WO1997000872A1 - Derives de 1,3,8-triaza et 3,8-diaza-1-oxaspiro(4,5)-decane - Google Patents

Derives de 1,3,8-triaza et 3,8-diaza-1-oxaspiro(4,5)-decane Download PDF

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WO1997000872A1
WO1997000872A1 PCT/EP1996/002554 EP9602554W WO9700872A1 WO 1997000872 A1 WO1997000872 A1 WO 1997000872A1 EP 9602554 W EP9602554 W EP 9602554W WO 9700872 A1 WO9700872 A1 WO 9700872A1
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formula
compound
alkyl
alkyloxy
halo
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PCT/EP1996/002554
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English (en)
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Jacob Berger
David Scott Carter
Lee Allen Flippin
Klaus Kurt Weinhardt
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F.Hoffmann-La Roche Ag
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Priority to AU61265/96A priority Critical patent/AU6126596A/en
Publication of WO1997000872A1 publication Critical patent/WO1997000872A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/16—Radicals substituted by halogen atoms or nitro radicals

Definitions

  • This application relates to a compound of Formula I:
  • n 2, 3, 4, 5 or 6
  • t is 1, 2, 3 or 4 and u is 0 or 1 (provided that t is not 1 when u is 0) ;
  • X is 0 or N(R 4 ) , in which R 4 is hydro, (C ⁇ _4) lkyl or aryl;
  • Y and Z are independently C(O), C(S) or CH2 (provided that Y and Z are not both CH2) ;
  • R 1 is independently amino, aryloxy, aryl(C ⁇ _4)alkyloxy, arylsulfonyl, arylthio, carbamoyl, cyano, halo, nitro, thiocarbamoyl, thioureido, ureido, a group selected from (C ] __4)alkyl, (C1-.4)alkyloxy and (C]__4) alkylthio (optionally further substituted with one to three halo atoms) , a group selected from -NHS0 2 R 5 , -NHC(0)R 5 , - HC(0)NHR 5 , -NHC(S)NHR 5 and
  • R 5 is (C ] __4)alkyl (optionally further substituted with one to three halo atoms) or a group selected from aryl, aryl (C1-.4)alkyl, heteroaryl and heteroaryl(C]__4)alkyl (optionally further substituted with one to two radicals independently selected from amino, carbamoyl, cyano, halo, nitro, a group selected from (C1--4)alkanoyl,
  • R 2 is hydroxy, halo, (C ⁇ _4>alkyloxy or aryl(C ⁇ _4)alkyloxy; and R 3 is hydro, (C]__g)alkyl (optionally substituted with a group selected from -C(0)0H, -C(0)0(C 1 _ 4 )alkyl, - HSO2R 5 and - HC(0)R 5 , in which R 5 is as defined above), hydroxyalkyi, phenyl (C1-.4)alkyl (optionally substituted with one or two radicals independently selected from amino, cyano, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, acetamido, methanesulfonamido, (C ] __ 4)alkyl, or (C]__4)alkyloxy) , or a group of Formula (a) :
  • n, t and R 1 are as defined above; and the pharmaceutically acceptable salts and N-oxides thereof.
  • a second aspect of this invention is a pharmaceutical composition which contains a compound of Formula I in admixture with one or more suitable excipients.
  • a third aspect of this invention is the processes for preparing the above-identified compounds. Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
  • Aryl as in aryl, aryl(C ⁇ _4)alkyl, aryl(C ⁇ _4)alkyloxy, aryloxy, arylsulfonyl and arylthio means an organic radical derived from an aromatic hydrocarbon containing 6 to 14 carbon atoms and includes monocyclic or condensed carbocyclic aromatic rings (e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.) optionally substituted with one or more radicals.
  • Alkyl as in (C ⁇ _g)alkyl, (C ⁇ _6)alkyloxy and ( ⁇ .4)- alkylthio, means a straight or branched saturated hydrocarbon radical having from one to the number of carbon atoms designated optionally substituted with one to three halo atoms (e.g., optionally substituted (C1-.4)alkylthio includes methylthio, ethylthio, 2,2,2-trifluoroethylthio, etc.; optionally substituted (C]__g)alkyl includes methyl, trifluoro ⁇ methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.; and optionally substituted (C]__g)alkyloxy includes methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isoprop
  • Hydrocarbon radical means a straight or branched monovalent hydrocarbon radical of two to four carbons substituted with one or two hydroxy groups, provided that: (1) the bonding carbon is unsubstituted with hydroxy, and (2) if two hydroxy groups are present, they are not both on the same carbon atom. Examples include 2-hydroxyethyl, 2-hydroxypropy1, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxy- butyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-
  • 2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1- (hydroxymethyl) -2-hydroxyethyl, and 2- (hydroxymethyl) -3-hydroxypropyl.
  • Alkanoyl means the radical —C(0)R, in which R is H or alkyl as the term is defined above (e.g., the term (Cj__4)- alkanoyl includes formyl, acetyl, propionyl, and butyryl) .
  • Carbamoyl means aminocarbonyl
  • Halo means fluoro, chloro, bromo, or iodo.
  • Heteroaryl as in heteroaryl, heteroaryl(C1-.4)alkyl, heteroaryloxy, heteroaryl(C _4)alkyloxy and heteroarylsulfonyl, means an organic radical derived from an aromatic hydrocarbon containing 5 to 14 atoms, 1 to 5 of which are hetero atoms chosen from N, 0, or S, and includes monocyclic, condensed heterocyclic and condensed carbocyclic and heterocyclic aromatic rings (e.g., thienyl, furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxazolyl, indolyl, benzo [b]thienyl, isobenzofuranyl, purinyl, isoquinolyl, pterdinyl, perimidinyl, imidazolyl, pyridyl, pyrazolyl, pyrazinyl, etc.) optionally substituted with one to two radicals independently selected from halo and
  • Thiocarbamoyl means the radical —C(S)NH2-
  • Leaving group has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under alkylating conditions, and includes halogen and alkane- or arenesulfonyloxy, such as mesyloxy, ethane- sulfonyloxy, benzenesulfonyloxy and tosyloxy, and thienyloxy, dihalophosphinoyloxy, tetrahalophosphaoxy, and the like.
  • Animal includes humans, non-human mammals, e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, and deer, and non-mammals, e.g., birds and the like.
  • Disease specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition which may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the "side effects" of such therapy.
  • Protective group has the meaning conventionally associated with it in synthetic organic chemistry, i.e., a group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site and which can be readily removed after the selective reaction is completed.
  • Protecting agent means an agent which will react with a multifunctional compound and create a protective group at reactive nitrogen atoms.
  • Protected in reference to a compound or a group means a derivative of compound or group in which a reactive site or sites are blocked with protective groups.
  • Deprotecting refers to removing any protective groups present after the selective reaction has been carried out.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” means salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid and the like; or with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, p-chlorobenzene-sulfonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, 1, 2-ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hexanoic acid, heptanoic acid, o- (4-hydroxybenzoyl)benzoic acid, 2-hydroxyethanesulfonic acid, hydroxynaphthoic
  • Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine , triethanolamine, tromethamine and the like.
  • N-Oxide when referring to a compound of Formula I, means such compound in which nitrogens are in an oxidized state, i.e., 0 ⁇ — ⁇ .
  • the N-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art.
  • “Therapeutically effective amount” means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
  • q.s means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%) .
  • Treating” or “treatment” of a disease includes:
  • Adjacent as in the term “two adjacent R 1 substituents form ethylenedioxy, methylenedioxy or butadienylene” means that two Rl radicals are at adjacent positions on the phenyl ring and together form a bivalent radical
  • preferred compounds of Formula I are those in which n is 3, 4, 5 or 6; u is 0; X is NH; Y is C(0); Z is C(0) or C(S); two adjacent R ⁇ radicals form ⁇ , ⁇ -ethylenedioxy; a third
  • R radical when present, is amino, phenyl, phenoxy, halo, nitro, ureido, thioureido, (C1-.4)alkyloxy, a group selected from -NHSO2R 5 , -NHC(0)R 5 , -NHC(0)NHR 5 and -NHC(S) HR 5 ⁇ which R 5 is (C ⁇ _4>alkyl or a group selected from phenyl, naphthyl and thienyl (optionally further substituted with one to two radicals independently selected from amino, carbamoyl, cyano, halo, nitro, a group selected from (C1.-.4)alkanoyl, (C ⁇ _4)aikylsulfonylamino, (C ⁇ _4)alkanoylamino, (C ⁇ -4)alkyl and (C]__4)alkyloxy, optionally further substituted with one to three halo atoms, and a group selected from aryl
  • n 3, 4, 5 or 6;
  • X is NH;
  • Y is C(O);
  • Z is C(O) or C(S);
  • u is
  • R ⁇ is amino, phenyl, phenoxy, halo, nitro, ureido, thioureido, (C1..4) alkyloxy, a group selected from -NHS0 2 R 5 , -NHC(0)R 5 , -NHC(0)NHR 5 and -NHC(S)NHR 5 ⁇ which R 5 is (C ⁇ _4)alkyl or a group selected from phenyl, naphthyl, thienyl (optionally further substituted with one to two radicals independently selected from amino, carbamoyl, cyano, halo, nitro, a group selected from (C1-.4)alkanoyl, (C1-.4)aikyl ⁇ sulfonylamino, (C1-.4)alkanoylamino, (C]__4)alkyl and (C__4>- alkyloxy, optionally further substituted with one to three halo
  • the compounds of this invention are selective 5-HT2C receptor antagonists. Affinities for the 5-HT2C receptor were measured by a cloned rat 5-HT2C receptor binding assay (for details see Example 30, infra.) . Antagonist properties were determined in NIH3T3 cells, transfected with cloned rat 5-HT2C receptor, by measuring the propensity of the compounds to inhibit 5-HT induced/5-HT2C mediated increases in cellular metabolic activity (for further details see Example 31, infra.). Accordingly, the compounds of this invention are useful for treating diseases which can be ameliorated by blocking 5-HT2C receptors. For example, clinical and experimental evidence support a therapeutic role for 5-HT2C receptor antagonists in treating anxiety.
  • mCPP also produces anxiogenic effects in rat, social interaction (SI) and elevated X-maze models of anxiety, which effects are blocked by non-selective 5-HT2C/2A receptor antagonists but not by selective 5-HT2A receptor antagonists (see Kennett et al . (1989), Bur. J. Pharmacol . , 164, 445-454 and Kennett (1993), supra.).
  • non-selective 5 ⁇ HT2c/2A receptor antagonists by themselves produce anxiolytic effects in the SI and Geller Seifter conflict tests, while selective 5-HT2A receptor antagonists do not share this property.
  • mCPP when administered to panic disorder patients or obsessive compulsive disorder patients increases levels of panic and/or anxiety (see Charney et al . (1987) , supra., and Zohar et al . (1987), Arch . Gen. Psychiat . , 44, 946-951) .
  • current evidence support the application of selective 5-HT2C receptor antagonists for treating generalized anxiety disorder, panic disorder and obsessive compulsive disorder.
  • Anxiolytic activity can be determined experimentally by the art-recognized Crawley and Goodwin two-compartment exploratory model (e.g., see Kilfoil et al . (1989),
  • Neuropharmacol ⁇ gy, 28(9), 901-905) measures the extent a compound affects the natural anxiety of mice in a novel, brightly lighted area (for further details see Example 32, infra.) .
  • Clinical and experimental evidence support a therapeutic role for selective 5-HT2C receptor antagonists in treating chemical dependency.
  • the 5-HT2C receptor agonist mCPP induces a craving for alcohol in abstaining alcoholics (see Benkelfat et al . (1991), Arch. Gen. Psychiat . , 48, 383) .
  • the non-selective 5-H 2C/2A receptor antagonist ritanserin reduces alcohol preference in rats (see Meert et al .
  • Ameliorating effects of compounds during withdrawal from drugs of abuse can be determined experimentally by the mouse, withdrawal anxiety test, an accepted assay (e.g., see Carboni et al . (1988), Bur. J. Pharmacol , 151, 159-160) .
  • This procedure utilizes the exploratory model described above to measure the extent a compound ameliorates the symptoms of withdrawal that occur after chronically treating with an addictive substance and then abruptly ceasing the treatments (for further details see Example 33, infra.) .
  • Clinical evidence support a therapeutic role for selective 5-HT2C receptor antagonists in treating depression.
  • non-selective 5 ⁇ HT2c 2A receptor antagonists show clinical efficacy in treating depression ' (see Murphy (1978), Brit. J. Pharmacol . , 5, 81S-85S; Klieser et al . (1988), Pharmacopsychiat . , 21, 391-393; and Camara (1991), Biol . Psychiat . , 29, 201A) .
  • experimental results suggest that the mechanism by which conventional antidepressant drugs exert their therapeutic efficacy is through adaptive changes in the serotonergic system (see Anderson (1983), Life Sci , 32, 1791-1801) .
  • the 5-HT2C receptor agonist mCPP when administered to human volunteers reduces total sleep time, sleep efficiency, slow wave sleep (S S) and rapid eye movement sleep (see Lawlor et al . (1991), Biol . Psychiat . , 29, 281-286) .
  • the non-selective 5-HT2Q/2A receptor antagonist ritanserin increases SWS, reduces sleep onset latency and improves subjective sleep quality in healthy volunteers (see Idzikowski et al . (1986), Brain Res . , 378, 164-168; Idzikowski et al . (1987), Psychopharmacology, 93, 416-420; Declerck et al . (1987), Curr. Therap. Res . , 41, 427-432; and Adam et al . (1989),
  • compounds of Formula I will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another compound of Formula I or with another therapeutic agent.
  • a therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • Therapeutically effective amounts of compounds of Formula I may range from 0.1 micrograms per kilogram body weight ( ⁇ g/kg) per day to 1 milligram per kilogram body weight (mg/kg) per day, typically 1 ⁇ g/kg/day to 10 ⁇ g/kg/day. Therefore, a therapeutically effective amount for a 80 kg human may range from 8 ⁇ g/day to 800 mg/day, typically 80 ⁇ g/day to 0.8 mg/day.
  • compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of Formula I in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non- oxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula I.
  • excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like.
  • Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral -oil, sesame oil, etc.) .
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose and glycols.
  • Compressed gases may be used to disperse the compound of Formula I in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, nitrous oxide, etc.
  • Other suitable pharmaceutical carriers and their formulations are described in A.R. Alfonso Remington ' s Pharmaceutical Sciences 1985, 17th ed. Easton, Pa.: Mack Publishing Company.
  • the amount of a compound of Formula I in the composition may vary widely depending upon the type of formulation, size of a unit dosage, kind of excipients and other factors known to those of skill in the art of pharmaceutical sciences.
  • the final composition will comprise from 0.000001%w to 10.0%w of the compound of Formula I, preferably 0.00001%w to 1.0%w, with the remainder being the excipient or excipients.
  • the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required.
  • Representative pharmaceutical formulations containing a compound of Formula I are described in Example 29.
  • the compounds of Formula I can be prepared by the process depicted in Scheme 1.
  • L is a leaving group
  • R ⁇ and R ⁇ form oxo or a carbonyl protective group and each n, t, u, X, Y, Z, R ⁇ -, R 2 and R 3 are as defined above with respect to Formula I.
  • Compounds of Formula I can be prepared by alkylating an appropriate heterocyclic spiro[4.5]decane (Formula 2), typically a salt thereof (e.g., hydrochloride, trifluoro ⁇ acetate, hydrobromide, sulfate, etc.), with an appropriate 1-phenyl-l- (C3-.7)alkanone or protected derivative thereof
  • the alkylation is carried out with 0.8 to 2 molar equivalents, typically 1 to 1.5 and preferably approximately 1.3 molar equivalents of the compound of Formula 2, in a suitable inert organic solvent (e.g., N, N-dimethylformamide (DMF), 1-methyl- 2-pyrrolidione, N, N-dimethylacetamide , dimethylsulfoxide, sulfolane, 1, 1,3,3-tetramethylurea, any appropriate mixture of suitable solvents, etc., preferably DMF) with a suitable base present, typically a nitrogen base (e.g., triethylamine, N, N-diisopropylethylamine , etc.) or a carbonate salt base (e.g., potassium carbonate, sodium carbonate, cesium carbonate, etc.) and preferably triethylamine, and optionally an iodide salt present (e.g., sodium iodide, lithium iodide, sodium iodide, lithium
  • R ⁇ and R " ? comprise a carbonyl protective group
  • R ⁇ and R " ? comprise a carbonyl protective group
  • a detailed description of the techniques applicable to protective groups and their removal can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.
  • a convenient method of deprotecting when the protective group is ethylenedioxy is carried out by acid-catalyzed exchange dioxolanation, by acid-catalyzed hydrolysis or oxidation.
  • a preferred method of cleaving a ethylenedioxy protective group is by acid-catalyzed hydrolysis and is carried out with an appropriate acid (e.g., hydrochloric acid, oxalic acid, sulfuric acid, etc., preferably hydrochloric acid) in a suitable inert organic solvent, typically an aqueous alcohol (e.g., methanol, ethanol, 2-ethoxyethanol, any appropriate mixture of suitable alcohols, etc.) and preferably methanol or a dilute aqueous acid alone or in combination with a suitable solvent (e.g., THF, dioxane, any appropriate mixture of suitable solvents, etc.) , typically at 20 to 85'C and preferably at approximately 65"C, requiring 0.2 to 2 hours (for further details see Example 24, infra.) ..
  • an appropriate acid e.g., hydrochloric acid, oxalic acid, sulfuric acid, etc., preferably hydrochloric acid
  • the compounds of Formula I can be prepared by acylating an appropriately substituted benzene derivative (Formula 4) with an activated _-spiro[4.5]dec-8-yl-l- (C3-.7)alkanone
  • the acylation is carried out in the presence of a Lewis acid (e.g., aluminum chloride (AICI3) , boron trifluoride, hydrogen fluoride, phosphosporic acid, etc., preferably AICI3) in a suitable solvent (e.g., ethylene dichloride (EDC) , methylene chloride, carbon disulfide, any appropriate mixture of suitable solvent, etc., preferably EDC) typically at 0 to 80'C and preferably at approximately 25 * C, requiring 12 to 48 hours.
  • a Lewis acid e.g., aluminum chloride (AICI3) , boron trifluoride, hydrogen fluoride, phosphosporic acid, etc., preferably AICI3
  • a suitable solvent e.g., ethylene dichloride (EDC) , methylene chloride, carbon disulfide, any appropriate mixture of suitable solvent, etc., preferably EDC
  • EDC ethylene dichloride
  • EDC ethylene dichloride
  • carbon disulfide any appropriate
  • R > and R 7 form a carbonyl protective group and each n, t, u, R 1 and R 2 are as defined above with respect Formula I.
  • Compounds of Formula I in which X is NH, Y is C(0), Z is C(O) and R 3 is hydro can be prepared by alkylating 4-piperidone with a compound of Formula 3 to give a corresponding 1- ( ⁇ -phenyl (C _7)alkyl) -4-piperidone (Formula 7) and then reacting the compound of Formula 7 with an excess, preferably approximately 3 molar equivalents, of a cyanide salt (e.g., potassium cyanide, sodium cyanide, etc.) and an excess, preferably approximately 5 molar equivalents, of ammonium carbonate and deprotecting.
  • a cyanide salt e.g., potassium cyanide, sodium cyanide, etc.
  • the alkylation is carried out by proceeding as described above with respect to Scheme 1 , but substituting the 4-piperidone for the compound of Formula 2.
  • the reaction with the potassium cyanide and ammonium carbonate is carried out in a suitable solvent (e.g., methanol, ethanol-water, any appropriate mixture of suitable solvents, etc.) typically at 20 to 100 * C and preferably at approximately 65 * C, requiring 2 to 8 hours.
  • a suitable solvent e.g., methanol, ethanol-water, any appropriate mixture of suitable solvents, etc.
  • the deprotection is carried out by proceeding as described above with respect to Scheme 1.
  • R ⁇ and R 7 form oxo or a carbonyl protective group and each n, t, u, Rl and R 2 are as defined above with respect to Formula I.
  • Compounds of Formula I in which X is 0, Y is C(O) , Z is C(O) and R 3 is hydro can be prepared by reacting a compound of Formula 7 with a slight excess, preferably approximately 1.4 molar equivalents, of a cyanide salt (e.g., potassium cyanide, sodium cyanide, etc.) and a slight excess, preferably approximately 1.1 molar equivalents, of sodium bisulfate to give a corresponding 4-hydroxy- 1- ( ⁇ -phenyl (C3-.7)alkyl) -4-piperidinecarbonitrile (Formula 9) and then reacting the compound of Formula 9 with chlorosulfonyl isocyanate and deprotecting when necessary.
  • a cyanide salt e.g., potassium cyanide, sodium cyanide, etc.
  • the reaction with the cyanide salt and sodium bisulfate is carried out in a suitable solvent (e.g., water, alcohol-water, acetonitrile, any appropriate mixture of suitable solvents, etc., preferably water) typically at 10 to 100'C and preferably at approximately 25'C, requiring 0.2 to 8 hours.
  • a suitable solvent e.g., toluene, dioxane, any appropriate mixture of suitable solvents, etc., preferably toluene
  • the deprotection is carried out by proceeding as described above with respect to Scheme 1.
  • R° and R 7 form oxo or a carbonyl protective group
  • R 9 is 0 or S and each n, t, u, R 1 , R 2 and R 3 are as defined above with respect to Formula I.
  • Compounds of Formula I in which X is 0, Y is CH2 and Z is C(O) or C(S) can be prepared by reacting a compound of Formula 7 with trimethylsulfoxonium iodide to give a corresponding CD- (6-aza-l-oxa-spiro[2.3]oct-6-yl) -1-phenyl- 1- (C3_7)alkanone (Formula 12), aminating the compound of Formula 12 with an amine of the formula NH2R 3 to give a corresponding ⁇ - (4-aminomethyl-4-hydroxypiperidin-l-yl) - 1-phenyl-l- (C3-.7)alkanone (Formula 11) and then reacting the compound of Formula 11 with 1, 1'-carbonyldiimidazole or 1, 1'-thiocarbonyldiimidazole, respectively, and deprotecting when necessary.
  • the reaction with the trimethylsulfoxonium iodide is carried out in the presence of a strong base (e.g., sodium hydride, potassium hydride, tert-butyllithium, sodium tert-butoxide, etc., preferably sodium hydride), typically under an inert atmosphere (e.g., argon, nitrogen, etc.), in a suitable solvent (e.g., DMSO, sulfolane, etc., preferably DMSO) , typically at 20 to 60 * C and preferably at approximately 50 * C and requires 0.5 to 2 hours.
  • a strong base e.g., sodium hydride, potassium hydride, tert-butyllithium, sodium tert-butoxide, etc., preferably sodium hydride
  • a suitable solvent e.g., DMSO, sulfolane, etc., preferably DMSO
  • the amination is carried out in a suitable solvent (e.g., 1-methylpyrrolidone, dioxane, THF, etc., preferably THF), typically at 50 to 120 * C and preferably at approximately 100"C and requires 16 to 24 hours.
  • a suitable solvent e.g., DMF, THF, dioxane, any appropriate mixture of suitable solvents, etc., preferably THF
  • the deprotection is carried out by proceeding as described above with respect to Scheme 1 .
  • R ⁇ and R 7 form a carbonyl protective group
  • R 9 is 0 or S and each n, t, u, R 1 , R 2 and R 3 are as defined above with respect to Formula I.
  • Compounds of Formula I in which X is NH, Y is C(S) and Z is C(0) or C(S) can be prepared by reacting a compound of Formula 7 with an excess, preferably approximately 2 molar equivalents of a cyanide salt (e.g., potassium cyanide, sodium cyanide, etc.) and an excess of an ammonium salt (e.g., ammonium hydroxide, ammonium chloride, any appropriate mixture of ammonium salts, etc.), preferably approximately 2.5 molar equivalents each of ammonium chloride and ammonium hydroxide, to give a corresponding 4-amino-l- (CO- phenyl (C3_7)alkyl) -piperidine-4-carbonitrile (Formula 14) and then reacting the compound of Formula 14 with carbon oxysulfide or carbon disulfide, respectively, and deprotecting when necessary.
  • a cyanide salt e.g., potassium cyanide, sodium cyanide, etc.
  • the reaction with the cyanide salt and ammonium salt is carried out in a suitable solvent, typically an aqueous alcohol (e.g., methanol, ethanol, 2-ethoxyethanol, any appropriate mixture of suitable alcohols, etc.) and preferably methanol, at 0 to 70 * C, typically at 25 to 50 * C and preferably at approximately 50 * C, requiring 2 to 16 hours (for further details see Example 20, infra.) .
  • the reaction with the carbon oxysulfide or carbon disulfide can be carried out in the same solvent system and essentially under the same reaction conditions as those describe above.
  • Scheme 1 can be carried out with the carbon oxysulfide or carbon disulfide present from the beginning and heating at 40 to 50"C for 4 to 24 hours. The deprotection is carried out by proceeding as described above with respect to Scheme 1 .
  • R ⁇ and R 7 form oxo or a carbonyl protective group
  • R 9 is O or S and each n, t, u, R ⁇ , R 2 , R 3 and R 4 are as defined above with respect to Formula I.
  • Compounds of Formula I in which X is NH, Y is C(O) and Z is C(O) or C(S) can be prepared by hydrolyzing a compound of Formula 14 to give a corresponding 4-amino- 1- ( ⁇ -phenyl(C ⁇ _7)alkyl) -4-piperidinecarboxamide (Formula 16) and then reacting the compound of Formula 16 with 1,1' -carbonyldiimidazole or 1,1' -thiocarbonyldiimidazole, respectively, and deprotecting when necessary.
  • the hydrolysis can be effected with an aqueous acid (e.g., sulfuric acid, hydrochloric acid, etc.) typically at 20 to 120 * C and preferably at approximately 100"C and requires 5 minutes to 2 hours (for further details see Example 21, infra.) or a base (e.g., potassium hydroxide or the like) at 20 to 80"C.
  • aqueous acid e.g., sulfuric acid, hydrochloric acid, etc.
  • a base e.g., potassium hydroxide or the like
  • the reaction with the diimidazole is carried out in a suitable solvent (e.g., DMF, THF, dioxane, any appropriate mixture of suitable solvents, etc., preferably DMF) typically at 15 to 75 * C and preferably at approximately 55"C, requiring 2 to 12 hours (for further details see Example 22, infra.) .
  • a suitable solvent e.g., DMF, THF, dioxane, any appropriate mixture of suitable solvents, etc., preferably DMF
  • Compounds of Formula I in which R ⁇ is amino can be prepared by reducing a compound of Formula I in which R ⁇ is nitro.
  • the reduction can be carried.out with a suitable chemical reducing agent or by catalytic hydrogenation.
  • the reduction is conveniently carried out by hydrogenating in the presence of a suitable catalyst (e.g., 5 or 10% Pd/C, palladium hydroxide, platinum oxide, palladium, palladium oxide, nickel, palladium acetate, etc., preferably 10% Pd/C) in a suitable solvent (e.g., THF, DMF, methanol, ethyl acetate, ethanol, acetic acid, any appropriate mixture of suitable solvents, etc.) at 20 to 40 * C, typically at 20 to 30'C and preferably at approximately 25 * C, and 15 to 70 psi, typically at 15 to 30 psi and preferably at approximately 15 psi, and requires 0.5 to 24 hours (for further details see Example 25, infra.).
  • Compounds of Formula I in which R 1 is -NHC(S)NHR 5 , in which R 5 is as defined above with respect to Formula I can be prepared by reacting a compound of Formula I in which R 1 is amino with an appropriate isothiocyanate of the formula R NC(S) .
  • the reaction is carried out in a suitable solvent (e.g., toluene, N-methyl-2-pyrrolidinone, DMF, 1, 1,3, 3-tetra ⁇ methylurea, THF, dioxane, any appropriate mixture of suitable solvents, etc., preferably toluene or N-methyl-
  • a suitable solvent e.g., toluene, N-methyl-2-pyrrolidinone, DMF, 1, 1,3, 3-tetra ⁇ methylurea, THF, dioxane, any appropriate mixture of suitable solvents, etc., preferably toluene or N-methyl-
  • Compounds of Formula I in which R 1 is —NHSO2R 5 , in which R 5 is as defined above with respect to Formula I can be prepared by reacting a compound of Formula I in which R 1 is amino with an appropriate sulfonyl halide (e.g., 4-trifluoro- benzenesulfonyl chloride, 1-pyrrolidine-sulfonyl chloride, 3- (5-trifluoromethyl-l-methylpyrazol-3-yl) -2-thiophene- sulfonyl chloride, etc.) .
  • an appropriate sulfonyl halide e.g., 4-trifluoro- benzenesulfonyl chloride, 1-pyrrolidine-sulfonyl chloride, 3- (5-trifluoromethyl-l-methylpyrazol-3-yl) -2-thiophene- sulfonyl chloride, etc.
  • reaction is carried out in the presence of a suitable base (e.g., triethylamine, diisopropylethylamine, etc.) and in a suitable solvent (e.g., THF, l-methyl-2-pyrrolidinone, DMF, dichloroethane, any appropriate mixture of suitable solvents, etc., preferably THF) at 0 to 60 * C, preferably at approximately 25'C, requiring 0.5 to 24 hours (for further details see Example 27, infra.) .
  • a suitable base e.g., triethylamine, diisopropylethylamine, etc.
  • a suitable solvent e.g., THF, l-methyl-2-pyrrolidinone, DMF, dichloroethane, any appropriate mixture of suitable solvents, etc., preferably THF
  • a group of Formula (a) can be prepared by reacting a compound of Formula I in which R 3 is hydro with a suitable alkylating agent (e.g., a compound of Formula 3) .
  • a suitable alkylating agent e.g., a compound of Formula 3
  • the reaction is carried out in a suitable solvent (e.g., DMF, any appropriate mixture of suitable solvents, etc.) typically at -10 to 40
  • the N-oxides of the compounds of Formula I can be prepared by treating an unoxidized form of the compound of Formula I with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, ineta-chloroperoxybenzoic acid, etc.) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as methylene chloride) at approximately O'C.
  • an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, ineta-chloroperoxybenzoic acid, etc.
  • a suitable inert organic solvent e.g., a halogenated hydrocarbon such as methylene chloride
  • Compounds of Formula I in unoxidized form can be prepared from N-oxides of compounds of Formula I by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80'C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.
  • an inert organic solvent e.g., acetonitrile, ethanol, aqueous dioxane, etc.
  • Compounds of Formula I may be prepared as pharmaceuti ⁇ cally acceptable acid addition salts by reacting the free base forms of a compound of Formula I with a pharmaceutically acceptable inorganic or organic acid.
  • the pharmaceutically acceptable base addition salts of compounds of Formula I may be prepared by reacting the free acid forms of compounds of Formula I with pharmaceutically acceptable inorganic or organic bases.
  • Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of Formula I are set forth in the definitions section of this application.
  • the salt forms of the compounds of Formula I may be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of Formula I can be prepared from the corresponding base addition salt or acid addition salt form.
  • compounds of Formula I in an acid addition salt form may be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.) .
  • a suitable base e.g., ammonium hydroxide solution, sodium hydroxide, etc.
  • Compounds of Formula I in a base addition salt form may be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc) .
  • an aspect of this invention is a process for preparing a compound of Formula I, in which each n, t and R ⁇ - are as defined above with respect to Formula I; and the pharmaceutically acceptable salts and N-oxides thereof, which process comprises:
  • R ⁇ and R 7 form oxo or a carbonyl protective group
  • R ⁇ and R 7 form oxo or a carbonyl protective group
  • R ⁇ and R 7 form oxo or a carbonyl protective group
  • R ⁇ and R 7 form oxo or a carbonyl protective group and (2) reacting the compound of Formula 14 with carbon oxysulfide or carbon disulfide and deprotecting when necessary to give a compound of Formula I in which X is NH, Y is C(S) and Z is C(0) or C(S), respectively; or
  • a reference to Formula I refers to such Formula wherein each n, t, u, X, Y, Z, R 1 , R 2 and R 3 are as defined in their broadest definitions, with the processes applying particularly well to the presently preferred embodiments.
  • Compounds of Formula 2 in which X is NH, Y is C(O), Z is C(O) and R 3 is hydro can be prepared by reacting a protected 4-piperidone (e.g., tert-butyl 4-oxopiperidine-l-carboxylate, l-benzyl-4-piperidone, etc.) with cyanide salt and ammonium carbonate and then deprotecting.
  • a protected 4-piperidone e.g., tert-butyl 4-oxopiperidine-l-carboxylate, l-benzyl-4-piperidone, etc.
  • the reaction for preparing the protected 1,3 ,8-triazaspiro[4.5]decane-2, 4-dione is carried out by proceeding as described above with respect to Scheme 3, but substituting the 4-piperidone for the compound of Formula 7.
  • a convenient method of deprotecting when the protective group is tert-butoxycarbonyl is carried out with acid (e.g., hydrochloric acid, trifluoroacetic acid, etc.) with or without a suitable co-solvent (e.g., methanol, ethanol, 2-ethoxyethanol, any appropriate mixture of suitable alcohols, etc., preferably ethanol) at 0 to 100'C, typically at 20 to 80 * C and preferably at reflux, requiring 0.1 to 2 hours. Further details of the reaction steps set forth in this paragraph are provided in Example 16, infra..
  • 1,3, 8-triazaspiro[4.5]decane-2,4-dithiones can be prepared by reacting a protected 4-piperidone with a cyanide salt and an ammonium salt to give the corresponding 4-aminopiperidine- 4-carbonitrile, reacting the nitrile with carbon oxysulfide or carbon disulfide, respectively, and deprotecting.
  • the process steps for preparing the protected 3,8-diaza-l- oxaspiro[4.5]decane-2-ones and 1,3, 8-triazaspiro[4.5]decane- 2,4-dithiones are carried out by proceeding as described above with respect to Scheme 6, but substituting the 4-piperidone for the compound of Formula 7.
  • the process steps for preparing the protected 1,3, 8-triazaspiro[4.5]decanones are carried out by proceeding as described above with respect to Scheme 7, but substituting the 4-aminopiperidine- 4-carbonitrile for the compound of Formula 14.
  • a convenient method of deprotecting when the protective group is benzyl is carried out by hydrogenating in the presence of a suitable catalyst (e.g., 10% Pd/C, palladium hydroxide, palladium, palladium oxide, nickel, palladium acetate, etc., preferably 10% Pd/C) optionally in the presence of acid and in a suitable solvent, typically an alcohol (e.g., methanol, ethanol,
  • 2-ethoxyethanol any appropriate mixture of suitable alcohols, etc.
  • an alcohol/water mixture and preferably ethanol typically at 0 to 100 * C and preferably at approximately 25 * C and typically at 15 to 60 psi and preferably at approximately 50 psi.
  • Compounds of Formula 2 in which R 3 is hydro, optionally substituted (C ⁇ _g)alkyl, hydroxyalkyi, or optionally substituted phenyl(C ] _-.4)alkyl can be prepared by alkylating a compound of Formula 2 in which R 3 is hydro.
  • the reaction is carried out with an appropriate alkylating agent (e.g., dimethylsulfate, N- (3-chloropropyl) -4-methoxybenzene- sulfonamide, etc.) in a suitable solvent (e.g., DMF, water, l-methyl-2-pyrrolidinone, any appropriate mixture of suitable solvents, etc., preferably DMF) at -20 to 40'C, typically at 0 to 40 * C and preferably at approximately 25 * C (for further details see Example 19, infra.).
  • a suitable solvent e.g., DMF, water, l-methyl-2-pyrrolidinone, any appropriate mixture of suitable solvents, etc., preferably DMF
  • Compounds of Formula 3 can be prepared by reacting an appropriately substituted benzoic acid chloride with
  • each t, u, R ⁇ - and R 2 are as defined above with respect to Formula I (provided that R ⁇ - cannot be amino, nitro, thiocarbamoyl, thioureido, ureido, -NHSO2R 5 . -NHC(0)R 5 , -NHC(O) HR 5 , -NHC(S)NHR 5 and -S0 2 NHR 5 ) and reacting the compound of Formula 19 with a 1-metalated ⁇ -halo(C2- )alkane, typically a lithium ⁇ -halo-1-(C2- )alkanide and preferably a lithium CO-chloro-1-(02-5)alkanide.
  • a 1-metalated ⁇ -halo(C2- )alkane typically a lithium ⁇ -halo-1-(C2- )alkanide and preferably a lithium CO-chloro-1-(02-5)alkanide.
  • Suitable benzoic acid chlorides are prepared by reacting a correspondingly substituted benzoic acid with an appropriate halogenating agent (e.g., thionyl chloride, oxalyl chloride, phosphorus pentachloride, etc.) and in a suitable solvent (e.g., methylene chloride, dichloroethane, any appropriate mixture of suitable solvents, etc., preferably methylene chloride) at 10 to 40 * C, typically at 15 to 30 * C and preferably at approximately 25 * C, and requires 2 to 18 hours.
  • an appropriate halogenating agent e.g., thionyl chloride, oxalyl chloride, phosphorus pentachloride, etc.
  • a suitable solvent e.g., methylene chloride, dichloroethane, any appropriate mixture of suitable solvents, etc., preferably methylene chloride
  • the reaction with the N,O-dimethylhydroxylamine hydro ⁇ chloride is carried out in a suitable solvent (e.g., methylene chloride, THF, ethyl acetate, any appropriate mixture of suitable solvents, etc., preferably a mixture of THF and methylene chloride) at -10 to 80 * C, typically at 0 to 50"C and preferably at 25 * C, and requires 0.2 to 6 hours.
  • a suitable solvent e.g., methylene chloride, THF, ethyl acetate, any appropriate mixture of suitable solvents, etc., preferably a mixture of THF and methylene chloride
  • the 1-metalated ⁇ -haloalkane is prepared by cooling a solution of an appropriate dihaloalkane, typically a C ⁇ -chloro-1-iodo- (C2-.5)alkane, in a suitable inert organic solvent, preferably an ether (e.g., THF, diethyl ether, any appropriate mixture of suitable solvents, etc., preferably a mixture of diethyl ether and pentane), typically to between -90 and -35 * C and preferably to approximately -65"C, adding an organometallic base, typically an alkylmetallic base and preferably an alkyl alkali metal base (e.g., t-butyllithium, n-butyllithium, s-butyllithium, n-butylsodium, n-butylpotassium, lithium diisopropylamide (LDA), etc., preferably t-butyllithium), at a rate such that the reaction temperature
  • the compound of Formula 17 is then added as a solution to the cooled mixture containing the 1-metalated ⁇ -haloalkane at a rate such that the reaction temperature remains below -40 * C and then the reaction mixture is allowed to gradually warm to between -20 to 20 * C, preferably to approximately 15"C, over
  • Compounds of Formula 3 in which R 1 is halo can be prepared by first halogenating the corresponding compound of Formula 17 in which R ⁇ is hydro.
  • the halogenation is carried out with a suitable halogenating agent (e.g., N-chloro ⁇ succinimide, chlorine, 1,3-dichloro-5, 5-dimethylhydantoin, etc.) in a suitable solvent (e.g., acetonitrile, acetic acid, DMF, any appropriate mixture of suitable solvents, etc., preferably acetonitrile) preferably at approximately 50 * C (for further details see Example 5, infra.) .
  • a suitable halogenating agent e.g., N-chloro ⁇ succinimide, chlorine, 1,3-dichloro-5, 5-dimethylhydantoin, etc.
  • a suitable solvent e.g., acetonitrile, acetic acid, DMF, any appropriate mixture of suitable solvents, etc.,
  • compounds of Formula 3 can be prepared by acylating an appropriately substituted benzene derivative of Formula 4 with an appropriate activated 1- (C3-.7)alkanone (i.e., of the formula LC(0) (CH2) n L ⁇ - n which L is a leaving group, preferably wherein n is 6) .
  • the acylation is carried out by proceeding as described above with respect to Scheme 2, but substituting the activated 1- (C3_7)alkanone for the compound of Formula 5 (for further details see Example 8, infra. ) .
  • Removal of the chloro groups can be effected by stirring under a hydrogen atmosphere with a suitable base (e.g., sodium hydroxide, lithium hydroxide, sodium acetate, etc.) and an appropriate catalyst (e.g., 10% Pd/C, nickel, etc, preferably 10% Pd/C) in a suitable solvent, typically an alcohol (e.g., methanol, ethanol, 2-ethoxyethanol, any appropriate mixture of suitable alcohols, etc.) and preferably methanol, at 0 to 60"C, typically at 15 to 40 * C and preferably at approximately 25'C, requiring 2 to 48 hours (for further details see Example 9, infra. ) .
  • a suitable base e.g., sodium hydroxide, lithium hydroxide, sodium acetate, etc.
  • an appropriate catalyst e.g., 10% Pd/C, nickel, etc, preferably 10% Pd/C
  • a suitable solvent typically an alcohol (e.g., methanol, ethanol, 2-ethoxyethanol, any appropriate
  • Compounds of Formula 3 in which R ⁇ and R 7 form a carbonyl protective group can be prepared by reacting a compound of Formula 3 in which R> and R 7 form oxo with a suitable protecting agent (e.g., ethylene glycol) .
  • a suitable protecting agent e.g., ethylene glycol
  • a compound of Formula 3 in which R ⁇ and R 7 form ethylenedioxy can be prepared by reacting the unprotected compound of
  • Formula 3 with ethylene glycol in a suitable inert organic solvent e.g. , toluene, benzene, any appropriate mixture of suitable solvents, etc., preferably toluene
  • a suitable inert organic solvent e.g. , toluene, benzene, any appropriate mixture of suitable solvents, etc., preferably toluene
  • at reflux for further details see Example 10, infra.
  • R 2 is (C ] __4)alkyloxy or aryl(C]__4)alkyloxy
  • R ⁇ and R 7 comprise a carbonyl protective group, preferably ethylenedioxy, when n is 2 or 3.
  • the alkylation is carried out in the presence of a suitable base (e.g., sodium hydride, potassium carbonate, diisopropylethylamine, etc., preferably sodium hydride) in a suitable inert organic solvent (e.g., DMF, 2-butanone, l-methyl-2-pyrrolidinone, any appropriate mixture of suitable solvents, etc., preferably DMF) at -10 to 60'C, typically at 0 to 40 * C and preferably at approximately 25'C, and requires 0.5 to 8 hours (for further details see Example 11, infra.) .
  • a suitable base e.g., sodium hydride, potassium carbonate, diisopropylethylamine, etc., preferably sodium hydride
  • a suitable inert organic solvent e.g., DMF, 2-butanone, l-methyl-2-pyrrolidinone, any appropriate mixture of suitable solvents, etc., preferably DMF
  • the protective group is optionally removed by proceeding as described
  • Compounds of Formula 3 in which R ⁇ is nitro can be prepared by nitrating a compound of Formula 3 in which R 1 is hydro with a suitable nitrating agent (e.g., acetyl nitrate, nitric acid, sodium nitrate, etc.) in a suitable solvent (e.g., acetic anhydride, acetic acid, any appropriate mixture of suitable solvents, etc., preferably acetic anhydride) .
  • a suitable nitrating agent e.g., acetyl nitrate, nitric acid, sodium nitrate, etc.
  • a suitable solvent e.g., acetic anhydride, acetic acid, any appropriate mixture of suitable solvents, etc., preferably acetic anhydride
  • the nitration can be conveniently carried out with acetyl nitrate, typically formed in situ by reaction of copper(II) nitrate with acetic anhydride, at 0 to 30 * C, typically at 5 to 20 * C and preferably at approximately 15 * C, and requires 2 to 8 hours (for further details see Example 12, infra. ) .
  • Compounds of Formula 3 in which R 1 is amino can be prepared by reducing a compound of Formula 3 in which R 1 is nitro.
  • the reduction can be carried out with a suitable chemical reducing agent or by catalytic hydrogenation.
  • the reduction is conveniently carried out by hydrogenating under conditions similar to those described above for reducing compounds of Formula I in which Rl is nitro (for further details see Example 13, infra.) .
  • Compounds of Formula 3 in which R 1 is -NHC(0)R 5 in which R 5 is as defined above with respect to Formula I can be prepared by reacting a compound of Formula 3 in which R 1 is amino with an appropriate acylating agent (e.g. , acyl halides such as acetyl chloride, benzoyi chloride, nicotinoyl chloride, etc.) .
  • an appropriate acylating agent e.g. , acyl halides such as acetyl chloride, benzoyi chloride, nicotinoyl chloride, etc.
  • the reaction is carried out in a suitable 5 solvent (e.g., methylene chloride, THF, pyridine, water, any appropriate mixture of suitable solvents, etc., preferably pyridine) at -10 to 40 * C, typically at 15 to 35 * C and preferably at approximately 25 * C, and requires 0.5 to 8 hours.
  • a suitable 5 solvent e.g., methylene
  • Compounds of Formula 3 in which R 1 is -NHC(S)NHR 5 or —NHC(0)NHR 5 can be prepared by reacting a compound of Formula 3 in which R ⁇ is amino with an isothiocyanate of the formula R 5 NC(S) or an isocyanate of the formula R 5 NC(0), in which R 5
  • R 2 is chloro (i.e., 6,7-dichloro-
  • 1, 4-benzodioxan can be prepared by halogenating 1,4-benzo- dioxan.
  • the halogenation is carried out with a suitable halogenating agent (e.g., N-chlorosuccinimide , chlorine, 1,3-dichloro-5, 5-dimethylhydantoin, etc.) in a suitable solvent (e.g., acetic acid, DMF, acetonitrile, any appropriate mixture of suitable solvents, etc., preferably acetic acid) at approximately 120 * C (for further details see Example 6, infra. ) .
  • a suitable halogenating agent e.g., N-chlorosuccinimide , chlorine, 1,3-dichloro-5, 5-dimethylhydantoin, etc.
  • a suitable solvent e.g., acetic acid, DMF, acetonitrile, any appropriate mixture of suitable solvents, etc., preferably acetic acid
  • Compounds of Formula 4 in which R ⁇ is - ⁇ HS02R ⁇ . in which R 5 is as defined above with respect to Formula I can be prepared by reacting a compound of Formula 4 in which R 1 is amino with an appropriate sulfonyl halide (e.g., 4-trifluoro- benzenesulfonyl chloride, 1-pyrrolidine-sulfonyl chloride, 3- (5-trifluoromethyl-l-methylpyrazol-3-yl) -2-thiophene- sulfonyl chloride, etc.) .
  • an appropriate sulfonyl halide e.g., 4-trifluoro- benzenesulfonyl chloride, 1-pyrrolidine-sulfonyl chloride, 3- (5-trifluoromethyl-l-methylpyrazol-3-yl) -2-thiophene- sulfonyl chloride, etc.
  • the reaction is carried out in the presence of a suitable base (e.g., triethylamine, diisopropylethylamine, etc.) and in a suitable solvent (e.g., THF, l-methyl-2-pyrrolidinone, DMF, dichloroethane, any appropriate mixture of suitable solvents, etc., preferably THF) at approximately reflux, requiring approximately 48 hours.
  • a suitable base e.g., triethylamine, diisopropylethylamine, etc.
  • a suitable solvent e.g., THF, l-methyl-2-pyrrolidinone, DMF, dichloroethane, any appropriate mixture of suitable solvents, etc., preferably THF
  • Compounds of Formula 5 can be prepared by reacting a protected acid of the formula L(CH2) n C00H (e.g., tert-butyl ⁇ -halo(C2-g)alkanoate) deprotecting and then activating (e.g., convert to the corresponding acid halide) .
  • a protected acid of the formula L(CH2) n C00H e.g., tert-butyl ⁇ -halo(C2-g)alkanoate
  • N-methoxy-N-methyl-2-methoxybenzamide N-methoxy-N-methyl-2,5-dichlorobenzaird.de, N-methoxy-N-methyl-2,5-dimethoxybenzamide, N-methoxy-N-methyl-2,4,5-trimethoxybenzamide, N-methoxy-N-methyl-5-chloro-2-ethoxybenzamide, N-methoxy-N-methyl-4-chloro-2-ethoxybenzamide, N-methoxy-N-methy1-4-methoxybipheny1-3-carboxamide, N-methoxy-N-methyl-4-chloro-2-methoxybenzamide, N-me thoxy-N-methyl-2-methoxy-1-naphthalenecarboxamide, N-methoxy-N-methy1-3-methoxynaphthalenecarboxamide,
  • N-methoxy-N-methy1-6-methoxy-2-naphthalenecarboxamide N-methoxy-N-methyl-2-methoxy-5-phenoxybenzamide, N-methoxy-N-methyl-2-benzyloxy-5-chlorobenzamide , N-methoxy-N-methyl-3,5-dichloro-2-methoxybenzamide, N-methoxy-N-methy1-6-bromo-2-methoxy-1-naphthalenecarboxamide and N-me thoxy-N-methyl-6-methoxy-1,3-benzodioxole-5-carboxamide.
  • N-chlorosuccinimide (4.8 ml, 36 mmol) and acetonitrile (100 ml) was heated 16 hours at 50 * C.
  • the mixture was concentrated and the residue was partitioned between ethyl acetate (300 ml) and saturated sodium bicarbonate (150 ml) .
  • the mixture was filtered and the organic layer was separated, washed with water (4x) and brine (lx) , dried ⁇ K2CO3), filtered through a short column of silica-gel and concentrated to give N-methoxy-N-methyl-5-chloro-2,4-dimethoxybenzamide (5.3 g, 20 mmol), m.p. 97-99'C.
  • the ethyl acetate phase was washed twice with water and once with brine, then dried over anhydrous sodium sulfate.
  • the solution was filtered and the solvent removed, then the resulting oil was dissolved in a warm 20% solution of ethyl acetate in hexane (250 ml) .
  • the solution was allowed to crystallize at room temperature for five hours, then at 4 * C for one hour. Filtration, washing the crystals with 10% ethyl acetate in hexane, and air-drying afforded 5-chloro-l-(2,4, 6-trimethoxyphenyl) -1-pentanone, 34 g (83% yield) , m.p. 53-5'C.
  • R 2 is methoxy and R ⁇ and R 7 form oxo.
  • R 2 is methoxy and R ⁇ and R 7 form oxo.
  • R 2 is methoxy and R ⁇ and R 7 form oxo.
  • R 2 is methoxy and R 6 and R 7 form oxo.
  • the mixture was purified by flash chromatography eluting first with methylene chloride and then with methylene chloride/methanol+ammonium hydroxide (9:1) .
  • the purified product was recrystallized from ethanol and then from a solution of hydrogen chloride in ethanol/ether to give N- ⁇ 5-[5- (2,4-dioxo-l,3, 8-triazaspiro- [4.5]dec-8-yl) -pentanoyl] -2,4-dimethoxyphenyl ⁇ -3- (5-trifluoro- methyl-l-methylpyrazol-3-yl) -2-thiophenesulfonamide hydrochloride (94 mg, 0.13 mmol), m.p. 162-170'C.
  • the product was purified by column chromatography eluting with methylenechloride/ methanol+ammonium hydroxide (20:1) to give 8-[5- (5-chloro-2-methoxyphenyl) -5-oxopentyl] -l-oxa-3, 8-triaza- spiro[4.5]decane-2-one (50 mg, 0.13 mmol).
  • the free base was recrystallized from a solution of hydrogen chloride in ethanol/ether to give 8-[5- (5-chloro-2-methoxyphenyl) - 5-oxopentyl] -l-oxa-3, 8-triazaspiro[4.5]decane-2-one hydrochloride, m.p. 130-134 * C.
  • a representative solution for oral administration contains: Compound of Formula I 100-1000 mg Citric Acid Monohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water q.s. to 100 ml
  • a representative solution for intravenous administration contains:
  • a representative tablet form of a compound of Formula I may contain:
  • Mouse NIH3T3 fibroblasts expressing a cloned rat 5-H-?2c receptor were maintained in Dulbecco's Modified Eagle medium with 10% Fetal Calf Serum and 250 ⁇ g/ml G418 in 95/5% O2/CO2.
  • the cells were harvested using 2 mM EDTA in phosphate buffered saline (calcium/magnesium free) and centrifuged (500 g) .
  • the cell pellet was homogenized using a Polytron P10 disrupter (setting 5, 5 sec) in homogenization buffer (Tris, 50 mM; N 2EDTA, 5 mM) and the homogenate was centrifuged at
  • the membranes were thawed at room temperature and diluted with assay buffer (NaCl, 118 mM; KCl, 4.5 mM; KH P0 , 1.2 mM; CaCl2*2H2 ⁇ , 2.5 mM; MgCl2, 1 mM; D-glucose, 10 mM; Tris, 25 mM) .
  • assay buffer NaCl, 118 mM; KCl, 4.5 mM; KH P0 , 1.2 mM; CaCl2*2H2 ⁇ , 2.5 mM; MgCl2, 1 mM; D-glucose, 10 mM; Tris, 25 mM
  • An optimal dilution ratio was predetermined for each batch of membranes to ensure that less than 10% of 5x10 " 10t ⁇ [3H] mesu ]_ er gi ne binds, specific binding is at least 10 times greater than a machine background of 23 dpm and
  • the membranes were homogenized (setting 5, 5 sec) and then added to assay tubes containing mesulergine (5X10 ⁇ 0M) , test compound (lxlO" 10 -lxlO” 4 M) and assay buffer (q.s. to 500 ⁇ L) .
  • the assay mixture was incubated at 32 * C for 60 minutes and then filtered over 0.1% polyethyleneimine pretreated glass fiber filtermats using a Brandel cell harvester.
  • the assay tubes were rinsed with cold O.l M sodium chloride (3x 3 sec) and dried by drawing air over the filter for 10 seconds. Radioactivity retained on the filters was determined by liquid scintillation counting. In a similar fashion, total binding was measured with methysergide (lxl0 ⁇ M) in the absence of test compound. For each compound tested the concentration producing 50% inhibition of binding (IC50) was determined using iterative curve fitting techniques.
  • Mouse NIH3T3 fibroblasts expressing cloned 5-HT2C receptor were maintained in high glucose Dulbecco's Minimal Essential Medium (DMEM) further comprising glutamine, sodium pyruvate and 10% Fetal Bovine.
  • DMEM Dulbecco's Minimal Essential Medium
  • the cells were harvested using 2 mM EDTA in phosphate buffered saline and transferred to 6.5 mm transwell capsule plates (3 micron pore size) to give approximately lxlO 5 cells/capsule.
  • the cells were allowed to adhere overnight and then transwell spacers and inserts were added to each transwell capsule.
  • the capsules were placed into sensor chambers and the sensor chambers were loaded onto a microphysiometer.
  • the 5-HT2C receptor antagonist properties of test compounds were appraised by determining their affect on 5-HT induced increases in cellular metabolic activity, expressed as percent increase in acidification rate.
  • Microphysiometer Running Medium high glucose, sodium bicarbonate free DMEM
  • Concentration-effect curves were constructed for 5-HT with and without the test compound present. Data was analyzed by iterative curve fitting techniques and the concentration ratio (CR) of 5-HT necessary to produce equiactive responses in the absence and presence of the test compound was determined. Relying on the concentration ratio, the molar concentration of the test compound, and the relationship:
  • the following describes an in vivo method for determining anxiolytic activity by measuring the extent the drug affects the natural anxiety of mice when exposed to a novel, brightly lighted environment.
  • Naive male C5BI/6J mice 18-20 g are kept in groups of 10 mice in quarters controlled for sound, temperature and humidity. Food and water are available ad libitum. The mice are kept on a 12 hour light and 12 hour dark cycle, with lights on at 6:00 a.m. and off at 6:00 p.m. All experiments begin at least 7 days after arrival on site.
  • the chamber consists of a plexiglass box (44 x 21 x 21 cm) , divided into two chambers by a black plexiglass partition.
  • the partition dividing the two chambers contains a 13 x 5 cm opening through which the mouse can easily pass.
  • the dark chamber has clear sides and a white floor.
  • a fluorescent tube light (40 watt) placed above the chambers provides the only illumination.
  • the Digiscan Animal Activity Monitor System RXYZCM16 (Omni-Tech Electronics) records the exploratory activity of the mice within the test chambers.
  • mice Prior to commencement of the study the mice are given 60 min to acclimatize to the laboratory environment. After a mouse receives an intraperitoneal (i.p.) injection of either test compound or vehicle it is returned to its home cage for a 15 min post-treatment period. The mouse is then placed in the center of the light chamber and monitored for 10 minutes.
  • i.p. intraperitoneal
  • Anxiolytic behavior is seen as a general increase in exploratory activity in the lighted area.
  • An increase in exploratory activity is reflected by increased latency (the time for the mouse to move to the dark chamber when first placed in the center of the lighted area) , increase in shuttle activity, increased or unaltered locomotor activity (number of grid lines crossed) and decreased time spent in the dark compartment.
  • the following describes an in vivo procedure for determining amelioration of the symptoms caused by withdrawal from addictive substances by measuring the extent the drug affects the anxiety that occurs in mice after chronically treating with an addictive substance and then abruptly ceasing the treatments.
  • Naive male BKW mice (25-30 g) are caged in groups of ten in quarters controlled for sound, temperature and humidity. Food and water are available ad libitum. The mice are kept on a 12 hour light cycle and 12 hour dark cycle, with lights on at 6:00 a.m. and off at 6:00 p.m. All experiments begin at least 7 days after arrival on site.
  • Levels of anxiety are determined by the two-compartment exploratory model of Crawley and Goodwin (see Example 14) .
  • Anxiolysis is seen as a general increase in exploratory activity in the lighted area.
  • An increase in exploratory activity is reflected by increased latency (the time for the mouse to move to the dark chamber when first placed in the center of the lighted area) , increased or unaltered locomotor activity (number of grid lines crossed) , increased number of rears and decreased time spent in the dark compartment.
  • Increased exploratory activity in the lighted area is induced by treating the mice for 14 days with ethanol (8.0 % w/v in drinking water), nicotine (0.1 mg/kg, i.p., twice daily) or cocaine (1.0 mg/kg, i.p., twice daily) .
  • Anxiolysis is assessed 1, 3, 7 and 14 days after commencement of the drug regime. The treatment is abruptly ceased and exploratory activity in the lighted area is determined 8, 24 and 48 hours thereafter. Vehicle or test compounds are administered during the withdrawal phase by intraperitoneal injection. Responses are represented as inhibition of the decrease in anxiolytic behavior after the ethanol, cocaine or nicotine treatment is ceased.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte à des composés hétérocycliques de formule générale (I), dans laquelle n vaut 2, 3, 4, 5 ou 6; t vaut 1, 2 ,3 ou 4; u vaut 0 ou 1 (à condition que t ne soit pas égal à 1 lorsque u vaut 0); X représente O ou N(R4) dans lequel R4 représente hydro, alkyle (C¿1-4?) ou aryle; Y et Z représentent indépendamment C(O), C(S) ou CH2 (à condition que Y et Z ne représentent pas tous les deux CH2); R?1, R2 et R3¿ sont tels que définis dans la description; ainsi qu'à leurs sels et N-oxides pharmaceutiquement acceptables, les formulations les contenant, leur utilisation en tant qu'agents thérapeutiques et leur synthèse. Les composés de cette invention sont des antagonistes sélectifs du récepteur 5-HT¿2?C.
PCT/EP1996/002554 1995-06-23 1996-06-13 Derives de 1,3,8-triaza et 3,8-diaza-1-oxaspiro(4,5)-decane WO1997000872A1 (fr)

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US494,134 1995-06-23

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU702587B2 (en) * 1995-05-17 1999-02-25 Les Laboratoires Servier New heterocyclic spiro compounds, process for the preparation thereof,and pharmaceutical compositions containing them
US6172076B1 (en) 1998-06-15 2001-01-09 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
EP1786816A1 (fr) * 2003-09-10 2007-05-23 Virochem Pharma Inc. Composes de spirohydantoine et procedes de modulation de l'activite des recepteurs de chimiokine
JP2007126474A (ja) * 1999-12-06 2007-05-24 Euro-Celtique Sa ノシセプチン受容体親和性を有するトリアゾスピロ化合物

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Publication number Priority date Publication date Assignee Title
DE1815450A1 (de) * 1967-12-29 1969-09-04 Science Union & Cie Neue Spiro-(4,5)-dekanverbindungen und Verfahren zu ihrer Herstellung
EP0450995A1 (fr) * 1990-02-28 1991-10-09 Jouveinal S.A. Nouvelles propanamines, leurs propriétés pharmacologiques et leur application à des fins thérapeutiques, notamment antidiarrhéiques

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Publication number Priority date Publication date Assignee Title
DE1815450A1 (de) * 1967-12-29 1969-09-04 Science Union & Cie Neue Spiro-(4,5)-dekanverbindungen und Verfahren zu ihrer Herstellung
EP0450995A1 (fr) * 1990-02-28 1991-10-09 Jouveinal S.A. Nouvelles propanamines, leurs propriétés pharmacologiques et leur application à des fins thérapeutiques, notamment antidiarrhéiques

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KIUTO SASAJIMA ET AL.: "Synthetic studies on psychotropic agents. I. A new synthesis of 2'-amino-4'-fluorobutyriphenone derivatives using a serective ortho-amination of 2',4'-difluorobutyrophenone derivatives", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 26, no. 8, 1978, TOKYO JP, pages 2502 - 2507, XP002013868 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU702587B2 (en) * 1995-05-17 1999-02-25 Les Laboratoires Servier New heterocyclic spiro compounds, process for the preparation thereof,and pharmaceutical compositions containing them
US6172076B1 (en) 1998-06-15 2001-01-09 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
JP2007126474A (ja) * 1999-12-06 2007-05-24 Euro-Celtique Sa ノシセプチン受容体親和性を有するトリアゾスピロ化合物
EP1786816A1 (fr) * 2003-09-10 2007-05-23 Virochem Pharma Inc. Composes de spirohydantoine et procedes de modulation de l'activite des recepteurs de chimiokine
EP1786816A4 (fr) * 2003-09-10 2009-11-04 Virochem Pharma Inc Composes de spirohydantoine et procedes de modulation de l'activite des recepteurs de chimiokine

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