Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
  • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
  • C07D221/20—Spiro-condensed ring 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
  • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
  • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

• the invention relates to organic compounds characterized as having a fused bicyclic ring system substituted with a spiro nitrogen-containing third ring.
• the compounds are effective for treating seizures and chronic pain in mammals.
• DRG Dorsal root ganglion
• TTX-resistant (TTX-R) current In rat DRG neurons, PGE2, adenosine and serotonin, three agents that produce hyperalgesia in vivo, increase the magnitude of the TTX-R current, and shift its conductance/voltage relationship in a hyperpolarized direction (Gold et al, 1996). Following nerve injury, TTX-R currents are down regulated in DRG neurons, and, in the same animals, TTX-S currents are upregulated (Cummings and Waxman, 1997). Using a Na channel specific antibody, Devor et al.
• Sodium channel blockers have been shown effective in chronic pain syndromes, including trigeminal neuralgia, diabetic neuropathy, migraine prophylaxia and cancer pain (review by McQuay et al. ,1995, British Medical Journal 1995; 311 : 1047-1052, and references cited therein).
• pain due to acute or chronic nerve injury is difficult to treat, and is often resistant to conventional analgesics.
• Such compounds include some local anesthetics and anticonvulsants, for example lidocaine, etidocaine, benzocaine, tetracain, riluzole, phenytoin, and gabapentin. Most of them, even though such agents modulate Na channels, have limited clinical use because of high risks of adverse events. Lidocaine, for example, can cause cardiovascular collapse and resultant cardiac arrest. Benzocaine, can cause respiratory distress, as well as skin rash, erythema and oedema. The use of phenytoin for seizure disorders can result in hyperglycemia.
• neuropathic pain e.g. chronic pain
• diseases such as cancer, as well as severe physical injuries and diabetic neuropathy
• the need continues to find compounds which can be utilized clinically without resulting in severe adverse events.
• the inventors have now discovered a series of tricyclic compounds which are potent antagonists of neuronal Na channels.
• the compounds are characterized as fused bicyclic ring systems having a spiro third ring substitution.
• the invention therefore provides tricyclic compounds of Formula I:
• R and R together are oxygen ;
• A is a bond, CH 2 , CH CH 3 , CH 2 CH 2 or C(CH 3 ) 2 ;
• R and R are the same or different and are hydrogen, halo, Ci- -C ⁇ alkyl,
• R are the same or different and are hydrogen, Ci-Cg alkyl or benzyl ;
• alkyl, alkenyl and cycloalkyl groups can be substituted by 1, 2 or 3 groups selected from halo, C3-C6 cycloalkyl, phenyl or substituted phenyl, and the pharmacentically acceptable salts thereof.
• the compounds of the invention are useful in the clinical management and treatment of various conditions such as seizure disorders, epilepsy, neuroprotection, preferably for conditions such as cerebral ischemia, hypoxia and head trauma, local anesthesia, pain, preferably acute, chronic, neuropathic, visceral and somatic pain, irritable bowel syndrom (IBS), the treatment of drug dependence, migraine and obsessional compulsive disorders.
• various conditions such as seizure disorders, epilepsy, neuroprotection, preferably for conditions such as cerebral ischemia, hypoxia and head trauma, local anesthesia, pain, preferably acute, chronic, neuropathic, visceral and somatic pain, irritable bowel syndrom (IBS), the treatment of drug dependence, migraine and obsessional compulsive disorders.
• IBS irritable bowel syndrom
• Preferred compounds are those of Formula I wherein R is hydrogen, C ⁇ -
• alkyl optionally substituted with phenyl or a C3-C6 cycloalkyl group.
• R is hydrogen or C1 -C 4 alkoxy.
• Most preferred compounds of the invention are compounds of Formula I wherein R 1 and R 2 together are oxygen and A is CH 2 .
• R is hydrogen or C 1 -C4 alkoxy.
• Another embodiment of this invention is a pharmaceutical formulation comprising a compound of Formula I admixed with a pharmaceutically acceptable carrier or diluent.
• a further embodiment of the present invention is a method for treating a mammal suffering from pain and in need of treatment, comprising administering an effective amount of a compound of Formula I.
• Still another embodiment of the invention is a method for treating a seizure disorder in a mammal in need of treatment, comprising administering a compound of Formula I.
• C -C ⁇ alkyl means a straight or branched carbon chain made up of from one to six carbon atoms.
• Examples of C ⁇ -C(, alkyl groups include methyl, ethyl, isopropyl, sec-butyl, tert-butyl, isopentyl and n- hexyl.
• Ci-C6 alkoxy means the foregoing alkyl groups bonded through oxygen, for example methoxy, isopropoxy, and »-hexyloxy.
• C 2 -C6 alkenyl means a straight or branched carbon chain having from two to six carbon atoms, with one carbon-carbon double bond present in the chain. Examples include ethenyl, 2-propenyl, l-methyl-3-pentenyl, l-ethyl-2-butenyl, and 5-hexenyl.
• C3-C6 cycloalkyl means a non-aromatic cyclic ring having from three to six carbon atoms, examples being cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• alkyl, alkenyl and cycloalkyl groups may be substituted by
• Halo means chloro, bromo, fluoro and iodo.
• Substituted phenyl means a phenyl group having 1, 2 or 3 substituents selected from halo, hydroxy, nitro, unsubstituted Cj-Cg alkyl, unsubstituted C1-C alkoxy, and NH 2 .
• Ci -C ⁇ alkyl groups substituted with cycloalkyl thus include cyclopropylmethyl, 1-cyclobutylethyl, 3-cyclohexylbutyl and 3,3-dicyclohexyl- propyl.
• Alkyl groups substituted with halo include chloromethyl, 1,2-dibromo- ethyl, trifluoromethyl, and l-bromo-3-chloro-6-iodohexyl.
• Alkyl groups substituted with phenyl or with substituted phenyl include benzyl, 1-phenylpropyl, l-methyl-3-phenyl-butyl, 3-chlorophenylmethyl, 2,3-dimethoxybenzyl, 3-(2- methyl-5-fluoro-6-nitrophenyl)-butyl, and 3,3-diphenylpropyl.
• substituted C 2 -C ⁇ alkenyl groups examples include 2-cyclobutylethenyl,
• substituted C3-C6 cycloalkyl groups include 3-cyclo- pentylcyclohexyl, 2-phenylcyclobutyl, 3-chlorocyclopentyl, 2,2-dibromo-3-nitro- cyclohexyl, and 2,2-di-(3-methoxyphenyl)-cyclopropyl.
• substituted Cj-C ⁇ alkoxy groups include trichloromethoxy, cyclopropylmethoxy, l-methyl-2-phenylpropoxy and 2,3-di-(2,4-dinitrophenyl)- hexyloxy.
• Examples include acetyl, pivaloyl, l-oxo-3- pentenyl, 1-oxocyclobutylmethyl, l-oxo-3-phenyl-4-cyclohexylpentyl, and 1-oxo- (3-phenylcyclopentyl)-methyl.
• the invention compounds can thus have the following general structures:
• Preferred compounds of the present invention include the following: 3,4-Dihydro-l-oxospiro[naphthalene-2(lH),4'-piperidine]; -cyclopropylmethyl-3,4-Dihydro-l-oxospiro[naphthalene-2(lH),4'-piperidine]; -cyclobutylmethyl-3,4-Dihydro-l-oxospiro[naphthalene-2(lH),4'-piperidine]; r-cyclohexylmethyl-3,4-Dihydro-l-oxospiro[naphthalene-2(lH),4'-piperidine]; l '-phenylethyl-3,4-Dihydro-l-oxospiro[naphthalene-2(lH),4'-piperidine]; r-cyclopropylethyl-3,4-Dihydro-l-oxospir
• More preferred compounds of the invention include the following:
• Most preferred compounds of the invention include the following: r-cyclopropylmethyl-3,4-Dihydro-l-oxospiro[naphthalene-2(lH),4'-piperidine]; r-cyclopropylethyl-3,4-Dihydro-l-oxospiro[naphthalene-2(lH),4'-piperidine]; r-cinnamyl-3,4-Dihydro-l-oxospiro[naphthalene-2(lH),4'-piperidine]; l '-(3,3-diphenylpropyl)-3,4-Dihydro-l-oxospiro[naphthalene-2(lH),4'- piperidine]; l'-(cyclopropylmethyl)-3,4-Dihydro-6-methoxy-l-oxospiro[naphthalene-2(lH),4'- piperidine]; l
• the compounds of Formula I are characterized by being bicyclic rings having a spiro ring as a substituent group.
• the spiro ring contains a nitrogen atom
• N-R which can be basic in nature when R is a group such as alkyl, alkenyl or cycloalkyl.
• Such basic compounds readily form pharmaceutically acceptable salts by reaction with common inorganic and organic acids.
• Typical acids utilized to form the pharmaceutically acceptable salts of the invention include hydro- chloric, sulfuric, sulfamic , phosphoric , citric , succinic , glutamic , maleic , lactic, tartaric, -toluenesulfonic, benzoic , oxalic and salicyclic acid.
• the salts are prepared by simply contacting the spiro base with the appropriate acid, generally in a solvent such as methanol or diethyl ether.
• the salts generally are highly crystalline, readily precipitate, and are recovered by filtration. They can be further purified if desired by recrystallization from common solvents such as methanol, ethyl acetate, acetone and tetrahydrofuran.
• R , R , R , and A have the meanings given above, and " L " is a normal leaving group (e.g. halo such as chloro or bromo, or a silyl derivative such as trimethylsilyl).
• L is a normal leaving group (e.g. halo such as chloro or bromo, or a silyl derivative such as trimethylsilyl).
• reaction is carried out by combining approximately equimolar quantities of the spiro amine with the alkylating or acylating agent
• L-R generally in an unreactive organic solvent such as tetrahydrofuran, dimethylsulfoxide, or N,N-dimethylformamide.
• a base such as triethylamine or
• NaHCO3 can be utilized to act as an acid scavenger if desired.
• the reaction typically is substantially complete after about 2 - 20 h, when conducted at a temperature is about 25°C to about 60°C.
• the product is readily isolated by removing the reaction solvent, and further purification can be achieved if desired by normal means such as salt formation, crystallization, and chromatography.
• the required starting material i.e. the spiro amine, can be synthesized from readily available reactants, utilizing any of several methods:
• P is an amine-protecting group that is easily removed, for example ethoxycarbonyl or benzyl.
• the protected diethylamine derivative is readily reacted with a bicyclic ketone in the presence of a strong base such as NaH.
• This reaction results in formation of the spiro amino derivative, which is readily de-protected by conventional means, for instance by reaction with hydrochloric acid.
• Scheme 2 illustrates the preparation of keto substituted starting materials
• the invention compounds of Formula I can alternatively be prepared by starting with a suitably substituted piperidine derivative, as shown in Scheme 4 :
• the cyclization reaction is accomplished by reacting the substituted piperidine with strong dehydrating agents such as phosphorus pentachloride and titanium tetrachloride, generally in an unreactive organic solvent such as benzene, toluene, xylene, or chloroform.
• strong dehydrating agents such as phosphorus pentachloride and titanium tetrachloride
• unreactive organic solvent such as benzene, toluene, xylene, or chloroform.
• the reaction normally is complete within 2 h when carried out at a temperature of 30°C to 60°C. 1 * >
• the cychzed product is a compound of Formula 1 wherein R and R " together are oxo, which, as noted abo ⁇ e in Scheme 3, can be reduced to the corresponding
• reaction carried out at about -20°C, generally is substantially complete after about 2 - 4 h.
• the alkylated piperidine can then be deprotected (removal of the L-protecting group) and cychzed by reaction with
• PCI5 and TiCl4 can be cychzed first, and the L-protecting group subsequently removed.
• Stage 1 Bis(2-bromoethyl)amine hydrobromide.
• Stage 3 Ethyl 3,4-dihydro- 1 -oxospiro [naphfhalene-2(lH),4'-piperidine]-r- carboxylate.
• the mixture is stirred and brought to reflux for 14 h. It is then cooled and extracted with twice 500 ml of ethyl ether.
• the aqueous phase is basified while cold with NaO ⁇ and extracted with 3 times 500 ml of ethyl ether.
• the organic phase is washed and dried over Na 2 SO 4 . After evaporating the solvent, the residue is purified by chromatography by eluting with C ⁇ 2 C1 2 gradually enriched with methanol containing 10% NH 4 OH.
• the hydrochloride is prepared by addition of approximately 5N ethereal hydrochloric acid to a solution of the crude product in
• IR 3400, 2900, 2650, 2500, 1680, 1590, 1430, 1360, 1300, 1220, 1140, 1100,
• Example 2 The method described for Example 2, using phenethyl bromide, results in the product in the hydrochloride form.
• IR 3400, 2900, 2500, 1670, 1600, 1450, 1360, 1290, 1220, 1110, 1010, 960, 820,
• the ethereal phase is extracted with 100 ml of IN HCl and then twice with 50 ml of water.
• the aqueous phase is basified while cold with concentrated NaOH and extracted 3 times with 50 ml of ether.
• the organic phase is washed with an NaCl solution and dried over Na 2 SO . The solvent is removed.
• the oily residue is purified by fast chromatography by eluting with CH 2 C1 2 enriched with methanol. 0.6 g is obtained, the hydrochloride of which is prepared by addition of approximately 5N ethereal hydrochloric acid to a solution of the crude product in CH 2 C1 2 . The mixture is concentrated to dryness and then the product is crystallized by addition of 30 ml of ether to a solution of the product in
• IR 3400, 2900, 2500, 1670, 1605, 1470, 1430, 1280, 1180, 1020, 970, 950, 880, 830 cm "1
• Stage 1 2.4 g (8.35 mmol) of ethyl 3,4-dihydro-l-oxospiro[na ⁇ hthalene-2(lH),4'- piperidine]- l'-carboxylate, prepared according to the method described in Stage 3 of Example 1, and 35 ml of concentrated sulphuric acid are introduced into a three-necked flask. 0.79 g (12.5 mmol) of fuming nitric acid is added to the solution cooled to 0°C. The mixture is stirred for 1 h at 0°C and then for 2 h at
• the solvent is removed and the residue is taken up in 20 ml of C ⁇ 2 CI 2 and extracted with 20 ml of N/1 HCl.
• the acidic phase is basified while cold with a dilute sodium hydroxide solution to pH 12 and extracted with 3 times 20 ml of CH 2 C1 2 .
• the residue is chromatographed by eluting with CH 2 C1 2 gradually enriched with methanol containing 10% NH OH. 0.130 g of 3,4-dihydro- l'-(cyclopropylmethyl)-7-nitro-l- oxospiro[naphthalene-2(lH),4'-piperidine] is obtained.
• the hydrochloride is prepared as described above.
• White powder, M.p. 256°C.
• Stage 1 Piperidine- 1 ,4-dicarboxylic acid, 4-ethyl 1 -t-butyl diester.
• 60 g (0.381 mol) of ethyl isonipecotate and 400 ml of T ⁇ F are placed in a three- necked flask which is protected from moisture and which is under an inert atmosphere, and 18.3 g (0.458 mol) of sodium hydroxide pellets are added.
• a solution of 100 g (0.458 mol) of di-t-butyl dicarbonate in 170 ml of T ⁇ F is added over 1 h with stirring to the suspension. The temperature reaches 45°C.
• Stage 2 4-(4-Chlorophenethyl)piperidine-l,4-dicarboxylic acid, 4-ethyl 1 -t-butyl diester
• Stage 3 Ethyl 4-(4-chlorophenethyl)piperidine-4-carboxylate 10.8 g of the product from the preceding Stage 2 and 50 ml of CH 2 C1 2 are introduced into a three-necked flask which is protected from moisture. The solution is stirred and 25 ml of trifluoroacetic acid are added at 20-25°C.
• Stage 6 7-Chloro-3,4-dihydro-l'-(cyclopropylmethyl)-l- oxospiro[naphthalene-2(lH),4'-piperidine].
• the aqueous phase is washed with ether and then basified to pH 12 with NaOH and extracted with ether.
• the organic phase is washed, dried and concentrated.
• the crude product is chromatographed by eluting with CH 2 C1 2 gradually enriched with methanol containing 10%> NH- 4 OH. 22 mg of product are obtained, which product is treated in solution in CH 2 C1 2 with 5N ethereal hydrochloric acid. After crystallization from ethyl acetate, the product is filtered off and dried at 50°C under vacuum.
• the invention compounds of Formula I are useful for treating chronic pain and other CNS disorders such as seizures, e.g. epilepsy.
• the compounds have been evaluated in standard assays to measure their ability to block isolated mammalian Na neuronal channels, as well as their ability to antagonize prostaglandin E 2 (PGE 2 ) production. Both assays are routinely utilized to indicate clinical utility of compounds for treating chronic pain and other CNS disorders (see Tonelian et al, Anesthesiology, 24: 949-951, 1991).
• EXAMPLE 71 EXAMPLE 71
• Cerebral cortices from male Sprague-Dawley rats were homogenized in a glass- Teflon homogenizer in 10 volumes of ice-cold 0.32 M sucrose, 5 mM K 2 HPO4
• the homogenate was centrifuged at 1000 g. for 10 min, the pellet was resuspended in the same volume of sucrose and recentrifuged. The pellet was discarded and the two supernatants resulting from these two centrifugations were pooled and centrifuged at 20000 g. for 10 min. The resulting pellet was resuspended in a Na-free assay buffer containing 50 mM HEPES, 5.4 mM KCl,
• Binding assay were initiated by the addition of 150-200 ⁇ g synaptosomal protein to an assay buffer containing 25 ⁇ g scorpion venom (Leirus quinquestriatus ' )-- 0.1 %
• Characterization of Na + channels activity is performed using human SK-N-SH cells in 96-well culture plates. The effect of tested compounds on Na + influx through the Na + channels is evaluated under stimulation by veratridine. SK-N-SH cells are preincubated for 15 min at 37°C in the presence of test compounds in a 25 mM hepes/Tris pH 7.5 buffer containing 5.4 mM KCl, 0.8 mM MgSO 4 , 1.8 mM CaCl 2 , 5mM glucose, 0.1% BSA, 140 mM choline chloride.
• the influx of Na + is induced by the incubation for 10 min at 37°C of SK-N-SH cells in the presence of test compound and veratridine in the incubation buffer supplemented with 1 ⁇ M ouabaine, 10 mM NaCl, 130 mM choline chloride and 22 Na + (Jacques, Y, Fosset, M. and Lazdunski, M., (1978), Molecular properties of the action potential Na+ ionophore in neuroblastoma cells. J. Biol. Chem., 253, 7383-7392). Following this 22 Na + uptake, cells are washed with 0.1 mM MgCl 2 .
• the radioactivity is then measured with a microplate reader (Topcount, Packard) after the addition of a scintillation liquid (Microscint 40, Packard).
• the reference compound is tetrodotoxin tested at 7 concentrations ranging from 10 "10 M to 10 "7 M in order to determine an IC 5 o value.
• the test consists in determining the analgesic effect of the test compound in rats by the Randall and Selitto test, in which chronic hyperalgesia has been triggered by intraplantar injection of PGE over 4 days into a leg, according to a protocol adapted from Nakamura-Craig et al (Pain, 63: 33-37, 1995).
• 100 ng of PGE is administered in a volume of 100 ⁇ l by the intraplantar route, for 4 consecutive days twice a day; this causes chronic hyperalgesia in the leg from the 5th day, for at least one week.
• the threshold of reaction to pain is checked by the Randall and Selitto test, and animals whose threshold is ⁇ lOO arbitrarily defined units are selected.
• the measurement is repeated after prior administration by the s.c. route of a solution of the test compound; this administration is carried out 30 min before measuring the pain threshold.
• the analgesic activity (%) is calculated from the means of the thresholds measured before and after treatment, as compared with that of the control animals, who received only the vehicle.
• Table 3 lists the Na channel binding and the analgesic activities of representative compounds of the invention when measured in the foregoing assays.
• the compounds are particularly well suited to the treatment of diabetic neuropathy, which is the most common complication accompanying diabetes mellitus.
• the compounds also are useful for prophylaxis and treatment of migraine.
• the invention compounds can be administered to humans who are in need of treatment for a chronic pain condition or seizure disorder by both the oral and parenteral routes, for instance as tablets or capsules, or as subcutaneous or intravenous injections.
• the compounds will be administered in an amount which is effective to control and treat the seizure disorder or relieve the neuropathic pain sensation.
• Such effective amounts will generally be from about 0.1 to about 2000 mg/kg of mammalian body weight. Commonly prescribed doses will be from about 5 mg/kg to about 500 mg/kg. Such dosage amounts can be administered to adult humans from 1 to 4 times a day for the relief of neuropathic pain and seizure disorders. The precise dose to be employed will depend upon the specific compound of Formula I utilized, the particular condition of the subject being treated, and generally will be dictated by the attending physician or other medical practitioner.
• the compounds can be formulated by normal methods for convenient oral or parenteral dosing. Typical oral forms are tablets, capsules, troches, elixirs, syrups, suspensions, and controlled sustained release forms, for example through osmotic pumps.
• the compounds can likewise be formulated for administration intraperitoneally, subcutaneously, intramuscularly, transdermally, sublingually or intravenously.
• the compounds are formulated by using conventional diluents, excipients, carriers and binders routinely used in the phamaceutical art.
• the compounds can be admixed with carriers, diluents and excipients such as starch, cellulose, PVP, methylcellulose, sugar, wax, talc, and with stabilizers and binders such as Mg stearate, MgO, CaCO3, methyl-/?- hydroxybenzoate (methylparaben), and w-propyl-p-hydrobenzoate (propylparaben).
• carriers diluents and excipients such as starch, cellulose, PVP, methylcellulose, sugar, wax, talc, and with stabilizers and binders such as Mg stearate, MgO, CaCO3, methyl-/?- hydroxybenzoate (methylparaben), and w-propyl-p-hydrobenzoate (propylparaben).
• the above ingredients are blended to uniformity and compressed into a tablet. Such tablets are administered at the rate of 1 to 4 times a day to a human suffering from chronic pain.
• the invention compound is dissolved in the acetate buffer and the pH is adjusted to 6.5.
• Isotonic saline is added to a volume of 1000 ml.
• the solution is filled into a sterile flexible plastic container equipped with a drip tube.
• the solution is administered IN to a patient suffering from diabetic neuropathy.

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