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WO1994013272A1 - Use of potassium channel activators for the manufacture of a medicament for the treatment of pain - Google Patents

Use of potassium channel activators for the manufacture of a medicament for the treatment of pain Download PDF

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Publication number
WO1994013272A1
WO1994013272A1 PCT/GB1993/002548 GB9302548W WO9413272A1 WO 1994013272 A1 WO1994013272 A1 WO 1994013272A1 GB 9302548 W GB9302548 W GB 9302548W WO 9413272 A1 WO9413272 A1 WO 9413272A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
hydrogen
optionally substituted
potassium channel
group
Prior art date
Application number
PCT/GB1993/002548
Other languages
French (fr)
Inventor
Jonathan Robert Sanders Arch
Geoffrey Douglas Clarke
Original Assignee
Smithkline Beecham Plc.
Smithkline Beecham Farmaceutici S.P.A.
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
Application filed by Smithkline Beecham Plc., Smithkline Beecham Farmaceutici S.P.A. filed Critical Smithkline Beecham Plc.
Priority to AU56580/94A priority Critical patent/AU5658094A/en
Publication of WO1994013272A1 publication Critical patent/WO1994013272A1/en

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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
    • 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
    • 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
    • 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
    • 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
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine

Definitions

  • the present invention relates to a method for the treatment of pain in mammals.
  • WO 89/05808 and WO 91/11446 (Beecham Group p.l.c.) describe classes of compounds which are believed to be potassium channel activator antihypertensive agents.
  • N-4-pyridyl-N'-1,2,2-trimethylpropylguanidine and, in Example 47, a process by which it can be prepared.
  • the compound, which is referred to herein by its common name, pinacidil is described in the patent as a hypotensive compound.
  • pinacidil is described as a vasodilator. It is now known that pinacidil is a potassium channel activator.
  • EP-A-112776 (Rhône-Poulenc Santé) discloses the compound
  • N-methyl-2-(3-pyridinyl)tetrahydrothiopyran- 2-carbothioamide-1-oxide which is known as RP 49356 (and includes its active enantiomer, aprikalim, and is a potassium channel activator antihypertensive agent.
  • potassium channel activators include RO-316930 (Roche), SDZ-PCO-400 (Sandoz), WAY 120491 (Wyeth-Ayerst) and HOE-234 (Hoechst).
  • EP-A-0430 621 and EP-A-0 385 584 (Beecham Group pic) describe the resolution of certain intermediates useful in the preparation of the compounds described in the above mentioned patent applications.
  • EP-A-0 194 885 (E. Lilly) describes certain amino substituted benzopyran derivatives possessing anti-convulsant activity.
  • EP-A-0509-762 (E.R. Squibb) describes certain indole and dihydroquinoline substituted derivatives which as disclosed as possessing inter alia anti-hypertensive activity.
  • EP-A-314446 (American Home Products Corporation), EP-A-296975 and 312432 (Sanofi), EP-A-298452 (F.
  • EP-A-273262, EP-A-308972 and 340718 (Merck Patent GmbH), EP-A-339562 (Yoshitomi Pharmaceutical Industries Ltd.), GB 2204868A (Sandoz Limited), EP-A-365416 (Adir and Co), EP-A-344747 (Fujisawa), and EP-A-326297 (Rhone-Poulenc) describe classes of benzopyran derivatives which are believed to be potassium channel activator antihypertensive agents.
  • the present invention provides a method for the treatment of pain in mammals, such as humans, which method comprises administering to the mammal in need of such treatment an effective amount of a potassium channel activator, such as a compound of formula (I), or a pharmaceutically acceptable salt thereof:
  • P is a ring system selected from the following:
  • R F is hydrogen or C 1-6 alkyl
  • J is carbon and M is nitrogen and J a and M a are hydrogen; or in which Z is oxygen or CH 2 ;
  • R 1 and R 2 is hydrogen and the other is selected from the class of hydrogen, C 3-8 cycloalkyl, C 1-6 alkyl optionally interrupted by oxygen or substituted by hydroxy, C 1-6 alkoxy or substituted aminocarbonyl, C 1 -6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkoxy, nitro, cyano, halo,
  • alkylsulphonyl C 1-6 alkylsulphonyl, C 1-6 alkoxysulphinyl, C 1-6 alkoxysulphonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulphinyl, heteroarylsulphinyl, arylsulphonyl,
  • heteroarylsulphonyl in which any aromatic moiety is optionally substituted, C 1-6 alkylcarbonylamino, C 1-6 alkoxycarbonylamino, C 1-6 alkyl-thiocarbonyl, C 1-6 alkoxy-thiocarbonyl, C 1-6 alkyl-thiocarbonyloxy, 1-mercapto C 2-7 alkyl, formyl, or aminosulphinyl, aminosulphonyl or aminocarbonyl, any amino moiety being optionally substituted by one or two C 1-6 alkyl groups, or C 1-6 alkylsulphinylamino, C 1-6 alkylsulphonylamino, C 1-6 alkoxysulphinylamino or C 1-6
  • R 3 and R 4 is hydrogen or C 1 -4 alkyl and the other is C 1 -4 alkyl, CF 3 or CH 2 X a where X a is fluoro, chloro, bromo, iodo, C 1 -4 alkoxy, hydroxy, C 1 -4 alkylcarbonyloxy, -S-C 1 -4 alkyl, nitro, amino optionally substituted by one or two C 1 -4 alkyl groups; cyano or C 1 -4 alkoxycarbonyl or R 3 and R 4 together are C 2-5 polymethylene optionally substituted by C 1 -4 alkyl;
  • R 5 is C 1-6 alkylcarbonyloxy, benzoyloxy, ONO 2 , benzyloxy, phenyloxy or C 1-6 alkoxy and R 6 and R 9 are hydrogen or R 5 is hydroxy and R 6 is hydrogen or C 1-2 alkyl and R 9 is hydrogen or R 5 together with R 9 represents a bond and R 6 is hydrogen or R 6 and R 9 represents a bond and R 5 is hydroxy;
  • R 7 is a group of structure i):
  • R 7 ' is hydrogen, C 1-6 alkyl optionally substituted by hydroxy, C 1-6 alkoxy, C 1-6 alkoxycarbonyl or carboxy, C 1-6 alkyl substituted by halogen, or C 2-6 alkenyl; aryl or heteroaryl either being optionally substituted by one or more groups or atoms selected from the class of CF 3 , CF 3 O-, C 1-6 alkoxy, hydroxy, halogen,
  • R 8 is hydrogen, C 1-6 alkyl, or a group OR p or NHCOR q wherein R p is hydrogen, C 1-6 alkyl, aralkyl, C 1-7 alkanoyl or aroyl and R q is as defined above for R 7 '; or
  • X is N-CN, N-NO 2 , N-COR 10 or N-SO 2 R 10 wherein R 10 is C 1 -3 alkyl, NH 2 , NH(C 1 -3 alkyl), CF 3 or phenyl optionally substituted as defined for R x ; and
  • R 7 ' is NHR 1 1 wherein R 1 1 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl; and
  • R 8 is hydrogen or C 1-6 alkyl
  • R 7 ' and R 8 together are C 2-4 polymethylene
  • R 7 is a group of structure ii):
  • A is O or NR14 wherein R 14 is hydrogen, C 1-4 alkyl, formyl, acetyl or
  • B is N or CR 15 wherein R 15 is hydrogen, halogen, formyl or hydroxymethyl;
  • C is CH 2 , O, S, CH- Halogen, amino or C 1-6 alkylamino
  • p 1, 2 or 3;
  • R 12 and R 13 are independently hydrogen or methyl or together are oxo- or thia-; or R 7 is a group of structure iii)
  • J' is O or NR 18 wherein R 18 is hydrogen or C 1-6 alkyl, and R 16 and R 17 are independently hydrogen, C 1-6 alkyl, or (when R 16 is hydrogen) then R 17 is allyl, propargyl or C 3-6 cycloalkyl; or R 7 is a group of structure iv)
  • R 19 is hydrogen or C 1-6 alkyl; and R 20 is halo, amino or methylamino;
  • R 7 is, or formula v);
  • R 7 is tetrahydroisoquinolinone, 2,3-dihydro-1H- isoindol-1-one, 2-pyridine
  • R 7 moiety being cis or trans to the R 5 group when R 5 is other than hydrogen or a bond.
  • variable groups or atoms in formula (I) are as described for the corresponding variables in the above-mentioned patents, the subject matter of which is incorporated herein by reference. It should be appreciated that further groups R 7 , which are incorporated herein by reference are described in WO ⁇ 92 ⁇ 02514 or SA ⁇ 91 ⁇ 5891 and EP-571822.
  • All C 1-6 alkyl or alkyl containing groups in formula (I) are preferably selected from methyl, ethyl, n - and iso-propyl, n -, iso-, sec- and tert-butyl.
  • C 3-8 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclcoctyl.
  • Aryl includes phenyl and naphthyl.
  • Heteroaryl includes a 5- or 6- membered monocyclic or 9- or 10- membered bicyclic of which 5- or 6- memebered monocyclic heteroaryl is preferred.
  • 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl preferably contains one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur and which, in the case of there being more than one heteroatom, are the same or different.
  • Examples of 5- or 6-membered monocyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen an d sulp hur include fury , thieny , pyrry , oxazolyl, thiazolyl, imidazolyl and thiadiazolyl, and pyridyl, pyridazyl, pyrimidyl, pyrazolyl and triazolyl.
  • Preferred examples of such groups include furanyl, thienyl, pyrryl and pyridyl, in particular 2- and 3-furyl, 2- and 3-pyrryl, 2- and 3-thienyl, and 2-, 3- and 4-pyridyl.
  • 9- or 10-membered bicyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur include benzofuranyl, benzothienyl, indolyl and indazolyl, quinolyl and isoquinolyl, and quinazolyl.
  • Preferred examples of such groups include 2- and 3-benzofuryl, 2- and 3-benzothienyl, and 2- and 3-indolyl, and 2- and 3-quinolyl.
  • Suitable examples of groups or atoms for optional substitution of aryl and heteroaryl include one, two or three substituents independently selected from C 1 -4 alkyl, C 1 -4 alkoxy, halo (such as fluoro, chloro, bromo), hydroxy, nitro and cyano.
  • Acyl groups are preferably carboxylic acyl, usually alkanoyl.
  • P is selected from e).
  • Y is preferably nitrogen and R 2 is hydrogen or Y is C-R 1 where R 1 is preferably cyano and R 2 is hydrogen.
  • R 3 and R 4 are preferably both methyl;
  • R 5 is preferably hydroxy and R 6 and R 9 are hydrogen.
  • X is preferably oxygen.
  • R 7 is preferably selected from group i);
  • R 7 is most preferably 2- oxo-1-pyrrolidinyl, or 2-oxo-1-piperidinyl.
  • a particularly preferred compound of formula (I) is the compound of Example 3 of EP-A-205292, ( ⁇ )trans -3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin- 1-yl)-2H-pyrano[3,2-c]pyridin-3-ol.
  • Another particularly preferred compound of formula (I) is the compound of
  • references to a potassium channel activator including pinacidil or a compound of formula (I) and salts thereof, include solvates such as hydrates.
  • Potassium channel activators may be identified by standard methods, such as those described in EP-A-176689.
  • a compound of formula (I) is in substantially pure
  • Examples of the compounds of formula (I) include the examples described in the aforementioned Patent Publications/References.
  • benzopyran compounds of formula (I) wherein R 5 is hydroxy, alkoxy, acyloxy or ONO 2 and/or wherein J is C 1-6 alkyl have an asymmetric centre at the 3- and 4- carbon atoms, and are capable of existing in the (3R, 4S), (3S, 4R), (3R, 4R) and (3S, 4S) forms.
  • the invention extends to each of these forms including racemates.
  • potassium channel activators such as those herein described, in particular cromakalim, attenuate the effects of ⁇ -receptor antagonists such as morphine.
  • the present invention therefore extends to the co- administration of a potassium channel activator and a ⁇ -receptor antagonist for treating pain in mammals, such as humans.
  • the administration of the potassium channel activator may be by way of oral, sublingual, transdermal or parenteral administration.
  • a unit dose will normally contain 0.1 to 50 mg for example 0.5 to 10 mg, of the potassium channel activator, such a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Unit doses will normally be administered once or more than once a day, for example 2, 3, or 4 times a day, more usually 1 to 3 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.1 to 50 mg, for example 0.5 to 10 mg, that is in the range of approximately 0.001 to 1 mg/kg/day, more usually 0.005 to 0.2 mg/kg/day.
  • the potassium channel activator is administered in the form of a unit-dose composition, such as a unit dose oral or parenteral composition.
  • compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories.
  • oral or parenteral administration may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories.
  • administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the an.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose,
  • non-aqueous vehicles which may include edible oils
  • preservatives for example methyl propyl p-hydroxybenzoate or sorbic acid , and if a desired conventional flavouring or colouring agents.
  • Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
  • fluid unit dose forms are prepared containing the potassium channel activator and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
  • compositions will usually be accompanied by written or printed directions for use in the treatment concerned.
  • the present invention also provides the use of a potassium channel activator, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of pain in mammals such as humans.
  • a potassium channel activator such as a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Such treatment and/or prophylaxis may be carried out as hereinbefore described.
  • the present invention further provides a pharmaceutical composition for use in the treatment of pain which comprises a potassium channel activator, such as or a compound of formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • a potassium channel activator such as or a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • a pharmaceutically acceptable carrier such as or a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • Types of pain that are particularly suitable for treatment by potassium channel activators include pain associated with inflammation (such as arthritis) and peripheral diabetic neuropathy, the stump pain associated with amputation, and the pain associated with cancer.
  • compositions may be prepared in the manner as hereinbefore described.
  • the following pharmacological data illustrates the present invention.
  • the tail was placed above a projector bulb which was focussed 10-12cm proximal to the tip of the tail.
  • a flick of the tail exposed the light beam to a photodetector which in turn stopped the beam and was linked to a timer displaying the reaction time, measured to within one hundredth of a second.
  • Reaction time to tail withdrawal was measured at 3 min intervals. Three successive readings were taken to establish the baseline reaction time. The experiment was not continued unless these three reaction times had a standard deviation of less than 10% of the mean.
  • the intensity of the bulb was set so that the baseline reaction time was a few seconds and was not adjusted thereafter. Trials were terminated automatically if a tail flick did not occur within 10 seconds. Prolonged noxious cutaneous stimulation by tail immersion
  • mice Para-phenylquinone-induced abdominal writhing test in mice The methodology employed is based on that described by Sigmund et al,
  • mice Male Charles River mice (Swiss Strain), 20-35g body weight, are used- Animals are allowed food and water ad libitum and are randomized into groups of 10 prior to experimentation. Test compounds are dissolved in either distilled water or distilled water plus 0.1 M AMS, and administered by the subcutaneous route in a final volume of 10 ml/Kg. Control animals receive 10 ml/Kg of the appropriate vehicle alone. Following a pretreatment period of 20 min., mice are injected intraperitoneally with p-phenylquinone, 2 mg/Kg at 37°C in a final volume of 10 mg/Kg.
  • mice are then placed, in groups of 3, in a compartmented perspex box maintained at room temperature and are observed for a period of 8 min. During this period the number of abdominal writhing responses per animal are recorded where writhing consists of an intermittent contraction of the abdomen associated with hind leg extension.
  • the degree of antinociceptive protection afforded by a test compound is determined as the mean number of writhing responses observed in the treated group (T) expressed as a percentage of the mean number of writhing responses in the control group (C) according to the following formula:
  • Cromakalim has an ED 50 of 15 mg/kg s.c. in the above test.
  • Levcromakalin has an ED 50 of 13 mg/kg s.c. in the above test.
  • Pinacidil 30 mg/kg s.c. 53%
  • mice 29-35 g body weight Male Charles River mice (Swiss Strain) 29-35 g body weight are used.
  • mice are allowed food and water ad libitum and are randomized into groups of 10 prior to experimentation. Before administration of the test compound, the reaction time of each animal is determined by focusing a beam of light onto the tail, eliciting a reflex withdrawal after a certain latency; only mice exhibiting a latency between 3-8 sec. are used subsequently in the evaluation of drug effects.
  • Test compounds are dissolved in either distilled water of distilled water plus 0.1M AMS and administered by the intrathecal route in a final volume of 5 ⁇ l/mouse, according to the method described by Hylden and Wilcox, Eur. J. Pharmacol. 67, 313 (1980).
  • mice are anaesthetized with pentobarbital (80mg/Kg i.p.) and a caudal cutaneous incision (1 cm) is performed on the back using a disposable 30 gauge 1/2 inch needles mated to a 50 ⁇ l luer siringe d(Hamilton).
  • the drug are delivered intrathecally between L5 and L6 of spinous process.
  • Control animals receive 5 ⁇ l/mouse of the appropriate vehicle alone.
  • mice are again placed under the heat source and the rection time re-determined.
  • Percentage quantal protection is determined as the number of mice in which the reaction time is doubled compared to pretreatment values, expressed as a apercentage of the total number of mice in the group.

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Abstract

A method for the treatment of pain in mammals, which comprises administering to the mammal in need of such treatment an effective amount of a potassium channel activator.

Description

USE OF POTASSIUM ACTIVATORS FOR THE MANUFACTURE OF A MEDICAMENT
FOR THE TREATEMENT OF PAIN.
The present invention relates to a method for the treatment of pain in mammals.
EP-A-76075, 91748, 93535, 95316, 107423, 120426, 120427, 126311,
126350, 126367, 138134, 139992, 168619, 205292, 214818, 250077, 321175, 359537, 375449, 426379, 431741, WO 89/05808 and WO 91/11446 (Beecham Group p.l.c.) describe classes of compounds which are believed to be potassium channel activator antihypertensive agents.
U.K. Patent No. 1489879 discloses the compound N"-cyano-
N-4-pyridyl-N'-1,2,2-trimethylpropylguanidine and, in Example 47, a process by which it can be prepared. The compound, which is referred to herein by its common name, pinacidil, is described in the patent as a hypotensive compound. In "Drugs of the Future" Vol. VI(3), 149, 1981, pinacidil is described as a vasodilator. It is now known that pinacidil is a potassium channel activator.
EP-A-112776 (Rhône-Poulenc Santé) discloses the compound
N-methyl-2-(3-pyridinyl)tetrahydrothiopyran- 2-carbothioamide-1-oxide, which is known as RP 49356 (and includes its active enantiomer, aprikalim, and is a potassium channel activator antihypertensive agent.
Other compounds currently being developed for use as potassium channel activators include RO-316930 (Roche), SDZ-PCO-400 (Sandoz), WAY 120491 (Wyeth-Ayerst) and HOE-234 (Hoechst).
EP-A-0 350 805 (Biersdorf), EP-A-0 277 611, EP-A-0 277612, EP-A-0 337 179, and EP-A-0 355 565 (Hoechst Aktiengesellschaft) EP-A-0 415 065 (E.Merck), EP-A-0-450415 (Squibb), EP-A-0-466 131 (Nissan Chemical Industries Ltd), EP-A- 0339562 (Yoshitomi Pharmaceuticals), EP-A-0 360 621 (Ortho Pharmaceuticals), EP-A 0 489 300 (Uriach), DE 3,831,697 (Hoechst), EP-A 0432 893 (Yamanouchi), DE 4,010,488 (Hoechst), EP-A-0482934, EP-A-0296975, JO-2004-791, EP-A 0571822, WO\92\02514, WO\89\11477 and WO\89\07103 also describe certain compounds which are believed to possess anti-hypertensive activity.
EP-A-0430 621 and EP-A-0 385 584 (Beecham Group pic) describe the resolution of certain intermediates useful in the preparation of the compounds described in the above mentioned patent applications.
EP-A-0 194 885 (E. Lilly) describes certain amino substituted benzopyran derivatives possessing anti-convulsant activity.
EP-A-0509-762 (E.R. Squibb) describes certain indole and dihydroquinoline substituted derivatives which as disclosed as possessing inter alia anti-hypertensive activity. EP-A-314446 (American Home Products Corporation), EP-A-296975 and 312432 (Sanofi), EP-A-298452 (F. Hoffmann-La Roche and Co.), EP-A-273262, EP-A-308972 and 340718 (Merck Patent GmbH), EP-A-339562 (Yoshitomi Pharmaceutical Industries Ltd.), GB 2204868A (Sandoz Limited), EP-A-365416 (Adir and Co), EP-A-344747 (Fujisawa), and EP-A-326297 (Rhone-Poulenc) describe classes of benzopyran derivatives which are believed to be potassium channel activator antihypertensive agents.
It has now been discovered that compounds of these classes have analgesic properties and are of potential use in the treatment of pain in mammals.
Accordingly, the present invention provides a method for the treatment of pain in mammals, such as humans, which method comprises administering to the mammal in need of such treatment an effective amount of a potassium channel activator, such as a compound of formula (I), or a pharmaceutically acceptable salt thereof:
Figure imgf000004_0002
wherein:
P is a ring system selected from the following:
a)
Figure imgf000004_0001
wherein;
Figure imgf000005_0001
and the other variables are as defined below:
Figure imgf000005_0002
in which either a and b together represent a bond or CH2 or a and b together represent a carbonyl group, a group C=NORF, CHORF or
Figure imgf000005_0004
F
C-O-C-R
where RF is hydrogen or C1-6 alkyl; or c)
Figure imgf000005_0003
in which either J is nitrogen and Ja is a lone pair of electrons, M is carbon and Ma is R5; or
J is carbon and M is nitrogen and Ja and Ma are hydrogen; or
Figure imgf000006_0001
in which Z is oxygen or CH2;
e)
Figure imgf000006_0002
in which X is oxygen or NR in which R is hydrogen or C1-4 alkyl; Y is nitrogen and R2 is hydrogen or Y is C-R1; and; where:
either one of R1 and R2 is hydrogen and the other is selected from the class of hydrogen, C3-8 cycloalkyl, C1-6 alkyl optionally interrupted by oxygen or substituted by hydroxy, C1-6 alkoxy or substituted aminocarbonyl, C1 -6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkoxy, nitro, cyano, halo,
trifluoromethyl, CF3S, or a group CF3-A-, where A is -CF2-, -CO-, -CH2-, CH(OH), SO2, SO, CH2-O, or CONH, or a group CF2H-A'- where A' is oxygen, sulphur, SO, SO2, CF2 or CFH; trifluoromethoxy, C1-6 alkylsulphinyl, perfluoro C2-6
alkylsulphonyl, C1-6 alkylsulphonyl, C1-6 alkoxysulphinyl, C1-6 alkoxysulphonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulphinyl, heteroarylsulphinyl, arylsulphonyl,
heteroarylsulphonyl in which any aromatic moiety is optionally substituted, C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl, C1-6 alkyl-thiocarbonyloxy, 1-mercapto C2-7 alkyl, formyl, or aminosulphinyl, aminosulphonyl or aminocarbonyl, any amino moiety being optionally substituted by one or two C1-6 alkyl groups, or C1-6 alkylsulphinylamino, C1-6 alkylsulphonylamino, C1-6 alkoxysulphinylamino or C1-6
alkoxysulphonylamino, or ethyleπyl terminally substituted by C1-6 alkylcarbonyl, nitro or cyano, or -C(C1-6 alkyl)NOH or -C(C1-6 alkyl)NNH2, or one of R1 and R2 is nitro, cyano or C1 -3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C1-6 alkyl or by C2-7 alkanoyl; or where possible R1 and R2 when adjacent together are -(CH2)4- or -CH = CH-CH = CH-, or form an optionally substituted triazole or oxadiazole ring;
one of R3 and R4 is hydrogen or C1 -4 alkyl and the other is C1 -4 alkyl, CF3 or CH2 Xa where Xa is fluoro, chloro, bromo, iodo, C1 -4 alkoxy, hydroxy, C1 -4 alkylcarbonyloxy, -S-C1 -4 alkyl, nitro, amino optionally substituted by one or two C1 -4 alkyl groups; cyano or C1 -4 alkoxycarbonyl or R3 and R4 together are C2-5 polymethylene optionally substituted by C1 -4 alkyl;
R5 is C1-6 alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy or C1-6 alkoxy and R6 and R9 are hydrogen or R5 is hydroxy and R6 is hydrogen or C1-2 alkyl and R9 is hydrogen or R5 together with R9 represents a bond and R6 is hydrogen or R6 and R9 represents a bond and R5 is hydroxy;
R7 is a group of structure i):
Figure imgf000007_0001
(i) wherein
either X is oxygen or sulphur, and
R7' is hydrogen, C1-6 alkyl optionally substituted by hydroxy, C1-6 alkoxy, C1-6 alkoxycarbonyl or carboxy, C1-6 alkyl substituted by halogen, or C2-6 alkenyl; aryl or heteroaryl either being optionally substituted by one or more groups or atoms selected from the class of CF3, CF3O-, C1-6 alkoxy, hydroxy, halogen,
trifluoromethyl, nitro, cyano, C1 - 12 carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two C1-6 alkyl groups; and
R8 is hydrogen, C1-6 alkyl, or a group ORp or NHCORq wherein Rp is hydrogen, C1-6 alkyl, aralkyl, C1-7 alkanoyl or aroyl and Rq is as defined above for R7'; or
R7 and R8 are joined together to form C3-4 polymethylene optionally substituted by one or two C1-6 alkyl groups or hydroxy C1-6 alkyl, or -CH2-(CH2)n-Z-(CH2)m- wherein m and n are integers 0 to 2 such that m+n is 1 or 2 and Z is oxygen, sulphur or NR9 wherein R9 is hydrogen, C1 -9 alkyl, C2-7 alkanoyl, phenyl C1 -4 alkyl, naphthylcarbonyl, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl or naphthyl ring by one or two C1-6 alkyl, C1-6 alkoxy or halogen; mono- or bi-cyclic heteroarylcarbonyl; or R7 and R8 are joined to form -B1=B2-B3=B4- wherein one of B1 to B4 is CRr or N and the other three are CRr wherein Rr is hydrogen or C1-6 alkyl;
or X is N-CN, N-NO2, N-COR 10 or N-SO2R10 wherein R10 is C1 -3 alkyl, NH2, NH(C1 -3 alkyl), CF3 or phenyl optionally substituted as defined for Rx; and
R7' is NHR1 1 wherein R1 1 is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl or C2-6 alkynyl; and
R8 is hydrogen or C1-6 alkyl; or
R7' and R8 together are C2-4 polymethylene;
or R7 is a group of structure ii):
Figure imgf000008_0001
(ϋ) wherein
A is O or NR14 wherein R 14 is hydrogen, C1-4 alkyl, formyl, acetyl or
hydroxymethyl;
B is N or CR15 wherein R15 is hydrogen, halogen, formyl or hydroxymethyl;
C is CH2, O, S, CH- Halogen, amino or C1-6 alkylamino;
p is 1, 2 or 3; and
R12 and R13 are independently hydrogen or methyl or together are oxo- or thia-; or R7 is a group of structure iii)
Figure imgf000008_0002
(iii) wherein
J' is O or NR18 wherein R18 is hydrogen or C1-6 alkyl, and R16 and R17 are independently hydrogen, C1-6 alkyl, or (when R16 is hydrogen) then R17 is allyl, propargyl or C3-6 cycloalkyl; or R7 is a group of structure iv)
Figure imgf000009_0001
(iv) wherein
R19 is hydrogen or C1-6 alkyl; and R20 is halo, amino or methylamino;
or R7 is, or formula v);
Figure imgf000009_0002
(v) or R7 is tetrahydroisoquinolinone, 2,3-dihydro-1H- isoindol-1-one, 2-pyridine
N-oxide, 2-hydroxyphenyl or 2-hydroxypyridine (all four possible isomers);
the R7 moiety being cis or trans to the R5 group when R5 is other than hydrogen or a bond.
Suitable and preferred values for the variable groups or atoms in formula (I) are as described for the corresponding variables in the above-mentioned patents, the subject matter of which is incorporated herein by reference. It should be appreciated that further groups R7, which are incorporated herein by reference are described in WO\92\02514 or SA\91\5891 and EP-571822.
All C1-6 alkyl or alkyl containing groups in formula (I) are preferably selected from methyl, ethyl, n - and iso-propyl, n -, iso-, sec- and tert-butyl.
C3-8 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclcoctyl.
Aryl includes phenyl and naphthyl.
Heteroaryl includes a 5- or 6- membered monocyclic or 9- or 10- membered bicyclic of which 5- or 6- memebered monocyclic heteroaryl is preferred. In addition, 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl preferably contains one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur and which, in the case of there being more than one heteroatom, are the same or different. Examples of 5- or 6-membered monocyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen an d sulp hur include fury , thieny , pyrry , oxazolyl, thiazolyl, imidazolyl and thiadiazolyl, and pyridyl, pyridazyl, pyrimidyl, pyrazolyl and triazolyl. Preferred examples of such groups include furanyl, thienyl, pyrryl and pyridyl, in particular 2- and 3-furyl, 2- and 3-pyrryl, 2- and 3-thienyl, and 2-, 3- and 4-pyridyl. Examples of 9- or 10-membered bicyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur include benzofuranyl, benzothienyl, indolyl and indazolyl, quinolyl and isoquinolyl, and quinazolyl. Preferred examples of such groups include 2- and 3-benzofuryl, 2- and 3-benzothienyl, and 2- and 3-indolyl, and 2- and 3-quinolyl.
Suitable examples of groups or atoms for optional substitution of aryl and heteroaryl include one, two or three substituents independently selected from C1 -4 alkyl, C1 -4 alkoxy, halo (such as fluoro, chloro, bromo), hydroxy, nitro and cyano.
Acyl groups are preferably carboxylic acyl, usually alkanoyl.
Preferably P is selected from e). Y is preferably nitrogen and R2 is hydrogen or Y is C-R1 where R1 is preferably cyano and R2 is hydrogen. R3 and R4 are preferably both methyl; R5 is preferably hydroxy and R6 and R9 are hydrogen. X is preferably oxygen. R7 is preferably selected from group i); R7 is most preferably 2- oxo-1-pyrrolidinyl, or 2-oxo-1-piperidinyl.
Other examples of compounds believed to be potassium channel activators are described in U.K. Patent No. 1489879 (E. Lilly) which in particular describes, in example 1, the t-butyl analogue of pinacidil known as P1060, EP-A-350805
(Beiersdorf), EP-A-365416 (Adir), EP-A-344747 (Fujisawa), EP-A-360621 (Ortho Pharmaceutical Corp.), EP-A-355565 (Hoechst AKliengesellschaft), EP-A-363883 (Merck Patent GmbH)), EP-A-354553 (E.R. Squibb and Sons Inc.) and EP-A-375449 and European Patent Application No. 90305690.1 (Beecham Group p.I.c), the subject matter of which are incorporated herein by reference.
A particularly preferred compound of formula (I) is the compound of Example 3 of EP-A-205292, (±)trans -3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin- 1-yl)-2H-pyrano[3,2-c]pyridin-3-ol.
Another particularly preferred compound of formula (I) is the compound of
Example 1 of EP-A-76075 and United States Patent No. 4446113,
(±)-6-cyano-3,4-dihydro-2,2-dimethyl-trαn s-4-(2-oxo-1-pyrrolidinyl)-2H- benzo[b]pyran-3-ol, also known as cromakalim; and its (-)-enantiomer, also known as levcromakalim, disclosed in EP-A-120428.
Other particularly preferred potassium channel activators include RO
316930, SDZ PCO-400, WAY-120491, HOE-234, HOE-231, S-0121, FR 119748, EMD 57283, YM 934, NIP-121, RWJ-29009, BRL 55834, BDF 9333, U-89, 232, KP294, SR 47063, Y27152, Y26763, UR 8225, KC-399, LP805, KRN 2391 and nicorandil.
Examples of pharmaceutically acceptable salts are as described in the aforementioned European Patent references, the subject matter of which are incorporated herein by reference.
Information with respect to structure and activity of the specific compounds listed hereinbefore may be obtained from well known pharmaceutical industry references, such as "Pharmaprojects", PJB publications Limited, Richmond, Surrey, U.K.
References to a potassium channel activator, including pinacidil or a compound of formula (I) and salts thereof, include solvates such as hydrates.
Potassium channel activators may be identified by standard methods, such as those described in EP-A-176689.
The compounds of formula (I), and salts thereof may be prepared as described in the aforementioned Patent Publications/References.
Preferably, a compound of formula (I) is in substantially pure
pharmaceutically acceptable form.
Examples of the compounds of formula (I) include the examples described in the aforementioned Patent Publications/References.
It will be appreciated that the benzopyran compounds of formula (I) wherein R5 is hydroxy, alkoxy, acyloxy or ONO2 and/or wherein J is C1-6 alkyl have an asymmetric centre at the 3- and 4- carbon atoms, and are capable of existing in the (3R, 4S), (3S, 4R), (3R, 4R) and (3S, 4S) forms. The invention extends to each of these forms including racemates.
It should also be appreciated that potassium channel activators such as those herein described, in particular cromakalim, attenuate the effects of μ-receptor antagonists such as morphine. The present invention therefore extends to the co- administration of a potassium channel activator and a μ-receptor antagonist for treating pain in mammals, such as humans.
The administration of the potassium channel activator may be by way of oral, sublingual, transdermal or parenteral administration.
An amount effective to treat the disorders hereinbefore described depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 0.1 to 50 mg for example 0.5 to 10 mg, of the potassium channel activator, such a compound of formula (I) or a pharmaceutically acceptable salt thereof. Unit doses will normally be administered once or more than once a day, for example 2, 3, or 4 times a day, more usually 1 to 3 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.1 to 50 mg, for example 0.5 to 10 mg, that is in the range of approximately 0.001 to 1 mg/kg/day, more usually 0.005 to 0.2 mg/kg/day.
Within the above indicated dosage range, no adverse toxicological effects are indicated with potassium channel activators in the method of treatment according to the invention.
For oral or parenteral administration, it is greatly preferred that the potassium channel activator is administered in the form of a unit-dose composition, such as a unit dose oral or parenteral composition.
Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally
administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the an.
Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
These solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose,
carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl propyl p-hydroxybenzoate or sorbic acid , and if a desired conventional flavouring or colouring agents.
Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
For parenteral administration, fluid unit dose forms are prepared containing the potassium channel activator and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.
Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
As is common practice, the compositions will usually be accompanied by written or printed directions for use in the treatment concerned.
The present invention also provides the use of a potassium channel activator, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of pain in mammals such as humans. Such treatment and/or prophylaxis may be carried out as hereinbefore described.
The present invention further provides a pharmaceutical composition for use in the treatment of pain which comprises a potassium channel activator, such as or a compound of formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
Types of pain that are particularly suitable for treatment by potassium channel activators such as or a compound of formula (I) or a pharmaceutically acceptable salt thereof, include pain associated with inflammation (such as arthritis) and peripheral diabetic neuropathy, the stump pain associated with amputation, and the pain associated with cancer.
Such compositions may be prepared in the manner as hereinbefore described. The following pharmacological data illustrates the present invention. Pharmacological Data
Method 1 Facilitation of the tail-flick reflex by noxious cutaneous stimulation in the rat
R. A. Cridland and J. L. Henry, Brain Res.462 (1988)15-21. MATERIALS AND METHODS
Anaesthesia
Experiments were done on lightly anaesthetised male Sprague-Dawley rats (250-350g). Anaesthesia was induced by an i.p. injection of a solution of sodium pentobarbital (20mg/kg).
Measurement of reaction time in the tail flick test
To elicit the tail withdrawal reflex, the tail was placed above a projector bulb which was focussed 10-12cm proximal to the tip of the tail. A flick of the tail exposed the light beam to a photodetector which in turn stopped the beam and was linked to a timer displaying the reaction time, measured to within one hundredth of a second. Reaction time to tail withdrawal was measured at 3 min intervals. Three successive readings were taken to establish the baseline reaction time. The experiment was not continued unless these three reaction times had a standard deviation of less than 10% of the mean. The intensity of the bulb was set so that the baseline reaction time was a few seconds and was not adjusted thereafter. Trials were terminated automatically if a tail flick did not occur within 10 seconds. Prolonged noxious cutaneous stimulation by tail immersion
After 3 readings were taken to establish the baseline reaction time, intense noxious stimulation was applied to the tail by immersing the distal 4cm in water maintained at 55±1°C for 1.5min. There was usually an initial withdrawal reflex but this subsided rapidly so that the tail remained flaccid in the water for the remainder of the immersion period. Immersion was timed to end 0.5min prior to the next test for reaction time. Four more readings were then taken and the animal was sacrificed. In a group of animals (±) trans-3,4- dihydro-2,2-dimethyl-4-(2-oxo- piperidin-1-yl)-2H-pyrano[3,2-c]pyridin-3-ol (HT 44033)(10mg/kg) was
administered s.c. 20 mins prior to establishing the mean baseline reaction time and the experiment was carried out as above.
Results
The following graph was obtained showing that the compound clearly attenuated the effects of tail-immersion on reaction time.
Method 2
Para-phenylquinone-induced abdominal writhing test in mice The methodology employed is based on that described by Sigmund et al,
Proc. Soc. Exptl. Biol. 95, 729/1957, modified by Milne and Twomey, Agents and Actions, 10, 31/1980.
Male Charles River mice (Swiss Strain), 20-35g body weight, are used- Animals are allowed food and water ad libitum and are randomized into groups of 10 prior to experimentation. Test compounds are dissolved in either distilled water or distilled water plus 0.1 M AMS, and administered by the subcutaneous route in a final volume of 10 ml/Kg. Control animals receive 10 ml/Kg of the appropriate vehicle alone. Following a pretreatment period of 20 min., mice are injected intraperitoneally with p-phenylquinone, 2 mg/Kg at 37°C in a final volume of 10 mg/Kg. The mice are then placed, in groups of 3, in a compartmented perspex box maintained at room temperature and are observed for a period of 8 min. During this period the number of abdominal writhing responses per animal are recorded where writhing consists of an intermittent contraction of the abdomen associated with hind leg extension.
The degree of antinociceptive protection afforded by a test compound is determined as the mean number of writhing responses observed in the treated group (T) expressed as a percentage of the mean number of writhing responses in the control group (C) according to the following formula:
1-T x 100% = % graded protection
C
Results
Cromakalim has an ED50 of 15 mg/kg s.c. in the above test. Levcromakalin has an ED50 of 13 mg/kg s.c. in the above test. Pinacidil 30 mg/kg s.c. = 53%
Figure imgf000017_0001
Method 3
Antinociception
Tail-flick test in mice
The methodology employed is based on that described by D'Amour and
Smith, J. Pharmacol. Exp. Ther. 72, 74 (1941).
Male Charles River mice (Swiss Strain) 29-35 g body weight are used.
Animals are allowed food and water ad libitum and are randomized into groups of 10 prior to experimentation. Before administration of the test compound, the reaction time of each animal is determined by focusing a beam of light onto the tail, eliciting a reflex withdrawal after a certain latency; only mice exhibiting a latency between 3-8 sec. are used subsequently in the evaluation of drug effects.
Test compounds are dissolved in either distilled water of distilled water plus 0.1M AMS and administered by the intrathecal route in a final volume of 5 μl/mouse, according to the method described by Hylden and Wilcox, Eur. J. Pharmacol. 67, 313 (1980).
Four hours prior the beginning of experiments, mice are anaesthetized with pentobarbital (80mg/Kg i.p.) and a caudal cutaneous incision (1 cm) is performed on the back using a disposable 30 gauge 1/2 inch needles mated to a 50 μl luer siringe d(Hamilton). The drug are delivered intrathecally between L5 and L6 of spinous process.
Control animals receive 5 μl/mouse of the appropriate vehicle alone.
Following a pretreatment period of 10 min., the mice are again placed under the heat source and the rection time re-determined.
Percentage quantal protection is determined as the number of mice in which the reaction time is doubled compared to pretreatment values, expressed as a apercentage of the total number of mice in the group.
Results
Interaction between Morphine and Cromakalim
Figure imgf000019_0001

Claims

Claims
1. A method for the treatment of pain in mammals, which comprises administering to the mammal in need of such treatment an effective amount of a potassium channel activator.
2. A method according to claim 1 in which the potasium channel activator is a compound of formula (I), or a pharmaceutically acceptable salt thereof:
Figure imgf000020_0004
wherein:
P is a ring system selected from the following:
a)
Figure imgf000020_0001
wherein;
Figure imgf000020_0002
Figure imgf000020_0003
and the other variables are as defined below:
b)
Figure imgf000021_0003
in which either a and b together represent a bond or CH2 or a and b together represent a carbonyl group, a group C=NORF CHORF or
Figure imgf000021_0005
F
C-O-C-R
where RF is hydrogen or C1-6 alkyl; or c)
Figure imgf000021_0002
in which either J is nitrogen and Ja is a lone pair of electrons, M is carbon and
Ma is R5; or
J is carbon and M is nitrogen and Ja and Ma are hydrogen; or d)
Figure imgf000021_0001
in which Z is oxygen or CH2;
e)
Figure imgf000021_0004
in which X is oxygen or NR in which R is hydrogen or C1 -4 alkyl; Y is nitrogen and R2 is hydrogen or Y is C-R1 ; and; where:
either one of R1 and R2 is hydrogen and the other is selected from the class of hydrogen, C3-8 cycloalkyl, C1-6 alkyl optionally interrupted by oxygen or substituted by hydroxy, C1-6 alkoxy or substituted aminocarbonyl. C1-6 alkylcarbonyl, C1-6 alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkoxy, nitro, cyano, halo,
trifluoromethyl, CF3S, or a group CF3-A-, where A is -CF2-, -CO-, -CH2-, CH(OH), SO2, SO, CH2-O, or CONH, or a group CF2H-A'- where A' is oxygen, sulphur, SO, SO2, CF2 or CFH; trifluoromethoxy, C1-6 alkylsulphinyl, perfluoro C2-6
alkylsulphonyl, C1-6 alkylsulphonyl, C1-6 alkoxysulphinyl, C1-6 alkoxysulphonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulphinyl, heteroarylsulphinyl, aiylsulphonyl,
heteroarylsulphonyl in which any aromatic moiety is optionally substituted, C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl, C1-6 alkyl-thiocarbonyloxy, 1-mercapto C2-7 alkyl, formyl, or aminosulphinyl, aminosulphonyl or aminocarbonyl, any amino moiety being optionally substituted by one or two C1-6 alkyl groups, or C1-6 alkylsulphinylamino, C1-6 alkylsulphonylamino,C1-6 alkoxysulphinylamino or C1-6
alkoxysulphonylamino, or ethylenyl terminally substituted by C1-6 alkylcarbonyl, nitro or cyano, or -C(C1-6 alkyl)NOH or -C(C1-6 alkyl)NNH2, or one of R1 and R2 is nitro, cyano or C1-3 alkylcarbonyl and the other is methoxy or amino optionally substituted by one or two C1-6 alkyl or by C2-7 alkanoyl; or where possible R1 and R2 when adjacent together are -(CH2)4- or -CH = CH-CH = CH-, or form an optionally substituted triazole or oxadiazole ring;
one of R3 and R4 is hydrogen or C1 -4 alkyl and the other is C1 -4 alkyl, CF3 or CH2 Xa where Xa is fluoro, chloro, bromo, iodo, C1 -4 alkoxy, hydroxy, C1 -4
alkylcarbonyloxy, -S-C1 -4 alkyl, nitro, amino optionally substituted by one or two C1 -4 alkyl groups; cyano or C1 -4 alkoxycarbonyl or R3 and R4 together are C2-5 polymethylene optionally substituted by C1-4 alkyl;
R5 is C1-6 alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy or C1-6 alkoxy and R6 and R9 are hydrogen or R5 is hydroxy and R6 is hydrogen or C1 -2 alkyl and R9 is hydrogen or R5 together with R9 represents a bond and R6 is hydrogen or R6 and R9 represents a bond and R5 is hydroxy,
R7 is a group of structure i):
Figure imgf000023_0001
(i) wherein
either X is oxygen or sulphur; and
R7 is hydrogen, C1-6 alkyl optionally substituted by hydroxy, C1-6 alkoxy, C1-6 alkoxycarbonyl or carboxy, C1-6 alkyl substituted by halogen, or C2-6 alkenyl; aryl or heteroaryl either being optionally substituted by one or more groups or atoms selected from the class of CF3, CF3O-, C1-6 alkoxy, hydroxy, halogen,
trifluoromethyl, nitro, cyano, C1 -12 carboxylic acyl, or amino or aminocarbonyl optionally substituted by one or two C1-6 alkyl groups; and
R8 is hydrogen, C1-6 alkyl, or a group ORp or NHCORq wherein Rp is hydrogen, C1-6 alkyl, aralkyl, C1-7 alkanoyl or aroyl and Rq is as defined above for R7 ; or
R7 and R8 are joined together to form C3-4 polymethylene optionally substituted by one or two C1-6 alkyl groups or hydroxy C1-6 alkyl, or -CH2-(CH2)n-Z-(CH2)m- wherein m and n are integers 0 to 2 such that m+n is 1 or 2 and Z is oxygen, sulphur or NR9 wherein R9 is hydrogen, C1-9 alkyl, C2-7 alkanoyl, phenyl C1 -4 alkyl, naphthylcarbonyl, phenylcarbonyl or benzylcarbonyl optionally substituted in the phenyl or naphthyl ring by one or two C1-6 alkyl, C1-6 alkoxy or halogen; mono- or bi-cyclic heteroarylcarbonyl; or R7 and R8 are joined to form -B 1=B2-B3=B4- wherein one of B 1 to B4 is CRr or N and the other three are CRr wherein Rr is hydrogen or C1-6 alkyl;
or X is N-CN, N-NO2, N-COR10 or N-SO2R10 wherein R10 is C1-3 alkyl, NH2, NH(C1-3 alkyl). CF3 or phenyl optionally substituted as defined for Rx; and
R7' is NHR11 wherein R1 1 is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl or C2-6 alkynyl; and
R8 is hydrogen or C1-6 alkyl; or
R7' and R8 together are C2-4 polymethylene;
or R7 is a group of structure ii):
Figure imgf000023_0002
(ii) wherein A is O or NR14 wherein R14 is hydrogen, C1 -4 alkyl, formyl, acetyl or hydroxymethyl;
B is N or CR15 wherein R15 is hydrogen, halogen, formyl or hydroxymethyl: C is CH2, O, S, CH-Halogen, amino or C1-6 alkylamino;
p is 1, 2 or 3; and
R12 and R13 are independently hydrogen or methyl or together are oxo- or thia-; or R7 is a group of structure iii)
Figure imgf000024_0001
(iϋ) wherein
J is O or NR18 wherein R18 is hydrogen or C1-6 alkyl, and R16 and R17 are independently hydrogen, C1-6 alkyl, or (when R16 is hydrogen) then R17 is allyl, propargyl or C3-6 cycloalkyl; or R7 is a group of structure iv)
(iv) wherein
R19 is hydrogen or C1-6 alkyl; and R20 is halo, amino or methylamino;
or R7 is, or formula v);
Figure imgf000024_0003
(v) or R7 is tetrahydroisoquinolinone, 2,3-dihydro-1H- isoindol-1-one, 2-pyridine N-oxide, 2-hydroxyphenyl or 2-hydroxypyridine (all our possible somers);
the R7 moiety being cis or trans to the R5 group when R5 is other than hydrogen or a bond.
3. A method according to claim 1 in which P is selected from e).
4. A method according to claim 2 or 3 in which Y is nitrogen and R2 is hydrogen.
5. A method according to claim 2 or 3 in which Y is C-R1 and R2 is hydrogen.
6. A method according to claim 5 in which R1 is cyano.
7. A method according to any one of claims 2 to 6 in which R3 and R4 are both methyl.
8. A method according to any one of claims 2 to 7 in which R5 is hydroxy and R8 and R9 are both hydrogen.
9. A method according to any one of claims 2 to 8 in which X is oxygen.
10. A method according to any one of claims 2 to 9 in which R7 is selected from i).
11. A method according to claim 10 in which R7 is 2-oxo-1-pyrrolidinyl or 2- oxo-1-piperidinyl.
12. A method according to claim 1 or 2 in which the potassium channel activator is (±)trans-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin-1-yl)-2H-pyrano- [3,2-c]pyridin-3-ol.
13. A method according to claim 1 or 2 in which the potassium channel activator is (±)-6-cyano-3,4-dihydro-2,2-dimethyl-trαns-4-(2-oxo-1-pyrrolidinyl)-2H- benzo[b]pyran-3-ol.
14. A method according to claim 1 or 2 in which the potassium channel activator is RO 316930, SDZ PCO-400, WAY- 120491, HOE-234, HOE-231, S-0121, FR 119748, EMD 57283, YM 934, NIP-121, RWJ-29009, BRL 55834, BDF 9333, U-89, 232, KP294, SR 47063, Y27152, Y26763, UR 8225, KC-399, LP805, KRN 2391 and nicorandil.
15. A method of treating pain in mammals comprising the co-administration to the sufferer in need thereof, a μ-receptor antagonist and a potassium channel activator.
16. A method according to claim 15 in which the μ-receptor antagonist is morphine.
17. A method according to claim 15 or 16 in which the potassium channel activator is cromakalim or levcromakalim.
18. The use of a potassium channel activator in the manufacture of a medicament for the treatment of pain in mammals.
19. A pharmaceutical composition for use in the treatment of pain which comprises a potassium channel activator and a pharmaceutically acceptable carrier.
PCT/GB1993/002548 1992-12-17 1993-12-14 Use of potassium channel activators for the manufacture of a medicament for the treatment of pain WO1994013272A1 (en)

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WO1999024435A1 (en) * 1997-11-06 1999-05-20 EGIS Gyógyszergyár Rt. Azachromachalime derivatives having hypotensive activity
WO2000034287A3 (en) * 1998-12-04 2000-10-12 Cambridge Bioclinical Limited Spirocyclic thienopyrans as potassium channel activators
US6342517B1 (en) 1998-12-04 2002-01-29 Cambridge Bioclinical Limited Potassium channel activators and their use
US9371329B2 (en) 2009-07-27 2016-06-21 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8952034B2 (en) 2009-07-27 2015-02-10 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9079901B2 (en) 2010-07-02 2015-07-14 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8703759B2 (en) 2010-07-02 2014-04-22 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9403782B2 (en) 2011-05-10 2016-08-02 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9115096B2 (en) 2011-05-10 2015-08-25 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9682998B2 (en) 2011-05-10 2017-06-20 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8962610B2 (en) 2011-07-01 2015-02-24 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9193694B2 (en) 2011-07-01 2015-11-24 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8697863B2 (en) 2011-07-01 2014-04-15 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8586732B2 (en) 2011-07-01 2013-11-19 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9598435B2 (en) 2011-07-01 2017-03-21 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9676760B2 (en) 2011-07-01 2017-06-13 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9695192B2 (en) 2011-07-01 2017-07-04 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators

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