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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole

Definitions

• the present invention relates to a new method of administering 3-[l-(lH- imidazol-4-yl)-ethyl]-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof. Accordingly, the present invention relates to an intraspinal administration of 3-[l-(lH-imidazol-4-yl)-ethyl]-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof to obtain analgesia.
• the intraspinal administration is intented to include epidural, intrathecal and intrarrhachidian administration.
• the present invention relates to a method for obtaining analgesia in a mammal by administering 3-[l-(lH-imidazol-4-yl)-ethyl]-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof intraspinally.
• the present invention relates to an intraspinal administration of 3-[l-(lH-imidazol-4-yl)-ethyl]- indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof for obtaining analgesia without sedation.
• the present invention relates to a method of using 3-[l-(lH-imidazol-4-yl)-ethyl]-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof as an adjunct to anaesthesia by administering the drug intraspinally.
• the present invention also relates to a method for treating a mammal by administering 3-[l-(lH-imidazol-4-yl)-ethyl]-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof intraspinally.
• the present invention relates to the use of 3-[l-(lH-imidazol-4-yl)-ethyl]-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt in the manufacture of a medicament for intraspinal administration.
• 3-[l-(lH-imidazol-4-yl)-ethyl]-indan-5-ol has the following formula:
• 3-[l-(lH-imidazol-4-yl)-ethyl]-indan-5-ol is described in WO 97/12874 as an ⁇ 2 - receptor agonist useful in the treatment of hypertension, glaucoma, migraine, diarrhea, ischemia, addiction to chemical substances, anxiety, especially preoperative anxiety, and different neurological, musculosketal, psychiatric and cognition disorders as well as a sedative and an analgesic agent, nasal decongestant, and as an adjunct to anaesthesia.
• Enteral, topical, and parenteral routes of administration and a method for producing the compound are discussed in WO 97/12874.
• Opioids especially morphine
• morphine are routinely used for intraspinal and epidural administration to give analgesia.
• Eisenach J. E. Exp. Opin. Invest. Drugs 3(10), 1994, 1005-1010) the major concern limiting the use of intraspinal morphine is the 0.1 to 0.2 % incidence of severe respiratory depression, occurring six to twelve hours after injection.
• ⁇ 2 -Receptor agonists are being evaluated for obtaining analgesia by administering them intrathecally or epidurally.
• the only ⁇ 2 -receptor agonist approved by the FDA for obtaining analgesia by epidural administration is clonidine (DURACLON ® ). According to Laitin S.
• an object of the invention is to provide a method for obtaining analgesia by administering 3-[l-(lH- imidazol-4-yl)-ethyl]-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof to a mammal intraspinally in an amount sufficient to give the desired therapeutic effect.
• intraspinal administration is intented to include epidural, intrathecal (i.e., within the spinal subarachnoid or subdural space), and intrarrhachidian administration.
• An object of the invention is also to provide a method for treating a mammal by administering 3-[l-(lH-imidazol-4-yl)-ethyl]-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof intraspinally for a time sufficient to give the therapeutic effect.
• An aspect of the invention is also to provide a method of using 3-[l-(lH- imidazol-4-yl)-ethyl]-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof intraspinally as an adjunct to anaesthesia.
• a further aspect of the invention relates to a use of 3-[l-(lH-imidazol-4-yl)- ethyl]-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof in the manufacture of a medicament for intraspinal administration.
• the invention relates to a use of 3-[l-(lH-imidazol-4-yl)- ethyl]-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof in an intraspinal administration to a mammal to obtain analgesia.
• Figure 1 shows the effect of 3-[l-(lH-imidazol-4-yl)-ethyl]-indan-5-ol (Compound A) and clonidine (Compound B) on tail-flick analgesia.
• 3-[l-(lH-imidazol-4-yl)-ethyl]- indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof is effective for obtaining analgesia when administered intraspinally to a mammal.
• 3-[l-(lH-imidazol-4-yl)-ethyl]-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof can be administered intraspinally to a mammal for obtaining selective analgesia.
• the method for obtaining analgesia in a mammal encompasses all of the potential conditions that require the treatment of pain, e.g., intraoperative pain; postoperative pain; obstetric pain; chronic pain, such as cancer-related pain and neuropathic pain; and spastic paraplegia.
• 3-[l-(lH-imidazol-4-yl)-ethyl]-indan-5-ol is a safer and more viable drug than clonidine to be administered to a mammal intraspinally. Accordingly, for example, administering 3-[l-(lH-imidazol-4-yl)-ethyl]-indan-5-ol intrathecally at an analgesic dose was found not to induce sedation in a rat as clonidine did (see Example 2, Table 2).
• 3-[l-(lH-imidazol-4-yl)-ethyl]-indan-5-ol is needed in approximately 2,4-times less when administered intrathecally to achieve sedation, but at least 125-times less is needed when administered intrathecally to achieve analgesia (see Example 3, Table 3).
• 3-[l-(lH-imidazol-4-yl)-ethyl]-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof is so selectively analgesic when administered intraspinally, it is very useful as an adjunct to anaesthesia.
• Anaesthesia is a loss of sensation resulting from pharmacologic depression of nerve function wherein the ability to perceive pain and/or other functions is lost.
• analgesia painful stimuli are so moderated that, though still perceived, they are no longer painful.
• the drug is used as an adjunct to anaesthesia, less anaesthesia are needed, and possible dosing problems would be avoided.
• 3-[l-(lH-imidazol-4-yl)-ethyl]-indan-5-ol, its enantiomer or a pharmaceutically acceptable ester or salt thereof can be administered into the spinal space, e.g., by an injection or a continuous infusion.
• the precise amount of the drug to be administered to a mammal intraspinally or epidurally is dependent on numerous factors known to one skilled in the art, such as, the type of mammal, the general condition of the patient, the condition to be treated, the desired duration of use, etc.
• the dose for a human can be from about 30 to 500 ⁇ g/patient, preferably about 50- 200 ⁇ g/patient.
• the dose for smaller mammals, e.g., dogs and cats can be about 1-100 ⁇ g/patient, preferably 3-30 ⁇ g/patient.
• the injections or infusions may contain one or more diluents or carriers.
• 3-[l-(lH-imidazol-4-yl)-ethyl]-indan-5-ol can be prepared, for example, as described in WO 97/12874. Accordingly, it can be prepared by heating a stirred mixture of 4-[l-(6-methoxyindan-l-yl)ethyl)-lH-imidazole hydrochloride (800 mg) and 48 % hydrobromic acid (35 ml) under reflux for 45 minutes; cooling the reaction mixture; pouring the reaction mixture into water and making it basic with ammonium hydroxide solution; extracting the product into ethyl acetate; washing the ethyl acetate phase with water; drying it with sodium sulphate; and finally evaporating to dryness.
• the crude product can be converted, e.g., to its hydrochloride salt in ethyl acetate using dry hydrochloric acid.
• Other acid addition salts may be formed with inorganic and organic acids.
• Typical acid addition salts in addition to chlorides are bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, and ascorbates.
• the hydroxy group can form esters and salts with alkali and alkaline earth metals.
• Typical esters include the lower alkyl esters, such as, the methyl, ethyl, and propyl esters.
• the experimental partition coefficients for 3-[l-(lH-imidazol-4-yl)-ethyl]-indan- 5-ol (compound A) and clonidine (compound B) were determined by the shake flash method.
• the hydrochloride salts of the above compounds were shaken for 90 minutes in a separatory funnel at room temperature with equal volumes (1:1, v/v) of an organic phase (water saturated 1-octanol) and an aqueous solution (0.1 M HC1 or 67 mM phosphate buffer pH 7.4), separating the two phases.
• the quantitations of the amounts of the studied compounds were performed by the RP-HPLC (reverse phase high pressure liquid chromatography) technique.
• the detection wavelength was 282 nm for 3-[l-(lH- imidazol-4-yl)-ethyl]-indan-5-ol and 272 nm for clonidine.
• methanol:15 mM phosphate buffer pH2 at the ratio 50:50 (v/v) was used as a mobile phase.
• the logarithm of the partition coefficient (logP) is used as a lipophilicity parameter for a neutral molecule.
• D is the partition coefficient measured at a pH where the molecules are partly or totally ionized.
• the rats (Sprague-Dawley, B&K, Sollentuna, Sweden) were anaesthetized by midazolam and fentanyl-fluanisone combination anaesthesia and then chronically catheterized according to the method described by Yaksh and Rudy (Physiology & Behaviour 17,1031-1036, 1976). Briefly, the atlanto-occipital membrane of the spine (directly below the skull) was incised. A polyethylene catheter (PE10 Intramedic, USA) filled with sterile saline was carefully and slowly pushed 8 cm into the spinal cavity. The end of the catheter is known to reach the close proximity of the lumbar enlargement of the spine. The location of the end of the catheter was tested by administering 0.5 mg lidocain approximately 3 days after catheterization. If both hindlegs were paralyzed, the rat was used in the drug tests. Measurement of analgesic and other pharmacological activities
• Tail-flick analgesia was tested by a tail-flick analgesy meter (Ugo Basile, Italy). The analgesia testing was done no earlier than four days after the catheterization. The rats were always habituated to the immobilization chambers that were used in the analgesia measurements. The tail of the rat was outside the chamber and it was placed on the heating spot of the apparatus. Thus, the hot infrared beam would hit the tail. When the rat reacted and moved the tail away from the beam, the analgesy meter automatically measured the latency of the tail-withdrawal. The tail-flick measurement was always repeated three times, one after another, to diminish the effect of a possible unspecific reaction.
• the heating spot of the tail was moved slightly towards the end of the tail, so that the beam did not hit the same area of the tail within one measurement.
• the maximal latency was set to 5 seconds in order to prevent burns of the tail.
• the predrug tail-flick latencies were first measured, and then the rats were administered 10 ⁇ l of the drug solution by a Hamilton syringe. Immediately thereafter the catheter was washed with 10 ⁇ l of sterile saline, and the tip was sealed by a lighter.
• the analgesia was tested after 30 minutes from the administration of the drug by measuring tail-flick analgesia as described above.
• the tail-flick analgesia data were represented as MPE% values (maximum possible effect %).
• the tail-flick latencies were calculated as MPE% values as follows: (postdrug latency - predrug latency) / (cut-off time - predrug latency) x 100%.
• the dose-response curves were drawn of the MPE% values, and the dose was on a logarithmic scale (see Figure 1).
• the ED 50 the dose inducing 50 % of the maximal effect values of the dose-response graphs were determined by the Graph Pad Prism v. 1.03 (San Diego, USA) software.
• Adverse effect evaluation evaluation of the dose-response graphs were determined by the Graph Pad Prism v. 1.03 (San Diego, USA) software.
• the effect on motor coordination was evaluated by a rotarod treadmill for rats (Ugo Basile, Italy). It consists of four drums (diameter of 70 mm) separated by five flanges. The drums were adjusted to rotate 4 revolutions per minute. The rod was rotated against the direction of the rat, so it had to walk forward to stay on the rod. The rats were first trained to stay on the rod for at least two minutes. If a rat was not able to fulfill this criteria, it was not used in the study. The selected animals were catheterized for testing of the effects of the drugs on the time they were able to stay on the drum.
• Sedative effects were measured in a polypropylene animal cage (38 x 22 x 15 cm) with a transparent polypropylene lid by Photobeam Activity System (PAS, Cage Rack, San Diego Instruments, San Diego, USA).
• PAS Photobeam Activity System
• the system consists of 16 separate enclosures connected to a computer control unit. There were three photobeams in each enclosure. The enclosures surrounded the cage at the height of 5 cm. The breaking of beams was counted as locomotor activity.
• the rat was placed on the rotarod apparatus, and the falling time was measured. After the rotarod measurement, the rat was placed into the motor activity measurement cage surrounded by the photobeam enclosures, and the activity was measured for 10 minutes. Immediately after the locomotor activity measurement (i.e. approximately after 30 min from administration), the core temperature was measured. The results are shown in Table 2. Results

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• 2000
  • 2000-06-22 EP EP00940441A patent/EP1196168A2/de not_active Withdrawn
  • 2000-06-22 WO PCT/FI2000/000566 patent/WO2001000192A2/en not_active Application Discontinuation
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