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WO2011025748A1 - Analogues diaryl[a,d]cycloheptènes substitués par un groupe amino comme agonistes muscariniques et procédés de traitement de troubles neuropsychiatriques - Google Patents

Analogues diaryl[a,d]cycloheptènes substitués par un groupe amino comme agonistes muscariniques et procédés de traitement de troubles neuropsychiatriques Download PDF

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WO2011025748A1
WO2011025748A1 PCT/US2010/046390 US2010046390W WO2011025748A1 WO 2011025748 A1 WO2011025748 A1 WO 2011025748A1 US 2010046390 W US2010046390 W US 2010046390W WO 2011025748 A1 WO2011025748 A1 WO 2011025748A1
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compound
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halogen
hydrogen
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Jorgen Ohlsson
Gilles Gaubert
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Acadia Pharmaceuticals Inc
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Acadia Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/20—Dibenz [b, e] azepines; Hydrogenated dibenz [b, e] azepines

Definitions

  • the present invention relates to the fields of chemistry and medicine. More particularly, disclose herein are compounds that modulate the activity of muscarinic receptors and methods for making such compounds.
  • Muscarinic cholinergic receptors mediate the actions of the neurotransmitter acetylcholine in the central and peripheral nervous systems, gastrointestinal system, heart, endocrine glands, lungs, and other tissues. Muscarinic receptors play a central role in the central nervous system for higher cognitive functions, as well as in the peripheral parasympathetic nervous system. Five distinct muscarinic receptor subtypes have been identified, ml-m5.
  • the ml subtype is the predominant subtype found in the cerebral cortex and is believed to be involved in the control of cognitive functions; m2 is the predominant subtype found in heart and is believed to be involved in the control of heart rate; m3 is believed to be involved in gastrointestinal and urinary tract stimulation as well as sweating and salivation; m4 is present in brain and may be involved in locomotion; and m5, present in brain, may be involved in certain functions of the central nervous system associated with the dopaminergic system.
  • acetylcholine Conditions associated with cognitive impairment, such as Alzheimer's disease, are accompanied by loss of acetylcholine in the brain. This is believed to be the result of degeneration of cholinergic neurons in the basal forebrain, which innervate areas of the association cortex, and hippocampus, which is involved in higher processes.
  • Efforts to increase acetylcholine levels have focused on increasing levels of choline, the precursor for acetylcholine synthesis, and on blocking acetylcholine esterase (AChE), the enzyme that metabolizes acetylcholine.
  • Administration of choline or phosphatidylcholine has not been very successful.
  • AChE inhibitors have shown some therapeutic efficacy, but may cause cholinergic side effects due to peripheral acetylcholine stimulation, including abdominal cramps, nausea, vomiting, diarrhea, anorexia, weight loss, myopathy and depression. Gastrointestinal side effects have been observed in about a third of the patients treated. In addition, some AChE inhibitors, such as tacrine, have also been found to cause significant hepatotoxicity, with elevated liver transaminases observed in about 30% of patients. The adverse effects of AChE inhibitors have limited their clinical utility.
  • ml muscarinic agonists such as arecoline have also been found to be weak agonists of m2 as well as m3 subtype and are not very effective in treating cognitive impairment, most likely because of dose- limiting side effects.
  • Some embodiments disclosed herein relate to a method of chemical synthesis that includes: (a) performing a metal catalyzed coupling reaction between a compound of Formula 2-C, and a compound of Formula 2-D, to provide a compound of Formula 2-E;
  • X b can be a halogen
  • n a can be 0, 1, or 2
  • PG a can be protecting group
  • R 2 b, R3b, Rib, Rsb, R ⁇ b, R7b, Rsb, and R 9b can be each independently selected from hydrogen, halogen, optionally substituted Ci_ 6 alkyl, optionally substituted C 2 _ 6 alkenyl, optionally substituted C 2 _ 6 alkynyl, perhaloalkyl, and CN.
  • the metal catalyzed coupling reaction of step (a) can be performed using a palladium catalyst and an inorganic base.
  • the palladium catalyst can be derived from a Pd(II) source; and the inorganic base can be selected from the group consisting of Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 , KHCO 3 , and CsHCO 3 .
  • the reducing of step (b) can comprise reduction with hydrogen gas in the presence of a catalyst selected from the group consisting of platinum catalyst, palladium catalyst, and Raney nickel catalyst; or reduction using sodium hydrosulfite (Na 2 S 2 O 4 ); or reduction using SnCl 2 ; or reduction using iron; or reduction using sodium sulfide; or reduction using hydrogen sulfide; or reduction using titanium(III) chloride; or reduction using zinc.
  • the reduction using iron can include iron in the presence of an acid.
  • the acid can be acetic acid.
  • the converting of step (c) can include using phosgene or a phosgene equivalent.
  • the phosgene equivalent can be selected from the group consisting of trichloromethyl chloroformate and triphosgene.
  • the converting of step (c) can include using a Lewis acid.
  • the Lewis acid can be selected from the group consisting of TiCl 4 , AICI 3 , AlBr 3 , BF 3 , ZnCl 2 , GaCl 3 , FeCl 3 , SbCl 5 , ZrCl 4 , SnCl 4 , SmI 3 , ytterbium triflate, Samarium triflate, and BCl 3 .
  • the converting of step (d) can include using a halogenating agent.
  • the halogenating agent can be selected from the group consisting of P(O)Cl 3 , PCl 3 , PCI 5 , TiCl 4 , and thionyl chloride.
  • the deprotecting of step (f) includes using an acid.
  • the acid can be selected from the group consisting of trifluoracetic acid and hydrochloric acid.
  • R 7b and R 8b can be each independently selected from the group consisting of hydrogen and halogen and R 5b can be an optionally substituted Ci -6 alkyl or halogen.
  • R2b, R3b, R4b, R ⁇ b, and Rt>b can each be hydrogen.
  • PG a can be tert-butoxycarbonyl (Boc).
  • R 7b and R 8b can be each independently selected from the group consisting of hydrogen and halogen and R 5b can be an optionally substituted Ci -6 alkyl or halogen.
  • R 2b , R ⁇ b , R 4b , R ⁇ b , and R 9b can each be hydrogen.
  • PG a can be tert-butoxycarbonyl (Boc).
  • n a , R 2 b, R3b, R4b, Rsb, R ⁇ b, R7b, Rsb, and R 9b are defined as above; and Rn b can be hydrogen.
  • Some embodiments disclosed herein relate to a method of chemical synthesis that includes: protecting compound of formula 4- A to obtain a compound of Formula 4-B and performing a coupling reaction between a compound of Formula 4-B and a compound of Formula 4-C to provide a compound of Formula (4-D).
  • the compound of Formula (4-D) is converted to a compound fo Formula (2-F), which is cyclized to give a compound of Formula (2-G) (above), which by following the above mentioned steps result in a compound of Formula (2-K) or (3-B).
  • Xc and X D independently can be halogen; n a , R 2 b, R3b, R 4 b, Rsb, R ⁇ b, R7b, R ⁇ b, and R(>b are defined as above; and Rub can be hydrogen.
  • the metal catalyzed coupling reaction of step (a) can be performed using a palladium catalyst and an inorganic base.
  • the palladium catalyst can be derived from a Pd(II) source; and the inorganic base can be selected from the group consisting of Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 , KHCO 3 , and CsHCO 3 .
  • the converting of step (d) includes using phosgene or a phosgene equivalent, preferably the phosgene equivalent is selected from the group consisting of trichloromethyl chloroformate and triphosgene. In some embodiments, the converting of step (d) can include using a Lewis acid.
  • the Lewis acid can be selected from the group consisting of TiCl 4 , AlCl 3 , AlBr 3 , BF 3 , ZnCl 2 , GaCl 3 , FeCl 3 , SbCl 5 , ZrCl 4 , SnCl 4 , SmI 3 , ytterbium triflate, Samarium triflate, and BCl 3 .
  • the converting of step (e) can include using a chlorinating agent.
  • the chlorinating agent can be selected from the group consisting of P(O)Cl 3 , PCl 3 , PCl 5 , TiCl 4 , and thionyl chloride.
  • R 7b , and Rs b can be each independently selected from the group consisting of hydrogen and halogen and R 5b can be an optionally substituted Ci_ 6 alkyl or halogen.
  • R 2 b, R3b, R 4 b, R ⁇ b, and R 9b can each be hydrogen.
  • Rn b is hydrogen.
  • Rs b and R 7b are independently selected from the group consisting of Ci -6 alkyl and halogen; or a pharmaceutically acceptable salt or a solvate thereof.
  • both Rs b and R 7b are halogens or Ci_ 6 alkyl; in one embodiment relating to a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, R 5b and R 7b are independently selected from the group consisting of methyl and halogen.
  • R 5b is methyl and R 7b is halogen.
  • R 5b is selected from the group consisting of methyl and halogen and R 7b is chloro.
  • R 7b is chloro.
  • Rs b is methyl.
  • R 7b is chloro and R 5b is selected methyl.
  • Some embodiments disclosed herein relate to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula I.
  • the compound of Formula I is 3-Chloro-10-methyl- 6-(piperazin-l-yl)-llH-dibenzo[&,e]azepine or 3,10-dichloro-6-(piperazin-l-yl)-l lH- dibenzo [b ,e] azepine.
  • the compound of Formula I is 3-Chloro-10-methyl- 6-(piperazin-l-yl)-llH-dibenzo[&,e]azepine hydrochloride or 3,10-dichloro-6-(piperazin- l-yl)-l lH-dibenzo[b,e]azepine hydrochloride.
  • Some embodiments disclosed herein relate to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof; and a compound of Formula I.
  • Some embodiments disclosed herein relate to a method of treating a neuropsychiatric disorder comprising administering to the patient a therapeutically effective amount of a compound of Formula I.
  • the neuropsychiatric disorder is selected from the group consisting of schizophrenia, schizophrenia related idiopathic psychosis, cognitive enhancement in schizophrenia, anxiety, sleep disorders, appetite disorders, affective disorders, drug-induced psychosis, cognitive impairment, and psychosis secondary to neurodegenerative disorders.
  • the affective disorders are selected from the list consisting of major depression, bipolar disorder, depression with psychotic features, and Tourette's Syndrome; and the psychosis secondary to neurodegenerative disorders are selected from the list consisting of Alzheimer's disease and Huntington's Disease.
  • Some embodiments disclosed herein relate to a method of treating a neuropsychiatric disorder comprising contacting a therapeutically effective amount of a compound of Formula I with the patient.
  • the neuropsychiatric disorder is selected from the group consisting of schizophrenia, schizophrenia related idiopathic psychosis, cognitive enhancement in schizophrenia, anxiety, sleep disorders, appetite disorders, affective disorders, drug-induced psychosis, cognitive impairment, and psychosis secondary to neurodegenerative disorders.
  • the affective disorders are selected from the list consisting of major depression, bipolar disorder, depression with psychotic features, and Tourette's Syndrome; and the psychosis secondary to neurodegenerative disorders are selected from the list consisting of Alzheimer's disease and Huntington's Disease.
  • the composition comprises a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, where both Rs b and R 7b are halogens or Ci_ 6 alkyl.
  • the composition comprises a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, where R 5b and R 7b are independently selected from the group consisting of methyl and halogen.
  • the composition comprises a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, where R 5b is methyl and R 7b is halogen. In one embodiment the composition comprises a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, where R 5b is selected from the group consisting of methyl and halogen and R 7b is chloro. In one embodiment, R 7b is chloro. In one embodiment the composition comprises a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, where Rs b is methyl. In one embodiment the composition comprises a compound having the Formula I, or a pharmaceutically acceptable salt or a solvate thereof, where R 7b is chloro and Rs b is methyl.
  • pharmaceutically acceptable salt refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound of the invention with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • Pharmaceutical salts can also be obtained by reacting a compound of the invention with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N- methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N- methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
  • EC 50 refers to an amount, concentration, or dosage of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound, in an assay that measures such response such as but not limited to R-SAT ® assay described herein.
  • esters refers to a chemical moiety with formula -(R) n - COOR', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.
  • An "amide” is a chemical moiety with formula -(R) n -C(O)NHR' or - (R) n -NHC(O)R', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.
  • An amide may be an amino acid or a peptide molecule attached to a molecule of the present invention, thereby forming a prodrug.
  • Any amine, hydroxy, or carboxyl side chain on the compounds of the present invention can be esterified or amidified.
  • the procedures and specific groups to be used to achieve this end are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety.
  • protecting group and “protecting groups” as used herein refer to any atom or group of atoms that is added to a molecule in order to prevent existing groups in the molecule from undergoing unwanted chemical reactions.
  • Examples of protecting group moieties are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999, and in J. F. W. McOmie, Protective Groups in Organic Chemistry Plenum Press, 1973, both of which are hereby incorporated by reference.
  • the protecting group moiety may be chosen in such a way, that they are stable to the reaction conditions applied and readily removed at a convenient stage using methodology known from the art.
  • protecting groups include benzyl; substituted benzyl; alkylcarbonyls (e.g., t-butoxycarbonyl (BOC)); arylalkylcarbonyls (e.g., benzyloxycarbonyl, benzoyl); substituted methyl ether (e.g.
  • methoxymethyl ether substituted ethyl ether; a substituted benzyl ether; tetrahydropyranyl ether; silyl ethers (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, t- butyldimethylsilyl, or t-butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g. methoxymethylcarbonate); sulfonates (e.g. tosylate, mesylate); acyclic ketal (e.g.
  • cyclic ketals e.g., 1,3-dioxane or 1,3-dioxolanes
  • acyclic acetal e.g., 1,3-dioxane or 1,3-dioxolanes
  • acyclic acetal e.g., 1,3-dioxane or 1,3-dioxolanes
  • acyclic acetal e.g., 1,3-dioxane or 1,3-dioxolanes
  • cyclic acetal e.g., 1,3-dioxane or 1,3-dioxolanes
  • cyclic acetal e.g., 1,3-dioxane or 1,3-dioxolanes
  • cyclic acetal e.g., 1,3-dioxane or 1,3-dioxolanes
  • cyclic acetal e.g., 1,
  • a “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • a group may be unsubstituted or substituted with one or more of the indicated substituents.
  • the group When the group is substituted, the group may be mono-substituted or poly-substituted. When the group is described as being “mono-substituted,” the group is only substituted with one substitutent. When the group is described as being “poly-substituted,” the group may have two or more substitutents, and each substitutent may be independently selected from any of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted,” if substituted, the substituent(s) may be independently selected from one or mmore of the indicated substituents.
  • substitutent itself may be unsubstituted or substituted with one ore more of the indicated substitutents.
  • substituted it is meant that one or more hydrogen atoms on the referenced substituent is replaced with a group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, alkoxy, mercapto, alkylthio, cyano, halogen, nitro, haloalkyl, haloalkoxy, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
  • C 1n to C n refers to the number of carbon atoms in the relevant group. That is, the group can contain from “m” to "n", inclusive, carbon atoms.
  • a “Ci to C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CHs) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-. If no "m” and "n” are designated with regard to a group, the broadest range described in these definitions is to be assumed.
  • alkyl refers to an aliphatic hydrocarbon group.
  • the alkyl moiety may be a "saturated alkyl” group, which means that it does not contain any alkene or alkyne moieties.
  • the alkyl moiety may also be an "unsaturated alkyl” moiety, which means that it contains at least one alkene or alkyne moiety.
  • An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • the alkyl moiety, whether saturated or unsaturated may be branched or straight chain.
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 5 carbon atoms.
  • the alkyl group of the compounds of the invention may be designated as "Ci-C 4 alkyl” or similar designations.
  • “Ci-C 4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent group(s) is(are) one or more group(s) individually and independently selected from alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, alkoxy, mercapto, alkylthio, cyano, halogen, nitro, haloalkyl, haloalkoxy, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • a substituent is described as being "optionally substituted” that substitutent may be substituted with one of the above substituents.
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
  • An alkenyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.
  • alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
  • An alkynyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.
  • hetero may be attached to a group and refers to one or more carbon atom(s) and the associated hydrogen atom(s) in the attached group have been independently replace with the same or different heteroatoms selected from nitrogen, oxygen and sulfur.
  • C m _ n or C 1n -C n is also indicated, it means that one or more carbon atom(s) and the associated hydrogen atom(s) in the C m _ n or C 1n -C n group have been independently replace with the same or different heteroatoms selected from nitrogen, oxygen and sulfur.
  • perhaloalkyl refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.
  • cycloalkyl refers to a completely saturated (no double bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. Cycloalkyl groups may range from C 3 to C 10 , in other embodiments it may range from C 3 to Ce. A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the substituent(s) may be an alkyl or selected from those indicated above with regard to substitution of an alkyl group unless otherwise indicated.
  • substituents on a cycloalkyl group may form an aromatic ring fused to the cycloalkyl group, including an aryl and a heteroaryl.
  • heteroalicyclic or “heteroalicyclyl” refers to a stable 3- to 18 membered ring which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • heteroalicyclic or “heteroalicyclyl” may be monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be joined together in a fused, bridged or spiro-connected fashion; and the nitrogen, carbon and sulfur atoms in the "heteroalicyclic” or “heteroalicyclyl” may be optionally oxidized; the nitrogen may be optionally quaternized; and the rings may also contain one or more double bonds provided that they do not form a fully delocalized pi- electron system throughout all the rings.
  • Heteroalicyclyl groups may be unsubstituted or substituted.
  • the substituent(s) may be one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-subs, al
  • heteroalicyclic or “heteroalicyclyl” include but are not limited to, azepinyl, dioxolanyl, imidazolinyl, morpholinyl, oxiranyl, piperidinyl N-Oxide, piperidinyl, piperazinyl, pyrrolidinyl, 4- piperidonyl, pyrazolidinyl, 2-oxopyrrolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone.
  • substituents on a heteroalicyclyl group may form an aromatic ring fused to the heteroalicyclyl group, including an aryl and a heteroaryl.
  • a heteroalicyclyl can further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio- systems such as lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, and the like.
  • heteroalicyclyls include, but are not limited to, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4- dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1 ,4-oxathiin, 1 ,4-oxathiane, tetrahydro- 1,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5- triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyr
  • aryl refers to a carbocyclic (all carbon) ring or two or more fused rings (rings that share two adjacent carbon atoms) that have a fully delocalized pi-electron system.
  • aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be optionally substituted.
  • substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthiocyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalome
  • substituents on an aryl group may form a non-aromatic ring fused to the aryl group, including a cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.
  • heteroaryl refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system), one or two or more fused rings that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
  • heteroaryl rings include, but are not limited to, furan, thiophene, phthalazine, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine and triazine.
  • a heteroaryl group may be optionally substituted.
  • substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amido, N-amido, S- sulfonamido, N-sulfonamido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,
  • substituents on a heteroayl group may form a non-aromatic ring fused to the aryl group, including a cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.
  • alkoxy refers to the formula -OR wherein R is an alkyl as defined above, e.g. methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n- butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amoxy, tert-amoxy and the like.
  • An alkoxy may be optionally substituted.
  • halo or halogen refers to F (fluoro), Cl (chloro), Br (bromo) or I (iodo).
  • One embodiment includes a method of synthesizing a compound of Formula 2-K comprising.
  • Xb is a halogen
  • n a is 0, 1, or 2;
  • PG a is protecting group
  • R 2 b, R3b, R4b, Rsb, R ⁇ b, R7b, Rsb, and R 9b are each independently selected from the group consisting of hydrogen, halogen, optionally substituted Ci_ 6 alkyl, optionally substituted C 2 - 6 alkenyl, optionally substituted C 2 - 6 alkynyl, perhaloalkyl, and CN.
  • the metal catalyzed coupling reaction of step (a) can be performed using a palladium catalyst and an inorganic base.
  • the palladium catalyst can be derived from a Pd(II) source, such as Pd(II)C ⁇ and the like
  • the inorganic base can be selected from the group consisting of Na 2 CO 3 , K 2 CO 3 , CS 2 CO 3 , NaHCO 3 , KHCO 3 , CsHCO 3 and the like.
  • R 7b and Rs b can be each independently selected from the group consisting of hydrogen and halogen; and Rs b can be an optionally substituted Ci -6 alkyl or halogen.
  • R 2 b, R3b, R4b, R ⁇ b, and R 9b can be each hydrogen.
  • PG a can be tert-butoxycarbonyl (Boc).
  • the metal catalyzed coupling reaction of step (a) can be performed using a palladium catalyst and an inorganic base.
  • the palladium catalyst can be derived from a Pd(II) source, such as Pd(II)Cl 2 and the like
  • the inorganic base can be selected from the group consisting of Na 2 CO 3 , K ⁇ CO 3 , Cs 2 CO 3 , NaHCO 3 , KHCO 3 , CsHCO 3 and the like.
  • R 7b and Rs b can be each independently selected from the group consisting of hydrogen and halogen; and Rs b can be selected from the goup consisting of an optionally substituted Ci -6 alkyl and halogen.
  • R 2 b, R3b, R 4 b, R ⁇ b, and R 9b can be each hydrogen.
  • Another embodiment includes a method of synthesizing a compound of Formula (3-B) comprising;
  • Xc and X D independently are halogen
  • n a is 0, 1, or 2;
  • R 2 b, R3b, R4b, Rsb, R ⁇ b, R7b, Rsb, and R 9b are each independently selected from the group consisting of hydrogen, halogen, optionally substituted Ci_ 6 alkyl, optionally substituted C 2 - 6 alkenyl, optionally substituted C 2 - 6 alkynyl, perhaloalkyl, and CN; and
  • R 7b and R 8b independently is selected from the group consisting of hydrogen and halogen; and R 5b can be selected from the goup consisting of an optionally substituted Ci -6 alkyl and halogen.
  • R 2b , R3b, R4b, R ⁇ b, and R 9b can be hydrogen.
  • Rsb and R 7 b is halogen or Ci_6 alkyl; or a pharmaceutically acceptable salt or a solvate thereof.
  • Rs b and R 7b are independently selected from the group consisting of methyl and halogen; or a pharmaceutically acceptable salt or a solvate thereof.
  • Rs b is methyl and R 7b is halogen; or a pharmaceutically acceptable salt or a solvate thereof
  • R 5b and R 7b are independently selected from the group consisting of methyl and halogen; or a pharmaceutically acceptable salt or a solvate thereof.
  • Rs b is methyl and R 7b is halogen; or a pharmaceutically acceptable salt or a solvate thereof.
  • the compound is 3-Chloro-10- methyl-6-(piperazin- 1 -yl)- 1 lH-dibenzo[&, e]azepine hydrochloride, 3 , 10-dichloro-6- (piperazin-l-yl)-HH-dibenzo[b,e]azepine hydrochloride, 3-Chloro-10-methyl-6- (piperazin- 1 -yl)- 11 ⁇ -dibenzo[&, e] azepine, or 3,10-dichloro-6-(piperazin- 1 -yl)- 1 IH- dibenzo [b ,e] azepine.
  • Formula 2-K may be made according to Scheme 4.
  • step (a) of Scheme 4 the carboxylic acid moiety of a compound of formula (2-A) can be reduced to provide an benzyl alcohol of formula (2-B);
  • R 2 b, R3b, R4b, Rsb, R ⁇ b, R7b, R ⁇ b, and Rt>b can be each independently selected from the group consisting of hydrogen, halogen, optionally substituted Ci_ 6 alkyl, optionally substituted C 2 - 6 alkenyl, optionally substituted C 2 - 6 alkynyl, perhaloalkyl, and CN;
  • R m can be hydrogen or a protecting group (PG a ); and
  • n a can be 0, 1, or 2.
  • a compound of formula (2-A) in an organic solvent such as diethyl ether, dioxane, dimethoxy ethane or THF
  • a reducing agent such as AlH 3 , BH 3 , DiBaIH, NaBH 4 and AlCl 3 , LiAlH(OMe) 3 , LiAlH 4 , and NaAlEt 2 H 2 to provide a compound of formula (2-B).
  • a compound of formula (2-A) in THF can be treated with BH 3 -SMe 2 to provide a compound of formula (2-B).
  • a compound of formula (2-B) can be transformed to a benzyl halide of formula (2-C).
  • an alcohol of formula (2-B) can be converted to benzyl halide of formula (2-C) using a halogenating agent.
  • an alcohol of formula (2-B) can be treated with a halogenating agent, such as P(O)Cl 3 , PCI 3 , PCI 5 , thionyl chloride, p-toluenesulfonyl chloride, P(O)Br 3 , PBr 3 , PBr 5 , thionyl bromide or p-toluenesulfonyl bromide, to provide a benzyl halide of formula (2-C).
  • a benzyl bromide of formula (2-C) can be formed by treating an alcohol of formula (2-B) in toluene with PBr 3 .
  • a compound of formula (2-E) can be formed by reaction of a benzyl halide of formula (2-C) with a boronic acid of formula (2-D) under metal catalyzed conditions.
  • a benzyl bromide of formula (2- C) can be reacted with a boronic acid of formula (2-D) in the presence of palladium to provide a compound of formula (2-E).
  • a mixture of a benzyl bromide of formula (2-C) and a boronic acid of formula (2-D) in an organic solvent, such as butyl alcohol, DMF, NMP, or acetone, and water can be treated with Pd(II) and an inorganic base, such as Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 , KHCO 3 , or CsHCO 3 , to provide a compound of formula (2-E).
  • an organic solvent such as butyl alcohol, DMF, NMP, or acetone
  • a mixture of a benzyl bromide of formula (2-C) and a boronic acid of formula (2-D) in an acetone and water can be treated with PdCl 2 and K 2 CO 3 to provide a compound of formula (2-E).
  • a compound of formula (2-F) can be formed by reduction of the nitro group of a compound of formula (2-E).
  • the nitro group of a compound of formula (2-E) can be reduced by hydrogenation, with sodium hydrosulfite (Na 2 S 2 O 4 ), with SnCl 2 , or with iron to provide a compound of formula (2-F).
  • a compound of formula (2-E) can be reduced with iron in the presence of acid.
  • a mixture of a compound of formula (2-E) in ethyl alcohol, and acetic acid can be treated with iron powder to provide a compound of formula (2-F).
  • a compound of formula (2-F) can be converted to a lactam of formula (2-G).
  • a compound of formula (2-F) can be converted to a lactam of formula (2-G) using a phosgene equivalent.
  • a compound of formula (2-F) can be converted to a lactam of formula (2-G) using a trichloromethyl chloroformate, to provide a lactam of formula (2-G).
  • the lactam of formula (2-G) can be formed using chloroformate as the phosgene equivalent and a Lewis acid.
  • a compound of formula (2-F) can be treated with trichloromethyl chloroformate in an organic solvent, such as diethyl ether, dimethoxyethane, THF and dioxane, then after reacting for an appropriate amount of time the organic solvent can be removed and replaced with a solvent, such as methylene chloride, carbon tetrachloride, dichloroethane, nitrobenzene, carbon disulfide or 1,2- dichlorobenzene, the mixture can then be combined with a Lewis acid, such as TiCl 4 , AlCl 3 , AlBr 3 , BF 3 , ZnCl 2 , GaCl 3 , FeCl 3 , SbCl 5 , ZrCl 4 , SnCl 4 , SmI 3 , ytterbium triflate, Samarium triflate, or BCl 3 , to provide a lactam of formula (2-G).
  • an organic solvent such as diethyl ether
  • a compound of formula (2-F) can be treated with trichloromethyl chloroformate in dioxane, then after reacting for an appropriate amount of time the dioxane can be removed and replaced with 1,2-dichlorobenzene, and the mixture can be added to a suspension of AlCl 3 in 1 ,2-dichlorobenzene to provide a lactam of formula (2- G).
  • Compound (2-F) is converted to compound (2-G) by the use of a phosgene equivalent, such as those mentioned above, via the formation of an isocyanate of formula (2-Fb)
  • a compound of formula (2-G) can be transformed to a compound of formula (2-H).
  • a lactam of formula (2-G) can be converted to an imidoylhalide using a halogenating agent.
  • a lactam of formula (2-G) can be treated with a halogenating agent, such as P(O)Cl 3 , PCl 3 , PCI 5 , TiCl 4 , thionyl chloride, or thionyl chloride with DMF, to provide a imidoylchloride of formula (2-H).
  • the imidoylchloride of formula (2-H) can be formed using P(O)Cl 3 as the chlorinating reagent and the solvent. In another embodiment, the imidoylchloride of formula (2-H) can be formed using thionyl chloride with catalytic DMF and toluene as the solvent.
  • a compound of formula (2-H) can be transformed to a compound of formula (2- J) by a nucleophilic substitution reaction.
  • a compound of formula (2- J) can be formed by reacting a compound of formula (2-H) with a compound of formula (2-1) under suitable nucleophilic substitution conditions.
  • an imidoylchloride of formula (2-H) can be reacted with a compound of formula (2-1) optionally in the presence of a base, such as triethylamine, diisopropylethylamine or N-methyl piperidine, in an organice solvent, such as methylene chloride, DMF, NMP, dimethoxyethane, THF, ethyl ether, or dioxane, to provide a compound of formula (2- J).
  • a base such as triethylamine, diisopropylethylamine or N-methyl piperidine
  • organice solvent such as methylene chloride, DMF, NMP, dimethoxyethane, THF, ethyl ether, or dioxane
  • Ru b of a compound of formula (2-1) can be Boc.
  • Ru b of a compound of formula (2-1) can be hydrogen and the compound of formula (2-K) can be formed directly without the deprotection step (
  • an imidoylchloride of formula (2-H) can be reacted with a piperizine in dioxane, to provide a compound of formula (2-K which is equivalent to 2-J where Rm, is hydrogen).
  • Rm, of a compound of formula (2-1) can be a protecting group PG a .
  • step (h) of Scheme 4 a compound of formula (2-J, where Ru b is a protecting group PG a ) can be deprotected to a provide a compound of formula (2-K).
  • R llb can be a Boc protecting group.
  • compound of formula (2-J), wherein R ⁇ b is a Boc group can be deprotected using an acid, such as trifluoracetic acid or hydrochloric acid, to provide a compound of formula (2-K).
  • the compound of formula (2-K) can be isolated as a free base or a salt following procedures know by those of skill in the art
  • X b can be chlorine
  • R 2 b, R3b, Rib, R ⁇ b, Rsb, and R 9b can be hydrogen
  • R 5b can be optionally substituted Ci -6 alkyl or halogen
  • R 7b can be halogen or optionally substituted Ci_ 6 alkyl
  • n a can be 1.
  • Rs b can be methyl and R 7b can be chlorine.
  • One embodiment includes a compound of Formula I:
  • R 5b and R 7b are independently selected from the group consisting of Ci -6 alkyl and halogen; or a pharmaceutically acceptable salt or a solvate thereof.
  • R 5b and R 7b are independently selected from the group consisting of methyl and halogen; or a pharmaceutically acceptable salt or a solvate thereof.
  • R 5b is methyl and R 7b is halogen; or a pharmaceutically acceptable salt or a solvate thereof.
  • the compound of Formula I is 3- Chloro- 10-methyl-6-(piperazin- 1 -yl)- 1 lH-dibenzo[&, ejazepine, 3 , 10-dichloro-6-
  • compounds of Formula I may be used to modulate the activity of a muscarinic receptor.
  • modulate refers to the ability of a compound disclosed herein to alter the function of a muscarinic receptor.
  • a modulator may activate the activity of a muscarinic receptor, may activate or inhibit the activity of a muscarinic receptor depending on the concentration of the compound exposed to the muscarinic receptor, or may inhibit the activity of a muscarinic receptor.
  • modulate also refers to altering the function of a muscarinic receptor by increasing or decreasing the probability that a complex forms between a muscarinic receptor and a natural binding partner.
  • a modulator may increase the probability that such a complex forms between the muscarinic receptor and the natural binding partner, may increase or decrease the probability that a complex forms between the muscarinic receptor and the natural binding partner depending on the concentration of the compound exposed to the muscarinic receptor, and or may decrease the probability that a complex forms between the muscarinic receptor and the natural binding partner.
  • modulation of the muscarinic receptor may be assessed using Receptor Selection and Amplification Technology (R-SAT) as described in U.S. Patent No. 5,707,798, the disclosure of which is incorported herein by reference in its entirety.
  • the term “activate” refers to increasing the cellular function of a muscarinic receptor.
  • the term “inhibit” refers to decreasing the cellular function of a muscarinic receptor.
  • the muscarinic receptor function may be the interaction with a natural binding partner or catalytic activity.
  • contacting refers to bringing a compound disclosed herein and a target muscarinic receptor together in such a manner that the compound can affect the activity of the muscarinic receptor, either directly; i.e., by interacting with the muscarinic receptor itself, or indirectly; i.e., by interacting with another molecule on which the activity of the muscarinic receptor is dependent.
  • Such "contacting” can be accomplished in a test tube, a petri dish or the like. In a test tube, contacting may involve only a compound and a muscarinic receptor of interest or it may involve whole cells. Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment.
  • the ability of a particular compound to affect a muscarinic receptor related disorder i.e., the IC 50 of the compound can be determined before use of the compounds in vivo with more complex living organisms is attempted.
  • multiple methods exist, and are well-known to those skilled in the art, to get the muscarinic receptors in contact with the compounds including, but not limited to, direct cell microinjection and numerous transmembrane carrier techniques.
  • the term "contacting" can also refer to bringing a compound disclosed herein to contact with a target muscarinic receptor in vivo.
  • a compound disclosed herein, or a prodrug thereof is administered to an organism and the compound is brought together with a muscarinic receptor within the organism, such contacting is within the scope of the present disclosure.
  • the compound of Formula I may be an agonist of said receptor, such as a muscarinic receptor, while in other embodiments, the compound may be an antagonist of said receptor. In yet other embodiments, the compound may be a partial agonist of said receptor.
  • a compound that is a partial agonists may in some cases be a partial activator of a receptor, while in other cases may be a partial repressor of a receptor. In yet other circumstances, the compound may be a tissue- specific modulator, while in other circumstances, the compound may be a gene-specific modulator.
  • Certain of the compounds disclosed herein may exist as stereoisomers including optical isomers.
  • the scope of the present disclosure includes all stereoisomers and both the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are well known to those of ordinary skill in the art.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a physiologically acceptable carrier, diluent, or excipient, or a combination thereof; and a compound of Formula I.
  • composition refers to a mixture of a compound of the invention with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration.
  • Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • carrier defines a chemical compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • carrier facilitates the uptake of many organic compounds into the cells or tissues of an organism.
  • the term "diluent” defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art.
  • One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.
  • physiologically acceptable defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.
  • compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s).
  • suitable carriers or excipient(s) include butylene glycol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, s thereof.
  • Techniques for formulation and administration of the compounds of the instant application may be found in "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, 18th edition, 1990.
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
  • compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.
  • the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks 's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks 's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination of the invention, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water- miscible organic polymer, and an aqueous phase.
  • a common cosolvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • VPD co-solvent system which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of POLYSORBATE 80TM; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • salts may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acid or base forms.
  • compositions suitable for use in the present invention include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. [0128] The exact formulation, route of administration and dosage for the pharmaceutical compositions of the present invention can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics," Ch. 1 p. 1).
  • the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient.
  • human dosages for treatment of at least some condition have been established.
  • the present invention will use those same dosages, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage.
  • a suitable human dosage can be inferred from ED 50 or ID 50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 500 mg of each ingredient, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of each ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceutical compositions of the present invention or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day.
  • compositions of the invention may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day.
  • the total daily dosage by oral administration of each ingredient will typically be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will typically be in the range 0.1 to 400 mg.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the present disclosure is related to a method of treating a neuropsychiatric disorder comprising administering to said patient a therapeutically effective amount of a compound of Formula I.
  • the neuropsychiatric disorder is selected from the group consisting of schizophrenia and related idiopathic psychosis, anxiety, sleep disorders, appetite disorders, affective disorders such as major depression, bipolar disorder, and depression with psychotic features, and Tourette's Syndrome, drug-induced psychosis, psychosis secondary to neurodegenerative disorders such Alzheimer's or Huntington's Disease.
  • the present disclosure is related to a method of treating a neuropsychiatric disorder comprising contacting a therapeutically effective amount of a compound of Formula I with said patient .
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I and a neuropsychiatric agent.
  • a neuropsychiatric agent refers to a compound, or a combination of compounds, that affects the neurons in the brain either directly or indirectly, or affects the signal transmitted to the neurons in the brain.
  • Neuropsychiatric agents therefore, may affect a person's psyche, such as the person's mood, perception, nociception, cognition, alertness, memory, etc.
  • the neuropsychiatric agent may be selected from the group consisting of a selective serotonin reuptake inhibitor, norepinephrine reuptake inhibitor, dopamine agonist, antipsychotic agent, serotonin 2A antagonists, and inverse serotonin 2A agonists.
  • the antipsychotic agent may be selected from the group consisting of a phenothiazine, phenylbutylpiperadine, dibenzapine, benzisoxidil, and salt of lithium.
  • the phenothiazine group of compounds may be selected from the group consisting of chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), and thioridazine (Mellaril®).
  • the phenylbutylpiperadine group of compounds may be selected from the group consisting of haloperidol (Haldol®), and pimozide (Orap®).
  • the dibenzapine group of compounds may be selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®) and quetiapine (Seroquel®).
  • the benzisoxidil group of compounds may be selected from the group consisting of resperidone (Resperidal®) and ziprasidone (Geodon®).
  • the salt of lithium may be lithium carbonate.
  • the antipsychotic agent may be selected from the group consisting of Aripiprazole (Abilify), Clozapine, Clozaril, Compazine, Etrafon, Geodon, Haldol, Inapsine, Loxitane, Mellaril, Moban, Navane, Olanzapine (Zyprexa), Orap, Permitil, Prolixin, Phenergan, Quetiapine (Seroquel), Reglan, Risperdal, Serentil, Seroquel, Stelazine, Taractan, Thorazine, Triavil, Trilafon, and Zyprexa, or pharmaceutically acceptable salts thereof.
  • Aripiprazole Abilify
  • Clozapine Clozaril
  • Compazine Etrafon
  • Geodon Haldol
  • Inapsine Loxitane
  • Mellaril Moban
  • Navane Olanzapine
  • Orap Permitil
  • Prolixin Phenergan
  • the selective serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram, sibutramine, duloxetine, and venlafaxine, and pharmaceutically acceptable salts or prodrugs thereof.
  • the norepinephrine reuptake inhibitor is selected from the group consisting of thionisoxetine and reboxetine.
  • the dopamine agonist is selected from the group consisting of sumatriptan, almotriptan, naratriptan, frovatriptan, rizatriptan, zomitriptan, cabergoline, amantadine, lisuride, pergolide, ropinirole, pramipexole, and bromocriptine.
  • the present disclosure is directed to a method of treating neuropsychiatric disorder in a patient comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula I and a neuropsychiatric agent.
  • the present disclosure is directed to a method of treating neuropsychiatric disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of Formula I and a therapeutically effective amount of a neuropsychiatric agent.
  • the patient may be a mammal.
  • the mammal may be selected from the group consisting of mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, primates, such as monkeys, chimpanzees, and apes, and humans.
  • the patient is a human.
  • the administering step in the above methods comprises administering said compound of Formula I and said neuropsychiatric agent nearly simultaneously.
  • the compound of Formula I and the neuropsychiatric agent are in the same administrable composition, i.e., a single tablet, pill, or capsule, or a single solution for intravenous injection, or a single drinkable solution, or a single dragee formulation or patch, contains both compounds.
  • the embodiments also include those in which each compound is in a separate administrable composition, but the patient is directed to take the separate compositions nearly simultaneously, i.e., one pill is taken right after the other or that one injection of one compound is made right after the injection of another compound, etc.
  • the administering step comprises administering one of the compound of Formula I and the neuropsychiatric agent first and then administering the other one of the compound of Formula I and the neuropsychiatric agent.
  • the patient may be administered a composition comprising one of the compounds and then at some time, a few minutes or a few hours, later be administered another composition comprising the other one of the compounds.
  • Also included in these embodiments are those in which the patient is administered a composition comprising one of the compounds on a routine or continuous basis while receiving a composition comprising the other compound occasionally.
  • the neuropsychiatric disorder to be treated by the methods and the compounds of the present disclosure is selected from the group consisting of schizophrenia and related idiopathic psychosis, anxiety, sleep disorders, appetite disorders, affective disorders such as major depression, bipolar disorder, and depression with psychotic features, and Tourette's Syndrome, drug-induced psychosis, psychosis secondary to neurodegenerative disorders such Alzheimer's or Huntington's Disease.
  • N-benzylidene-S-chloro ⁇ -iodoaniline (33) (1.0 g, 2.93 mmol) was dissolved in THF and cooled to -15 0 C.
  • Isopropyl magnesium chloride (1.8 M in THF, 3.22 mmol, 1.79 mL) was added and the reaction was stirred at -15 0 C for Ih.
  • Freshly prepared CuCN-2LiCl solution (1 M in THF, 2.93 mmol, 2.9 mL) was added and the reaction was stirred for 30 min at -15 0 C.
  • l-(bromomethyl)-2-chlorobenzene (1.20 g, 5.86 mmol) was added and reaction was allowed to warm-up to room temperature.
  • N-benzylidene-5-chloro-2-(2-chlorobenzyl)aniline (34) (crude oil, 1.4 g) was dissolved in THF (50 mL) and aqueous hydrochloric acid (4 N, 50 mL) was added. The reaction was stirred at room temperature for 15h then was basified by slow addition of potassium carbonate. The reaction was diluted with ethyl acetate (100 mL) and washed with aqueous sodium hydroxide (2 N, 100 mL).
  • the reaction was stirred at 100 0 C for 15 h then cooled to room temperature and concentrated.
  • the reaction was diluted with ethyl acetate (50 mL) and washed with aqueous sodium hydroxide (2 N, 50 mL).
  • the organic phase was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by silica gel chromatography (gradient: 0-10% methanol :dichloromethane) to give the title compound (0.14 g) as the free base.
  • the free base was dissolved in acetone (5 mL) and HCl (0.1 mL, 4 N in dioxane) was added.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

l'invention concerne des analogues de clozapine et leurs sels, esters, amides ou promédicaments pharmaceutiquement acceptables, des procédés de synthèse des analogues, et des procédés d'utilisation des analogues pour traiter des troubles neuropsychiatriques. Dans certains modes de réalisation, les analogues sont des diaryl[a,d]cycloheptènes substitués par un groupe amino.
PCT/US2010/046390 2009-08-26 2010-08-23 Analogues diaryl[a,d]cycloheptènes substitués par un groupe amino comme agonistes muscariniques et procédés de traitement de troubles neuropsychiatriques Ceased WO2011025748A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN105218423A (zh) * 2015-09-08 2016-01-06 李强 一种芳基取代吡咯化合物的合成方法
CN105957638A (zh) * 2016-05-05 2016-09-21 国网江西省电力科学研究院 一种导电纳米二氧化硅的制备方法

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Publication number Priority date Publication date Assignee Title
US20050192268A1 (en) * 2003-12-22 2005-09-01 Fredrik Ek Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders
US20060194784A1 (en) * 2003-12-22 2006-08-31 Fredrik Ek Amino substituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders
US20060199798A1 (en) * 2003-12-22 2006-09-07 Fredrik Ek Amino bustituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders
US20070197502A1 (en) * 2003-12-22 2007-08-23 Fredrik Ek AMINO SUBSTITUTED DIARYL[a,d]CYCLOHEPTENE ANALOGS AS MUSCARINIC AGONISTS AND METHODS OF TREATMENT OF NEUROPSYCHIATRIC DISORDERS

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105218423A (zh) * 2015-09-08 2016-01-06 李强 一种芳基取代吡咯化合物的合成方法
CN105957638A (zh) * 2016-05-05 2016-09-21 国网江西省电力科学研究院 一种导电纳米二氧化硅的制备方法

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