WO2012170209A2 - Composés benzofurane-2 carboxamide - Google Patents

Composés benzofurane-2 carboxamide Download PDF

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Publication number
WO2012170209A2
WO2012170209A2 PCT/US2012/039226 US2012039226W WO2012170209A2 WO 2012170209 A2 WO2012170209 A2 WO 2012170209A2 US 2012039226 W US2012039226 W US 2012039226W WO 2012170209 A2 WO2012170209 A2 WO 2012170209A2
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substituted
unsubstituted
butyl
piperazin
benzofuran
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Ramesh Sesha
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Nectid Inc
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Nectid Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention describes a number of novel benzofuran-2carboxamide compounds that are useful for treating a disorder in a mammal.
  • Benzofuran-2-carboxamide compounds have valuable properties, in particular those which can be used for the preparation of medicaments.
  • Vilazodone (5-(4-[4-(5-cyano-lH-indol- 3-yl) butyl] piperazin-l-yl) benzofuran-2-carboxamide), (Benzofuran-2carboxamide compound having formula A) is a dual acting serotonin reuptake inhibitor and 5-HT 1A receptor partial agonist.
  • vilazodone for oral administration lead to reports of a number of adverse events (AEs) such as diarrhea, nausea, vomiting and insomnia.
  • AEs adverse events
  • gastrointestinal side in Vilazodone patients include effects increased appetite, diarrhea, nausea, dry mouth, flatulence, dyspepsia, vomiting, and
  • benzofuran-2carboxamide compounds (prodrugs) disclosed herein have valuable properties, in particular those compounds that can be used for the preparation of medicaments. These compounds are particularly valuable because they avoid or minimize the adverse gastrointestinal side effects associated with vilazodone administration and improve the pharmacokinetic properties of known benzofuran-2carboxamide drugs.
  • R 3 is -CR 5 -NR 6 R 7 , substituted or unsubstituted (C 1 -C 12 )alkyl, substituted or unsubstituted (C 3 -C 1 o)cycloalkyl, substituted or unsubstituted (C 4 -C 22 )cycloalkylalkyl, substituted or unsubstituted (Ce-C ⁇ aryl, substituted or unsubstituted (C 7 -C22)arylalkyl, substituted or unsubstituted (Cs-Cc heteroaryl, substituted or unsubstituted (C 6 -C2i)heteroarylalkyl, substituted or unsubstituted heterocyclic group or substituted or unsubstituted (C 6 -C2i)heterocycloalkyl group;
  • R 4 is -CR 5 -NR 6 R 7 , -NR 8 R 9 , substituted or unsubstituted (C 1 -C 12 )alkyl, substituted or unsubstituted (C 3 -C 1 o)cycloalkyl, substituted or unsubstituted (C 4 -C22)cycloalkylalkyl, substituted or unsubstituted (C 6 -C 1 o)aryl, substituted or unsubstituted
  • each R 5 is independently hydrogen, substituted or unsubstituted (C 1 -C 1 2)alkyl, substituted or unsubstituted (C 3 -C 1 o)cycloalkyl, substituted or unsubstituted (C 4 - C 22 )cycloalkylalkyl, substituted or unsubstituted (C 6 -C 1 o)aryl, or substituted or unsubstituted (C 7 -C22)arylalkyl;
  • each R 6 and R 7 is independently substituted or unsubstituted (C 1 -C 1 2)alkyl, substituted or unsubstituted (C 3 -C 1 o)cycloalkyl, substituted or unsubstituted (C 4 - C 22 )cycloalkylalkyl, substituted or unsubstituted (C 6 -C 1 o)aryl, or substituted or unsubstituted (C 7 -C22)arylalkyl;
  • each R 8 and R 9 is independently substituted or unsubstituted (C 1 -C 1 2)alkyl, substituted or unsubstituted (C 3 -C 1 o)cycloalkyl, substituted or unsubstituted (C 4 -
  • C 22 cycloalkylalkyl, substituted or unsubstituted (C 6 -C 1 o)aryl, or substituted or unsubstituted (C7-C22)arylalkyl;
  • each R 10 is independently substituted or unsubstituted (C 1 -C 1 2)alkyl, substituted or unsubstituted (C 3 -C 1 o)cycloalkyl, substituted or unsubstituted (C 4 -C22)cycloalkylalkyl, substituted or unsubstituted (C 6 -C 1 o)aryl, or substituted or unsubstituted (C 7 -
  • substituents for the alkyl, aryl, (C 3 -Cg)cycloalkyl, or heterocyclic groups include (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (Q-C ⁇ haloalkyl, fluoro, chloro, bromo, cyano, amino, or nitro;
  • R 1 and R 2 are not both hydrogen, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted
  • heterocyclylalkyl group -COR 3 , -COCH(R 4 )NH 2 , -CH 2 NHCOPh, - COOCH(CH 3 )OCOR 3 , -S0 2 R 5 or -S0 2 NR 6 R 7 , at each occurrence;
  • the invention provides compounds having formula II-A,
  • each R 3 is independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl;
  • the invention provides compounds having formula II-A, wherein each R is independently (C Cs kyl, preferably methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl orl,l-dimethylethyl (t-butyl).
  • the invention provides compounds having formula II-A, wherein each R is independently (C 3 -C 12 )cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the invention provides compounds having formula II-A, wherein each R is independently substituted or unsubstituted aryl preferably phenyl wherein the substituents are halogen, cyano, nitro or (Ci-C4)alkyl preferably methyl.
  • the invention provides compounds having formula II-B,
  • each R 4 is independently substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl.
  • the invention provides compounds having formula II-B, wherein each R 4 is independently substituted or unsubstituted (C 1 -C 4 )alkyl wherein the substituents are halogens.
  • the invention provides compounds having formula II-B, wherein each R 4 is independently substituted or unsubstituted arylalkyl preferably benzyl, or substituted or unsubstituted aryl preferably phenyl and the substitution on phenyl are halogen, (Ci-C 4 )alkyl preferably methyl, (C 1 -C 4 )alkoxy preferably methoxy, amino or nitro.
  • the invention provides compounds having formula II-C,
  • each R 8 and R 9 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl.
  • each R 8 is independently hydrogen or (C 1 -C 4 )alkyl, preferably methyl and each R 8 is independently (Ci-C 4 )alkyl, cycloalkyl, preferably cyclohexyl, substituted or unsubstituted aryl preferably, phenyl or substituted or unsubstituted arylalkyl, preferably benzyl or-CH(CH 3 )Ph.
  • the invention provides compounds having formula II-D,
  • each R 5 is independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted arylalkyl.
  • the invention provides compounds having formula II-D, wherein each R 5 independently is hydrogen, (Ci-C 4 )alkyl or arylalkyl, preferably benzyl.
  • the invention provides compounds having formula II-E,
  • R 10 at each occurrence is substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.
  • R 10 is -(C 1 -C 4 )alkyl or (C3-C 1 2)cycloalkyl preferably cyclopropyl, cyclobutyl or cyclohexyl.
  • R is independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl.
  • the invention provides compounds having formula III-A, wherein R is -(Ci-C8)alkyl, preferably methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n- pentyl or 1,1-dimethylethyl (t-butyl).
  • the invention provides compounds having formula III-A, wherein R is -(C3-C 1 2)cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the invention provides compounds of formula III-A, wherein R 3 is substituted or unsubstituted aryl, preferably phenyl wherein the substituents are halogen, cyano, nitro or -(C 1 -C 4 )alkyl preferably methyl.
  • the invention provides compounds having formula III-B,
  • R 4 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl.
  • the invention provides compounds having formula III-B, wherein R 4 is substituted or unsubstituted (Ci-C 4 )alkyl wherein the substituents are halogen.
  • the invention provides compounds having formula III-B, wherein R 4 is substituted or unsubstituted arylalkyl, preferably benzyl, or substituted or unsubstituted aryl, preferably phenyl, where the substitutes are halogen, (Ci-C 4 )alkyl, preferably methyl, (C - C 4 ) alkoxy, preferably methoxy, amino, or nitro.
  • the invention provides compounds having formula III-C,
  • R 8 and R 9 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl.
  • the invention provides compounds having formula III-C, wherein
  • R is hydrogen or (C 1 -C 4 )alkyl, preferably methyl and R is (Q-G ⁇ alkyl, cycloalkyl, preferably cyclohexyl, substituted or unsubstituted aryl, preferably phenyl, or substituted or unsubstituted arylalkyl, preferably benzyl or-CH(CH 3 )Ph.
  • R 5 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted arylalkyl.
  • the invention provides compounds having formula III-D, wherein R 5 is hydrogen, (Ci-C 4 )alkyl or arylalkyl, preferably benzyl. [0036] In another aspect, the invention provides compounds having formula III-E,
  • R 10 is substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.
  • the invention provides compounds having formula III-E, wherein R is -(C 1 -C 4 )alkyl or (C 3 -C 12 )cycloalkyl preferably cyclopropyl, cyclobutyl or cyclohexyl.
  • the invention provides compounds having formula IV-A,
  • R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl.
  • the invention provides compounds having formula IV-A, wherein R is -(C 1 -Cg)alkyl, preferably methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n- pentyl or 1,1-dimethylethyl (t-butyl).
  • the invention provides compounds having formula IV-A, wherein R is -(C 3 -C 12 )cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the invention provides compounds having formula IV-A, wherein R is substituted or unsubstituted aryl, preferably phenyl wherein the substituents are halogen, cyano, nitro or -(Ci-C 4 )alkyl, preferably methyl.
  • the invention provides compounds having formula IV-B,
  • R 4 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl.
  • the invention provides compounds having formula IV-B, wherein R 4 is substituted or unsubstituted (Ci-C4)alkyl, wherein substituent are halogen.
  • the invention provides compounds having formula IV-B, wherein R 4 is substituted or unsubstituted arylalkyl, preferably benzyl, or substituted or unsubstituted aryl, preferably phenyl, wherein the substitutients on phenyl are halogen,
  • (C 1 -C 4 )alkyl preferably methyl
  • (C 1 -C 4 )alkoxy preferably methoxy, amino or nitro.
  • the invention provides compounds having formula IV-C,
  • R 8 and R 9 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted cycloalkyl.
  • R 8 and R 9 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted cycloalkyl.
  • R 8 is hydrogen or (Ci methyl and R 9
  • -C 4 )alkyl preferably is (Ci-C 4 )alkyl, cycloalkyl, preferably cyclohexyl, substituted or unsubstituted aryl, preferable phenyl or substituted or unsubstituted arylalkyl, preferable benzyl or-CH(CH 3 )Ph.
  • the invention provides compounds having formula IV-D,
  • R 5 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted arylalkyl.
  • the invention provides compounds having formula IV-D, wherein R is hydrogen, (Ci-C 4 ) alkyl or arylalkyl, preferable benzyl.
  • the invention provides compounds having formula IV-E,
  • R 10 is substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.
  • the invention provides compounds having formula IV-E, wherein R 10 is (CrC 4 ) alkyl or (C 3 -C 12 ) cycloalkyl, preferably cyclopropyl, cyclobutyl or cyclohexyl.
  • the present invention provides vilazodone prodrugs or bio precursors that are useful for treating a disorder.
  • the invention specifically provides vilazodone prodrugs of the disclosed compounds Formulas I, II-A to II-E, III-A to III-E, or IV-A to IV-E.
  • the invention provides pharmaceutical compositions comprising a compound of formula la, as disclosed herein, and a pharmaceutically acceptable carrier.
  • the carrier is liquid or solid.
  • the invention provides a composition in the form of a kit.
  • the invention provides a method for prevention or treatment of a pathological condition or disorder in a mammal wherein the condition or disorder is depression, cancer, pain, inflammatory disease and rheumatoid arthritis, comprising administering to said mammal an effective amount of a compound of any of claims 1-9.
  • the mammal is human.
  • the invention provides a pharmaceutical composition comprising a compound of formula II, as disclosed herein, or pharmaceutically acceptable salt, for use in medical treatment.
  • disorders include cancer, pain, inflammatory disease and rheumatoid arthritis.
  • the invention provides a method for the use of a therapeutically effective amount of a compound of formula II, as disclosed herein, or pharmaceutically acceptable salts thereof to prepare a medicament for treatment of depression or pain in a mammalian species (for example, a human).
  • the present invention provides pharmaceutical compositions of the disclosed compounds.
  • the pharmaceutical compositions generally comprise one or more of the disclosed compounds, and a pharmaceutically acceptable vehicle or carrier.
  • the invention specifically provides pharmaceutical composition comprising vilazodone prodrugs of Formulas I, II-A to II-E, III-A to III-E, or IV-A to IV-E and all variations thereof.
  • FIGs. 1-12 illustrate methods for synthesizing the disclosed compounds. Detailed Description
  • an element means one element or more than one element.
  • the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix -C j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
  • C Cs kyl refers to alkyl of one to eight carbon atoms, inclusive.
  • the disclosed compounds are generally named according to the IUPAC or CAS nomenclature system.
  • Halo or halogen is fluoro, chloro, bromo, or iodo.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from 1 to 12 carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n- propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, heptyl, octyl and the like.
  • (C 1 -C 6 )haloalkyl or halo(C 1 -C 6 )alkyl can be iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, or pentafluoroethyl;
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon- carbon double bond and which can be a straight or branched chain having 2 to about 12 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1- butenyl, 2-butenyl and the like.
  • alkoxy refers to a straight or branched, saturated aliphatic hydrocarbon radical having from one to six carbon atoms, bonded to an oxygen atom that is attached to a core structure.
  • alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3-methyl butoxy, and the like.
  • (C3-C 12 )cycloalkyl denotes a non-aromatic mono or multicyclic ring system having from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, bicycloalkyl (norbornyl, 2.2.2-bicyclooctyl, etc.), tricycloalkyl (adamantyl, etc.), bridged cyclic groups or sprirobicyclic groups, e.g., spiro(4,4) non-2-yl, optionally comprising 1-2 N, O or S.
  • (C 4 -C 24 )cycloalkylalkyl refers to a cyclic ring-containing radical having 3 to about 12 carbon atoms directly attached to an alkyl group.
  • the cycloalkylalkyl group can be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Non-limiting examples of such groups include cyclopropylmethyl,
  • (C 6 -C 1 o)aryl means a carbocyclic aromatic system containing one, or two rings wherein such rings can be fused. If the rings are fused, one of the rings must be fully unsaturated and the fused ring(s) can be fully saturated, partially unsaturated or fully unsaturated.
  • fused means that a second ring is present (i.e., attached or formed) by having two adjacent atoms in common (i.e., shared) with the first ring.
  • fused is equivalent to the term “condensed”.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and biphenyl.
  • (C7-C 22 )arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 or -C 2 H 4 C 6 H 5 .
  • (Cs-Cc heterocycle” generally represents a non-aromatic heterocyclic group, having from 3 to about 10 ring atoms, which includes monocyclic, bicyclic, tricyclic, fused, bridged or spiro ring systems, saturated or partially unsaturated, and containing at least one heteroatom (e.g., 1, 2, 3, or 4).
  • the heteroatoms, nitrogen, phosphorus, carbon, oxygen or sulfur in the heterocyclic ring radical can be optionally oxidized to various oxidation states.
  • the nitrogen atom are optionally quaternized.
  • (C 6 -C 21 ) heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
  • the heterocyclylalkyl radical can be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • (C5-C9) heteroaryl refers to an aromatic heterocyclic ring radical.
  • the heteroaryl ring radical can be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • (C6-C2i)heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • the heteroarylalkyl radical can be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrol
  • heterocycle groups include 1,3-dioxolane, 1,4-dioxane, 1,4-dithiane, 2H-pyran, 2-pyrazoline, 4H-pyran, chromanyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, morpholine, piperazinyl, piperidine, piperidyl,
  • pyrazolidine pyrazolidinyl, pyrazolinyl, pyrrolidine, pyrroline, quinuelidine, thiomorpholine, and the like.
  • Non-limiting examples of heteroaryl groups include furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyraxolyl, pyrrolyl, pyrazinyl, tetrazolyl, puridyl (or its N-oxide), thientyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).
  • salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutylate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate,
  • Acids commonly employed to form acid addition salts are inorganic acids, such as for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p- toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as p- toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • Base addition salts include those derived from inorganic bases, such as for example, ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.
  • bases useful in preparing the salts of the disclosed compounds include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • the compounds of formula I have more than one chiral center and can be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism.
  • the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, the disclosed compounds, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, or enzymatic techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine suitable activity using the tests described herein, or using other similar tests which are well known in the art.
  • Enantiomeric ally enriched compounds disclosed can also be obtained from enantiomerically enriched precursors.
  • R 3 is -CR 5 -NR 6 R 7 , methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methyl-l -propyl, 2- butyl, n-pentyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, (C 6 -C 1 o)aryl or (C 7 -C 22 )arylalkyl; wherein the aryl groups are optionally substituted;
  • R 4 is -CR 5 -NR 6 R 7 , -NR 8 R 9 , methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methyl-l- propyl, 2-butyl, n-pentyl, t-butyl, (C Ce ⁇ aloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, (C 6 -C 1 o)aryl or (C 7 -C 22 )arylalkyl; wherein the aryl groups are optionally substituted;
  • each R 8 and R 9 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, 2- methyl-1 -propyl, 2-butyl, n-pentyl,t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, (C 6 -C 1 o)aryl or (C 7 -C 22 )ary kyl; wherein the aryl groups are optionally substituted;
  • each R 10 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methyl-l - propyl, 2-butyl, n-pentyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, (C 6 -
  • aryl substituents are (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, fluoro, chloro, bromo, cyano, amino, or nitro; or
  • R 2 groups include hydrogen; and R 3 is -CR 5 -NR 6 R 7 , methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methyl-l -propyl, 2-butyl, n-pentyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or optionally substituted phenyl.
  • R 2 groups include hydrogen; and R 4 is-CR 5 -NR 6 R 7 , -NR 8 R 9 , methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methyl-l -propyl, 2-butyl, n-pentyl,t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or optionally substituted phenyl
  • a specific R 4 group is -NR 8 R 9 .
  • a specific haloalkyl group is CF 3 .
  • a specific R 3 group is -CR 5 -NR 6 R 7 .
  • the disclosed compounds are prepared by techniques known in the art. See, for example, the procedures disclosed in WO2009/120999; WO2010075520; US 6825350; Naik et al, ARKIVOC 2004 (i) 55-63; J. Org. Chem. 36(11), 1971, 829-832; and/or Vogel's Practical Organic Chemistry: 5 th edition.
  • the starting materials e.g., vilazodone » HCl (CAS number 163521-12-8) are either commercially available or can be prepared by the procedures known in the art.
  • Scheme 2 depicts the general procedure for the preparation of sulfonamide derivative.
  • Compound of formula A on reaction with appropriately substituted sulfonyl halide (in excess) or sulfonyl anhydride (in excess) under the existence of suitable organic base and suitable organic solvent provides compound of formula II-B wherein R 4 is as defined above.
  • compound of formula II-C wherein R 8 and R 9 are as defined above can be prepared by reacting compound of formula A with thionyl chloride (in excess) followed by reaction with amine of formula R 7 R 8 NH (in excess) in suitable organic solvent.
  • compound of formula A can react with dimethylsulfamoyl chloride (in excess) in presence of suitable base and in suitable solvent to provide compound of formula II-C wherein both R 7 and R 8 are methyl.
  • Scheme 6 depicts the general procedure for the preparation of sulfonamide derivative.
  • a compound of formula A on reaction with appropriately substituted sulfonyl halide or sulfonyl anhydride under the existence of suitable organic base and suitable organic solvent provides compound of formula III-B wherein R 4 is as defined above.
  • a compound of formula III-C wherein R 8 and R 9 are as defined above can be prepared by reacting compound of formula A with thionyl chloride followed by reaction with amine of formula R 8 R 9 NH in suitable organic solvent.
  • compound of formula A can react with dimethylsulfamoyl chloride in presence of suitable base and in suitable solvent to provide compound of formula III-
  • a general procedure for the preparation of compound of formula IV-A wherein R 3 is as defined above, is depicted in Scheme 9 (Fig. 9).
  • a compound of general formula IV-A, wherein R is as defined above can be prepared by a process known in the art.
  • the amide group of compound of formula A-9 can be protected by suitable protective group known in the art, for example, compound A-9 reacts with dibutyl pyrocarbonate to provide N-BOC compound of formula B-9.
  • Compound B-9 reacts with appropriate carboxylic acid anhydride or carboxylic acid chloride in presence of a suitable solvent to afford compound C-9 which on deprotection by using suitable reagent, (for example trifluoroacetic acid) provides compound of formula IV-A.
  • suitable reagent for example trifluoroacetic acid
  • Scheme 10 depicts the general procedure for the preparation of sulfonamide derivative.
  • Compound B-9 after reaction with a suitably substituted sulfonyl halide or sulfonyl anhydride with a suitable organic base and a suitable organic solvent provides compound D-10 wherein R 4 is as defined above.
  • Compound IV-B can be obtained by amide deprotection of compound D-10 by using suitable de-protecting reagent such as trifluoroacetic acid.
  • compound IV-C wherein R 5 and R 6 are as defined above , can be prepared by reacting compound B-9 with thionyl chloride to provide compound E-10.
  • a compound E-10 after reaction with an amine of formula R 8 R 9 NH in a suitable organic solvent provides compound F- 10, which on deprotection, following similar procedure as discussed above provides compound of formula IV-C.
  • a compound of formula B-9 can react with dimethylsulfamoyl chloride in presence of a suitable base and a suitable solvent followed by amide deprotection to provide compound of formula IV-C wherein both R 8 and R 9 are methyl.
  • Compound 1-A In heterogeneous suspension of 5-(4-[4-(5-cyano-lH-indol-3-yl) butyl] piperazin-l-yl) benzofuran-2-carboxamide (1 mmol) in water (5 mL), add 6N HCl (in the volume range of 240-400 ⁇ ) until the solution become homogeneous (pH ca.1.5). Cool the resulting homogenous solution in an ice bath. Add acetic anhydride (2.5-3.0 mmol) followed by solid sodium bicarbonate (185-300 mg) until there is no further effervescence or pH of the mixture becomes ca 5.5.
  • Compound 2-A Add benzenesulfonyl chloride (2.5 mmol) drop wise to a stirring solution of 5-(4-[4-(5-cyano-lH-indol-3-yl) butyl] piperazin-l-yl) benzofuran-2-carboxamide (1 mmol), dichlormethane and pyridine. Stir the reaction at room temperature for four hours and then concentrate in vacuo. Purify the residue by flash column chromatography followed by recrystallization from appropriate solvent to get the desired product.
  • Compound 2-B Add methanesulfonic anhydride (2.5 mmol) drop wise to a stirring solution of 5-(4-[4-(5-cyano-lH-indol-3-yl) butyl] piperazin-l-yl) benzofuran-2-carboxamide (1 mmol) and acetonitrile. A precipitate forms within a minutes. Remove the solvent and partition the residue between dichloromethane and saturated aqueous sodium bicarbonate. Separate the fraction and dry the organic fraction over anhydrous magnesium sulfate. Filter the crude, concentrate and recrystallize from appropriate solvent to get the desired product.
  • Compound 4-C Add triethyl amine in solution of 5-(4-[4-(5-cyano-lH-indol-3-yl) butyl] piperazin-l-yl) benzofuran-2-carboxamide (1 eq.) in dichloromethane. Cool the mixture and add activated form of N-Boc-valine (e.g. O-t-butyloxycarbonyl valine) (2.2 eq.). Stir the mixture for 10- 12h; quench the reaction by adding aqueous sodium bicarbonate. Wash the mixture by dilute HCl (aq.) and extract with ethyl acetate.
  • N-Boc-valine e.g. O-t-butyloxycarbonyl valine
  • Compound 6-A In heterogeneous suspension of 5-(4-[4-(5-cyano-lH-indol-3-yl) butyl] piperazin-l-yl) benzofuran-2-carboxamide (1 mmol) in water (5 mL), add 6N HCl (in the volume range of 240-400 ⁇ ) until the solution become homogeneous (pH ca.1.5). Cool the resulting homogenous solution in an ice bath. Add acetic anhydride (1-1.5 mmol) followed by solid sodium bicarbonate (185-300 mg) until there is no further effervescence or pH of the mixture becomes ca 5.5.
  • Compound 7 -A Add benzenesulfonyl chloride (3.5 mmol) drop wise to a stirring solution of 5-(4-[4-(5-cyano-lH-indol-3-yl) butyl] piperazin-l-yl) benzofuran-2-carboxamide (3.2 mmol), dichlormethane and pyridine. Stir the reaction at room temperature for four hours and then concentrate in vacuo. Purify the residue by flash column chromatography followed by recrystallization from appropriate solvent to get the desired product.
  • Compound 7-B Add methanesulfonic anhydride (3.4 mmol) drop wise to a stirring solution of 5-(4-[4-(5-cyano-lH-indol-3-yl) butyl] piperazin-l-yl) benzofuran-2-carboxamide (3.2 mmol) and acetonitrile. A precipitate forms within a minutes. Remove the solvent and partition the residue between dichloromethane and saturated aqueous sodium bicarbonate.
  • Compound 8-A Place 5-(4-[4-(5-cyano-lH-indol-3-yl) butyl] piperazin-l-yl) benzofuran-2-carboxamide in 2 dram (7.4 mL) vial and add dichloromethane (2 mL) and diisopropylethylamine (1.2 eq.). Add dimethylsulfamoly chloride (1.1 eq.) and place the vial on shaker for about 2-4 hours at ambient temperature. Analyze the reaction mixture by LC/MS to confirm the formation of the desired product. Remove the solvent and purify the residue by semi- preparative HPLC to get the desired product.
  • Compound 8-B Place 5-(4-[4-(5-cyano-lH-indol-3-yl) butyl] piperazin-l-yl) benzofuran-2-carboxamide in 2 dram (7.4 mL) vial and add 4-(dimethylamino)pyridine (1 eq.) and dichloromethane (800 ⁇ ). Seal the vial and cool to -78° C in a dry ice/acetone bath. Add sulfuryl chloride (186 of 1 M in dichloromethane) and put the vial on shaker for about 30 minutes. Cool down the vial to -78° C. Charge a separate vial with appropriate amine (e.g.
  • Formula 11-A Step-1: Protection of amide NH7 ofvilazodone: Add 5-(4-[4-(5- cyano-lH-indol-3-yl) butyl] piperazin-l-yl) benzofuran-2-carboxamide (10 mmol) in a mixture of dioxane (20 ml), water (10 ml) and 1M sodium hydroxide (10 ml). Stir the mixture and cool on an ice-water bath. Add di-t-butyl pyrocarbonate (11 mmol) and continue the stirring for 30 minutes at room temperature. Concentrate the solution in vacuo to about 10-15 ml.
  • Step-2 N-acylation of Vilazodone Add 6N HC1 (in the volume range of 240-400 ⁇ ) in a heterogeneous suspension of tert-butyl (5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l- yl)benzofuran-2-carbonyl)carbamate (1 mmol) in water (5 mL) until the solution become homogeneous (pH ca.1.5). Cool the resulting homogenous solution in an ice bath. Add acetic anhydride (1-1.5 mmol) followed by solid sodium bicarbonate (185-300 mg) until there is no further effervescence or pH of the mixture becomes ca 5.5. Filter the precipitate product, wash with water (2 x 1 mL), and dry by pressing between folds of filter paper and finally in a vacuum desiccator.
  • Step-3 Deprotection of amide group: Dissolve the product obtained in step 2 in dichloromethane or other suitable organic solvent. Cool the solution, add trifluoroacetic acid and stir the mixture for l-8h. Quench the reaction by adding aqueous sodium bicarbonate or other quenching reagent. Extract the mixture with ethyl acetate or other suitable organic solvent. Dry the combined organic extract over suitable desiccant (e.g. magnesium sulfate anhydrous). Filter the mixture and remove the organic solvent to furnish the desired compound. Yield: 66%.
  • desiccant e.g. magnesium sulfate anhydrous
  • Compound 12-B Add methanesulfonic anhydride (3.4 mmol) drop wise to a stirring solution of tert-butyl (5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l-yl)benzofuran-2- carbonyl)carbamate (3.2 mmol) (obtained in step-1 of Formula 1) and acetonitrile. A precipitate forms within a minutes. Remove the solvent and partition the residue between dichloromethane and saturated aqueous sodium bicarbonate. Separate the fraction and dry the organic fraction over anhydrous magnesium sulfate. Filter the crude, concentrate and recrystallize from appropriate solvent to get the BOC protected product.
  • Compound 13- A Place tert-butyl (5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l- yl)benzofuran-2-carbonyl)carbamate (obtained in step-1 of Formula 1) in 2 dram (7.4 mL) vial and add dichloromethane (2 mL) and diisopropylethylamine (1.2 eq.). Add dimethylsulfamoyl chloride (1.1 eq.) and place the vial on shaker for about 2-4 hours at ambient temperature.
  • Compound 13-B Place tert-butyl (5-(4-(4-(5-cyano-lH-indol-3-yl)butyl)piperazin-l- yl)benzofuran-2-carbonyl)carbamate (obtained in step-1 of Formula 1) in 2 dram (7.4 mL) vial and add 4-(dimethylamino)pyridine (1 eq.) and dichloromethane (800 ⁇ ). Seal the vial and cool to -78° C in a dry ice/acetone bath. Add sulfuryl chloride (186 ⁇ ⁇ of 1 M in dichloromethane) and put the vial on shaker for about 30 minutes.
  • Compound 14-C Add triethyl amine in solution of ieri-butyl (5-(4-(4-(5-cyano-lH-indol-3- yl)butyl)piperazin-l-yl)benzofuran-2-carbonyl)carbamate (as obtained in Formula 1, step 1) in dichloromethane. Cool the mixture and add activated form of N-Boc-valine (e.g. O-t- butyloxycarbonyl valine). Stir the mixture for 10-12 h, quench the reaction by adding aqueous sodium bicarbonate. Wash the mixture by dilute HC1 (aq.) and extract with ethyl acetate.
  • N-Boc-valine e.g. O-t- butyloxycarbonyl valine
  • mice and Wistar rats The study used male Swiss mice and Wistar rats.
  • the mice 23 -28 g housed in groups of tens and the Wistar rats (260-280 g for microdialysis experiments and 180-220 g for all other studies) housed in groups of fives.
  • animals were used only once and were kept in conditions of constant temperature (22 + 1° C) controlled lighting on a 12-h light/dark cycle and free access to food and water.
  • Formula 10-A was dissolved in dimethyl-sulfoxide, stored as frozen aliquots and diluted before each experiment. All other drugs were dissolved in saline.
  • NRT-500 or fluoxetine were administered i.p. or p.o. to rats 45 or 60 min, respectively, before killing the animals.
  • [ H]5-HT uptake was measured as above described.
  • Fetal rat brains were used for preparing cultures according to Wichems et al., 1995.
  • the rostral region includes the 5-HT containing cell groups B7-9 which in the adult animal are located within the dorsal and median raphe nucleus.
  • the cell culture was maintained in culture for 5 -7 days before performing the experiments.
  • the investigative compound was approximately 15 times more potent as a [ H]5-HT uptake than as a [3H] -noradrenaline uptake inhibitor.
  • Formula 14-D was dissolved in dimethyl-sulfoxide, stored as frozen aliquots and diluted before each experiment. All other drugs were dissolved in saline.
  • Fetal rat brains were used for preparing cultures according to Wichems et al., 1995.
  • the rostral region includes the 5-HT containing cell groups B7-9 which in the adult animal are located within the dorsal and median raphe nucleus.
  • the cell culture was maintained in culture for 5 -7 days before performing the experiments.
  • Paroxetine was a very potent and selective inhibitor of

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Abstract

L'invention concerne des dérivés de composés vilazodones ayant des propriétés de valeur. Les dérivés peuvent être utilisés pour la préparation de médicaments. Ces composés sont particulièrement de valeur parce qu'ils évitent ou rendent minimaux les effets secondaires gastro-intestinaux défavorables associés à une administration de vilazodone et améliorent les propriétés pharmacocinétiques de la vilazodone.
PCT/US2012/039226 2011-05-23 2012-05-23 Composés benzofurane-2 carboxamide Ceased WO2012170209A2 (fr)

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US201161489153P 2011-05-23 2011-05-23
US61/489,153 2011-05-23
US201161490152P 2011-05-26 2011-05-26
US61/490,152 2011-05-26
US201161493366P 2011-06-03 2011-06-03
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103360373A (zh) * 2013-07-12 2013-10-23 苏州永健生物医药有限公司 维拉唑酮中间体及其盐的合成方法
CN106065018A (zh) * 2015-04-23 2016-11-02 广东东阳光药业有限公司 取代的吲哚化合物及其使用方法和用途
US9598401B2 (en) 2013-07-29 2017-03-21 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use thereof
US10316025B2 (en) 2015-06-03 2019-06-11 Sunshine Lake Pharma Co., Ltd. Substituted piperazine compounds and methods of use and use thereof
JP2021517164A (ja) * 2018-03-05 2021-07-15 テオン セラピューティクス，インク． アデノシン受容体アンタゴニストおよびその使用
US20220226279A1 (en) * 2019-04-25 2022-07-21 Bayer Aktiengesellschaft Acyl sulfonamides for treating cancer
JP2024527574A (ja) * 2021-07-07 2024-07-25 テラン バイオサイエンシズ インコーポレイテッド Ｎ，ｎ－ジメチルトリプタミン及び関連する幻覚剤ならびにその使用

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103360373A (zh) * 2013-07-12 2013-10-23 苏州永健生物医药有限公司 维拉唑酮中间体及其盐的合成方法
US9598401B2 (en) 2013-07-29 2017-03-21 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use thereof
CN106065018A (zh) * 2015-04-23 2016-11-02 广东东阳光药业有限公司 取代的吲哚化合物及其使用方法和用途
CN106065018B (zh) * 2015-04-23 2020-04-21 广东东阳光药业有限公司 取代的吲哚化合物及其使用方法和用途
US10316025B2 (en) 2015-06-03 2019-06-11 Sunshine Lake Pharma Co., Ltd. Substituted piperazine compounds and methods of use and use thereof
JP2021517164A (ja) * 2018-03-05 2021-07-15 テオン セラピューティクス，インク． アデノシン受容体アンタゴニストおよびその使用
US20220226279A1 (en) * 2019-04-25 2022-07-21 Bayer Aktiengesellschaft Acyl sulfonamides for treating cancer
US12357603B2 (en) * 2019-04-25 2025-07-15 Bayer Aktiengesellschaft Acyl sulfonamides for treating cancer
JP2024527574A (ja) * 2021-07-07 2024-07-25 テラン バイオサイエンシズ インコーポレイテッド Ｎ，ｎ－ジメチルトリプタミン及び関連する幻覚剤ならびにその使用

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