US20060025601A1 - Tricyclic indeno-pyrrole derivatives as serotonin receptor modulators - Google Patents

Tricyclic indeno-pyrrole derivatives as serotonin receptor modulators Download PDF

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US20060025601A1
US20060025601A1 US11/189,952 US18995205A US2006025601A1 US 20060025601 A1 US20060025601 A1 US 20060025601A1 US 18995205 A US18995205 A US 18995205A US 2006025601 A1 US2006025601 A1 US 2006025601A1
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pyrrole
methyl
hexahydroindeno
mmol
observed
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Youssef Bennani
Bayard Huck
Michael Robarge
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Athersys Inc
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Athersys Inc
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Assigned to ATHERSYS, INC. reassignment ATHERSYS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BENNANI, YOUSSEF L., ROBARGE, MICHAEL J., HUCK, BAYARD
Publication of US20060025601A1 publication Critical patent/US20060025601A1/en
Assigned to VENTURE LENDING & LEASING IV, INC. reassignment VENTURE LENDING & LEASING IV, INC. SECURITY AGREEMENT Assignors: ATHERSYS, INC.
Assigned to VENTURE LENDING & LEASING IV, INC., AS AGENT reassignment VENTURE LENDING & LEASING IV, INC., AS AGENT RELEASE Assignors: ATHERSYS, INC.
Priority to US12/478,362 priority patent/US7935830B2/en
Priority to US13/071,732 priority patent/US8232311B2/en
Priority to US13/526,249 priority patent/US8716324B2/en
Priority to US14/221,809 priority patent/US9096520B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/90—Benzo [c, d] indoles; Hydrogenated benzo [c, d] indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/70—[b]- or [c]-condensed containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention generally relates to a series of compounds, to pharmaceutical compositions containing the compounds, and to use of the compounds and compositions as therapeutic agents. More specifically, compounds of the present invention are tricyclic indeno-pyrrole compounds. These compounds are serotonin receptor (5-HT) ligands and are useful for treating diseases, disorders, and conditions wherein modulation of the activity of serotonin receptors (5-HT) is desired (e.g. addiction, anxiety, depression and obesity).
  • 5-HT serotonin receptor
  • Serotonin has been implicated in a number of diseases, disorders, and conditions that originate in the central nervous system, including diseases, disorders, and conditions related to, for example, sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, anxiety, addiction and schizophrenia. Serotonin also plays an important role in peripheral systems, such as the gastrointestinal system, where it has been found to mediate a variety of contractile, secretory, and electrophysiologic effects.
  • serotonin receptors 5-HT 1-7 ) contain one to seven separate receptors that have been formally classified. See Glennon, et al., Neuroscience and Behavioral Reviews, 1990, 14, 35; and D. Hoyer, et al. Pharmacol. Rev. 1994, 46, 157-203.
  • the 5-HT 2 family of receptors contains 5-HT 2a , 5-HT 2b , and 5-HT 2c subtypes, which have been grouped together on the basis of primary structure, secondary messenger system, and operational profile. All three 5-HT 2 subtypes are G-protein coupled, activate phospholipase C as a principal transduction mechanism, and contain a seven-transmembrane domain structure. There are distinct differences in the distribution of the three 5-HT 2 subtypes in a mammal.
  • the 5-HT 2b and 5-HT 2a receptors are widely distributed in the peripheral nervous system, with 5-HT 2a also found in the brain.
  • the 5-HT 2 , receptor has been found only in the central nervous system, being highly expressed in many regions of the human brain. See G. Baxter, et al. Trends in Pharmacol. Sci. 1995, 16, 105-110.
  • Subtype 5-HT 2a has been associated with effects including vasoconstriction, platelet aggregation, and bronchoconstriction, as well as certain CNS effects, while subtype 5-HT 2c has been associated with diseases that include depression, anxiety, obsessive compulsive disorder, addiction, panic disorders, phobias, psychiatric syndromes, and obesity. Very little is known about the pharmocologic role of the 5-HT 2b receptor. See F. Jenck, et al., Exp. Opin. Invest. Drugs, 1998, 7, 1587-1599; M. Bos, et al., J. Med. Chem., 1997, 40, 2762-2769; J. R.
  • the present invention is directed to compounds of the formula: where
  • Another embodiment of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Still another embodiment of the present invention provides a method of treating a disease, disorder and/or condition in a mammal (e.g., animal or human), wherein a 5-HT 2c receptor is implicated and modulation of a 5-HT 2c function is desired.
  • the method comprises administering a therapeutically effective amount of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, to the mammal.
  • Yet another embodiment of the present invention comprises a method of modulating 5-HT receptor function with an effective amount of compound of Formula (1), or a pharmaceutically acceptable salt thereof.
  • a further embodiment of the present invention provides a method of treating or preventing diseases, disorders, and/or conditions of the central nervous system.
  • the method comprises administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the mammal.
  • Specific diseases, disorders and/or conditions for which compounds of the Formula (I) may have activity include cardiovascular disorders, obesity, depression, schizophrenia, anxiety, obsessive compulsive disorder, addiction, panic disorders, sleep disorders, migraine, Type 11 diabetes, epilepsy, phobias and psychiatric syndromes.
  • alkyl includes straight chained and branched hydrocarbon groups containing the indicated number of carbon atoms, typically methyl, ethyl, and straight chain and branched propyl and butyl groups.
  • the term “alkyl” also encompasses cycloalkyl, i.e., a cyclic C 3 -C 8 hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • a branched chain isomer, such as “isopropyl,” is specifically referred to.
  • alkynyl refers to a substituted or unsubstituted straight or substituted or unsubstituted branched chain alkynyl radical containing from 2 to 10 carbon atoms.
  • examples of such radicals include, but are not limited to, ethynyl, propynyl, propargyl, butynyl, hexynyl, decynyl and the like.
  • alkoxy refers to an alkyl ether radical, wherein the term “alkyl” is as defined above.
  • suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
  • halo is defined herein to include fluoro, chloro, bromo, or iodo.
  • halogen is defined herein to include fluorine, chlorine, bromine, and iodine.
  • amino alone or in combination, includes the group —NH 2 or —NR a R b wherein R a and R b are independently hydrogen, alkyl or aryl.
  • aryl alone or in combination, is defined herein as a monocyclic or bicyclic aromatic group (e.g., phenyl or naphthyl) that can be unsubstituted or substituted, for example, with one or more, and in particular one to three of the following substituents selected from the group consisting of H, halo, CN, NO 2 , CF 3 , N 3 , C 1-6 alkyl, OH, NR a R b , OC 1-6 alkyl, OR a , C( ⁇ O)NR a R b , C( ⁇ S)NR a R b , tetrazoyl, triazoyl, amidinyl, guanidinyl, thioguanidinyl, cyanoguanadinyl, and aryl.
  • substituents selected from the group consisting of H, halo, CN, NO 2 , CF 3 , N 3 , C 1-6 alkyl, OH
  • aryl denotes a phenyl group, or an ortho-fused bicyclic carbocyclic group having nine to ten ring atoms in which at least one ring is aromatic (e.g. naphthyl or tetrahydronaphthyl).
  • aromatic e.g. naphthyl or tetrahydronaphthyl.
  • aryl also is abbreviated in the various chemical structures as “Ar.”
  • Carbocyclic includes any closed ring of carbon atoms, including alicyclic and aromatic structures.
  • heteroaryl is defined herein as a monocyclic, bicyclic, or tricyclic ring system containing one, two, or three aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring, and which can be unsubstituted or substituted, for example, with one or more, and in particular one to three, substituents, like halo, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, nitro, amino, alkylamino, acylamino, alkylthio, alkylsulfonyl, and alkylsulfonyl.
  • heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, 4H-carbazolyl, acridinyl, benzo[b]thienyl, benzothiazolyl, 1,3-carbolinyl, carbazolyl, chromenyl, cinnaolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, naptho[2,3-b], oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,
  • heteroaryl denotes a monocyclic aromatic ring containing five or six ring atoms containing carbon and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of non-peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H, O, C 1-4 alkyl, phenyl or benzyl.
  • heteroaryl denotes an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, or tetramethylene diradical thereto.
  • Het generally represents a heterocyclic group, saturated or partially unsaturated, containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, and optionally substituted with C 1-6 alkyl or C( ⁇ O)OR b .
  • Het is a monocyclic, bicyclic, or tricyclic group containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.
  • a “Het” group also can contain an oxo group ( ⁇ O) attached to the ring.
  • Het groups include 1,3-dihydrobenzofuran, 1,3-dioxolane, 1,4-dioxane, 1,4-dithiane, furanyl, imidazolyl, 2H-pyran, 2-pyrazoline, 4H-pyran, chromanyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, morpholine, oxazolyl, piperazinyl, piperidine, piperidynyl, pyrazolidine, pyrimidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidine, pyrroline, quinuclidine, and thiomorpholine.
  • R 1 is C 1-5 alkyl, halogen, CF 3 , aryl, heteroaryl or H
  • R 2 , R 3 and R 4 are independently C 1-5 alkyl, —O—R 6 , halogen, CF 3 , aryl, heteroaryl or H
  • R 5 is C 1-5 -alkyl, —OR 6 or C 2-6 alkene
  • R 6 is C 1-5 alkyl or H.
  • Presently preferred compounds include:
  • Certain compounds of the invention may exist in different isomeric (e.g. enantiomers and distereoisomers) forms.
  • the invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.
  • the compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemi-hydrate.
  • solvated forms including hydrated forms, e.g., hemi-hydrate.
  • pharmaceutically acceptable solvents such as water, ethanol, and the like are equivalent to the unsolvated forms for the purposes of the invention.
  • Certain compounds of the invention also form pharmaceutically acceptable salts, e.g., acid addition salts.
  • the nitrogen atoms may form salts with acids.
  • suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral carboxylic acids well known to those in the art.
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
  • the free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous hydroxide potassium carbonate, ammonia, and sodium bicarbonate.
  • a suitable dilute aqueous base solution such as dilute aqueous hydroxide potassium carbonate, ammonia, and sodium bicarbonate.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid salts are equivalent to their respective free base forms for purposes of the invention. (See, for example S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 66: 1-19 (1977) which is incorporated herein by reference.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from a combination of the specified ingredients in the specified amounts.
  • the compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
  • pharmaceutically acceptable salt means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid.
  • Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate.
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl
  • acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
  • Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium among others.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
  • Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • a therapeutically effective amount of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form.
  • the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients.
  • therapeutically effective amount means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • the total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.0001 to about 1000 mg/kg/day.
  • more preferable doses can be in the range of from about 0.001 to about 5 mg/kg/day.
  • the effective daily dose can be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • the present invention also provides pharmaceutical compositions that comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions can be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
  • compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • the present invention provides a pharmaceutical composition comprising a component of the present invention and a physiologically tolerable diluent.
  • the present invention includes one or more compounds as described above formulated into compositions together with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein as diluents, for parenteral injection, for intranasal delivery, for oral administration in solid or liquid form, for rectal or topical administration, among others.
  • compositions can also be delivered through a catheter for local delivery at a target site, via an intracoronary stent (a tubular device composed of a fine wire mesh), or via a biodegradable polymer.
  • the compounds may also be complexed to ligands, such as antibodies, for targeted delivery.
  • compositions suitable for parenteral injection may comprise physiologically acceptable, sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), vegetable oils (such as olive oil), injectable organic esters such as ethyl oleate, and suitable mixtures thereof.
  • compositions can also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • the absorption of the drug in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h)
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as
  • the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfumingagents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfumingagents.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like.
  • the preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.
  • prodrugs of the compounds of the present invention may be rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, Pro - drugs as Novel Delivery Systems , V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design , American Pharmaceutical Association and Pergamon Press (1987), hereby incorporated by reference.
  • the compounds of the present invention may be prepared by the procedures set forth in Schemes 1, 2 and 3.
  • the general analytical conditions set forth after the Schemes were utilized in all examples.
  • N-bromosuccinimide (12.1 g, 67.9 mmol) and 2,2′-azobisisobutyronitrile (0.1 g, 0.6 mmol) were added to a solution of 5-methoxy-1-indanone (10.0 g, 61.7 mmol) in carbon tetrachloride (104 mL).
  • the reaction mixture was stirred for 3 hours at 85° C. and then allowed to cool to room temperature.
  • the reaction mixture was filtered through Celite, which was then-washed with CH 2 Cl 2 (100 mL). The filtrate was washed with brine (50 mL), dried over MgSO 4 , and concentrated to afford the subtitle compound, which was used without further purification.
  • Methyltriphenylphosphonium bromide (18.1 g, 50.7 mmol) and potassium tert-butoxide (5.7 g, 50.7) were added to a solution of 2-benzyl-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (9.9 g, 33.8 mmol) in anhydrous ether (68 mL). The reaction mixture was stirred for 1 hour at room temperature then filtered through celite. The celite was washed with ether (200 mL), and the filtrate was concentrated.
  • N-Ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (12 mg, 0.045 mmol) was dissolved in concentrated HCl (2 mL) and stirred for 20 hours at 120° C. The reaction solution was cooled to room temperature, diluted with H 2 O (2 mL), and washed with EtOAc (5 mL). The aqueous solution was concentrated on a speed vac to afford the title compound as the hydrochloride salt. MS calculated for C 12 H 15 NO+H: 190, observed: 190.
  • N-chlorosuccinimide (0.22 g, 1.6 mmol) and acetic acid (8 mL) were added to a solution of N-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a, 8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, Step A) (0.45 g, 1.6 mmol) in DCE (8 mL), and stirred for 3 hours at 60° C.
  • the reaction mixture was cooled to room temperature, diluted with CH 2 Cl 2 (50 mL), and washed with H 2 O (50 mL). The organic extract was dried over MgSO 4 and concentrated.
  • Step B 5-Methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • Step B N-Ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole, O-trifluoromethanesulfonate
  • Step B 5-(4-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 6, Step A utilizing N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 5, Step A) and benzyl bromide.
  • the crude product was obtained without further purification. MS calculated for C 22 H 24 ClNO 3 +H: 386, observed: 386.
  • Step B 5-Benzyloxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 6, Step A utilizing N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 5, Step A) and 2-fluorobenzyl bromide.
  • the crude product was obtained without further purification. MS calculated for C 22 H 23 ClFNO 3 +H: 404, observed: 404.
  • Step B 5-(2-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-5-(2-fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.
  • the crude product was purified by reverse-phase liquid chromatography to afford the title compound.
  • Step A N-Ethylcarbamate-5-(3-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 1)
  • the subtitle compound was prepared by the method of Example 6, Step A utilizing N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 5 Step A) and 3-fluorobenzyl bromide.
  • the crude product was obtained without further purification. MS calculated for C 22 H 23 ClFNO 3 +H: 404, observed: 404.
  • Step B 5-(3-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-5-(3-fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.
  • the crude product was purified by reverse-phase liquid chromatography to afford the title compound.
  • Step B 2,2a,7,7a-Tetrahydro-cyclobuta[a]inden-1-one oxime
  • N-tert-Butylcarbamate-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (110 mg, 0.42 mmol) was dissolved in a HCl solution (5 mL, 4.0 M solution in 1,4-dioxane) and stirred for 2 hours at room temperature. The reaction was concentrated by rotary evaporation. The crude product was purified by reverse-phase liquid chromatography to afford the title compound.
  • Step B 5-Chloro-2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one
  • the subtitle compound was prepared by the method of Example 10, Step A utilizing 6-chloro-1H-indene (3.4 g, 22.6 mmol). The crude product was obtained without further purification.
  • Step C 5-Chloro-2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one oxime
  • the subtitle compound was prepared by the method of Example 10, Step B utilizing 5-chloro-2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one (2.0 g, 10.4 mmol). The crude product was obtained without further purification. MS calculated for C 11 H 10 ClNO+H: 208, observed: 208.
  • the subtitle compound was prepared by the method of Example 10, Step C utilizing 5-chloro-2,2a,7,7a-tetrahydro-cyclobuta[a]inden-1-one (2.0 g, 10.4 mmol)
  • the crude product was obtained without further purification.
  • the subtitle compound was prepared by the method of Example 10, Step D utilizing 6-chloro-3,3a,8,8a-tetrahydro-2H-2-aza-cyclopenta[a]inden-1-one (2.0 g, 10.4 mmol). The crude product was obtained without further purification. MS calculated for C 11 H 12 ClN+H: 194, observed: 194.
  • Step F N-tert-Butylcarbamate-6-chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 10, Step E utilizing 6-chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (2.0 g, 10.4 mmol). The crude product was obtained without further purification. MS calculated for C 16 H 20 ClNO 2 +H: 294, observed: 294.
  • Triphenylphosphine (2 mg), palladium(II) acetate (1 mg), 2,6-difluorophenyl boronic acid (20 mg, 0.12 mmol), and aqueous sodium carbonate (0.15 mL, 0.3 mmol) were added to a solution of (N-tert-butylcarbamate-6-chloro-1,2,3,3a,8,8a-hexahydroindeno[112-c]pyrrole (from Example 11, Step F) (30 mg, 0.1 mmol) in acetonitrile (1 mL), and stirred for 24 h at 80° C.
  • the reaction mixture was concentrated, diluted with EtOAc (5 mL) and washed with H 2 O (5 mL).
  • the organic extract was dried over MgSO 4 and concentrated to give the subtitle compound, which was used without further purification.
  • Step B 6-(2,6-Difluorophenyl)-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • Step B 1-Benzyl-4-m-tolyl-pyrrolidine-3-carboxylic acid ethyl ester
  • the subtitle compound was prepared by the method of Example 1, Step C utilizing 3-m-tolyl-acrylic acid ethyl ester (18.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 10-50% ethyl acetate-hexanes gradient to afford 4.7 g (81%—two steps) of the subtitle compound.
  • the subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-5-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (3.2 mmol).
  • the crude product was purified by silica plug eluting with ethyl acetate-hexanes (3/1, v/v) to afford 0.88 g (98%) of the subtitled compound.
  • the subtitle compound was prepared by the method of Example 13, Step A utilizing o-tolualdehyde (9.0 mmol). The crude product was obtained without further purification. MS calculated for C 12 H 14 O 2 +H: 191, observed: 191.
  • Step B 1-Benzyl-4-o-tolyl-pyrrolidine-3-carboxylic acid ethyl ester
  • the subtitle compound was prepared by the method of Example 1, Step C utilizing 3-O-tolyl-acrylic acid ethyl ester (9.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 10-50% ethyl acetate-hexanes gradient to afford 2.3 g (79%—two steps) of the subtitle compound.
  • the subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-o-tolyl-pyrrolidine-3-carboxylic acid ethyl ester (7.1 mmol). The crude product was obtained without further purification. MS calculated for C 19 H 21 NO 2 +H: 296, observed: 296.
  • the subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-o-tolyl-pyrrolidine-3-carboxylic acid (7.1 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 15-60% EtOAc—hexanes gradient to afford 0.73 g (37%—two steps) of the subtitle compound.
  • the subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-4-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (2.6 mmol).
  • the crude product was purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) to afford the subtitled compound.
  • Step F 4-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 13, Step A utilizing p-tolualdehyde (4.5 mmol). The crude product was obtained without further purification. MS calculated for C 12 H 14 O 2 +H: 191, observed: 191.
  • Step B 1-Benzyl-4-p-tolyl-pyrrolidine-3-carboxylic acid ethyl ester
  • the subtitle compound was prepared by the method of Example 1, Step C utilizing 3-p-tolyl-acrylic acid ethyl ester (4.5 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 10-60% EtOAc—hexanes gradient to afford 1.15 g (79%—two steps) of the subtitle compound.
  • the subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-p-tolyl-pyrrolidine-3-carboxylic acid ethyl ester (3.6 mmol). The crude product was obtained without further purification. MS calculated for C 19 H 21 NO 2 +H: 296, observed: 296.
  • the subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-p-tolyl-pyrrolidine-3-carboxylic acid (3.6 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 15-60% EtOAc—hexanes gradient to afford 0.50 g (50%—two steps) of the subtitle compound.
  • the subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-6-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (1.8 mmol).
  • the crude product was purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) to afford the subtitle compound.
  • Step F 6-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-7-methyl-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from Example 13, Step D, regioisomer) (0.43 mmol).
  • the crude product was purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) to afford the subtitle compound. MS calculated for C 20 H 21 N+H: 276, observed: 276.
  • Step B 7-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 13, Step A utilizing 2-fluorobenzaldehyde (9.0 mmol). The crude product was obtained without further purification. MS calculated for C 11 H 11 FO 2 +H: 195, observed: 195.
  • Step B 1-Benzyl-4-o-fluoro-pyrrolidine-3-carboxylic acid ethyl ester
  • the subtitle compound was prepared by the method of Example 1, Step C utilizing 3-o-fluoro-acrylic acid ethyl ester (9.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 10-50% EtOAc—hexanes gradient to afford the subtitle compound in quantitative yield.
  • the subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-o-fluoro-pyrrolidine-3-carboxylic acid ethyl ester (9.0 mmol). The crude product was obtained without further purification. MS calculated for C 18 H 18 FNO 2 +H: 300, observed: 300.
  • the subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-o-fluoro-pyrrolidine-3-carboxylic acid (9.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-50% EtOAc—hexanes gradient to afford 0.59 g (23%—four steps) of the subtitle compound.
  • the subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-4-fluoro-2,3,3a, 8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (2.1 mmol).
  • the crude product was purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) to afford the subtitle compound.
  • Step F 4-Fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 13, Step A utilizing m-fluorobenzaldehyde (18.0 mmol). The crude product was obtained without further purification. MS calculated for C 11 H 11 FO 2 +H: 195, observed: 195.
  • Step B 1-Benzyl-4-m-fluoro-pyrrolidine-3-carboxylic acid ethyl ester
  • the subtitle compound was prepared by the method of Example 1, Step C utilizing 3-m-fluoro-acrylic acid ethyl ester (18.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 10-50% EtOAc—hexanes gradient to afford the subtitle compound in quantitative yield.
  • the subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-m-fluoro-pyrrolidine-3-carboxylic acid ethyl ester (18.0 mmol). The crude product was obtained without further purification. MS calculated for C 18 H 18 FNO 2 +H: 300, observed: 300.
  • the subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-m-fluoro-pyrrolidine-3-carboxylic acid (18.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-50% EtOAc—hexanes gradient to afford 2.7 g (53%—four steps) of the subtitle compound.
  • the subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-5-fluoro-2,3,3a, 8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (9.6 mmol).
  • the crude product was purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) to afford the subtitle compound.
  • Step F 5-Fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 13, Step A utilizing p-fluorobenzaldehyde (9.0 mmol). The crude product was obtained without further purification. MS calculated for C 11 H 11 FO 2 +H: 195, observed: 195.
  • Step B 1-Benzyl-4-p-fluoro-pyrrolidine-3-carboxylic acid ethyl ester
  • the subtitle compound was prepared by the method of Example 1, Step C utilizing 3-p-fluoro-acrylic acid ethyl ester (9.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 10-50% EtOAc—hexanes gradient to afford the subtitle compound in quantitative yield.
  • the subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-p-fluoro-pyrrolidine-3-carboxylic acid ethyl ester (9.0 mmol). The crude product was obtained without further purification. MS calculated for C 18 H 18 FNO 2 +H: 300, observed: 300.
  • the subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-p-fluoro-pyrrolidine-3-carboxylic acid (9.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-50% EtOAc—hexanes gradient to afford 1.12 g (44%—four steps) of the subtitle compound.
  • the subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-6-fluoro-2,3,3a, 8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (4.0 mmol).
  • the crude product was purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) to afford the subtitle compound.
  • Step F 6-Fluoro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 13, Step A utilizing 3-chlorobenzaldehyde (9.0 mmol). The crude product was obtained without further purification. MS calculated for C 11 H 11 ClO 2 +H: 211, observed: 211.
  • Step B 1-Benzyl-4-m-chloro-pyrrolidine-3-carboxylic acid ethyl ester
  • the subtitle compound was prepared by the method of Example 1, Step C utilizing 3-m-chloro-acrylic acid ethyl ester (9.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 10-50% EtOAc—hexanes gradient to afford the subtitle compound in quantitative yield.
  • the subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-m-chloro-pyrrolidine-3-carboxylic acid ethyl ester (9.0 mmol). The crude product was obtained without further purification. MS calculated for C 18 H 18 ClNO 2 +H: 316, observed: 316.
  • the subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-m-chloro-pyrrolidine-3-carboxylic acid (9.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-50% EtOAc—hexanes gradient to afford 0.59 g (22%—four steps) of the subtitle compound and 0.20 g (8%—four steps) of the regioisomeric 2-benzyl-7-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one.
  • the subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-5-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (2.0 mmol).
  • the crude product was purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) to afford the subtitle compound.
  • Step F 5-Chloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene
  • Step G N-tert-Butyl carbamate-5-chloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene
  • Step H N-tert-Butyl carbamate-5-chloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene
  • N-tert-Butyl carbamate-5-chloro-8-methylene-1,2,3,3a, 8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.6 g, 2.0 mmol) was dissolved in EtOAc (10 mL) and purged with N 2 . Palladium on carbon (0.2 g, 10 wt. %) was added and the flask was purged with N 2 , and then charged with a balloon of H 2 . The reaction mixture was stirred for 2 hours at room temperature then filtered through celite. The celite was washed with EtOAc, and the filtrate was concentrated to afford the subtitle compound in quantitative yield. MS calculated for C 17 H 22 ClNO 2 +H: 308, observed: 308.
  • N-tert-Butyl carbamate-5-chloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (10 mg, 0.03 mmol) was dissolved in an HCl solution (3 mL, 4 M in dioxane). The reaction was stirred for 2 hours at room temperature, and then concentrated to afford the title compound. An aliquot of the crude product was purified by reverse-phase liquid chromatography to afford the title compound.
  • Step A N-Ethylcarbamate-5-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 3)
  • Step B N-Ethylcarbamate-5-methyl-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • NCS 27 mg, 0.2 mmol
  • acetic acid 1 mL
  • DCE DCE
  • the reaction solution was stirred for 3 hours at 60° C.
  • the reaction was diluted with CH 2 Cl 2 (3 mL) and H 2 O (3 mL) and filtered through an Extrelut column. The column was washed with CH 2 Cl 2 and the filtrate was concentrated.
  • Step A N-Ethylcarbamate-5-methyl-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 3)
  • NBS 34 mg, 0.2 mmol
  • N-Ethylcarbamate-5-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 21, Step A) (50 mg, 0.2 mmol) in acetonitrile (1 mL), and stirred overnight at room temperature.
  • the reaction was diluted with CH 2 Cl 2 (3 mL) and H 2 O (3 mL) and filtered through an Extrelut column. The column was washed with CH 2 Cl 2 and the filtrate was concentrated.
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-50% EtOAc—hexanes gradient to afford the subtitle compound.
  • Step A N-Ethylcarbamate-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 3)
  • the subtitle compound was prepared by the method of Example 21, Step A utilizing 6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 15, Step F) (1.8 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 10-60% EtOAc—hexanes gradient to afford 0.25 g (54%) of the subtitle compound.
  • Step B N-Ethylcarbamate-5-chloro-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 21, Step B utilizing N-Ethylcarbamate-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.2 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-60 EtOAc—hexanes gradient to afford the subtitle compound.
  • Step A N-Ethylcarbamate-5-bromo-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 3)
  • the subtitle compound was prepared by the method of Example 22, Step A utilizing N-Ethylcarbamate-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 23, Step A) (0.2 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-50% EtOAc—hexanes gradient to afford the subtitle compound. MS calculated for C 16 H 20 BrNO 2 +H: 338, observed: 338.
  • Step B 5-Bromo-6-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • N-chlorosuccinimide (0.39 g, 2.9 mmol) and acetic acid (3 mL) were added to a solution of N-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, Step A) (0.80 g, 2.9 mmol) in DCE (3 mL). The resulting solution was stirred for 3 hours at 60° C. The reaction mixture was cooled to room temperature, diluted with CH 2 Cl 2 (50 mL), and washed with H 2 O (50 mL). The organic extract was dried over MgSO 4 and concentrated.
  • Step B 4-Chloro-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • Step B 1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester
  • the subtitle compound was prepared by the method of Example 1, Step C utilizing 3-(3,4-dichloro-phenyl)-acrylic acid ethyl ester (9.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 10-50% EtOAc—hexanes gradient to afford the subtitle compound in quantitative yield.
  • the subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (9.0 mmol). The crude product was obtained without further purification. MS calculated for C 18 H 18 Cl 2 NO 2 +H: 350, observed: 350.
  • the subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid (9.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-50% EtOAC—hexanes gradient to afford 0.59 g (20%—four steps) of the subtitle compound and 0.30 g (10%—four steps) of the regioisomeric 2-benzyl-6,7-dichloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one.
  • the subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-5,6-dichloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (0.9 mmol).
  • the crude product was purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) to afford the subtitle compound.
  • Step F 5,6-Dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene
  • the subtitle compound was prepared by the method of Example 20, Step F utilizing 2-benzyl-5,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.9 mmol).
  • the crude product was obtained without further purification. MS calculated for C 12 H 12 Cl 2 N+H: 240, observed: 240.
  • Step G N-tert-Butyl carbamate-5,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene
  • the subtitle compound was prepared by the method of Example 20, Step G utilizing 5,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.9 mmol).
  • the crude product was obtained without further purification. MS calculated for C 17 H 20 Cl 2 NO 2 +H: 340, observed: 340.
  • Step H N-tert-Butyl carbamate-5,6-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene
  • the subtitle compound was prepared by the method of Example 20, Step H utilizing N-tert-butyl carbamate-5,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.9 mmol).
  • the crude product was obtained without further purification. MS calculated for C 17 H 22 Cl 2 NO 2 +H: 342, observed: 342.
  • the subtitle compound was prepared by the method of Example 20, Step I utilizing N-tert-butyl carbamate-5,6-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene. An aliquot of the crude product was purified by reverse-phase liquid chromatography to afford the title compound. MS calculated for C 12 H 14 Cl 2 N+H: 242, observed: 242.
  • the subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-6,7-dichloro-2,3,3a, 8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from Example 26, Step D, regioisomer) (1.8 mmol).
  • the crude product was purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) to afford the subtitle compound.
  • Step B 6,7-Dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene
  • the subtitle compound was prepared by the method of Example 20, Step F utilizing 2-benzyl-6,7-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (1.8 mmol).
  • the crude product was obtained without further purification. MS calculated for C 12 H 12 Cl 2 N+H: 240, observed: 240.
  • Step C N-tert-Butyl carbamate-6,7-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene
  • the subtitle compound was prepared by the method of Example 20, Step G utilizing 6,7-dichloro-8-methylene-1,2,3,3a, 8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.9 mmol).
  • the crude product was obtained without further purification.
  • Step D N-tert-Butyl carbamate-6,7-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene
  • the subtitle compound was prepared by the method of Example 20, Step H utilizing N-tert-butyl carbamate-6,7-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (1.8 mmol).
  • the crude product was obtained without further purification. MS calculated for C 17 H 22 Cl 2 NO 2 +H: 342, observed: 342.
  • Step B 1-Benzyl-4-(2,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester
  • the subtitle compound was prepared by the method of Example 1, Step C utilizing 3-(2,4-dichloro-phenyl)-acrylic acid ethyl ester (18.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 10-50% EtOAc—hexanes gradient to afford the subtitle compound in quantitative yield. MS calculated for C 20 H 22 Cl 2 NO 2 +H: 378, observed: 378.
  • the subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-(2,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (18.0 mmol). The crude product was obtained without further purification. MS calculated for C 18 H 18 Cl 2 NO 2 +H: 350, observed: 350.
  • the subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-(2,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid (18.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-50% EtOAc—hexanes gradient to afford 1.5 g (25%—four steps) of the subtitle compound.
  • the subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-4,6-dichloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (4.5 mmol).
  • the crude product was purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) to afford the subtitle compound.
  • Step F 4,6-Dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene
  • the subtitle compound was prepared by the method of Example 20, Step F utilizing 2-benzyl-4,6-dichloro-8-methylene-1,2,3,3a, 8,8a-hexahydro-2-aza-cyclopenta[a]indene (4.5 mmol).
  • the crude product was obtained without further purification. MS calculated for C 12 H 12 Cl 2 N+H: 240, observed: 240.
  • Step G N-tert-Butyl carbamate-4,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene
  • the subtitle compound was prepared by the method of Example 20, Step G utilizing 4,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (4.5 mmol).
  • the crude product was obtained without further purification.
  • Step H N-tert-Butyl carbamate-4,6-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene
  • the subtitle compound was prepared by the method of Example 20, Step H utilizing N-tert-butyl carbamate-4,6-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.9 mmol) to afford 0.33 g (22%—4 steps) of the subtitle compound. MS calculated for C 17 H 22 Cl 2 NO 2 +H: 342, observed: 342.
  • Step I 4,6-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.
  • Step B N-Ethylcarbamate-5-ethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • NBS (70 mg, 0.4 mmol) was added to a solution of N-methylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, step A) (0.1 g, 0.36 mmol) in CH 3 CN (3.6 mL), and stirred overnight at room temperature.
  • the reaction was diluted with H 2 O and EtOAc and filtered through an Extrelut column. The column was washed with EtOAc and the filtrate was concentrated to afford 120 mg (94%) of the subtitle compound.
  • Step B 5-Methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 29, Step A utilizing N-ethylcarbamate-5-methoxy-6-bromo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 30, Step A) (0.09 mmol).
  • the crude product was obtained without further purification. MS calculated for C 15 H 18 BrNO 3 +H: 340, observed: 340.
  • Step A N-Ethylcarbamate-5-methoxy-6-(2-th ienyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.
  • Step B 5-Methoxy-6-(2-thienyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the title compound was prepared by the method of Example 3, Step B utilizing N-ethylcarbamate-5-methoxy-6-(2-thienyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.17 mmol).
  • the crude product was purified by reverse-phase liquid chromatography to afford the title compound.
  • Step B 5-Methoxy-6-cyano-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 1, Step A utilizing 4,5-dimethoxy-1-indanone (26.0 mmol). The crude product was obtained without further purification. MS calculated for C 11 H 11 BrO 3 +H: 271, observed: 271.
  • the subtitle compound was prepared by the method of Example 1, Step B utilizing 3-bromo-4,5-dimethoxy-1-indanone (26.0 mmol). The crude product was obtained without further purification. MS calculated for C 11 H 10 O 3 +H: 191, observed: 191.
  • the subtitle compound was prepared by the method of Example 1, Step C utilizing 4,5-dimethoxy-inden-1-one (26.0 mmol).
  • the crude product was purified by silica plug eluting with hexanes/EtOAc(3/1, v/v) to afford 4.2 g (50%-3 steps) of the subtitle compound.
  • the subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-4,5-dimethoxy-2,3,3a, 8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (13.0 mmol).
  • the crude product was purified by silica plug eluting with hexanes/EtOAc (3/1, v/v) to afford the subtitle compound in quantitative yield.
  • Step E 4,5-Dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 1, Step E utilizing 2-benzyl-4,5-dimethoxy-8-methylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (13.0 mmol).
  • the crude product was obtained without further purification. MS calculated for C 14 H 19 NO 2 +H: 234, observed: 234.
  • Step F N-Ethylcarbamate-4,5-dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 2, Step A utilizing 4,5-dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (13.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-50% EtOAc—hexanes gradient to afford the subtitle compound.
  • Step G 4,5-Dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • Step A N-Ethylcarbamate-4,5-dimethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole. (Scheme 3)
  • the subtitle compound was prepared by the method of Example 3, Step A utilizing N-ethylcarbamate-4,5-dimethoxy-8-methyl-1,2,3,3a, 8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 34, Step F) (0.58 mmol).
  • the crude product was obtained without further purification. MS calculated for C 17 H 22 ClNO 4 +H: 340, observed: 340.
  • Step B 5-Methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 1, Step A utilizing 5,6-dimethoxy-1-indanone (52.0 mmol). The crude product was obtained without further purification. MS calculated for C 11 H 11 BrO 3 +H: 271, observed: 271.
  • the subtitle compound was prepared by the method of Example 1, Step B utilizing 3-bromo-5,6-dimethoxy-1-indanone (52.0 mmol). The crude product was obtained without further purification. MS calculated for C 11 H 10 O 3 +H: 191, observed: 191.
  • the subtitle compound was prepared by the method of Example 1, Step C utilizing 5,6-dimethoxy-inden-1-one (52.0 mmol).
  • the crude product was purified by silica plug eluting with hexanes/EtOAc (3/1, v/v) to afford the subtitle compound.
  • the subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-5,6-dimethoxy-2,3,3a, 8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (3.1 mmol).
  • the crude product was purified by silica plug eluting with hexanes/EtOAc (3/1, v/v) to afford the subtitle compound in quantitative yield.
  • the subtitle compound was prepared by the method of Example 1, Step E utilizing 2-benzyl-5,6-dimethoxy-8-methylene-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (3.1 mmol). The crude product was obtained without further purification. MS calculated for C 14 H 19 NO 2 +H: 234, observed: 234.
  • Step F N-tert-Butylcarbamate-4,5-dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 20, Step G utilizing 5,6-dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (3.1 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-50% EtOAc—hexanes gradient to afford the subtitle compound.
  • Step G 4,5-Dimethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 1, Step E utilizing 2-benzyl-5-methoxy-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (3.4 mmol).
  • the crude product was obtained without further purification.
  • the subtitle compound was prepared by the method of Example 2, Step A utilizing 5-methoxy-1,2,3,3a,8,8a-hexahydroindeno[112-c]pyrrole (3.4 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-50% EtOAc—hexanes gradient to afford the subtitle compound. MS calculated for C 15 H 19 NO 3 +H: 262, observed: 262.
  • Step E N-Ethylcarbamate-5-methoxy-6-chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 3, Step A utilizing N-ethylcarbamate-5-methoxy-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.19 mmol). The crude product was obtained without further purification. MS calculated for C 15 H 18 ClNO 3 +H: 296, observed: 296.
  • Step F 5-Methoxy-6-chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • Step B 4,6-Dichloro-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • BBr 3 (1.1 mL, 1.0 M in dichloromethane) was added to a solution of N-ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 2, step A) (0.31 g, 1.1 mmol) in CH 2 Cl 2 (10 mL) at 0° C., and stirred overnight. The excess BBr 3 was quenched with the dropwise addition of water (2 mL), and washed with saturated aqueous NaHCO 3 (10 mL) and brine (10 mL). The organic extract was dried over MgSO 4 and concentrated. The subtitle compound was obtained without further purification. MS calculated for C 15 H 19 NO 3 +H: 262, observed: 262.
  • Step B N-Ethylcarbamate-5-cyclopropylmethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • Step C N-Ethylcarbamate-5-cyclopropylmethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • Step D 5-Cyclopropylmethoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • Step A 3-(3-Trifluoromethoxy-phenyl)-acrylic acid ethyl ester. (Scheme 3)
  • Step B 1-Benzyl-4-(3-trifluoromethoxy-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester
  • the subtitle compound was prepared by the method of Example 1, Step C utilizing 3-(3-trifluoromethoxy-phenyl)-acrylic acid ethyl ester (12.5.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 10-50% EtOAc—hexanes gradient to afford 3.5 g (72%—two steps) of the subtitle compound.
  • the subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-(3-trifluoromethoxy-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (8.9 mmol). The crude product was obtained without further purification. MS calculated for C 19 H 18 F 3 NO 3 +H: 366, observed: 366.
  • the subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-(3-trifluoromethoxy-phenyl)-pyrrolidine-3-carboxylic acid (8.9 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 15-60% EtOAc—hexanes gradient to afford 0.50 g (16%—two steps) of the subtitle compound.
  • the subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-5-trifluoromethoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (0.5 mmol).
  • the crude product was purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) to afford the subtitled compound.
  • Step F 5-Trifluoromethoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • Step A 3-(2,3-Dichloro-phenyl)-acrylic acid ethyl ester
  • Step B 1-Benzyl-4-(2,3-dichloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester
  • the subtitle compound was prepared by the method of Example 1, Step C utilizing 3-(2,3-dichloro-phenyl)-acrylic acid ethyl ester (29.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-70% EtOAc—hexanes gradient to afford 5.3 g (49%—two steps) of the subtitle compound.
  • the subtitle compound was prepared by the method of Example 13, Step C utilizing 1-benzyl-4-(2,3-dichloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (14.0 mmol). The crude product was obtained without further purification. MS calculated for C 18 H 18 Cl 2 NO 2 +H: 350, observed: 350.
  • the subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-(2,3-dichloro-phenyl)-pyrrolidine-3-carboxylic acid (14.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-50% EtOAc—hexanes gradient to afford the subtitle compound.
  • the subtitle compound was prepared by the method of Example 1, Step D utilizing 2-benzyl-4,5-dichloro-2,3,3a, 8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (14.0 mmol).
  • the crude product was purified by silica plug eluting with EtOAc—hexanes (3/1, v/v) to afford 1.7 g (35%—three steps) of the subtitle compound.
  • Step F 4,5-Dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene
  • the subtitle compound was prepared by the method of Example 20, Step F utilizing 2-benzyl-4,5-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (4.9 mmol).
  • the crude product was obtained without further purification. MS calculated for C 12 H 12 Cl 2 N+H: 240, observed: 240.
  • Step G N-Ethyl carbamate-4,5-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene
  • the subtitle compound was prepared by the method of Example 2, Step A utilizing 4,5-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (4.9 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-60% EtOAc—hexanes gradient to afford 0.32 g (21%—two steps) of the subtitle compound.
  • Step H N-Ethyl carbamate-4,5-dichloro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene
  • the subtitle compound was prepared by the method of Example 20, Step H utilizing N-ethyl carbamate-4,5-dichloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (1.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-60% EtOAc—hexanes gradient to afford 0.10 g (32%) of the subtitle compound. MS calculated for C 15 H 17 Cl 2 NO 2 +H: 314, observed: 314.
  • Step I 4,5-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.
  • Step B 1-Benzyl-4-(3-fluoro-4-chloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester
  • the subtitle compound was prepared by the method of Example 1, Step C utilizing 3-(3-fluoro-4-chloro-phenyl)-acrylic acid methyl ester (34.0 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-45% EtOAc—hexanes gradient to afford 6.3 g (53%—two steps) of the subtitle compound.
  • Step D 2-Benzyl-6-chloro-7-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one
  • the subtitle compound was prepared by the method of Example 13, Step D utilizing 1-benzyl-4-(3-fluoro-4-chloro-phenyl)-pyrrolidine-3-carboxylic acid (18.1 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-50% EtOAc—hexanes gradient to afford the subtitle compound.
  • the subtitle compound was prepared by the method of Example 20, Step F utilizing 2-benzyl-6-chloro-7-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (2.1 mmol).
  • the crude product was obtained without further purification. MS calculated for C 11 H 9 ClFNO+H: 226, observed: 226.
  • Step F N-Ethyl carbamate-6-chloro-7-fluoro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one
  • the subtitle compound was prepared by the method of Example 2, Step A utilizing 6-chloro-7-fluoro-2,3,3a, 8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (2.2 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-55% EtOAc—hexanes gradient to afford the subtitle compound in quantitative yield.
  • Step G N-Ethyl carbamate-6-chloro-7-fluoro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene
  • the subtitle compound was prepared by the method of Example 2, Step A utilizing 4,5-dichloro-8-methylene-1,2,3,3a, 8,8a-hexahydro-2-aza-cyclopenta[a]indene (1.5 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 10-55% EtOAc—hexanes gradient to afford 0.43 g (66%—two steps) of the subtitle compound in quantitative yield. MS calculated for C 15 H 15 ClFNO 2 +H: 296, observed: 296.
  • Step H N-Ethyl carbamate-6-chloro-7-fluoro-8-methyl-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene
  • the subtitle compound was prepared by the method of Example 20, Step H utilizing N-ethyl carbamate-6-chloro-7-fluoro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (0.2 mmol).
  • the crude product was purified by column chromatography (SiO 2 ) using a 0-60% EtOAc—hexanes gradient to afford the subtitle compound in quantitative yield. MS calculated for C 15 H 17 ClFNO 2 +H: 298, observed: 298.
  • Step B N-Ethylcarbamate-5-benzyloxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 43, Step B utilizing N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 43, Step A) (0.1 mmol) and 2-fluorobenzyl bromide.
  • the crude product was obtained without further purification. MS calculated for C 22 H 24 FNO 3 +H: 370, observed: 370.
  • Step B 5-(2-Fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 43, Step B utilizing N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a, 8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 43, Step A) (0.1 mmol) and 3-fluorobenzyl bromide.
  • the crude product was obtained without further purification. MS calculated for C 22 H 24 FNO 3 +H: 370, observed: 370.
  • Step B 5-(3-Fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • the subtitle compound was prepared by the method of Example 43, Step B utilizing N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 43, Step A) (0.1 mmol) and 4-fluorobenzyl bromide.
  • the crude product was obtained without further purification. MS calculated for C 22 H 24 FNO 3 +H: 370, observed: 370.
  • Step B 5-(4-Fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • Step B N-Ethylcarbamate-5-(2,6-difluorophenyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • Step C 5-(2,6-Difluorophenyl)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • Step B 5-Methoxy-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • Step B N-Ethylcarbamate-5-hydroxy-6-iodo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • Step C N-Ethylcarbamate-5-allyloxy-6-iodo-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • Step D N-Ethylcarbamate-5,6(2-(3-methyl)furan)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
  • Step A N-Ethyl carbamate-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one. (Scheme 1)
  • Step B N-Ethyl carbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one
  • NCS (0.25 g, 1.9 mmol) and acetic acid (10 mL) were added to a solution of ethyl carbamate-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (0.52 g, 1.9 mmol) in DCE (10 mL), and stirred overnight at 60° C. The reaction was quenched with aqueous HCl (1 M) and washed with brine. The organic extracts were dried over MgSO 4 , and concentrated.
  • Step C 4-Chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one
  • the subtitle compound was prepared by the method of Example 2, Step B utilizing N-ethyl carbamate-4-chloro-5-methoxy-2,3,3a, 8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (0.32 mmol).
  • the crude product was obtained without further purification as a mixture of regioisomers. MS calculated for C 12 H 12 ClNO 2 +H: 238, observed: 238.
  • Step D N-tert-butyl carbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one
  • the subtitle compound was prepared by the method of Example 20, Step G utilizing 4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (1.02 mmol).
  • the crude product was purified and separated by column chromatography (SiO 2 ) using a 0-60% EtOAc—hexanes gradient to afford the subtitle compound and its regioisomer, N-tert-butyl carbamate-5-methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one.
  • Step E 4-Chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one
  • Step A N-tert-Butyl carbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol. (Scheme 1)
  • Step B 4-Chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol
  • Step A N-tert-Butyl carbamate-5-methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol
  • Step B 5-Methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol
  • HEK 293 EBNA expressing the human 5HT2c receptor (VSV Isoform; Burns et al., NATURE 387:30308,1997) were grown in DMEM containing 10% dialysed FBS, 9 ⁇ g/ml blasticidin at 37° C. in 5% CO 2 atmosphere.
  • HEK 293 EBNA cells expressing human 5HT2 c receptor (2 ⁇ 10 4 /well) were seeded in black 384-well collagen coated plates and incubated overnight at 37° C. in a 5% CO2/95% atmosphere. After removing medium, cells were treated with HBSS buffer (137 mM NaCl, 5.4 mM KCl, 5.5 mM Glucose, 20 mM Hepes, pH 7.5, 2.1 mM MgCl 2 , 0.3 mM CaCl 2 ,0.02 mM MgSO 4 , 3.0 mM NaHCO 3 , and 0.64 mM KH 2 PO 4 ) containing the Calcium3 dye (Molecular Device, CA), 2.5 mM probenecid and 0.08% pluronic acid for 60 minutes according to manufacture's instruction.
  • HBSS buffer 137 mM NaCl, 5.4 mM KCl, 5.5 mM Glucose, 20 mM Hepes, pH
  • Example 5-HT2c EC50 Number Molecule (hVSV, ⁇ M) 1 1, Enantiomer 2 >10 ⁇ 1 2 2, Enantiomer 1 2, Enantiomer 2 ⁇ 0.1 ⁇ 1 ⁇ 0.1 3 3, Enantiomer 2 ⁇ 0.1 ⁇ 0.1 4 4, Enantiomer 2 ⁇ 1 ⁇ 0.1 5 5, Enantiomer 1 5, Enantiomer 2 ⁇ 0.1 ⁇ 1 ⁇ 1 6 6, Enantiomer 2 ⁇ 1 ⁇ 1 7 ⁇ 10 8 ⁇ 10 9 ⁇ 10 10 ⁇ 10 11 ⁇ 0.1 ⁇ 0.1 ⁇ 0.1 12 >10 13 ⁇ 1 14 ⁇ 1 15 15, Enantiomer 1 15, Enantiomer 2 ⁇ 1 ⁇ 0.1 ⁇ 1 16 ⁇ 1 17 ⁇ 10 18 ⁇ 1 19 ⁇ 1 20 ⁇ 10 21 21, Enantiomer 1 21, Enantiomer 2 ⁇ 0.1 ⁇ 1 ⁇ 0.1 22 ⁇ 1 23 23, Enantiomer 1 23, Enantiomer 2 ⁇ 1 ⁇ 1 ⁇ 0.1 24 ⁇ 1 25, Enantiomer 2

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WO2007132841A1 (ja) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited 縮合複素環化合物およびその用途
WO2009063992A1 (ja) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited 縮合ピリジン誘導体およびその用途
US20110178134A1 (en) * 2008-02-07 2011-07-21 Sanofi-Aventis Novel phenyl-substituted imidazolidines, process for preparation thereof, medicaments comprising said compounds and use thereof
US8242151B2 (en) 2007-02-07 2012-08-14 Kyowa Hakko Kirin Co., Ltd. Tricyclic compounds
WO2012120055A1 (de) 2011-03-08 2012-09-13 Sanofi Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung
WO2012120056A1 (de) 2011-03-08 2012-09-13 Sanofi Tetrasubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung
WO2012120052A1 (de) 2011-03-08 2012-09-13 Sanofi Mit carbozyklen oder heterozyklen substituierte oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung
WO2012120053A1 (de) 2011-03-08 2012-09-13 Sanofi Verzweigte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung
WO2012120054A1 (de) 2011-03-08 2012-09-13 Sanofi Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung
US8486980B2 (en) 2008-08-06 2013-07-16 Kyowa Hakko Kirin Co., Ltd. Tricyclic compound
WO2019131902A1 (ja) 2017-12-27 2019-07-04 武田薬品工業株式会社 腹圧性尿失禁および便失禁の治療薬

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TW201041851A (en) 2009-03-10 2010-12-01 Organon Nv Tricyclic heterocyclic derivatives
CN106380440B (zh) * 2016-08-30 2019-02-01 华东师范大学 一种茚酮并吡咯类衍生物及其合成方法和应用
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Cited By (15)

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WO2007132841A1 (ja) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited 縮合複素環化合物およびその用途
EP2742936A1 (en) 2006-05-16 2014-06-18 Takeda Pharmaceutical Company Limited Fused heterocyclic compound and use thereof
EP2727585A1 (en) 2006-05-16 2014-05-07 Takeda Pharmaceutical Company Limited In-vivo screening method
US8242151B2 (en) 2007-02-07 2012-08-14 Kyowa Hakko Kirin Co., Ltd. Tricyclic compounds
WO2009063992A1 (ja) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited 縮合ピリジン誘導体およびその用途
EP2789338A2 (en) 2007-11-15 2014-10-15 Takeda Pharmaceutical Company Limited Condensed pyridine derivate and use thereof
US20110178134A1 (en) * 2008-02-07 2011-07-21 Sanofi-Aventis Novel phenyl-substituted imidazolidines, process for preparation thereof, medicaments comprising said compounds and use thereof
US8486980B2 (en) 2008-08-06 2013-07-16 Kyowa Hakko Kirin Co., Ltd. Tricyclic compound
US9475805B2 (en) 2008-08-06 2016-10-25 Kyowa Hakko Kirin Co., Ltd. Tricyclic compound
WO2012120054A1 (de) 2011-03-08 2012-09-13 Sanofi Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung
WO2012120053A1 (de) 2011-03-08 2012-09-13 Sanofi Verzweigte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung
WO2012120052A1 (de) 2011-03-08 2012-09-13 Sanofi Mit carbozyklen oder heterozyklen substituierte oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung
WO2012120056A1 (de) 2011-03-08 2012-09-13 Sanofi Tetrasubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung
WO2012120055A1 (de) 2011-03-08 2012-09-13 Sanofi Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung
WO2019131902A1 (ja) 2017-12-27 2019-07-04 武田薬品工業株式会社 腹圧性尿失禁および便失禁の治療薬

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