1999-01-28 | 2000-08-03 | Boehringer Ingelheim Pharma Kg | Anellierte dihydropyridine und verwendung von anellierten dihydropyridinen für die herstellung von mitteln für die behandlung von epilepsie |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003014089A1 (en) * | 2001-07-31 | 2003-02-20 | Virginia Commonwealth University | Aminotetrahydroisoquinoline derivatives as analgesics |
RU2711646C1 (ru) * | 2019-04-08 | 2020-01-17 | Федеральное государственное бюджетное учреждение науки Институт молекулярной генетики Российской академии наук | Синтез меченного тритием 6,7-диметокси-4,4-диметил-1-[4-(4-трифторметилфенокси)фенил]-3Н-изохинолина |
Also Published As
Publication number | Publication date |
---|---|
DE10035997A1 (de) | 2002-02-07 |
UY26852A1 (es) | 2002-02-28 |
WO2002007714A3 (en) | 2002-09-06 |
AU2001289719A1 (en) | 2002-02-05 |
AR029981A1 (es) | 2003-07-23 |
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