US20090170835A1 - Isoindoline derivatives - Google Patents

Isoindoline derivatives Download PDF

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US20090170835A1
US20090170835A1 US12/318,453 US31845308A US2009170835A1 US 20090170835 A1 US20090170835 A1 US 20090170835A1 US 31845308 A US31845308 A US 31845308A US 2009170835 A1 US2009170835 A1 US 2009170835A1
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dimethyl
mmol
fluorophenyl
phh
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Kouhei Toyooka
Norimasa Kanamitsu
Masakazu Yoshimura
Haruo Kuriyama
Takashi Tamura
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Maruishi Pharmaceutical Co Ltd
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Maruishi Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • 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
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • 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
    • C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
    • C07D209/64—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles with an oxygen atom in position 1
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel isoindoline derivatives.
  • the derivatives of the invention are useful for manufacturing pharmaceutical compositions, especially anesthetics.
  • anesthetic compounds are also desired to be water-soluble.
  • clinically used anesthetic compounds for example propofol (2,6-diisopropylphenol), are slightly water-soluble and thus, the clinically used intravenous anesthetics are provided in the form of emulsion with soy-oil, glycerin and purified egg phospholipid. Due to the formulation, the clinical intravenous products have side effects such as venous pain during injection and lipid deposition as well as high susceptibility to microbial infection.
  • One object of the present invention is to provide a water-soluble or water-miscible novel compound useful for manufacturing an anesthetic, especially intravenous anesthetic.
  • the present invention provides a compound represented by formula (I):
  • R 1 s are the same or different 1-3 groups, each of them is selected from the group consisting of C1-3 alkyl and C1-3 alkoxy, or when R 1 s are two adjacent groups, the two R 1 s taken together may form a saturated or unsaturated 5- or 6-membered cyclic group which may have 1 or 2 hetero atoms selected from the group consisting of sulfur, nitrogen and oxygen:
  • X is oxygen or sulfur
  • R 2 is selected from the group consisting of phenyl, benzyl, pyridyl, pyridylmethyl, pyrimidinyl, cyclohexyl, methylpiperazinyl, indanyl and naphthyl, all of which may optionally be substituted; provided that when R 2 is phenyl, the 3- and 4-positions of the phenyl moiety are not substituted by alkoxy groups at the same time:
  • n is an integer of 1-8;
  • R 3 is selected from the group consisting of hydrogen, linear or branched C1-8 alkyl, C1-3 alkyl substituted by at least one fluorine atoms, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexylmethyl, benzyl, 2-pyridyl and 2-pyrimidinyl groups, n′ is an integer of 1-3;
  • A is selected from the group consisting of linear or branched C1-5 alkyl, 2-dimethylaminoethylamino, 2-thiazolylamino, 4-methylhomopiperazinyl, 4-piperidinopiperidino, dimethylaminoanilino, pyridylamino, piperidino, 4-ethoxycarbonyl piperidino, 4-carboxypiperidino and a group represented by formula (J)
  • R 3 is as defined above, n′′ is an integer of 0-3;
  • E is selected from the group consisting of hydrogen, linear or branched C1-6 alkyl or alkenyl, C1-3 alkyl substituted by at least one fluorine atoms, 2-methoxyethyl, 2-methylthioethyl, 2-dimethylaminoethyl, phenyl, pyridyl, benzyl, pyridylmethyl, cyclopentyl, cyclohexyl, tetrahydro-2 H -pyranyl, cyclohexylmethyl, 1-methyl-4-piperidyl indanyl, 1,3-benzodioxolyl and 1 H -indolyl, wherein phenyl and pyridyl may optionally be substituted by the group consisting of halogen, methyl, methoxy, isopropyl and allyl, provided that when R 1 is 7-methoxy and R 2 is phenyl, E is not alkyl, n′′ is an integer
  • T oxygen, sulfur or NH
  • G is selected from the group consisting of hydrogen, linear or branched C1-5 alkyl, C1-3 alkyl substituted by at least one fluorine atoms, 2-methoxyethyl and alkylcarbonyl, n′ is an integer of 1-3;
  • R 3 is as defined above;
  • R 3 is as defined above;
  • R 3 is as defined above;
  • the compound of the present invention can induce an excellent sedative action in a mammalian subject and therefore, is preferably used for manufacturing an anesthesia.
  • the present invention further provides anesthetic composition for inducing sedative effect and anesthesia in a mammal comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle.
  • the anesthetic composition of the invention is especially useful as an intravenous anesthesia.
  • the present invention provides use of the compound of formula (I) or a pharmaceutical salt thereof for manufacturing a pharmaceutical composition for inducing sedative effect and anesthesia in a mammal.
  • the present invention provides a method for providing anesthesia in a mammalian subject in need of anesthesia, comprising administering an effective amount of compound formula (I) or a pharmaceutically acceptable salt thereof to the subject.
  • L is described with or without the bonding between the isoindoline skeleton.
  • the definition with the bonding defines and that without the bonding defines “L”.
  • R 1 s of formula (I) may be one or two groups, which may be same or different, and selected from the group consisting of methyl, ethyl and methoxy.
  • the number of R 1 is preferably 2.
  • 5,6-dimethyl compound, i.e. compound of formula (I) wherein both of the 5 and 6 positions are substituted by methyl are substituted by methyl.
  • two R 1 s on 5,6 positions of the isoindoline structure taken together form 5-membered cyclic group which may have one or two oxygen atoms.
  • X represents oxygen or sulfur, and oxygen is preferable.
  • R 2 is selected from the group consisting of phenyl, benzyl, pyridyl, pyridylmethyl, pyrimidinyl, cyclohexyl, methylpiperazinyl, indanyl and naphthyl, all of which may optionally be substituted.
  • R 2 is phenyl
  • the 3- and 4-positions of the phenyl are not substituted by alkoxy groups at the same time.
  • optionally substituted phenyl and optionally substituted pyridyl are especially preferable.
  • R 2 may optionally have 1-3, more preferably 1 or 2 substituents.
  • substituents may include halogen such as fluorine, chlorine, bromine and iodine, hydroxy, C1-4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl and isobutyl, C1-4 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy and butoxy, trifluoromethyl, C1-3 alkyl substituted by at least one fluorine atoms, such as trifluoromethoxy, trifluoroethoxy and trifluoropropoxy, amide, carboxy, cyano, C1-4 alkylthio such as methylthio, ethylthio, propylthio and butylthio, nitro, amino, methylamino, dimethylamino, dimethylaminomethyl, dipropylaminomethyl, methylenedioxy, phenoxy, benzyloxy, C2
  • R 2 When R 2 has a substituent, the substituent may be at any position of R 2 .
  • R 2 When R 2 is phenyl, the phenyl moiety preferably has no substituent or has a substituent of fluorine at 3- or 4-position, of C1-4 alkoxy at 4-position, of alkoxycarbonyl, methylamino or dimethylamino at 3-position.
  • R 2 When R 2 is pyridine, no substituent is preferable.
  • W represents oxygen or sulfur and oxygen is preferable.
  • A is selected from the group consisting of linear or branched C1-5 alkyl, 2-dimethylaminoethylamino, 2-thiazolylamino, 4-methylhomopiperazinyl, 4-piperidinopiperidino, dimethylaminoanilino, pyridylamino, piperidino, 4-ethoxycarbonyl piperidino, 4-carboxypiperidino and a group of formula (J)
  • examples of R 3 may include hydrogen, linear or branched C1-8 alkyl, C1-3 alkyl substituted by at least one fluorine atoms such as 3,3,3-trifluoropropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexylmethyl, benzyl, 2-pyridyl and 2-pyrimidinyl.
  • Preferred A is C1-5 alkyl, especially, linear alkyl, or the group of formula (J), especially the group (J) wherein R 3 is methyl or isopropyl.
  • n′′ is preferably 1 or 2, and especially 1.
  • E is selected from the group consisting of hydrogen, linear or branched C1-6 alkyl or alkenyl, C1-3 alkyl substituted by at least one fluorine atoms such as 3,3,3-trifluoropropyl, 2-methoxyethyl, 2-methylthioethyl, 2-dimethylaminoethyl, phenyl, pyridyl, benzyl, pyridylmethyl, cyclopentyl, cyclohexyl, tetrahydro-2 H -pyranyl, cyclohexylmethyl, 1-methyl-4-piperidyl, indanyl, 1,3-benzodioxolyl and 1 H -indolyl.
  • R 1 is methoxy at 7-position of the isoindoline structure (7-methoxy) and R 2 is phenyl
  • E is not an alkyl.
  • E When E is phenyl or pyridyl, it may be substituted by halogen, methyl, methoxy, isopropyl or allyl. When E is an alkyl, propyl and isobutyl are preferable. Preferable E also includes phenyl substituted by methyl and/or methoxy.
  • n′′ represents an integer of 0-3 and especially 1 or 0.
  • n′ is an integer of 1-3 and 2 is preferable.
  • T is oxygen, sulfur or NH, especially oxygen or sulfur is preferable.
  • G is selected from the group consisting of hydrogen, linear or branched C1-5 alkyl, C1-3 alkyl substituted by at least one fluorine atoms, 2-methoxyethyl and alkylcarbonyl. Ethyl and propyl are especially preferable.
  • R 2 and L are selected from the combinations shown below:
  • R 4 is selected from the group consisting of C1-5 alkyl, optionally substituted phenyl and optionally substituted benzyl, and L is
  • substituents on the phenyl or benzyl of R 4 may include halogen, methyl, methoxy, isopropyl and allyl.
  • Preferable R 4 is alkyl or phenyl.
  • n′′ and E are as defined above may be prepared by, for example, hydrolyzing the compound (II)
  • 3,5-Dimethylphthalic anhydride (III-1) may be prepared by heating the mixture of 4,6-dimethyl-2-pyrone and chloro maleic anhydride.
  • 4,5-Dimethylphthalic anhydride (III-2) may be prepared by heating the acid anhydride, which is obtained by reacting 2,3-dimethyl-1,3-butadiene and maleic anhydride, in acetic acid together with bromine.
  • 3,4-Dimethylphthalic anhydride may be obtained from 3-methyl-1,3-pentadiene and maleic anhydride in the same manner as compound (1II-2).
  • 3,6-Dimethylphthalic anhydride may be obtained according to J. Amer. Chem. Soc., 66, 733 (1944).
  • 4,5-Diethylphthalic anhydride (III-3) may be prepared by converting the dicyano compound obtained according to J. Heterocyclic Chem., 22, 575 (1985) into the corresponding dicarboxylic acid with sulfuric acid followed by dehydrating (cyclizing) with acetic anhydride.
  • 4,5-Dimethoxyphthalic anhydride may be prepared by heating 3,4-dimethoxybenzoic acid in formalin saturated with hydrogen chloride gas to give the corresponding lactone, converting the lactone to dicarboxylic acid with sodium hydroxide and potassium permanganate followed by dehydrating (cyclizing) with acetic anhydride.
  • 5,6-Indandicarboxylic anhydride (III-5) may be prepared by reacting 1,6-heptadiyne and diethyl acetylenedicarboxylate to give the diester compound, converting the diester compound into dicarboxylic acid compound with hydrochloric acid followed by dehydrating (cyclizing) with acetic anhydride.
  • 5,6,7,8-Tetrahydro-2,3-naphthalenedicarboxylic anhydride and 1,3-dihydro-2-benzofuran-5,6-dicarboxylic anhydride may be prepared from 1,7-octadiyne and propargyl ether respectively in the same manner as compound (III-5).
  • 1,3-Benzodioxole-5,6-dicarboxylic anhydride can be obtained from 1,2-dibromo-4,5-(methylenedioxy)benzene in the same manner as compound (III-3).
  • the compound (IV) is reduced with sodium borohydride in a mixed solution of methanol and tetrahydrofuran to give compound (V), and the compound (V) in toluene is heated with Ph 3 P ⁇ CHCOOCH 2 CH 3 to give compound (II-a) and then, the compound (II-a) is hydrolyzed to give compound (II-1a).
  • the compound (II-a) can be reduced by heating the compound in methanol with excess sodium borohydride.
  • the compound (III) is reduced with lithium tri-tert-butoxyaluminohydride according to Tetrahedron, 24, 2443 (1968) to give compound (III-a), and then converted to (III-b) according to Aust. J. Chem., 34, 151 (1981).
  • the compound (III-b) is reacted with an amine compound R 2 —NH 2 [wherein R 2 is as defined above] to give compound (III-c).
  • compound (III-c) is reacted with cyanotrimethylsilane according to J. Org. Chem., 54, 2417 (1989) to effect the cyclization and the compound (II-c) is obtained.
  • the compound (II-1c) is obtained by hydrolyzing the compound (II-c) with an acid.
  • the compound (II-2) can be obtained by reacting a carboxylic acid compound (II-1) with a corresponding alcohol, phenol or hydroxyl compound in the presence of WSC [1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride] and DMAP (4-dimethylaminopyridine).
  • R 1 , R 2 , A and n′′ are as defined above is prepared by the following methods:
  • Compound (II-3) wherein A is not an alkyl group may be prepared by reacting the carboxylic acid compound (II-1) with a corresponding amine compound in the presence of WSC [1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride] and HOBT (1-hydroxybenzotriazole hydrate) in dimethylformamide or tetrahydrofuran.
  • WSC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • HOBT 1-hydroxybenzotriazole hydrate
  • R 8 is selected from the group consisting of linear or branched C3-8 alkyl, C1-3 alkyl substituted by at least one fluorine atoms, cyclopentyl, cycloheptyl and cyclohexylmethyl, may be obtained according to J. Med. Chem., 42, 2870 (1999).
  • Compound (I), wherein L has an alkylketone moiety on its terminal, or compound (1I-3) wherein A is C1-5 alkyl, can be obtained by reacting the above described compound (V) with compound (VIII):
  • R 1 and R 2 are as above defined, R 5 is alkyl
  • T, G and n′ are as defined above with the exception that G is not hydrogen or alkylcarbonyl
  • T, G and n′ are as defined above with the exception that G is not hydrogen or alkylcarbonyl
  • G-T-H an alcohol, thiol or amine represented by: G-T-H (wherein G and T are as defined above, with the exception that G is not hydrogen or alkylcarbonyl).
  • T oxygen or sulfur
  • G linear or branched C1-5 alkyl, C1-3 alkyl substituted by at least one fluorine or 2-methoxyethyl
  • n′ is an integer of 1-3
  • T oxygen or sulfur
  • G linear or branched C1-5 alkyl
  • n′ is an integer of 1-3
  • the alcoholate or thiolate can be prepared from the corresponding alcohol or thiol and metallic sodium.
  • T oxygen and G is alkylcarbonyl or the compound shown below:
  • R 9 is lower alkyl
  • R 9 is lower alkyl
  • n′ and R 3 are as defined above for example, the compound shown below:
  • R 1 , R 2 and R 3 are as defined above may be prepared by reacting the compound of formula (IX):
  • R 1 , R 2 and L are as defined above may be obtained by reacting a compound of
  • R 1 , R 2 and L are as defined above with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) in toluene on heating.
  • Lawesson's reagent 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide
  • R 3 is as defined above may be obtained by reacting the compound (V) with the compound
  • R 3 is as defined above according to Japanese Patent Application Laid Open No. 47 ⁇ circle around (9) ⁇ Compound of formula (I), wherein L is
  • R 3 and E are as defined above may be obtained by reacting the compound (V) with sodium hydride and then reacted with ethyl bromoacetate to give the compound (X), and then hydrolyzing the compound (X) with an alkali to give the carboxylic acid compound (II-1d) and followed by esterification or amidation.
  • R 3 is as defined above, or
  • E is as defined above
  • E may be obtained by converting the compound (III) to the compound (XI) below according to Aust. J. Chem., 35, 2077 (1982), and reacting the compound with an amine of :R 2 —NH 2 (wherein R 2 is as defined above) on heating to give the compound (XII). Then, the compound is hydrolyzed with an alkali and then, esterify or amidate to give the desired compound.
  • Compounds of formula (I), wherein the end of L is carboxyl group, such as that of (II-1), may be provided as a metal salt with sodium, potassium or calcium.
  • the compound When the compound of formula (I) is basic, the compound may be provided as an acid addition salt, especially pharmaceutically acceptable salt with an acid.
  • the salt may include inorganic salts such as hydrochloride, sulfate, nitrate, phosphate and hydrobromide, and organic salt such as acetate, propionate, fumarate, maleate, tartrate, citrate, malate, oxalate, benzoate, methanesulfonate and benzenesulfonate.
  • the compound of the invention may have optical isomers and the scope of the invention covers both optical isomers and the racemic compound.
  • the compound of the present invention is obtained as racemic and may be divided into the optical isomers in a conventional manner known to the art.
  • the compound of the invention is useful for anesthesia by inducing sedation in mammal.
  • the three components of anesthesia are sedation (unconsciousness), analgesia (blocking receipt and transmittance of pain sensation) and muscular relaxation (blocking unwanted body move or harmful reflex response).
  • analgesia blocking receipt and transmittance of pain sensation
  • muscular relaxation blocking unwanted body move or harmful reflex response
  • compounds having respective activities are used in combination upon anesthesia based on the necessity.
  • the isoindoline derivatives of the present invention have excellent sedative properties on mammalian such as human beings and therefore, effectively used as an anesthetic for mammal.
  • the compound of the present invention has a wider safety margin than commercially available intravenous anesthetics such as propofol or thiopental sodium as well as rapid introduction and recovery from anesthesia.
  • the compound of the present invention can easily be made being water-soluble or water-miscible by forming a pharmaceutically acceptable salt thereof, or preparing a solution with a solubilizer. Accordingly, the compound of the present invention is useful for manufacturing an ideal intravenous anesthetic composition.
  • pharmaceutically acceptable salts may include those disclosed above.
  • the anesthetic composition of the present invention may be formulated for administering orally or parenterally such as intravenously, epidurally, spinally, subcutaneously or intramuscularly to a mammal such as a human.
  • parenterally such as intravenously, epidurally, spinally, subcutaneously or intramuscularly
  • Examples of the dosage form of the composition may include tablet, granule, capsule, injectable solution, ophthalmic solution, ocular ointment and suppository.
  • the composition of the invention is intravenous anesthetic composition prepared by dissolving the compound with or without a solubilizer in a pharmaceutically acceptable vehicle.
  • Examples of the pharmaceutically acceptable vehicles used in the composition of the present invention may include purified water, saline, injection solvent and Ringer's solution, and saline is preferable.
  • solubilizer may include cyclodextrin, glycerin, ethanol, propylene glycol and polyethylene glycol.
  • the anesthetic composition of the invention may be formulated as powdery composition to be dissolved in an appropriate vehicle such as water or saline before use.
  • the anesthetic composition of the invention may further comprise other ingredients, which are used in a conventional anesthetic composition.
  • the other ingredients may include, but not limited to, isotonic agent such as sodium chloride and glucose; buffering agent such as calcium citrate, sodium citrate, potassium acetate, sodium acetate, sodium hydrogen phosphate and potassium dihydrogen phosphate; antiseptic such as benzylalcohol and phenol; antioxidant such as sodium pyrosulfite, sodium hydrogen sulfite and ascorbic acid; preservative such as benzethonium chloride, benzalkonium chloride, phenol, cresol, chlorobutanol and benzylalcohol; and chelating reagent such as EDTA, thioglycolic acid, thiolactic acid and thioglycerin.
  • the anesthetic composition of the invention may contain other pharmacologically active ingredients, as far as they are not contrary to the objects of the present invention.
  • the anesthetic composition of the invention can be administrated intravenously to induce general anesthesia.
  • the composition is effective for induction and maintenance anesthesia state upon surgical operation as well as postoperative sedation control, and for sedation control in a ventilated patient undergoing intensive treatment.
  • the anesthetic composition of the invention may be used in any stage of anesthesia in combination of a suitable analgesic and/or muscular relaxant if desired.
  • the anesthetic effective amount of the compound (I) or a salt thereof is not limited and may vary depending on the age, sex, body weight and physical condition of the subject to be treated, desired depth or retention time of anesthesia and the like.
  • typically about 0.1-10 mg/kg, preferably 1.0-5.0 mg/kg bolus of the compound of the present invention is administrated intravenously.
  • 0.5-25 mg/kg/hour, preferably 1.0-15 mg/kg/hour of the compound may be continuously administrated intravenously.
  • 0.05-10 mg/kg/hour, preferably 0.1-5.0 mg/kg/hour of the composition may be continuously administrated intravenously.
  • 1,2-dicyano-4,5-diethylbenzene (2.3 g, 12 mmol) was stirred with heating in 75% sulfuric acid (30 ml) at 150° C. for 3.5 hrs.
  • the reaction solution was poured into ice-cold water.
  • the precipitated crystals were collected by filtration, washed with water, and dissolved in 10% aqueous sodium hydroxide solution.
  • the insoluble materials were separated by filtration, and the resulting filtrate was made acid with concentrated hydrochloric acid.
  • the precipitated crystals were collected by filtration, washed with water, and dried to give 1.5 g of 4,5-diethylphthalic acid.
  • 3,4-dimethoxybenzoic acid (5.0 g, 27 mmol) was added to Formalin (36 ml) saturated with hydrogen chloride gas, and stirred with bubbling hydrogen chloride gas at 65° C. for 2 hrs.
  • the precipitated crystals were collected by filtration, washed with water, followed by drying to give 4.0 g of 4,5-dimethoxyphthalide.
  • Diethyl acetylenedicarboxylate (1.0 ml, 6.3 mmol) and dicarbonylcyclopentadienylcobalt (0.1 ml, 0.62 mmol) were added dropwise to a solution of 1,6-heptadiyne (0.72 ml, 6.3 mmol) in xylene (5 ml), and stirred at 80° C. for 5 days.
  • 4,5-dimethylphthalic anhydride (1.7 g, 9.6 mmol) and 4-fluoroaniline (1.1 g, 9.6 mmol) were stirred with heating in dimethylformamide at 150° C. for 1 hr. After cooling, water was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water, and dried. The resulting crystals were purified by silica gel chromatography (chloroform) to give 2.0 g of 5,6-dimethyl-2-(4-fluorophenyl)isoindolin-1,3-dione.
  • E Ethyl (E)-5,6-dimethyl-3-oxo-1,3-dihydroisobenzofuran-1-ylideneacetate (0.20 g, 0.81 mmol) and 4-fluoroaniline (0.10 g, 0.89 mmol) were stirred with heating in acetic acid at 110° C. for 7 hrs. The reaction solution was concentrated under reduced pressure, and methanol was added to the residue.
  • (+)-5,6-dimethyl-3-propoxycarbonylmethyl-2-(3-pyridyl)-isoindolin-1-one [IUPAC name: propyl (+)-2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetate] and ( ⁇ )-5,6-dimethyl-3-propoxycarbonylmethyl-2-(3-pyridyl)-isoindolin-1-one [IUPAC name: propyl ( ⁇ )-2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetate]
  • (+)-5,6-dimethyl-3-carboxymethyl-2-(3-pyridyl)-isoindolin-1-one [IUPAC name: (+)-2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetic acid] and ( ⁇ )-5,6-dimethyl-3-carboxymethyl-2-(3-pyridyl)isoindolin-1-one [IUPAC name: ( ⁇ )-2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetic acid]
  • Racemic 5,6-dimethyl-3-carboxymethyl-2-(3-pyridyl)-isoindolin-1-one [IUPAC name: 2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetic acid] was reacted with ( ⁇ )-phenylethylamine to form a salt, and the salt was subjected to fractional recrystallization using ethanol.
  • (+)-phenylethylamine By using (+)-phenylethylamine, ( ⁇ )-5,6-dimethyl-3-carboxymethyl-2-(3-pyridyl)isoindolin-1-one [IUPAC name: ( ⁇ )-2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetic acid] was obtained according to the above-mentioned method.
  • (+)-5,6-dimethyl-3-propoxycarbonylmethyl-2-(3-pyridyl)isoindolin-1-one [IUPAC name: propyl (+)-2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetate] and ( ⁇ )-5,6-dimethyl-3-propoxycarbonylmethyl-2-(3-pyridyl)isoindolin-1-one [IUPAC name: propyl ( ⁇ )-2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetate]
  • Hydrochloride salt of the compound was dissolved in saline to give the test composition.
  • T.I. Therapeutic index of the compound was determined.
  • the T.I. of clinically used intravenous anesthetics, propofol and thiopental sodium, which were disclosed in Japanese Patent Application Laid Open No. 50-154410, are shown in the table.
  • the 50% lethal dose (LD 50 ) of the test compound is much higher than the HD 50 , which is an indicator of the anesthetic action, and the highest LD 50 among the test compounds was more than 120 mg/kg (i.v.).
  • LD 50 50% lethal dose
  • the anesthetic composition of the invention has a very wide safety margin.
  • the isoindoline derivatives of the invention can provide rapid induction and recovery from anesthesia.

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Abstract

Provided is a novel isoindoline compound of the formula (I):
Figure US20090170835A1-20090702-C00001
The compound is useful for anesthesia by inducing sedation in a mammal.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a Continuation of application Ser. No. 10/534,414, which is the US National Stage application of PCT/JP2003/014986, filed Nov. 25, 2003, which claims priority from Japanese patent application 2002-342399, filed Nov. 26, 2002. The entire contents of each of the aforementioned applications are incorporated herein by reference.
    • FIELD OF THE INVENTION
  • The present invention relates to novel isoindoline derivatives. The derivatives of the invention are useful for manufacturing pharmaceutical compositions, especially anesthetics.
    • RELATED ART
  • Many compounds having isoindoline structure have been reported to have effects on central nerves system. Most of those reports aimed for developing tranquilizers, antispasmodics or anxiolytics (Japanese Patent Application Laid Open Nos. 47-12322 and 58-189163). Heretofore, no isoindoline derivative having anesthetic property has been reported.
  • As for agents affecting on the CNS, especially intravenous anesthetics, rapid induction and recovery from anesthesia are desired. In order to prepare an injectable dosage form, the anesthetic compounds are also desired to be water-soluble. However, clinically used anesthetic compounds, for example propofol (2,6-diisopropylphenol), are slightly water-soluble and thus, the clinically used intravenous anesthetics are provided in the form of emulsion with soy-oil, glycerin and purified egg phospholipid. Due to the formulation, the clinical intravenous products have side effects such as venous pain during injection and lipid deposition as well as high susceptibility to microbial infection.
  • Heretofore, no CNS active agent that is enough soluble or miscible in water as well as induces no or little side effect has been reported.
    • SUMMARY OF THE INVENTION
  • One object of the present invention is to provide a water-soluble or water-miscible novel compound useful for manufacturing an anesthetic, especially intravenous anesthetic.
  • The present invention provides a compound represented by formula (I):
  • Figure US20090170835A1-20090702-C00002
  • wherein R1s are the same or different 1-3 groups, each of them is selected from the group consisting of C1-3 alkyl and C1-3 alkoxy, or when R1s are two adjacent groups, the two R1s taken together may form a saturated or unsaturated 5- or 6-membered cyclic group which may have 1 or 2 hetero atoms selected from the group consisting of sulfur, nitrogen and oxygen:
  • X is oxygen or sulfur:
  • R2 is selected from the group consisting of phenyl, benzyl, pyridyl, pyridylmethyl, pyrimidinyl, cyclohexyl, methylpiperazinyl, indanyl and naphthyl, all of which may optionally be substituted; provided that when R2 is phenyl, the 3- and 4-positions of the phenyl moiety are not substituted by alkoxy groups at the same time:
  • Figure US20090170835A1-20090702-P00001
    represents a single bond or double bond: and
  • L is

  • —(CH2)n—H
  • wherein n is an integer of 1-8;
  • Figure US20090170835A1-20090702-C00003
  • wherein R3 is selected from the group consisting of hydrogen, linear or branched C1-8 alkyl, C1-3 alkyl substituted by at least one fluorine atoms, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexylmethyl, benzyl, 2-pyridyl and 2-pyrimidinyl groups, n′ is an integer of 1-3;
  • Figure US20090170835A1-20090702-C00004
  • wherein W is oxygen or sulfur atom, A is selected from the group consisting of linear or branched C1-5 alkyl, 2-dimethylaminoethylamino, 2-thiazolylamino, 4-methylhomopiperazinyl, 4-piperidinopiperidino, dimethylaminoanilino, pyridylamino, piperidino, 4-ethoxycarbonyl piperidino, 4-carboxypiperidino and a group represented by formula (J)
  • Figure US20090170835A1-20090702-C00005
  • wherein R3 is as defined above,
    n″ is an integer of 0-3;
  • Figure US20090170835A1-20090702-C00006
  • wherein E is selected from the group consisting of hydrogen, linear or branched C1-6 alkyl or alkenyl, C1-3 alkyl substituted by at least one fluorine atoms, 2-methoxyethyl, 2-methylthioethyl, 2-dimethylaminoethyl, phenyl, pyridyl, benzyl, pyridylmethyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, cyclohexylmethyl, 1-methyl-4-piperidyl indanyl, 1,3-benzodioxolyl and 1H-indolyl, wherein phenyl and pyridyl may optionally be substituted by the group consisting of halogen, methyl, methoxy, isopropyl and allyl, provided that when R1 is 7-methoxy and R2 is phenyl, E is not alkyl, n″ is an integer of 0-3;

  • —(CH2)n′-T-G
  • wherein T is oxygen, sulfur or NH, G is selected from the group consisting of hydrogen, linear or branched C1-5 alkyl, C1-3 alkyl substituted by at least one fluorine atoms, 2-methoxyethyl and alkylcarbonyl, n′ is an integer of 1-3;
  • Figure US20090170835A1-20090702-C00007
  • wherein R3 is as defined above;
  • Figure US20090170835A1-20090702-C00008
  • wherein R3 is as defined above;
  • Figure US20090170835A1-20090702-C00009
  • wherein E is as defined above;
  • Figure US20090170835A1-20090702-C00010
  • wherein R3 is as defined above; or
  • Figure US20090170835A1-20090702-C00011
  • wherein E is as defined above
    or a salt thereof.
  • The compound of the present invention can induce an excellent sedative action in a mammalian subject and therefore, is preferably used for manufacturing an anesthesia.
  • The present invention further provides anesthetic composition for inducing sedative effect and anesthesia in a mammal comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle. The anesthetic composition of the invention is especially useful as an intravenous anesthesia.
  • Still further, the present invention provides use of the compound of formula (I) or a pharmaceutical salt thereof for manufacturing a pharmaceutical composition for inducing sedative effect and anesthesia in a mammal.
  • Furthermore, the present invention provides a method for providing anesthesia in a mammalian subject in need of anesthesia, comprising administering an effective amount of compound formula (I) or a pharmaceutically acceptable salt thereof to the subject.
  • In the present specification and claims, the compound is described using the numbering system of the isoindoline skeleton (I) shown below unless there is specific indication.
  • Figure US20090170835A1-20090702-C00012
  • In the present specification and claims, the definitions of L are described with or without the bonding between the isoindoline skeleton. The definition with the bonding defines
    Figure US20090170835A1-20090702-P00002
    and that without the bonding defines “L”.
    • DETAILED DESCRIPTION OF THE INVENTION
  • In a preferred embodiment of the instant invention, R1s of formula (I) may be one or two groups, which may be same or different, and selected from the group consisting of methyl, ethyl and methoxy. The number of R1 is preferably 2. Especially 5,6-dimethyl compound, i.e. compound of formula (I) wherein both of the 5 and 6 positions are substituted by methyl. In another preferable embodiment of the invention, two R1s on 5,6 positions of the isoindoline structure taken together form 5-membered cyclic group which may have one or two oxygen atoms.
  • X represents oxygen or sulfur, and oxygen is preferable.
  • R2 is selected from the group consisting of phenyl, benzyl, pyridyl, pyridylmethyl, pyrimidinyl, cyclohexyl, methylpiperazinyl, indanyl and naphthyl, all of which may optionally be substituted. When R2 is phenyl, the 3- and 4-positions of the phenyl are not substituted by alkoxy groups at the same time. For R2, optionally substituted phenyl and optionally substituted pyridyl are especially preferable.
  • R2 may optionally have 1-3, more preferably 1 or 2 substituents. Examples of the substituents may include halogen such as fluorine, chlorine, bromine and iodine, hydroxy, C1-4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl and isobutyl, C1-4 alkoxy such as methoxy, ethoxy, propoxy, isopropoxy and butoxy, trifluoromethyl, C1-3 alkyl substituted by at least one fluorine atoms, such as trifluoromethoxy, trifluoroethoxy and trifluoropropoxy, amide, carboxy, cyano, C1-4 alkylthio such as methylthio, ethylthio, propylthio and butylthio, nitro, amino, methylamino, dimethylamino, dimethylaminomethyl, dipropylaminomethyl, methylenedioxy, phenoxy, benzyloxy, C2-5 alkanoyloxy such as acetoxy, propionyloxy and butyryloxy, C1-3 ω-hydroxyalkyl such as hydroxymethyl and hydroxyethyl, C2-5 alkanoyloxy-C1-3 alkyl such as acetyloxymethyl, acetyloxyethyl and propionyloxymethyl; C2-5 alkanoylamino such as acetylamino and propionylamino; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and butoxycarbonyl, phenoxycarbonyl and benzyloxycarbonyl.
  • When R2 has a substituent, the substituent may be at any position of R2. When R2 is phenyl, the phenyl moiety preferably has no substituent or has a substituent of fluorine at 3- or 4-position, of C1-4 alkoxy at 4-position, of alkoxycarbonyl, methylamino or dimethylamino at 3-position. When R2 is pyridine, no substituent is preferable.
  • According to the present invention, when L is
  • Figure US20090170835A1-20090702-C00013
  • W represents oxygen or sulfur and oxygen is preferable. A is selected from the group consisting of linear or branched C1-5 alkyl, 2-dimethylaminoethylamino, 2-thiazolylamino, 4-methylhomopiperazinyl, 4-piperidinopiperidino, dimethylaminoanilino, pyridylamino, piperidino, 4-ethoxycarbonyl piperidino, 4-carboxypiperidino and a group of formula (J)
  • Figure US20090170835A1-20090702-C00014
  • When A is (J), examples of R3 may include hydrogen, linear or branched C1-8 alkyl, C1-3 alkyl substituted by at least one fluorine atoms such as 3,3,3-trifluoropropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexylmethyl, benzyl, 2-pyridyl and 2-pyrimidinyl. Preferred A is C1-5 alkyl, especially, linear alkyl, or the group of formula (J), especially the group (J) wherein R3 is methyl or isopropyl. n″ is preferably 1 or 2, and especially 1.
  • According to the instant invention, when L is
  • Figure US20090170835A1-20090702-C00015
  • E is selected from the group consisting of hydrogen, linear or branched C1-6 alkyl or alkenyl, C1-3 alkyl substituted by at least one fluorine atoms such as 3,3,3-trifluoropropyl, 2-methoxyethyl, 2-methylthioethyl, 2-dimethylaminoethyl, phenyl, pyridyl, benzyl, pyridylmethyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl, cyclohexylmethyl, 1-methyl-4-piperidyl, indanyl, 1,3-benzodioxolyl and 1H-indolyl. When R1 is methoxy at 7-position of the isoindoline structure (7-methoxy) and R2 is phenyl, E is not an alkyl.
  • When E is phenyl or pyridyl, it may be substituted by halogen, methyl, methoxy, isopropyl or allyl. When E is an alkyl, propyl and isobutyl are preferable. Preferable E also includes phenyl substituted by methyl and/or methoxy.
  • n″ represents an integer of 0-3 and especially 1 or 0.
  • When L is —(CH2)n′-T-G, n′ is an integer of 1-3 and 2 is preferable. T is oxygen, sulfur or NH, especially oxygen or sulfur is preferable.
  • G is selected from the group consisting of hydrogen, linear or branched C1-5 alkyl, C1-3 alkyl substituted by at least one fluorine atoms, 2-methoxyethyl and alkylcarbonyl. Ethyl and propyl are especially preferable.
  • According to the instant invention, especially preferable compounds are as follows:
  • Figure US20090170835A1-20090702-C00016
  • wherein R2 and L are selected from the combinations shown below:
  • R2 L
    Figure US20090170835A1-20090702-C00017
    Figure US20090170835A1-20090702-C00018
    Figure US20090170835A1-20090702-C00019
    Figure US20090170835A1-20090702-C00020
    Figure US20090170835A1-20090702-C00021
    Figure US20090170835A1-20090702-C00022
    Figure US20090170835A1-20090702-C00023
    Figure US20090170835A1-20090702-C00024
    Figure US20090170835A1-20090702-C00025
    Figure US20090170835A1-20090702-C00026
    Figure US20090170835A1-20090702-C00027
    Figure US20090170835A1-20090702-C00028
    Figure US20090170835A1-20090702-C00029
    Figure US20090170835A1-20090702-C00030
  • R2 L
    Figure US20090170835A1-20090702-C00031
    Figure US20090170835A1-20090702-C00032
    Figure US20090170835A1-20090702-C00033
    Figure US20090170835A1-20090702-C00034
    Figure US20090170835A1-20090702-C00035
         		CH2CH2OCH2CH3
    Figure US20090170835A1-20090702-C00036
         		CH2CH2OCH2CH2CH3
    Figure US20090170835A1-20090702-C00037
    Figure US20090170835A1-20090702-C00038
  • In addition to the above, the compound of either of the above formulae wherein R2 is
  • Figure US20090170835A1-20090702-C00039
  • wherein R4 is selected from the group consisting of C1-5 alkyl, optionally substituted phenyl and optionally substituted benzyl, and L is
  • Figure US20090170835A1-20090702-C00040
  • is also preferably used.
  • Examples of substituents on the phenyl or benzyl of R4 may include halogen, methyl, methoxy, isopropyl and allyl. Preferable R4 is alkyl or phenyl.
    • Synthesis of the Compound
  • Methods for synthesizing the compound of the invention are illustrated below. The methods below are only example and the compound of the invention may be prepared by any of the known methods.
  • {circle around (1)} Compound of formula (I) wherein L is
  • Figure US20090170835A1-20090702-C00041
  • wherein n″ and E are as defined above
    may be prepared by, for example, hydrolyzing the compound (II)
  • Figure US20090170835A1-20090702-C00042
  • wherein the R1, R2 and n″ are as defined above, Z is COOCH2CH3 or CN and then, if desired, esterifying the carboxylic acid obtained. More precisely:
    (1) Compound of formula (II) wherein Z is carboxyl group, such as formula (II-1)
  • Figure US20090170835A1-20090702-C00043
  • wherein R1, R2 and n″ are as defined above may be prepared according to the method described below:
    i) The compound wherein n″=1 may be prepared according to the scheme shown below.
  • Figure US20090170835A1-20090702-C00044
  • (R1 and R2 are as defined above)
  • Method for Preparing the Starting Material of Formula (III):
  • 3,5-Dimethylphthalic anhydride (III-1) may be prepared by heating the mixture of 4,6-dimethyl-2-pyrone and chloro maleic anhydride.
  • 4,5-Dimethylphthalic anhydride (III-2) may be prepared by heating the acid anhydride, which is obtained by reacting 2,3-dimethyl-1,3-butadiene and maleic anhydride, in acetic acid together with bromine.
  • 3,4-Dimethylphthalic anhydride may be obtained from 3-methyl-1,3-pentadiene and maleic anhydride in the same manner as compound (1II-2).
  • 3,6-Dimethylphthalic anhydride may be obtained according to J. Amer. Chem. Soc., 66, 733 (1944).
  • 4,5-Diethylphthalic anhydride (III-3) may be prepared by converting the dicyano compound obtained according to J. Heterocyclic Chem., 22, 575 (1985) into the corresponding dicarboxylic acid with sulfuric acid followed by dehydrating (cyclizing) with acetic anhydride.
  • 4,5-Dimethoxyphthalic anhydride (III-4) may be prepared by heating 3,4-dimethoxybenzoic acid in formalin saturated with hydrogen chloride gas to give the corresponding lactone, converting the lactone to dicarboxylic acid with sodium hydroxide and potassium permanganate followed by dehydrating (cyclizing) with acetic anhydride.
  • 5,6-Indandicarboxylic anhydride (III-5) may be prepared by reacting 1,6-heptadiyne and diethyl acetylenedicarboxylate to give the diester compound, converting the diester compound into dicarboxylic acid compound with hydrochloric acid followed by dehydrating (cyclizing) with acetic anhydride.
  • 5,6,7,8-Tetrahydro-2,3-naphthalenedicarboxylic anhydride and 1,3-dihydro-2-benzofuran-5,6-dicarboxylic anhydride may be prepared from 1,7-octadiyne and propargyl ether respectively in the same manner as compound (III-5).
  • 1,3-Benzodioxole-5,6-dicarboxylic anhydride can be obtained from 1,2-dibromo-4,5-(methylenedioxy)benzene in the same manner as compound (III-3).
  • Figure US20090170835A1-20090702-C00045
  • Thus obtained appropriate starting compound (III) is heated in acetic acid or dimethylformamide with an amine compound of formula: R2—NH2 (wherein R2 is as defined above) to give the compound (IV).
  • According to the method described in Japanese Patent Application Laid Open No. 58-189163, the compound (IV) is reduced with sodium borohydride in a mixed solution of methanol and tetrahydrofuran to give compound (V), and the compound (V) in toluene is heated with Ph3 P═CHCOOCH2CH3 to give compound (II-a) and then, the compound (II-a) is hydrolyzed to give compound (II-1a).
  • ii) Compound of formula (II-1b) (Compound of Formula (II-1) wherein n″=2)
  • The compound (II-1b) may be obtained according to the scheme as below by using the compound (II-a) (n″=1) as a starting material.
  • Figure US20090170835A1-20090702-C00046
  • [In the above scheme, R1 and R2 are as defined above, Ms represents a methanesulfonyl group]
    According to the method described in Japanese Patent Application Laid Open No. 58-189163, the compound (II-a) in tetrahydrofuran is reduced with lithium borohydride to give the compound (VI), then reacted with methanesulfonyl chloride to give the mesylated compound (VII). The compound is then heated with potassium cyanide in aqueous ethanol to give the compound (II-b) and hydrolyzed with an acid to give the compound (II-1b) wherein n″ is 2.
  • When R2 is pyridyl group, the compound (II-a) can be reduced by heating the compound in methanol with excess sodium borohydride.
  • iii) n″=0
  • The compound (II-1c), or the compound (II-1) wherein n″=0, can be obtained according to the scheme shown below using the compound (III) shown above as a starting material.
  • Figure US20090170835A1-20090702-C00047
  • [R1 and R2 are as defined above]
  • The compound (III) is reduced with lithium tri-tert-butoxyaluminohydride according to Tetrahedron, 24, 2443 (1968) to give compound (III-a), and then converted to (III-b) according to Aust. J. Chem., 34, 151 (1981). The compound (III-b) is reacted with an amine compound R2—NH2 [wherein R2 is as defined above] to give compound (III-c). Thus obtained compound (III-c) is reacted with cyanotrimethylsilane according to J. Org. Chem., 54, 2417 (1989) to effect the cyclization and the compound (II-c) is obtained. Then, the compound (II-1c) is obtained by hydrolyzing the compound (II-c) with an acid.
    • (2) Compound (II-2)
  • Figure US20090170835A1-20090702-C00048
  • [R1 and R2 are as defined above, E is as defined above with the exception that E is not hydrogen]
  • The compound (II-2) can be obtained by reacting a carboxylic acid compound (II-1) with a corresponding alcohol, phenol or hydroxyl compound in the presence of WSC [1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride] and DMAP (4-dimethylaminopyridine).
  • {circle around (2)} Compound of formula (I) wherein L is
  • Figure US20090170835A1-20090702-C00049
  • or compound (II-3):
  • Figure US20090170835A1-20090702-C00050
  • wherein R1, R2, A and n″ are as defined above is prepared by the following methods:
  • Compound (II-3) wherein A is not an alkyl group may be prepared by reacting the carboxylic acid compound (II-1) with a corresponding amine compound in the presence of WSC [1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride] and HOBT (1-hydroxybenzotriazole hydrate) in dimethylformamide or tetrahydrofuran.
  • The amine compound of the formula:
  • Figure US20090170835A1-20090702-C00051
  • wherein R8 is selected from the group consisting of linear or branched C3-8 alkyl, C1-3 alkyl substituted by at least one fluorine atoms, cyclopentyl, cycloheptyl and cyclohexylmethyl,
    may be obtained according to J. Med. Chem., 42, 2870 (1999).
  • Compound (I), wherein L has an alkylketone moiety on its terminal, or compound (1I-3) wherein A is C1-5 alkyl, can be obtained by reacting the above described compound (V) with compound (VIII):
  • Ph3P═CHCO—R7 (VIII) wherein, R7 is C1-5 alkyl. The compound (VIII) can be obtained according to Synthesis, 1055 (1987).
  • {circle around (3)} Compound (1), wherein L is —(CH2)n—H may be obtained according to the scheme shown below by using the compound (IV) as the starting material.
  • Figure US20090170835A1-20090702-C00052
  • [wherein, R1 and R2 are as above defined, R5 is alkyl]
  • Compound (IV) is reacted with a Grignard reagent of R6—MgBr (wherein R6 is alkyl) to give compound (IV-a), and further reacted in the presence of triethylsilane and trifluoroacetic acid in dichloromethane to give compound (IV-b), and then, reduced with palladium on carbon catalyst to give the compound (IV-c).
  • {circle around (4)} Compound (I), wherein L is

  • —(CH2)n′-T-G
  • wherein T, G and n′ are as defined above with the exception that G is not hydrogen or alkylcarbonyl may be prepared by reacting the compound (VII) with an alcohol, thiol or amine represented by: G-T-H (wherein G and T are as defined above, with the exception that G is not hydrogen or alkylcarbonyl).
  • (1) The compound wherein T is oxygen or sulfur, or the compound shown below:
  • Figure US20090170835A1-20090702-C00053
  • wherein, R1 and R2 are as defined above, T is oxygen or sulfur, G is linear or branched C1-5 alkyl, C1-3 alkyl substituted by at least one fluorine or 2-methoxyethyl, n′ is an integer of 1-3 may be obtained by reacting the compound (VII) with corresponding alcoholate or thiolate on heating. The alcoholate or thiolate can be prepared from the corresponding alcohol or thiol and metallic sodium.
    (2) The compound wherein T is NH or the compound shown below:
  • Figure US20090170835A1-20090702-C00054
  • wherein R1, R2 and n′ are as defined above, G is lower alkyl
    may be obtained by the compound (VII) with the corresponding amine.
    {circle around (5)} The compound of formula (I) wherein L is

  • —(CH2)n′-T-G
  • wherein T is oxygen and G is alkylcarbonyl
    or the compound shown below:
  • Figure US20090170835A1-20090702-C00055
  • wherein R1, R2 and n′ are as defined above, R9 is lower alkyl
    may be obtained by reacting the compound (VI) with an acid chloride compound of :Cl—CO—R9 wherein R9 is as defined above.
    {circle around (6)} The compound of formula (I) wherein L is
  • Figure US20090170835A1-20090702-C00056
  • wherein n′ and R3 are as defined above
    for example, the compound shown below:
  • Figure US20090170835A1-20090702-C00057
  • wherein R1, R2 and R3 are as defined above may be prepared by reacting the compound of formula (IX):
  • Figure US20090170835A1-20090702-C00058
  • (IX) wherein R3 is as defined above
    with the compound (VII) in the presence of triethylamine.
    {circle around (7)} Compound of formula (I) wherein X is sulfur or the compound shown below:
  • Figure US20090170835A1-20090702-C00059
  • wherein R1, R2 and L are as defined above may be obtained by reacting a compound of
  • Figure US20090170835A1-20090702-C00060
  • wherein R1, R2 and L are as defined above
    with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) in toluene on heating.
    {circle around (8)} Compound of formula (I), wherein L is
  • Figure US20090170835A1-20090702-C00061
  • wherein R3 is as defined above
    may be obtained by reacting the compound (V) with the compound
  • Figure US20090170835A1-20090702-C00062
  • wherein R3 is as defined above
    according to Japanese Patent Application Laid Open No. 47
    {circle around (9)} Compound of formula (I), wherein L is
  • Figure US20090170835A1-20090702-C00063
  • or
  • Figure US20090170835A1-20090702-C00064
  • wherein, R3 and E are as defined above
    may be obtained by reacting the compound (V) with sodium hydride and then reacted with ethyl bromoacetate to give the compound (X), and then hydrolyzing the compound (X) with an alkali to give the carboxylic acid compound (II-1d) and followed by esterification or amidation.
  • Figure US20090170835A1-20090702-C00065
  • {circle around (10)} The compound of formula (I), wherein L is
  • Figure US20090170835A1-20090702-C00066
  • wherein R3 is as defined above,
    or
  • Figure US20090170835A1-20090702-C00067
  • wherein E is as defined above
    may be obtained by converting the compound (III) to the compound (XI) below according to Aust. J. Chem., 35, 2077 (1982), and reacting the compound with an amine of :R2—NH2 (wherein R2 is as defined above) on heating to give the compound (XII). Then, the compound is hydrolyzed with an alkali and then, esterify or amidate to give the desired compound.
  • Figure US20090170835A1-20090702-C00068
  • Compounds of formula (I), wherein the end of L is carboxyl group, such as that of (II-1), may be provided as a metal salt with sodium, potassium or calcium.
  • When the compound of formula (I) is basic, the compound may be provided as an acid addition salt, especially pharmaceutically acceptable salt with an acid. Examples of the salt may include inorganic salts such as hydrochloride, sulfate, nitrate, phosphate and hydrobromide, and organic salt such as acetate, propionate, fumarate, maleate, tartrate, citrate, malate, oxalate, benzoate, methanesulfonate and benzenesulfonate.
  • The compound of the invention may have optical isomers and the scope of the invention covers both optical isomers and the racemic compound. Usually, the compound of the present invention is obtained as racemic and may be divided into the optical isomers in a conventional manner known to the art.
  • The compound of the invention is useful for anesthesia by inducing sedation in mammal.
  • The three components of anesthesia are sedation (unconsciousness), analgesia (blocking receipt and transmittance of pain sensation) and muscular relaxation (blocking unwanted body move or harmful reflex response). Upon clinical anesthesia, compounds having respective activities are used in combination upon anesthesia based on the necessity. The isoindoline derivatives of the present invention have excellent sedative properties on mammalian such as human beings and therefore, effectively used as an anesthetic for mammal.
  • The compound of the present invention has a wider safety margin than commercially available intravenous anesthetics such as propofol or thiopental sodium as well as rapid introduction and recovery from anesthesia.
  • The compound of the present invention can easily be made being water-soluble or water-miscible by forming a pharmaceutically acceptable salt thereof, or preparing a solution with a solubilizer. Accordingly, the compound of the present invention is useful for manufacturing an ideal intravenous anesthetic composition. Examples of pharmaceutically acceptable salts may include those disclosed above.
  • The anesthetic composition of the present invention may be formulated for administering orally or parenterally such as intravenously, epidurally, spinally, subcutaneously or intramuscularly to a mammal such as a human. Examples of the dosage form of the composition may include tablet, granule, capsule, injectable solution, ophthalmic solution, ocular ointment and suppository. Preferably, the composition of the invention is intravenous anesthetic composition prepared by dissolving the compound with or without a solubilizer in a pharmaceutically acceptable vehicle.
  • Examples of the pharmaceutically acceptable vehicles used in the composition of the present invention may include purified water, saline, injection solvent and Ringer's solution, and saline is preferable.
  • Most of pharmaceutically acceptable salts of compound (I) are water-soluble and some water-insoluble compounds may be dissolved in water with a solubilizer. Examples of solubilizer may include cyclodextrin, glycerin, ethanol, propylene glycol and polyethylene glycol.
  • The anesthetic composition of the invention may be formulated as powdery composition to be dissolved in an appropriate vehicle such as water or saline before use.
  • The anesthetic composition of the invention may further comprise other ingredients, which are used in a conventional anesthetic composition. The other ingredients may include, but not limited to, isotonic agent such as sodium chloride and glucose; buffering agent such as calcium citrate, sodium citrate, potassium acetate, sodium acetate, sodium hydrogen phosphate and potassium dihydrogen phosphate; antiseptic such as benzylalcohol and phenol; antioxidant such as sodium pyrosulfite, sodium hydrogen sulfite and ascorbic acid; preservative such as benzethonium chloride, benzalkonium chloride, phenol, cresol, chlorobutanol and benzylalcohol; and chelating reagent such as EDTA, thioglycolic acid, thiolactic acid and thioglycerin.
  • The anesthetic composition of the invention may contain other pharmacologically active ingredients, as far as they are not contrary to the objects of the present invention.
  • The anesthetic composition of the invention can be administrated intravenously to induce general anesthesia. The composition is effective for induction and maintenance anesthesia state upon surgical operation as well as postoperative sedation control, and for sedation control in a ventilated patient undergoing intensive treatment. The anesthetic composition of the invention may be used in any stage of anesthesia in combination of a suitable analgesic and/or muscular relaxant if desired.
  • The anesthetic effective amount of the compound (I) or a salt thereof is not limited and may vary depending on the age, sex, body weight and physical condition of the subject to be treated, desired depth or retention time of anesthesia and the like. For induction of anesthesia, typically about 0.1-10 mg/kg, preferably 1.0-5.0 mg/kg bolus of the compound of the present invention is administrated intravenously. For maintenance, 0.5-25 mg/kg/hour, preferably 1.0-15 mg/kg/hour of the compound may be continuously administrated intravenously. For maintenance of sedation in a patient undergoing intensive treatment or for postoperative sedation, 0.05-10 mg/kg/hour, preferably 0.1-5.0 mg/kg/hour of the composition may be continuously administrated intravenously. These amounts are only examples and do not limit the scope of the invention.
  • The present invention will be further illustrated by the following Test Examples, Reference Examples and Examples; however, the present invention is not limited to these examples.
    • REFERENCE EXAMPLE 1 4,5-Diethylphthalic Anhydride (a) 4,5-Diethylphthalic Acid
  • 1,2-dicyano-4,5-diethylbenzene (2.3 g, 12 mmol) was stirred with heating in 75% sulfuric acid (30 ml) at 150° C. for 3.5 hrs. The reaction solution was poured into ice-cold water. The precipitated crystals were collected by filtration, washed with water, and dissolved in 10% aqueous sodium hydroxide solution. The insoluble materials were separated by filtration, and the resulting filtrate was made acid with concentrated hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried to give 1.5 g of 4,5-diethylphthalic acid.
    • (b) 4,5-diethylphthalic Anhydride
  • The product of above-mentioned (a) (1.5 g, 6.7 mmol) was heated under reflux in acetic anhydride (10 ml) for 1 hr. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in 10% aqueous sodium hydroxide solution. The insoluble materials were collected by filtration, washed with water, and dried to give 0.31 g of the title compound.
    • REFERENCE EXAMPLE 2 3,5-dimethylphthalic Anhydride
  • 4,6-dimethyl-2-pyrone (1.0 g, 8.1 mmol) and 2-chloromaleic anhydride (1.5 g, 11 mmol) were stirred with heating at 160° C. for 3 hrs, and the precipitated crystals were purified by silica gel chromatography (chloroform) to give 0.91 g of the title compound.
    • REFERENCE EXAMPLE 3 4,5-dimethylphthalic Anhydride (a) 5,6-dimethyl-3a,4,7,7a-tetrahydro-2-benzofuran-1,3-dione
  • To a solution of maleic anhydride (5.4 g, 55 mmol) in benzene (50 ml) was added dropwise 2,3-dimethyl-1,3-butadiene (6.3 ml, 55 mmol), and stirred overnight at 25° C. After separating the insoluble materials by filtration, the filtrate was concentrated under reduced pressure to give 9.5 g of 5,6-dimethyl-3a,4,7,7a-tetrahydro-2-benzofuran-1,3-dione.
    • (b) 4,5-dimethylphthalic Anhydride
  • To a solution of above-mentioned (a) (9.5 g, 53 mmol) in acetic acid (28 ml) was added dropwise a solution of bromine (6.1 ml, 0.12 mol) in acetic acid (28 ml) at 115° C. over a period of 45 minutes, and heated under reflux for 1 hr. The reaction solution was left overnight, and the precipitated crystals were collected by filtration, washed with diethyl ether, followed by drying to give 3.5 g of the title compound.
    • REFERENCE EXAMPLE 4 4,5-dimethoxyphthalic Anhydride (a) 4,5-dimethoxyphthalide
  • 3,4-dimethoxybenzoic acid (5.0 g, 27 mmol) was added to Formalin (36 ml) saturated with hydrogen chloride gas, and stirred with bubbling hydrogen chloride gas at 65° C. for 2 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (16 ml), followed by neutralizing with dilute aqueous ammonia (concentrated aqueous ammonia:water=2:3). The precipitated crystals were collected by filtration, washed with water, followed by drying to give 4.0 g of 4,5-dimethoxyphthalide.
    • (b) 4,5-dimethoxyphthalic Acid
  • An aqueous 2N sodium hydroxide solution of the product of above-mentioned (a) (3.0 g, 15 mmol) was added dropwise with stirring to a 6% aqueous solution of potassium permanganate (50 ml) under ice cooling, and the reaction solution was stirred overnight with gradually raising the temperature to 25° C. To the reaction solution was added ethanol and the precipitated manganese dioxide was filtered off. The filtrate was acidified with concentrated hydrochloric acid and concentrated under reduced pressure. To the residue was added methanol and stirred for 10 minutes. After the insoluble materials were filtered off, the filtrate was concentrated under reduced pressure to give 4.1 g of 4,5-dimethoxyphthalic acid.
    • (c) 4,5-dimethoxyphthalic Anhydride
  • The product of above-mentioned (b) (4.1 g, 18 mmol) was heated under reflux in acetic anhydride (14 ml) for 10 minutes. The reaction solution was poured into ice-cold water, and extracted with chloroform. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and then water, dried and concentrated under reduced pressure to give 1.8 g of the title compound.
    • REFERENCE EXAMPLE 5 5,6-indandicarboxylic Anhydride (a) Diethyl 5,6-indandicarboxylate
  • Diethyl acetylenedicarboxylate (1.0 ml, 6.3 mmol) and dicarbonylcyclopentadienylcobalt (0.1 ml, 0.62 mmol) were added dropwise to a solution of 1,6-heptadiyne (0.72 ml, 6.3 mmol) in xylene (5 ml), and stirred at 80° C. for 5 days. To the reaction solution was added dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure, followed by purifying the residue by silica gel chromatography (chloroform, successively hexane:ethyl acetate=10:1) to give 0.36 g of diethyl 5,6-indandicarboxylate.
    • (b) 5,6-indandicarboxylic Acid
  • To a solution of the product of above-mentioned (a) (0.36 g, 1.4 mmol) in acetic acid (0.8 ml) was added concentrated hydrochloric acid (0.4 ml) and stirred at 80° C. overnight. To the reaction solution was added ice-cold water, and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.28 g of 5,6-indandicarboxylic acid.
    • (c) 5,6-indandicarboxylic Anhydride
  • The product of above-mentioned (b) (0.28 g, 1.4 mmol) was heated under reflux in acetic anhydride (6.7 ml) overnight. The reaction solution was poured into ice-cold water, and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.25 g of the title compound.
    • REFERENCE EXAMPLE 6 5,6,7,8-tetrahydro-2,3-naphthalenedicarboxylic Anhydride
  • By using 1,7-octadiyne as starting material, the title compound was obtained according to Reference Example 5.
    • REFERENCE EXAMPLE 7 1,3-dihydro-2-benzofuran-5,6-dicarboxylic Anhydride
  • By using propargyl ether as starting material, the title compound was obtained according to Reference Example 5.
    • REFERENCE EXAMPLE 8 1,3-benzodioxole-5,6-dicarboxylic Anhydride
  • By using 1,2-dibromo-4,5-(methylenedioxy)benzene, the title compound was obtained according to the synthesis of 4,5-diethylphthalic anhydride.
    • EXAMPLE 1 5,6-dimethyl-2-(4-fluorophenyl)-3-carboxymethylisoindolin-1-one [IUPAC name: 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]acetic acid] (1-a) 5,6-dimethyl-2-(4-fluorophenyl)isoindolin-1,3-dione
  • 4,5-dimethylphthalic anhydride (1.7 g, 9.6 mmol) and 4-fluoroaniline (1.1 g, 9.6 mmol) were stirred with heating in dimethylformamide at 150° C. for 1 hr. After cooling, water was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water, and dried. The resulting crystals were purified by silica gel chromatography (chloroform) to give 2.0 g of 5,6-dimethyl-2-(4-fluorophenyl)isoindolin-1,3-dione.
  • 1H-NMR (CDCl3) δ: 2.44 (6H, s, CH3), 7.15-7.22 (2H, m, PhH), 7.38-7.45 (2H, m, PhH), 7.71 (2H, s, C4-7—H)
    • (1-b) 5,6-dimethyl-2-(4-fluorophenyl)-3-hydroxyisoindolin-1-one
  • The product of above-mentioned (1-a) (1.0 g, 3.7 mmol) was suspended in methanol (9 ml) and tetrahydrofuran (9 ml), and sodium borohydride (0.15 g, 3.9 mmol) was added by portions thereto with stirring under ice cooling, followed by stirring at the same temperature for 30 minutes. To the reaction solution was added water, and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.95 g of 5,6-dimethyl-2-(4-fluorophenyl)-3-hydroxyisoindolin-1-one.
    • (1-c) 5,6-dimethyl-2-(4-fluorophenyl)-3-ethoxycarbonyl-methylisoindolin-1-one [IUPAC name: ethyl 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]acetate]
  • The product of above-mentioned (1-b) (0.90 g, 3.3 mmol) and (carboethoxymethylene)triphenylphosphorane (1.4 g, 3.9 mmol) was heated under reflux in toluene (15 ml) under an argon atmosphere for 3.5 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=50:1) to give 0.37 g of 5,6-dimethyl-2-(4-fluorophenyl)-3-ethoxycarbonylmethylisoindolin-1-one [IUPAC name: ethyl 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]acetate].
  • 1H-NMR (CDCl3) δ: 1.18 (3H, t, CH2CH 3), 2.36 (3H, s, CH3), 2.38 (3H, s, CH3), 2.50 (1H, dd, CH2), 2.85 (1H, dd, CH2), 4.02-4.15 (2H, m, CH 2CH3), 5.46 (1H, dd, CH), 7.10-7.18 (2H, m, PhH), 7.27 (1H, s, C7—H), 7.48-7.54 (2H, m, PhH), 7.68 (1H, s, C4-H)
    • (1-d) 5,6-dimethyl-2-(4-fluorophenyl)-3-carboxymethyl-isoindolin-1-one [IUPAC name: 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]acetic acid]
  • The product of above-mentioned (1-c) (0.20 g, 0.59 mmol) was stirred with heating in methanol (1.5 ml) and 15% aqueous solution of potassium carbonate (0.46 ml) at 75° C. for 4 hrs. The reaction solution was concentrated under reduced pressure, and water was added to the residue followed by extracting with diethyl ether. The water layer was made acid with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.12 g of the title compound.
  • 1H-NMR (DMSO-d6) δ: 2.32 (3H, s, CH3), 2.34 (3H, s, CH3), 2.52 (1H, dd, CH2), 2.80 (1H, dd, CH2), 5.55 (1H, dd, CH), 7.26-7.30 (2H, m, PhH), 7.44 (1H, s, C7—H), 7.54 (1H, s, C4—H), 7.57-7.61 (2H, m, PhH)
    • EXAMPLE 2
  • By using 5,6-dimethyl-2-substituted-isoindolin-1,3-dione as starting material, 5,6-dimethyl-3-carboxymethyl-2-substituted-isoindolin-1-one was obtained according to Example 1.
    • EXAMPLE 3 5,6-dimethyl-2-(3-fluorophenyl)-3-(4-methyl-1-piperazinyl)-carbonylmethylisoindolin-1-one
  • 5,6-dimethyl-2-(3-fluorophenyl)-3-carboxymethyl-isoindolin-1-one [IUPAC name: 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]acetic acid] (0.50 g, 1.6 mmol), 1-methylpiperazine (0.16 g, 1.6 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.31 g, 1.6 mmol) and 1-hydroxybenzotriazole hydrate (0.25 g, 1.6 mmol) were stirred in tetrahydrofuran (40 ml) at 25° C. for 16 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give 0.56 g of the title compound.
  • 1H-NMR (CDCl3) δ: 2.16-2.26 (2H, m, piperazine), 2.27 (3H, s, NCH3), 2.36 (3H, s, CH3), 2.37 (3H, s, CH3), 2.34-2.42 (2H, m, piperazine), 2.41 (1H, dd, CH2), 2.91 (1H, dd, CH2), 3.20-3.31 (2H, m, piperazine), 3.64-3.72 (2H, m, piperazine), 5.77 (1H, dd, CH), 6.88-6.93 (1H, m, PhH), 7.38 (1H, s, C4-H), 7.35-7.42 (2H, m, PhH), 7.58-7.62 (1H, m, PhH), 7.68 (1H, s, C7—H)
    • EXAMPLE 4 5,6-dimethyl-2-(4-fluorophenyl)-3-carboxyethylisoindolin-1-one [IUPAC name: 3-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]propionic acid] (4-a) 5,6-dimethyl-2-(4-fluorophenyl)-3-(2-hydroxyethyl)-isoindolin-1-one
  • To a solution of lithium borohydride (80 mg, 3.7 mmol) in tetrahydrofuran was added with stirring 5,6-dimethyl-2-(4-fluorophenyl)-3-ethoxycarbonylmethylisoindolin-1-one [IUPAC name: ethyl 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]acetate] (0.63 g, 1.9 mmol) under ice cooling and stirred at 25° C. for 39 hrs. To the reaction solution was added water, and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.51 g of 5,6-dimethyl-2-(4-fluorophenyl)-3-(2-hydroxyethyl)isoindolin-1-one.
  • 1H-NMR (CDCl3) δ: 2.01-2.25 (2H, m, CH 2CH2O), 2.37 (3H, s, CH3), 2.40 (3H, s, CH3), 3.50 (2H, dd, CH2CH 2O), 5.28 (1H, dd, CH), 7.12-7.16 (2H, m, PhH), 7.32 (1H, s, C4—H), 7.52-7.55 (2H, m, PhH), 7.68 (1H, s, C7—H)
    • (4-b) 5,6-dimethyl-2-(4-fluorophenyl)-3-mesyloxyethyl-isoindolin-1-one
  • To a solution of the product of above-mentioned (4-a) (0.20 g, 0.67 mmol) and triethylamine (0.14 ml, 1.0 mmol) in dichloromethane was added mesyl chloride (0.06 ml, 0.78 mmol) and stirred at 25° C. for 30 minutes. The reaction solution was washed with water, dried, and the solvent was distilled away under reduced pressure to give 0.23 g of 5,6-dimethyl-2-(4-fluorophenyl)-3-mesyloxyethylisoindolin-1-one.
  • 1H-NMR (CDCl3) δ: 2.26-2.45 (2H, m, CH 2CH2O), 2.38 (3H, s, CH3), 2.41 (3H, s, CH3), 2.79 (3H, s, CH3SO2), 3.90-4.04 (2H, m, CH2CH 2O), 5.29 (1H, dd, CH), 7.14-7.18 (2H, m, PhH), 7.31 (1H, s, C4—H), 7.51-7.54 (2H, m, PhH), 7.70 (1H, s, C7—H)
    • (4-c) 5,6-dimethyl-2-(4-fluorophenyl)-3-cyanoethyl-isoindolin-1-one [IUPAC name: 3-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]propanenitrile]
  • To a 806 ethanol solution of the product of above-mentioned (4-b) (0.23 g, 0.63 mmol) was added potassium cyanide (0.12 g, 1.9 mmol) and heated under reflux for 4 hrs. To the reaction solution was added water, and extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled away under reduced pressure to give 0.19 g of 5,6-dimethyl-2-(4-fluorophenyl)-3-cyanoethylisoindolin-1-one [IUPAC name: 3-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]propanenitrile].
  • 1H-NMR (CDCl3) δ: 1.77-1.99 (2H, m, CH2CH 2CN), 2.28-2.41 (2H, m, CH 2CH2CN), 2.38 (3H, s, CH3), 2.42 (3H, s, CH3), 5.29 (1H, dd, CH), 7.15-7.20 (2H, m, PhH), 7.26 (1H, s, C7—H), 7.50-7.53 (2H, m, PhH), 7.70 (1H, s, C4—H)
    • (4-d) 5,6-dimethyl-2-(4-fluorophenyl)-3-carboxyethyl-isoindolin-1-one [IUPAC name: 3-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]propionic acid]
  • The product of above-mentioned (4-c) (0.18 g, 0.58 mmol) was heated under reflux in concentrated hydrochloric acid (10 ml) overnight. To the reaction solution was added water, and the precipitated crystals were collected by filtration, washed with water, and dried to give 0.15 g of the title compound.
    • EXAMPLE 5 5,6-dimethyl-2-(4-fluorophenyl)-3-(4-methyl-1-piperazinyl)-carbonylethylisoindolin-1-one
  • By using 5,6-dimethyl-2-(4-fluorophenyl)-3-carboxy-ethylisoindolin-1-one [IUPAC name: 3-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]propionic acid], the title compound was obtained according to Example 3.
  • 1H-NMR (CDCl3) δ: 1.64-1.98 (2H, m, CH 2CH2C═O), 2.10-2.21 (2H, m, piperazine), 2.24 (3H, s, NCH3), 2.24-2.27 (2H, m, piperazine), 2.27-2.37 (2H, m, CH2CH 2C═O), 2.37 (3H, s, CH3), 2.39 (3H, s, CH3), 3.04-3.07 (2H, m, piperazine), 3.41-3.56 (2H, m, piperazine), 5.32 (1H, dd, CH), 7.12-7.16 (2H, m, PhH), 7.26 (1H, s, C4—H), 7.55-7.58 (2H, m, PhH), 7.68 (1H, s, C7—H)
    • EXAMPLE 6
  • Compounds shown in Table 1 and 2, were obtained in a manner similar to those described in Example 3 and 5.
    • Table 1
  • TABLE 1
    Figure US20090170835A1-20090702-C00069
    No. R1 R2 melting point [° C.]
    1 5-CH3
    Figure US20090170835A1-20090702-C00070
         		white crystals
    2 4,5-di-CH3
    Figure US20090170835A1-20090702-C00071
         		153-162 (1-hydrochloride salt)
    3 4,6-di-CH3
    Figure US20090170835A1-20090702-C00072
         		161-168 (1-hydrochloride salt)
    4 4,7-di-CH3
    Figure US20090170835A1-20090702-C00073
         		160.5-170  
    5 5,7-di-CH3
    Figure US20090170835A1-20090702-C00074
         		155-163 (1-hydrochloride salt)
    6 6,7-di-CH3
    Figure US20090170835A1-20090702-C00075
         		154-162 (1-hydrochloride salt)
    7 5,6-di-CH3CH2
    Figure US20090170835A1-20090702-C00076
         		white crystals
    8 5,6-di-CH3O
    Figure US20090170835A1-20090702-C00077
         		white crystals
  • The NMR data of each compound in Table 1 are shown below:
  • No. 1 1H-NMR (CDCl3) δ: 2.17-2.25 (2H, m, piperazine), 2.27 (3H, s, NCH3), 2.34-2.40 (2H, m, piperazine), 2.44 (1H, dd, CH2), 2.47 (3H, s, CH3), 2.83 (1H, dd, CH2), 3.18-3.33 (2H, m, piperazine), 3.58-3.76 (2H, m, piperazine), 5.78 (1H, dd, CH), 7.10-7.18 (2H, m, PhH), 7.33 (1H, br d, C6—H), 7.41 (1H, br s, C4—H), 7.56-7.63 (2H, m, PhH), 7.79 (1H, d, C7—H)
  • No. 2 1H-NMR (CDCl3) δ: 1.92-2.23 (4H, m, piperazine), 2.22 (3H, s, NCH3), 2.33 (3H, s, CH3), 2.39 (3H, s, CH3), 2.64 (1H, dd, CH2), 2.82 (1H, dd, CH2), 3.03-3.25 (2H, m, piperazine), 3.50-3.58 (2H, m, piperazine), 6.02 (1H, dd, CH), 6.87-6.91 (1H, m, PhH), 7.30-7.46 (3H, m, PhH and C6—H), 7.60-7.66 (2H, m, PhH and C7—H)
  • No. 3 1H-NMR (CDCl3) δ: 2.01-2.33 (4H, m, piperazine), 2.23 (3H, s, NCH3), 2.39 (3H, s, CH3), 2.43 (3H, s, CH3), 2.65 (1H, dd, CH2), 2.82 (1H, dd, CH2), 3.07-3.27 (2H, m, piperazine), 3.49-3.60 (2H, m, piperazine), 5.98 (1H, dd, CH), 6.87-6.92 (1H, m, PhH), 7.22 (1H, s, C5—H), 7.34-7.45 (2H, m, PhH), 7.56 (1H, s, C7—H), 7.62-7.66 (1H, m, PhH)
  • No. 4 1H-NMR (CDCl3) δ: 1.98-2.05 (1H, m, piperazine), 2.16-2.35 (3H, m, piperazine), 2.22 (3H, s, NCH3), 2.39 (3H, s, CH3), 2.63 (1H, dd, CH2), 2.71 (3H, s, CH3), 2.83 (1H, dd, CH2), 3.07-3.27 (2H, m, piperazine), 3.46-3.60 (2H, m, piperazine), 5.97 (1H, dd, CH), 6.87-6.92 (1H, m, PhH), 7.16 (1H, d, C6—H), 7.26 (1H, d, C5-H), 7.33-7.45 (2H, m, PhH), 7.63-7.66 (1H, m, PhH)
  • No. 5 1H-NMR (CDCl3) δ: 2.20-2.25 (2H, m, piperazine), 2.27 (3H, s, NCH3), 2.37-2.41 (2H, m, piperazine), 2.42 (3H, s, CH3), 2.44 (1H, dd, CH2), 2.71 (3H, s, CH3), 2.88 (1H, dd, CH2), 3.21-3.31 (2H, m, piperazine), 3.64-3.76 (2H, m, piperazine), 5.75 (1H, dd, CH), 6.88-6.92 (1H, m, PhH), 7.07 (1H, s, C6—H), 7.21 (1H, s, C4—H), 7.34-7.41 (2H, m, PhH), 7.59-7.62 (1H, m, PhH)
  • No. 6 1H-NMR (CDCl3) δ: 2.20-2.23 (2H, m, piperazine), 2.26 (3H, s, NCH3), 2.36-2.38 (2H, m, piperazine), 2.36 (3H, s, CH3), 2.41 (1H, dd, CH2), 2.72 (3H, s, CH3), 2.87 (1H, dd, CH2), 3.19-3.30 (2H, m, piperazine), 3.63-3.72 (2H, m, piperazine), 5.74 (1H, dd, CH), 6.89-6.94 (1H, m, PhH), 7.31-7.42 (4H, m, PhH and C4,5—H), 7.57-7.61 (1H, m, PhH)
  • No. 7 1H-NMR (CDCl3): 1.25 (3H, t, CH2CH 3), 1.29 (3H, t, CH2CH 3), 2.20-2.22 (2H, m, piperazine), 2.26 (3H, s, NCH3), 2.35-2.37 (2H, m, piperazine), 2.43 (1H, dd, CH2), 2.72-2.77 (4H, m, CH 2CH3), 2.81 (1H, dd, CH2), 3.19-3.31 (2H, m, piperazine), 3.60-3.74 (2H, m, piperazine), 5.77 (1H, dd, CH), 7.11-7.15 (2H, m, PhH), 7.38 (1H, s, C4—H), 7.58-7.61 (2H, m, PhH), 7.73 (1H, s, C7—H)
  • No. 8 1H-NMR (CDCl3) δ: 2.22-2.41 (4H, m, piperazine), 2.26 (3H, s, NCH3), 2.38 (1H, dd, CH2), 2.85 (1H, dd, CH2), 3.24-3.34 (2H, m, piperazine), 3.65-3.73 (2H, m, piperazine), 3.95 (3H, s, OCH3), 3.97 (3H, s, OCH3), 5.71 (1H, dd, CH), 7.12-7.16 (2H, m, PhH), 7.15 (1H, s, C4—H), 7.36 (1H, s, C7—H), 7.56-7.60 (2H, m, PhH)
  • TABLE 2
    Figure US20090170835A1-20090702-C00078
    No. R2 L melting point [° C.]
     1
    Figure US20090170835A1-20090702-C00079
    Figure US20090170835A1-20090702-C00080
         		124-132 (1-hydrochloride salt)
     2
    Figure US20090170835A1-20090702-C00081
    Figure US20090170835A1-20090702-C00082
         		137-138 (1-hydrochloride salt)
     3
    Figure US20090170835A1-20090702-C00083
    Figure US20090170835A1-20090702-C00084
         		79-84
     4
    Figure US20090170835A1-20090702-C00085
    Figure US20090170835A1-20090702-C00086
         		white crystals
     5
    Figure US20090170835A1-20090702-C00087
    Figure US20090170835A1-20090702-C00088
         		  170-170.5 (1-hydrochloride salt)
     6
    Figure US20090170835A1-20090702-C00089
    Figure US20090170835A1-20090702-C00090
         		white crystals
     7
    Figure US20090170835A1-20090702-C00091
    Figure US20090170835A1-20090702-C00092
         		  141-141.5 (1-hydrochloride salt)
     8
    Figure US20090170835A1-20090702-C00093
    Figure US20090170835A1-20090702-C00094
         		white crystals
     9
    Figure US20090170835A1-20090702-C00095
    Figure US20090170835A1-20090702-C00096
         		100.5-128   (1-hydrochloride salt)
    10
    Figure US20090170835A1-20090702-C00097
    Figure US20090170835A1-20090702-C00098
         		115.5-123.5 (1-hydrochloride salt)
    11
    Figure US20090170835A1-20090702-C00099
    Figure US20090170835A1-20090702-C00100
         		112.5-119   (1-hydrochloride salt)
    12
    Figure US20090170835A1-20090702-C00101
    Figure US20090170835A1-20090702-C00102
         		white crystals
    13
    Figure US20090170835A1-20090702-C00103
    Figure US20090170835A1-20090702-C00104
         		142.5-144   (1-hydrochloride salt)
    14
    Figure US20090170835A1-20090702-C00105
    Figure US20090170835A1-20090702-C00106
         		121-139 (1-hydrochloride salt)
    15
    Figure US20090170835A1-20090702-C00107
    Figure US20090170835A1-20090702-C00108
         		108.5-116.5 (1-hydrochloride salt)
    16
    Figure US20090170835A1-20090702-C00109
    Figure US20090170835A1-20090702-C00110
         		174.5-180   (1-hydrochloride salt)
    17
    Figure US20090170835A1-20090702-C00111
    Figure US20090170835A1-20090702-C00112
         		146-151 (1-hydrochloride salt)
    18
    Figure US20090170835A1-20090702-C00113
    Figure US20090170835A1-20090702-C00114
         		185-193 (1-hydrochloride salt)
    19
    Figure US20090170835A1-20090702-C00115
    Figure US20090170835A1-20090702-C00116
         		white crystals
    20
    Figure US20090170835A1-20090702-C00117
    Figure US20090170835A1-20090702-C00118
         		  158-158.5
    21
    Figure US20090170835A1-20090702-C00119
    Figure US20090170835A1-20090702-C00120
         		159.5-164.5 (1-hydrochloride salt)
    22
    Figure US20090170835A1-20090702-C00121
    Figure US20090170835A1-20090702-C00122
         		189-192
    23
    Figure US20090170835A1-20090702-C00123
    Figure US20090170835A1-20090702-C00124
         		  207-207.5
    24
    Figure US20090170835A1-20090702-C00125
    Figure US20090170835A1-20090702-C00126
         		156.5-160   (1-hydrochloride salt)
    25
    Figure US20090170835A1-20090702-C00127
    Figure US20090170835A1-20090702-C00128
         		  152-157.5 (1-hydrochloride salt)
    26
    Figure US20090170835A1-20090702-C00129
    Figure US20090170835A1-20090702-C00130
         		white crystals
    27
    Figure US20090170835A1-20090702-C00131
    Figure US20090170835A1-20090702-C00132
         		247.5-250  
    28
    Figure US20090170835A1-20090702-C00133
    Figure US20090170835A1-20090702-C00134
         		145-146 (1-hydrochloride salt)
    29
    Figure US20090170835A1-20090702-C00135
    Figure US20090170835A1-20090702-C00136
         		  138-144.5 (1-hydrochloride salt)
    30
    Figure US20090170835A1-20090702-C00137
    Figure US20090170835A1-20090702-C00138
         		201.5-208.5 (1-hydrochloride salt)
    31
    Figure US20090170835A1-20090702-C00139
    Figure US20090170835A1-20090702-C00140
         		  105-105.5 (1-hydrochloride salt)
    32
    Figure US20090170835A1-20090702-C00141
    Figure US20090170835A1-20090702-C00142
         		174.5-183   (1-hydrochloride salt)
    33
    Figure US20090170835A1-20090702-C00143
    Figure US20090170835A1-20090702-C00144
         		  136-141.5 (1-hydrochloride salt)
    34
    Figure US20090170835A1-20090702-C00145
    Figure US20090170835A1-20090702-C00146
         		164.5-166.5 (1-hydrochloride salt)
    35
    Figure US20090170835A1-20090702-C00147
    Figure US20090170835A1-20090702-C00148
         		156-161
    36
    Figure US20090170835A1-20090702-C00149
    Figure US20090170835A1-20090702-C00150
         		163.5-167   (1-hydrochloride salt)
    37
    Figure US20090170835A1-20090702-C00151
    Figure US20090170835A1-20090702-C00152
         		259.5-261.5 (1-hydrochloride salt)
    38
    Figure US20090170835A1-20090702-C00153
    Figure US20090170835A1-20090702-C00154
         		163.5-164   (1-hydrochloride salt)
    39
    Figure US20090170835A1-20090702-C00155
    Figure US20090170835A1-20090702-C00156
         		169.5-170  
    40
    Figure US20090170835A1-20090702-C00157
    Figure US20090170835A1-20090702-C00158
         		140-146 (1-hydrochloride salt)
    41
    Figure US20090170835A1-20090702-C00159
    Figure US20090170835A1-20090702-C00160
         		146-151 (1-hydrochloride salt)
    42
    Figure US20090170835A1-20090702-C00161
    Figure US20090170835A1-20090702-C00162
         		226.5 (decomposed) (1-hydrochloride salt)
    43
    Figure US20090170835A1-20090702-C00163
    Figure US20090170835A1-20090702-C00164
         		150-151 (1-hydrochloride salt)
    44
    Figure US20090170835A1-20090702-C00165
    Figure US20090170835A1-20090702-C00166
         		  141-146.5 (1-hydrochloride salt)
    45 (−)
    Figure US20090170835A1-20090702-C00167
    Figure US20090170835A1-20090702-C00168
         		90.5-98   (1-hydrochloride salt)
    46
    Figure US20090170835A1-20090702-C00169
    Figure US20090170835A1-20090702-C00170
         		  257-258.5
    47
    Figure US20090170835A1-20090702-C00171
    Figure US20090170835A1-20090702-C00172
         		219-226 (1-hydrochloride salt)
    48
    Figure US20090170835A1-20090702-C00173
    Figure US20090170835A1-20090702-C00174
         		  172-175.5 (1-hydrochloride salt)
    49
    Figure US20090170835A1-20090702-C00175
    Figure US20090170835A1-20090702-C00176
         		175-181 (1-hydrochloride salt)
    50
    Figure US20090170835A1-20090702-C00177
    Figure US20090170835A1-20090702-C00178
         		194.5-195.5 (1-hydrochloride salt)
    51
    Figure US20090170835A1-20090702-C00179
    Figure US20090170835A1-20090702-C00180
         		183.5-184   (1-hydrochloride salt)
    52
    Figure US20090170835A1-20090702-C00181
    Figure US20090170835A1-20090702-C00182
         		158.5-162.5 (1-hydrochloride salt)
    53
    Figure US20090170835A1-20090702-C00183
    Figure US20090170835A1-20090702-C00184
         		157-158 (1-hydrochloride salt)
    54
    Figure US20090170835A1-20090702-C00185
    Figure US20090170835A1-20090702-C00186
         		197.5-203   (1-hydrochloride salt)
    55
    Figure US20090170835A1-20090702-C00187
    Figure US20090170835A1-20090702-C00188
         		  126-126.5 (1-hydrochloride salt)
    56 (−)
    Figure US20090170835A1-20090702-C00189
    Figure US20090170835A1-20090702-C00190
         		74.5-82   (1-hydrochloride salt)
    57
    Figure US20090170835A1-20090702-C00191
    Figure US20090170835A1-20090702-C00192
         		156.5-168   (1-hydrochloride salt)
    58
    Figure US20090170835A1-20090702-C00193
    Figure US20090170835A1-20090702-C00194
         		145-146 (1-hydrochloride salt)
    59
    Figure US20090170835A1-20090702-C00195
    Figure US20090170835A1-20090702-C00196
         		138-145
    60
    Figure US20090170835A1-20090702-C00197
    Figure US20090170835A1-20090702-C00198
         		150-161 (1-hydrochloride salt)
    61
    Figure US20090170835A1-20090702-C00199
    Figure US20090170835A1-20090702-C00200
         		148.5-149   (1-hydrochloride salt)
    62
    Figure US20090170835A1-20090702-C00201
    Figure US20090170835A1-20090702-C00202
         		white crystals
    63
    Figure US20090170835A1-20090702-C00203
    Figure US20090170835A1-20090702-C00204
         		170.5-179   (1-hydrochloride salt)
    64
    Figure US20090170835A1-20090702-C00205
    Figure US20090170835A1-20090702-C00206
         		white crystals
    65
    Figure US20090170835A1-20090702-C00207
    Figure US20090170835A1-20090702-C00208
         		  198-210.5 (1-hydrochloride salt)
    66
    Figure US20090170835A1-20090702-C00209
    Figure US20090170835A1-20090702-C00210
         		180.5-185   (1-hydrochloride salt)
    67
    Figure US20090170835A1-20090702-C00211
    Figure US20090170835A1-20090702-C00212
         		  161-165.5 (1-hydrochloride salt)
    68
    Figure US20090170835A1-20090702-C00213
    Figure US20090170835A1-20090702-C00214
         		  180-184.5 (1-hydrochloride salt)
    69
    Figure US20090170835A1-20090702-C00215
    Figure US20090170835A1-20090702-C00216
         		decomposed 85 (1-hydrochloride salt)
    70
    Figure US20090170835A1-20090702-C00217
    Figure US20090170835A1-20090702-C00218
         		white crystals
    71
    Figure US20090170835A1-20090702-C00219
    Figure US20090170835A1-20090702-C00220
         		183.5-191.5 (1-hydrochloride salt)
    72
    Figure US20090170835A1-20090702-C00221
    Figure US20090170835A1-20090702-C00222
         		  178-180.5 (1-hydrochloride salt)
    73
    Figure US20090170835A1-20090702-C00223
    Figure US20090170835A1-20090702-C00224
         		217.5-221.5
    74
    Figure US20090170835A1-20090702-C00225
    Figure US20090170835A1-20090702-C00226
         		174.5-176   (1-hydrochloride salt)
    75
    Figure US20090170835A1-20090702-C00227
    Figure US20090170835A1-20090702-C00228
         		white crystals
    76
    Figure US20090170835A1-20090702-C00229
    Figure US20090170835A1-20090702-C00230
         		white crystals
    77
    Figure US20090170835A1-20090702-C00231
    Figure US20090170835A1-20090702-C00232
         		197-201 (1-hydrochloride salt)
    78
    Figure US20090170835A1-20090702-C00233
    Figure US20090170835A1-20090702-C00234
         		116-118
    79
    Figure US20090170835A1-20090702-C00235
    Figure US20090170835A1-20090702-C00236
         		174-177
    80
    Figure US20090170835A1-20090702-C00237
    Figure US20090170835A1-20090702-C00238
         		64-68
    81
    Figure US20090170835A1-20090702-C00239
    Figure US20090170835A1-20090702-C00240
         		118.5-122.5
    82
    Figure US20090170835A1-20090702-C00241
    Figure US20090170835A1-20090702-C00242
         		134-137
    83
    Figure US20090170835A1-20090702-C00243
    Figure US20090170835A1-20090702-C00244
         		213-218
    84
    Figure US20090170835A1-20090702-C00245
    Figure US20090170835A1-20090702-C00246
         		210.5-212.5
    85
    Figure US20090170835A1-20090702-C00247
    Figure US20090170835A1-20090702-C00248
         		182-190
    86
    Figure US20090170835A1-20090702-C00249
    Figure US20090170835A1-20090702-C00250
         		172-175
    87
    Figure US20090170835A1-20090702-C00251
    Figure US20090170835A1-20090702-C00252
         		157.5-160.5
    88
    Figure US20090170835A1-20090702-C00253
    Figure US20090170835A1-20090702-C00254
         		138-141
    89
    Figure US20090170835A1-20090702-C00255
    Figure US20090170835A1-20090702-C00256
         		81-84
    90
    Figure US20090170835A1-20090702-C00257
    Figure US20090170835A1-20090702-C00258
         		81-84
    91
    Figure US20090170835A1-20090702-C00259
    Figure US20090170835A1-20090702-C00260
         		64-67
    • EXAMPLE 7 5,6-dimethyl-3-carboxymethyl-2-(3-pyridyl)isoindolin-1-one [IUPAC name: 2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetic acid] (7-a) 5,6-dimethyl-2-(3-pyridyl)isoindolin-1,3-dione
  • 4,5-dimethylphthalic anhydride (2.0 g, 11 mmol) and 3-aminopyridine (1.0 g, 11 mmol) were heated under ref lux in acetic acid (30 ml) for 1.5 hrs. After standing to cool, water was added thereto, the precipitated crystals were collected by filtration, washed with water, followed by drying to give 2.3 g of 5,6-dimethyl-2-(3-pyridyl)isoindolin-1,3-dione.
  • 1H-NMR (CDCl3) δ: 2.46 (6H, s, CH3), 7.44 (1H, dd, PyH), 7.73 (2H, s, C4,7—H), 7.83 (1H, ddd, PyH), 8.62 (1H, dd, PyH), 8.78 (1H, d, PyH)
    • (7-b) 5,6-dimethyl-3-hydroxy-2-(3-pyridyl)isoindolin-1-one
  • The product of above-mentioned (7-a) (0.50 g, 2.0 mmol) was suspended in methanol (10 ml) and tetrahydrofuran (10 ml), and sodium borohydride (75 mg, 2.0 mmol) was added by portions thereto with stirring under ice cooling, followed by stirring at the same temperature for 30 minutes. To the reaction solution was added water, and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.40 g of 5,6-dimethyl-3-hydroxy-2-(3-pyridyl)isoindolin-1-one.
    • (7-c) 5,6-dimethyl-3-ethoxycarbonylmethyl-2-(3-pyridyl)-isoindolin-1-one [IUPAC name: ethyl 2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetate]
  • The product obtained in the above-mentioned (7-b) (0.40 g, 1.6 mmol) and (carboethoxymethylene)triphenyl-phosphorane (0.66 g, 1.9 mmol) was heated under reflux in toluene (10 ml) under an argon atmosphere for 4.0 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:acetone=5:1) to give 0.37 g of 5,6-dimethyl-3-ethoxycarbonylmethyl-2-(3-pyridyl)isoindolin-1-one [IUPAC name: ethyl 2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetate].
  • 1H-NMR (CDCl3) δ: 1.19 (3H, t, CH2CH 3), 2.37 (3H, s, CH3), 2.39 (3H, s, CH3), 2.54 (1H, dd, CH2), 2.91 (1H, dd, CH2) 4.03-4.15 (2H, m, CH 2CH3), 5.58 (1H, dd, CH), 7.30 (1H, s, C7—H), 7.40 (1H, dd, PyH), 7.69 (1H, s, C4—H), 8.10 (1H, ddd, PyH), 8.48 (1H, dd, PyH), 8.79 (1H, d, PyH)
    • (7-d) 5,6-dimethyl-3-carboxymethyl-2-(3-pyridyl)isoindolin-1-one [IUPAC name: 2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetic Acid]
  • The product obtained in the above-mentioned (7-c) (0.20 g, 0.59 mmol) was stirred with heating in methanol (1.5 ml) and 15% aqueous solution of potassium carbonate (0.46 ml) at 75° C. for 4 hrs. The reaction solution was concentrated under reduced pressure, and water was added to the residue followed by extracting with diethyl ether. The water layer was made acid with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, followed by drying to give 0.12 g of the title compound.
  • 1H-NMR (CDCl3) δ: 2.34 (3H, s, CH3), 2.36 (3H, s, CH3), 2.61 (1H, dd, CH2), 2.87 (1H, dd, CH2), 5.69 (1H, dd, CH), 7.49 (1H, s, C7—H), 7.50 (1H, dd, PyH), 7.58 (1H, s, C4—H), 8.02 (1H, br dd, PyH), 8.44 (1H, br d, PyH), 8.84 (1H, d, PyH), 12.31 (1H, br s, COOH)
    • EXAMPLE 8 5,6-dimethyl-3-propoxycarbonylmethyl-2-(3-pyridyl)-isoindolin-1-one [IUPAC name: propyl 2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetate]
  • To a solution of 5,6-dimethyl-3-carboxymethyl-2-(3-pyridyl)isoindolin-1-one [IUPAC name: 2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetic acid] (74 mg, 0.25 mmol), n-propyl alcohol (16 mg, 0.27 mmol) and 4-dimethylaminopyridine (3 mg, 0.025 mmol) in dichloromethane was added 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (53 mg, 0.27 mmol) at 5° C. and the temperature was raised to 25° C. over a period of 1.5 hrs. The reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extracting with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, successively water, dried, and concentrated under reduced pressure to give 34 mg of the title compound.
  • 1H-NMR (CDCl3) δ: 0.88 (3H, t, CH2CH2CH 3), 1.58 (2H, sextet, CH2CH 2CH3), 2.37 (3H, s, CH3), 2.39 (3H, s, CH3), 2.55 (1H, dd, CH2), 2.93 (1H, dd, CH2), 3.94-4.06 (2H, m, CH 2CH2CH3), 5.58 (1H, dd, CH), 7.30 (1H, s, C7—H), 7.40 (1H, dd, PyH), 7.69 (1H, s, C4-H), 8.10 (1H, ddd, PyH), 8.48 (1H, dd, PyH), 8.79 (1H, d, PyH)
    • EXAMPLE 9
  • The compounds shown in Table 3 were obtained according to Example 8.
  • TABLE 3
    Figure US20090170835A1-20090702-C00261
    No. R2 L melting point [° C.]
     1
    Figure US20090170835A1-20090702-C00262
    Figure US20090170835A1-20090702-C00263
         		230-232 (1-hydrochloride salt)
     2
    Figure US20090170835A1-20090702-C00264
    Figure US20090170835A1-20090702-C00265
         		173.5-174  
     3
    Figure US20090170835A1-20090702-C00266
    Figure US20090170835A1-20090702-C00267
         		  81-81.5 (1-hydrochloride salt)
     4
    Figure US20090170835A1-20090702-C00268
    Figure US20090170835A1-20090702-C00269
         		white crystals
     5
    Figure US20090170835A1-20090702-C00270
    Figure US20090170835A1-20090702-C00271
         		  170-171.5
     6
    Figure US20090170835A1-20090702-C00272
    Figure US20090170835A1-20090702-C00273
         		  209-210.5 (1-hydrochloride salt)
     7
    Figure US20090170835A1-20090702-C00274
    Figure US20090170835A1-20090702-C00275
         		white crystals
     8
    Figure US20090170835A1-20090702-C00276
    Figure US20090170835A1-20090702-C00277
         		154.5-158  
     9
    Figure US20090170835A1-20090702-C00278
    Figure US20090170835A1-20090702-C00279
         		white crystals
    10
    Figure US20090170835A1-20090702-C00280
    Figure US20090170835A1-20090702-C00281
         		white crystals
    11
    Figure US20090170835A1-20090702-C00282
    Figure US20090170835A1-20090702-C00283
         		93.5-101 
    12
    Figure US20090170835A1-20090702-C00284
    Figure US20090170835A1-20090702-C00285
         		white crystals
    13
    Figure US20090170835A1-20090702-C00286
    Figure US20090170835A1-20090702-C00287
         		162.5-169.5 (1-hydrochloride salt)
    14
    Figure US20090170835A1-20090702-C00288
    Figure US20090170835A1-20090702-C00289
         		125.5-126.5
    15
    Figure US20090170835A1-20090702-C00290
    Figure US20090170835A1-20090702-C00291
         		141.5-145  
    16
    Figure US20090170835A1-20090702-C00292
    Figure US20090170835A1-20090702-C00293
         		  124-124.5
    17
    Figure US20090170835A1-20090702-C00294
    Figure US20090170835A1-20090702-C00295
         		140-142
    18
    Figure US20090170835A1-20090702-C00296
    Figure US20090170835A1-20090702-C00297
         		white crystals
    19
    Figure US20090170835A1-20090702-C00298
    Figure US20090170835A1-20090702-C00299
         		white crystals
    20 (−)
    Figure US20090170835A1-20090702-C00300
    Figure US20090170835A1-20090702-C00301
         		140.5-143  
    21 (−)
    Figure US20090170835A1-20090702-C00302
    Figure US20090170835A1-20090702-C00303
         		129.5-133.5
    22
    Figure US20090170835A1-20090702-C00304
    Figure US20090170835A1-20090702-C00305
         		141-143
    23
    Figure US20090170835A1-20090702-C00306
    Figure US20090170835A1-20090702-C00307
         		116.5-117.5
    24 (−)
    Figure US20090170835A1-20090702-C00308
    Figure US20090170835A1-20090702-C00309
         		134.5-135.5
    25 (−)
    Figure US20090170835A1-20090702-C00310
    Figure US20090170835A1-20090702-C00311
         		128.5-130.5
    26 (−)
    Figure US20090170835A1-20090702-C00312
    Figure US20090170835A1-20090702-C00313
         		  124-124.5
    27
    Figure US20090170835A1-20090702-C00314
    Figure US20090170835A1-20090702-C00315
         		130-131
    28 (−)
    Figure US20090170835A1-20090702-C00316
    Figure US20090170835A1-20090702-C00317
         		138.5-140  
    29 (−)
    Figure US20090170835A1-20090702-C00318
    Figure US20090170835A1-20090702-C00319
         		111-115
    30 (−)
    Figure US20090170835A1-20090702-C00320
    Figure US20090170835A1-20090702-C00321
         		129.5-130  
    31
    Figure US20090170835A1-20090702-C00322
    Figure US20090170835A1-20090702-C00323
         		113-114
    32 (−)
    Figure US20090170835A1-20090702-C00324
    Figure US20090170835A1-20090702-C00325
         		  126-127.5
    33 (−)
    Figure US20090170835A1-20090702-C00326
    Figure US20090170835A1-20090702-C00327
         		148.5-149  
    34 (−)
    Figure US20090170835A1-20090702-C00328
    Figure US20090170835A1-20090702-C00329
         		108-110
    35 (−)
    Figure US20090170835A1-20090702-C00330
    Figure US20090170835A1-20090702-C00331
         		134.5-135.5
    36 (−)
    Figure US20090170835A1-20090702-C00332
    Figure US20090170835A1-20090702-C00333
         		114.5-116.5
    37
    Figure US20090170835A1-20090702-C00334
    Figure US20090170835A1-20090702-C00335
         		118-121
    38
    Figure US20090170835A1-20090702-C00336
    Figure US20090170835A1-20090702-C00337
         		114.5-116  
    39
    Figure US20090170835A1-20090702-C00338
    Figure US20090170835A1-20090702-C00339
         		  85-87.5
    40 (−)
    Figure US20090170835A1-20090702-C00340
    Figure US20090170835A1-20090702-C00341
         		187.5-191  
    41 (−)
    Figure US20090170835A1-20090702-C00342
    Figure US20090170835A1-20090702-C00343
         		  169-169.5
    42 (−)
    Figure US20090170835A1-20090702-C00344
    Figure US20090170835A1-20090702-C00345
         		159.5-160  
    43 (−)
    Figure US20090170835A1-20090702-C00346
    Figure US20090170835A1-20090702-C00347
         		  141-141.5
    44 (−)
    Figure US20090170835A1-20090702-C00348
    Figure US20090170835A1-20090702-C00349
         		165.5-166  
    45
    Figure US20090170835A1-20090702-C00350
    Figure US20090170835A1-20090702-C00351
         		119.5-122  
    46 (−)
    Figure US20090170835A1-20090702-C00352
    Figure US20090170835A1-20090702-C00353
         		162.5-163.5
    47 (−)
    Figure US20090170835A1-20090702-C00354
    Figure US20090170835A1-20090702-C00355
         		143-144
    48 (−)
    Figure US20090170835A1-20090702-C00356
    Figure US20090170835A1-20090702-C00357
         		201.5-202  
    49 (−)
    Figure US20090170835A1-20090702-C00358
    Figure US20090170835A1-20090702-C00359
         		  160-160.5
    50 (−)
    Figure US20090170835A1-20090702-C00360
    Figure US20090170835A1-20090702-C00361
         		200.5-202  
    51 (−)
    Figure US20090170835A1-20090702-C00362
    Figure US20090170835A1-20090702-C00363
         		141.5-148.5
    52 (−)
    Figure US20090170835A1-20090702-C00364
    Figure US20090170835A1-20090702-C00365
         		140.5-141.5
    53 (−)
    Figure US20090170835A1-20090702-C00366
    Figure US20090170835A1-20090702-C00367
         		  128-141.5
    54 (−)
    Figure US20090170835A1-20090702-C00368
    Figure US20090170835A1-20090702-C00369
         		  155-155.5
    55 (−)
    Figure US20090170835A1-20090702-C00370
    Figure US20090170835A1-20090702-C00371
         		142.5-145.5
    56 (−)
    Figure US20090170835A1-20090702-C00372
    Figure US20090170835A1-20090702-C00373
         		162.5-167.5
    57 (−)
    Figure US20090170835A1-20090702-C00374
    Figure US20090170835A1-20090702-C00375
         		  172-172.5
    58 (−)
    Figure US20090170835A1-20090702-C00376
    Figure US20090170835A1-20090702-C00377
         		157.5-159  
    59 (−)
    Figure US20090170835A1-20090702-C00378
    Figure US20090170835A1-20090702-C00379
         		139-143
    60 (−)
    Figure US20090170835A1-20090702-C00380
    Figure US20090170835A1-20090702-C00381
         		180-184
    61 (−)
    Figure US20090170835A1-20090702-C00382
    Figure US20090170835A1-20090702-C00383
         		142.5-143  
    62 (−)
    Figure US20090170835A1-20090702-C00384
    Figure US20090170835A1-20090702-C00385
         		  150-151.5
    63
    Figure US20090170835A1-20090702-C00386
    Figure US20090170835A1-20090702-C00387
         		  140-144.5
    64
    Figure US20090170835A1-20090702-C00388
    Figure US20090170835A1-20090702-C00389
         		120.5-125  
    65
    Figure US20090170835A1-20090702-C00390
    Figure US20090170835A1-20090702-C00391
         		  143-143.5
    66
    Figure US20090170835A1-20090702-C00392
    Figure US20090170835A1-20090702-C00393
         		195.5-196.5 (1-hydrochloride salt)
    67
    Figure US20090170835A1-20090702-C00394
    Figure US20090170835A1-20090702-C00395
         		123-124
    • EXAMPLE 10 5,6-dimethyl-3-hexyl-2-(3-pyridyl)isoindolin-1-one (10-a) 5,6-dimethyl-3-hexyl-3-hydroxy-2-(3-pyridyl)-isoindolin-1-one
  • Metal magnesium (0.14 g, 5.6 mmol) and 1-bromohexane (0.78 ml, 5.6 mmol) were stirred with heating at 65° C. in anhydrous tetrahydrofuran (24 ml) under an argon atmosphere for 2 hrs, and 5,6-dimethyl-2-(3-pyridyl)isoindolin-1,3-dione (0.40 g, 1.6 mmol) was added thereto, followed by stirring at 25° C. for 15 minutes. The reaction solution was poured into saturated aqueous NH4Cl solution, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:acetone=5:1) to give 0.23 g of 5,6-dimethyl-3-hexyl-3-hydroxy-2-(3-pyridyl)isoindolin-1-one.
  • 1H-NMR (CDCl3) δ: 0.56-1.09 (8H, m, CH2CH 2CH 2CH 2CH 2CH3), 0.73 (3H, t, CH2CH 3), 1.85-2.07 (2H, m, CH 2CH2CH2CH2CH2CH3), 2.27 (3H, s, CH3), 2.38 (3H, s, CH3), 5.20 (1H, br s, OH), 7.22 (1H, dd, PyH), 7.31 (1H, s, C4—H), 7.34 (1H, s, C7—H), 7.96 (1H, ddd, PyH), 8.29 (1H, dd, PyH), 8.78 (1H, d, PyH)
    • (10-b) 5,6-dimethyl-3-hexylidene-2-(3-pyridyl)isoindolin-1-one
  • The product of above-mentioned (10-a) (0.23 g, 0.69 mmol) was added into a mixed solvent of methylene chloride (3.5 ml) and trifluoroacetic acid (1.4 ml), and triethylsilane (0.15 ml, 0.96 mmol) was added dropwise thereto, followed by stirring at 25° C. for 2 hrs. The reaction solution was added into 1N aqueous K2CO3 solution, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:acetone=5:1) to give 91 mg of 5,6-dimethyl-3-hexylidene-2-(3-pyridyl)isoindolin-1-one.
  • 1H-NMR (CDCl3) δ: 0.91 (3H, t, CH2CH 3), 1.32-1.61 (6H, m, CH2CH 2CH 2CH 2CH3), 2.42 (3H, s, CH3), 2.47 (3H, s, CH3), 2.66 (2H, q, ═CHCH 2), 5.47 (1H, t, ═CHCH2), 7.70 (1H, s, C4—H), 7.73 (1H, s, C7—H), 8.04 (1H, dd, PyH), 8.48 (1H, br d, PyH), 8.91 (1H, br d, PyH), 9.00 (1H, br s, PyH)
    • (10-c) 5,6-dimethyl-3-hexyl-2-(3-pyridyl)isoindolin-1-one
  • To a solution of the product of above-mentioned (10-b) (88 mg, 0.27 mmol) in ethanol (10 ml) was added 18 mg of 10% palladium on carbon, and stirred vigorously under a hydrogen atmosphere at 25° C. for 2 hrs. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:acetone=5:1) to give 20 mg of the title compound.
  • 1H-NMR (CDCl3) δ: 0.77 (3H, t, CH2CH 3), 0.77-1.20 (8H, m, CH2CH 2CH 2CH 2CH 2CH3), 1.85-2.02 (2H, m, CH 2CH2CH2CH2CH2CH3), 2.37 (3H, s, CH3), 2.41 (3H, s, CH3), 5.26 (1H, dd, CH), 7.26 (1H, s, C4—H), 7.39 (1H, dd, PyH), 7.68 (1H, s, C7—H), 8.15 (1H, br dd, PyH), 8.45 (1H, br d, PyH), 8.77 (1H, br s, PyH)
    • EXAMPLE 11 5,6-dimethyl-2-(3-pyridyl)-3-(2-oxopentyl)isoindolin-1-one
  • 5,6-dimethyl-3-hydroxy-2-(3-pyridyl)isoindolin-1-one (0.30 g, 1.2 mmol) and 2-oxo-1-triphenylphosphoranylidene-pentane (0.61 g, 1.8 mmol) was heated under reflux in toluene (20 ml) under an argon atmosphere for 20 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:acetone=10:1) to give 0.14 g of the title compound.
  • 1H-NMR (CDCl3) δ: 0.88 (3H, t, CH2CH2CH 3), 1.58 (2H, d sextet, CH2CH 2CH3), 2.33 (2H, t, CH 2CH2CH3), 2.36 (6H, br s, CH3), 2.61 (1H, dd, CH2), 2.99 (1H, dd, CH2), 5.73 (1H, dd, CH), 7.22 (1H, s, C4—H), 7.39 (1H, dd, PyH), 7.68 (1H, s, C7—H), 8.10 (1H, ddd, PyH), 8.47 (1H, br d, PyH), 8.78 (1H, br s, PyH)
    • EXAMPLE 12
  • The compounds shown in Table 4 were obtained according to Example 10 and 11.
  • TABLE 4
    Figure US20090170835A1-20090702-C00396
    melting
    No. R2 L point [° C.]
    1
    Figure US20090170835A1-20090702-C00397
         		CH2CH3   141-150.5 (1-hydro- chloride salt)
    2
    Figure US20090170835A1-20090702-C00398
         		CH2CH2CH2CH2CH2CH3 137.5-139.5
    3
    Figure US20090170835A1-20090702-C00399
    Figure US20090170835A1-20090702-C00400
         		141.5-144  
    4
    Figure US20090170835A1-20090702-C00401
    Figure US20090170835A1-20090702-C00402
         		135-137
    5
    Figure US20090170835A1-20090702-C00403
    Figure US20090170835A1-20090702-C00404
         		118-120
    6
    Figure US20090170835A1-20090702-C00405
    Figure US20090170835A1-20090702-C00406
         		128-131
    • EXAMPLE 13 5,6-dimethyl-2-(3-pyridyl)-3-mesyloxyethylisoindolin-1-one (13-a) 5,6-dimethyl-2-(3-pyridyl)-3-(2-hydroxyethyl)-isoindolin-1-one
  • To a solution of 5,6-dimethyl-3-ethoxycarbonylmethyl-2-(3-pyridyl)isoindolin-1-one [IUPAC name: ethyl 2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetate] (8.4 g, 26 mmol) in methanol (250 ml) was added by portions sodium borohydride (11 g, 0.52 mmol), and the reaction mixture was stirred with heating at 80° C. for 3 hrs. To the reaction solution was added ice-cold water, and the precipitated crystals were collected by filtration, washed with water, and dried to give 6.0 g of 5,6-dimethyl-2-(3-pyridyl)-3-(2-hydroxyethyl)isoindolin-1-one.
  • 1H-NMR (CDCl3) δ: 2.05-2.13 (1H, m, CH 2CH2OH), 2.22-2.30 (1H, m, CH 2CH2OH), 2.38 (3H, s, CH3), 2.41 (3H, s, CH3), 3.53 (2H, t, CH2CH 2OH), 5.42 (1H, dd, CH), 7.35 (1H, s, C4—H), 7.40 (1H, dd, PyH), 7.70 (1H, s, C7—H), 8.16 (1H, ddd, PyH), 8.45 (1H, dd, PyH), 8.81 (1H, d, PyH)
    • (13-b) 5,6-dimethyl-2-(3-pyridyl)-3-mesyloxyethyl-isoindolin-1-one
  • To a solution of the product of above-mentioned (13-a) (5.5 g, 20 mmol) in methylene chloride (140 ml) was added triethylamine (5.4 ml, 29 mmol) and methanesulfonyl chloride (2.4 ml, 21 mmol), and stirred at 25° C. for 2 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give 5.5 g of the title compound.
  • 1H-NMR (CDCl3) δ: 2.32-2.50 (2H, m, CH2CH2O), 2.39 (3H, s, CH3), 2.42 (3H, s, CH3), 2.81 (3H, s, CH3SO2), 3.39-3.94 (1H, m, CH2CH 2O), 4.03-4.09 (1H, m, CH2CH 2O), 5.43 (1H, dd, CH), 7.34 (1H, s, C4—H), 7.42 (1H, dd, PyH), 7.71 (1H, s, C7—H), 8.15 (1H, br dd, PyH), 8.49 (1H, br d, PyH), 8.82 (1H, d, PyH)
    • EXAMPLE 14 5,6-dimethyl-2-(3-pyridyl)-3-(2-propoxyethyl)isoindolin-1-one
  • Metal sodium (6.4 mg, 0.28 mmol) was stirred with heating in propanol (2 ml) at 110° C. for 1 hr, and 5,6-dimethyl-2-(3-pyridyl)-3-mesyloxyethylisoindolin-1-one (50 mg, 0.14 mmol) was added thereto, followed by stirring with heating at 90° C. for 3 hrs. To the reaction solution was added water, and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:ethyl acetate=1:1) to give 12 mg of the title compound.
  • 1H-NMR (CDCl3) δ: 0.85 (3H, t, OCH2CH2CH 3), 1.50 (2H, sextet, OCH2CH 2CH3), 2.03-2.09 (1H, m, CH 2CH2O), 2.20-2.26 (1H, m, CH 2CH2O), 2.37 (3H, s, CH3), 2.40 (3H, s, CH3), 3.17-3.33 (4H, m, CH2CH 2OCH 2CH2CH3), 5.39 (1H, dd, CH), 7.33 (1H, s, C4—H), 7.39 (1H, dd, PyH), 7.69 (1H, s, C7—H), 8.13 (1H, ddd, PyH), 8.46 (1H, dd, PyH), 8.84 (1H, d, PyH)
    • EXAMPLE 15 5,6-dimethyl-2(3-pyridyl)-3[2-(propylamino)ethyl]isoindolin-1-one
  • 5,6-Dimethyl-2-(3-pyridyl)-3-mesyloxyethylisoindolin-1-one (0.11 g, 0.31 mmol) was stirred in n-propylamine (3 ml) at 25° C. for 6 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform methanol=15:1) to give 85 mg of the title compound.
  • 1H-NMR (CDCl3) δ: 0.81 (3H, t, NHCH2CH2CH 3), 1.38 (2H, sextet, NHCH2CH 2CH3), 2.07-2.33 (6H, m, CH 2CH 2NHCH 2CH2CH3), 2.37 (3H, s, CH3), 2.40 (3H, s, CH3), 5.39 (1H, dd, CH), 7.31 (1H, s, C4—H), 7.39 (1H, dd, PyH), 7.68 (1H, s, C7—H), 8.14 (1H, ddd, PyH), 8.44 (1H, dd, PyH), 8.82 (1H, d, PyH)
    • EXAMPLE 16 5,6-dimethyl-2-(4-fluorophenyl)-3-(4-methyl-1-piperazinyl)-ethylisoindolin-1-one
  • A solution of 5,6-dimethyl-2-(4-fluorophenyl)-3-mesyloxyethylisoindolin-1-one (0.27 g, 0.74 mmol), N-methylpiperazine (74 mg, 0.74 mmol) and triethylamine (74 mg, 0.74 mmol) in dichlorometane was stirred at 25° C. for 60 hrs. The reaction solution was washed with water, dried, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=15:1) to give 33 mg of the title compound.
  • 1H-NMR (CD3OD) δ: 1.93-2.34 (12H, m, piperazine and CH 2CH 2), 2.20 (3H, s, NCH3), 2.39 (3H, s, CH3), 2.43 (3H, s, CH3), 5.41 (1H, dd, CH), 7.18-7.23 (2H, m, PhH), 7.42 (1H, s, C4—H), 7.57-7.61 (2H, m, PhH), 7.59 (1H, s, C7—H)
    • EXAMPLE 17 5,6-dimethyl-3-ethylcarbonyloxyethyl-2-(3-pyridyl)-isoindolin-1-one [IUPAC name: 2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]ethyl propionate]
  • A solution of 5,6-dimethyl-2-(3-pyridyl)-3-(2-hydroxyethyl)isoindolin-1-one (50 mg, 0.18 mmol), propionyl chloride (16 mg, 0.18 mmol) and triethylamine (18 mg, 0.18 mmol) in dichlorometane was stirred at 25° C. for 3 hrs. The reaction solution was washed with water, dried, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give 43 mg of the title compound.
  • 1H-NMR (CDCl3) δ: 1.00 (3H, t, CH2CH 3), 2.11 (2H, q, CH 2CH3), 2.20-2.41 (2H, m, CH 2CH2O), 2.38 (3H, s, CH3), 2.41 (3H, s, CH3), 3.76-3.96 (2H, m, CH2CH 2O) 5.37 (1H, dd, CH), 7.30 (1H, s, C7—H), 7.41 (1H, dd, PyH), 7.69 (1H, s, C4—H), 8.18 (1H, br d, PyH), 8.47 (1H, br d, PyH), 8.79 (1H, br s, PyH)
    • EXAMPLE 18
  • The compounds shown in Table 5 were obtained according to Example 14, 15, 16 and 17.
  • TABLE 5
    Figure US20090170835A1-20090702-C00407
    No. R2 L melting point [° C.]
    1
    Figure US20090170835A1-20090702-C00408
         		CH2CH2OH 153-155
    2
    Figure US20090170835A1-20090702-C00409
         		CH2CH2OCH3 200-202 (1-hydrochloride salt)
    3
    Figure US20090170835A1-20090702-C00410
         		CH2CH2OCH2CH3 157-176 (1-hydrochloride salt)
    4
    Figure US20090170835A1-20090702-C00411
         		CH2CH2OCH2CH2CH3 121.5-123.5
    5
    Figure US20090170835A1-20090702-C00412
         		CH2CH2OCH2CH2CH2CH3   95-97.5
    6
    Figure US20090170835A1-20090702-C00413
         		CH2CH2OCH(CH3)2 127-130
    7
    Figure US20090170835A1-20090702-C00414
         		CH2CH2OCH2CH(CH3)2   110-111.5
    8
    Figure US20090170835A1-20090702-C00415
         		CH2CH2OCH2CH2OCH3 94-96
    9
    Figure US20090170835A1-20090702-C00416
         		CH2CH2CH2OCH2OCH3 119-122
    10
    Figure US20090170835A1-20090702-C00417
         		CH2CH2CH2OCH2CH2CH3   108-111.5
    11
    Figure US20090170835A1-20090702-C00418
         		CH2CH2CH2OCH2CH2CH2CH3 white crystals
    12
    Figure US20090170835A1-20090702-C00419
         		CH2CH2NHCH2CH2CH3 117.5-122.5
    13
    Figure US20090170835A1-20090702-C00420
    Figure US20090170835A1-20090702-C00421
         		265.4-269.5 (1-hydrochloride salt)
    14
    Figure US20090170835A1-20090702-C00422
    Figure US20090170835A1-20090702-C00423
         		126.5-128.5
    15
    Figure US20090170835A1-20090702-C00424
         		CH2CH2OCH2CH2CH3 138-140
    • EXAMPLE 19 5,6-dimethyl-2-(4-fluorophenyl)-3-(4-methyl-1-piperazinyl)-carbonylmethylisoindolin-1-thione and 5,6-dimethyl-2-(4-fluorophenyl)-3-(4-methyl-1-piperazinyl)thiocarbonylmethyl-isoindolin-1-thione
  • 5,6-dimethyl-2-(4-fluorophenyl)-3-(4-methyl-1-piperazinyl)carbonylmethylisoindolin-1-one (60 mg, 0.15 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (67 mg, 0.17 mmol) were heated under reflux in toluene (0.5 ml) under an argon atmosphere for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=30:1) to give 14 mg and 25 mg of the title compound, respectively. 5,6-dimethyl-2-(4-fluorophenyl)-3-(4-methyl-1-piperazinyl)-carbonylmethylisoindolin-1-thione
  • 1H-NMR (CDCl3) δ: 2.16-2.42 (4H, m, piperazine), 2.27 (3H, s, NCH3), 2.37 (3H, s, CH3), 2.38 (3H, s, CH3), 2.48 (1H, dd, CH2), 2.73 (1H, dd, CH2), 3.18-3.36 (2H, m, piperazine), 3.49-3.76 (2H, m, piperazine), 5.80 (1H, dd, CH), 7.14-7.24 (2H, m, PhH), 7.33 (1H, s, C4-H), 7.47-7.56 (2H, m, PhH) 7.89 (1H, s, C7-H)
    • 5,6-dimethyl-2-(4-fluorophenyl)-3-(4-methyl-1-piperazinyl)-thiocarbonylmethylisoindolin-1-thione
  • 1H-NMR (CDCl3) δ: 2.09-2.60 (4H, m, piperazine), 2.28 (3H, s, NCH3), 2.37 (3H, s, CH3), 2.38 (3H, s, CH3), 2.87 (1H, dd, CH2), 3.08 (1H, dd, CH2), 3.39-3.55 (2H, m, piperazine), 4.15-4.61 (2H, m, piperazine), 6.31 (1H, dd, CH), 7.15-7.24 (2H, m, PhH), 7.34 (1H, s, C4—H), 7.56-7.66 (2H, m, PhH), 7.90 (1H, s, C7—H)
    • EXAMPLE 20 5,6-dimethyl-3-ethoxycarbonylmethyl-2-(3-pyridyl)-isoindolin-1-thione [IUPAC name: ethyl 2-[5,6-dimethyl-2-(3-pyridinyl)-3-thioxo-2,3-dihydro-1H-isoindol-1-yl]acetate]
  • 5,6-Dimethyl-3-ethoxycarbonylmethyl-2-(3-pyridyl)-isoindolin-1-one [IUPAC name: ethyl 2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetate] (0.10 g, 0.31 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (69 mg, 0.17 mmol) were heated under reflux in toluene (1.5 ml) under an argon atmosphere for 1 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:acetone=10:1) to give 97 mg of the title compound.
  • 1H-NMR (CDCl3) δ: 1.15 (3H, t, CH2CH 3), 2.39 (6H, br s, CH3), 2.65 (1H, dd, CH2), 2.79 (1H, dd, CH2), 3.98-4.05 (2H, m, CH 2CH3), 5.63 (1H, dd, CH), 7.28 (1H, s, C7—H), 7.47 (1H, dd, PyH), 7.91 (1H, s, C4—H), 7.97 (1H, ddd, PyH), 8.65 (1H, dd, PyH), 8.75 (1H, d, PyH)
    • EXAMPLE 21
  • The compounds shown in Table 6 were obtained according to Example 19 and 20.
  • TABLE 6
    Figure US20090170835A1-20090702-C00425
    melting
    No. R2 L point [° C.]
    1
    Figure US20090170835A1-20090702-C00426
    Figure US20090170835A1-20090702-C00427
         		217.5~218.5 (1- hydrochloride salt)
    2
    Figure US20090170835A1-20090702-C00428
    Figure US20090170835A1-20090702-C00429
         		179.5~180   (1- hydrochloride salt)
    3
    Figure US20090170835A1-20090702-C00430
    Figure US20090170835A1-20090702-C00431
         		199.5~202.5
    4
    Figure US20090170835A1-20090702-C00432
    Figure US20090170835A1-20090702-C00433
         		169.5~175  
    5
    Figure US20090170835A1-20090702-C00434
    Figure US20090170835A1-20090702-C00435
         		124~127
    6 (−)
    Figure US20090170835A1-20090702-C00436
    Figure US20090170835A1-20090702-C00437
         		  118~122.5
    • EXAMPLE 22 5,6-dimethyl-2-(4-fluorophenyl)-3-[(E)-2-(4-methyl-1-piperazinyl)-2-oxoethylidene]isoindolin-1-one (22-a) 5,6-dimethyl-3-[(E)-2-ethoxy-2-oxoethylidene]-2-(4-fluorophenyl)isoindolin-1-one [IUPAC name: ethyl 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylidene]acetate]
  • Ethyl (E)-5,6-dimethyl-3-oxo-1,3-dihydroisobenzofuran-1-ylideneacetate (0.20 g, 0.81 mmol) and 4-fluoroaniline (0.10 g, 0.89 mmol) were stirred with heating in acetic acid at 110° C. for 7 hrs. The reaction solution was concentrated under reduced pressure, and methanol was added to the residue. The resulting crystals were collected by filtration, and dried to give 0.24 g of 5,6-dimethyl-3-[(E)-2-ethoxy-2-oxoethylidene]-2-(4-fluoro-phenyl)isoindolin-1-one [IUPAC name: ethyl 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylidene]acetate].
  • 1H-NMR (CDCl3) δ: 1.30 (3H, t, CH2CH 3), 2.42 (3H, s, CH3), 2.46 (3H, s, CH3), 4.23 (2H, q, CH 2CH3), 5.41 (1H, s, CH), 7.21-7.30 (4H, m, PhH), 7.70 (1H, s, C7—H), 8.89 (1H, s, C4—H)
    • (22-b) 5,6-dimethyl-3-[(E)-2-hydroxy-2-oxoethylidene]-2-(4-fluorophenyl)isoindolin-1-one [IUPAC name: 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylidene]acetic acid]
  • 5,6-dimethyl-3-[(E)-2-hydroxy-2-oxoethylidene]-2-(4-fluorophenyl)isoindolin-1-one [IUPAC name: 2-[2-(4-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-ylidene]acetic acid] was obtained from the product of above-mentioned (22-a) according to (1-d) of Example 1.
  • 1H-NMR (DMSO-d6) δ: 2.40 (6H, s, CH3), 5.23 (1H, s, CH), 7.40-7.49 (4H, m, PhH), 7.69 (1H, s, C7—H), 8.84 (1H, s, C4—H)
    • (22-c) 5,6-dimethyl-2-(4-fluorophenyl)-3-[(E)-2-(4-methyl-1-piperazinyl)-2-oxoethylidene]isoindolin-1-one
  • The title compound was obtained from the product of above-mentioned (22-b) according to Example 3.
  • 1H-NMR (CDCl3) δ: 2.28-2.35 (2H, m, piperazine), 2.30 (3H, s, NCH3), 2.39 (3H, s, CH3), 2.40 (3H, s, CH3), 2.46-2.48 (2H, m, piperazine), 3.44-3.46 (2H, m, piperazine), 3.79-3.81 (2H, m, piperazine), 5.54 (1H, s, CH), 7.20-7.25 (2H, m, PhH), 7.31-7.36 (2H, m, PhH), 7.68 (1H, s, C7—H), 7.89 (1H, s, C4—H)
    • EXAMPLE 23
  • The compounds shown in Table 7 were obtained according to Example 22.
  • TABLE 7
    Figure US20090170835A1-20090702-C00438
    melting
    point
    No. R2 L [° C.]
    1
    Figure US20090170835A1-20090702-C00439
    Figure US20090170835A1-20090702-C00440
         		135-139
    2
    Figure US20090170835A1-20090702-C00441
    Figure US20090170835A1-20090702-C00442
         		78-82
    3
    Figure US20090170835A1-20090702-C00443
    Figure US20090170835A1-20090702-C00444
         		151-155
    • EXAMPLE 24
  • The compounds shown in Table 8 were obtained according to Example 1 and 3.
  • TABLE 8
    Figure US20090170835A1-20090702-C00445
    No. M R2 L melting point [° C.]
    1 CH2CH2CH2
    Figure US20090170835A1-20090702-C00446
    Figure US20090170835A1-20090702-C00447
         		182-184
    2 CH2CH2CH2CH2
    Figure US20090170835A1-20090702-C00448
    Figure US20090170835A1-20090702-C00449
         		172-175
    3 CH2OCH2
    Figure US20090170835A1-20090702-C00450
    Figure US20090170835A1-20090702-C00451
         		185-187
    4 OCH2O
    Figure US20090170835A1-20090702-C00452
    Figure US20090170835A1-20090702-C00453
         		185.5-187.5
    5 (−) CH2CH2CH2
    Figure US20090170835A1-20090702-C00454
    Figure US20090170835A1-20090702-C00455
         		63-66
    6 CH═CH—CH═CH
    Figure US20090170835A1-20090702-C00456
    Figure US20090170835A1-20090702-C00457
         		  203-205.5
    • EXAMPLE 25 5,6-dimethyl-2-(3-fluorophenyl)-3-carboxylsoindolin-1-one [IUPAC name: 2-(3-fluorophenyl)-5,6-dimethyl-3-oxo-1-isoindolinecarboxylic acid] (25-a) methyl 4,5-dimethyl-2-formylbenzoate
  • To a solution of 4,5-dimethylphthalic anhydride (1.5 g, 8.5 mmol) in anhydrous tetrahydrofuran (25 ml) was added a 1.0 mol/L solution of tri-tert-butoxy aluminohydride in anhydrous tetrahydrofuran (8.5 ml) under ice cooling and argon atmosphere, and stirred for 1 hr under ice cooling. To the reaction solution was added ice-cold water, and the insoluble materials was filtered off. The filtrate was concentrated under reduced pressure to give crude 5,6-dimethyl-3-hydroxyphthalide. To this was added methyl iodide (12 g, 85 mmol) and K2CO3 (9.4 g, 68 mmol), and heated under reflux in acetone solvent for 5 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform) to give 0.64 g of methyl 4,5-dimethyl-2-formylbenzoate.
  • 1H-NMR (CDCl3) δ: 2.35 (6H, s, CH3), 3.95 (3H, s, CH3), 7.72 (1H, s, PhH), 7.74 (1H, s, PhH), 10.59 (1H, s, C(═O)H)
    • (25-b) methyl 4,5-dimethyl-2-{[(3-fluorophenyl)imino]-methyl}benzoate
  • To a solution of the product of above-mentioned (25-a) (0.64 g, 3.3 mmol) in absolute ethanol (16 ml) was added 3-fluoroaniline (0.37 g, 3.3 mmol), and stirred at 25° C. for 2 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform) to give 0.45 g of methyl 4,5-dimethyl-2-{[(3-fluorophenyl)imino]methyl}benzoate.
  • 1H-NMR (CDCl3) δ: 2.35 (3H, s, CH3), 2.37 (3H, s, CH3), 3.93 (3H, s, CH3), 6.90-7.05 (3H, m, PhH), 7.31-7.36 (1H, m, PhH), 7.78 (1H, s, PhH), 8.00 (1H, s, PhH), 9.20 (1H, s, C(═N)H)
    • (25-c) 5,6-dimethyl-2-(3-fluorophenyl)-3-cyanoisoindolin-1-one [IUPAC name: 2-(3-fluorophenyl)-5,6-dimethyl-3-oxo-1-isoindolinecarbonitrile]
  • The product of above-mentioned (25-b) (0.45 g, 1.6 mmol), cyanotrimethylsilane (0.40 ml, 3.2 mmol) and aluminum chloride (13 mg) were stirred in anhydrous benzene (5.5 ml) at 25° C. for 20 hrs under an argon atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was washed with petroleum ether to give 0.35 g of 5,6-dimethyl-2-(3-fluorophenyl)-3-cyano-isoindolin-1-one [IUPAC name: 2-(3-fluorophenyl)-5,6-dimethyl-3-oxo-1-isoindolinecarbonitrile].
  • 1H-NMR (CDCl3) δ: 2.41 (3H, s, CH3), 2.44 (3H, s, CH3), 5.79 (1H, s, CH), 6.96-7.02 (1H, m, PhH), 7.40-7.47 (2H, m, PhH), 7.48 (1H, s, PhH), 7.65-7.70 (1H, m, PhH), 7.73 (1H, s, PhH)
    • (25-d) 5,6-dimethyl-2-(3-fluorophenyl)-3-carboxylsoindolin-1-one [IUPAC name: 2-(3-fluorophenyl)-5,6-dimethyl-3-oxo-1-isoindolinecarboxylic acid]
  • The title compound (24 mg) was obtained from the product (0.34 g, 1.2 mmol) of above-mentioned (25-c) according to (4-d) of Example 4.
    • EXAMPLE 26 5,6-dimethyl-2-(3-fluorophenyl)-3-(4-methyl-1-piperazinyl)-carbonylisoindolin-1-one
  • By using 24 mg of 5,6-dimethyl-2-(3-fluorophenyl)-3-carboxylsoindolin-1-one [IUPAC name: 2-(3-fluorophenyl)-5,6-dimethyl-3-oxo-1-isoindolinecarboxylic acid], 10 mg of the title compound was obtained according to Example 3.
  • melting point: 200-202° C.
  • 1H-NMR (CDCl3) δ: 2.00-2.38 (4H, m, piperazine), 2.20 (3H, s, NCH3), 2.37 (3H, s, CH3), 2.38 (3H, s, CH3), 3.15-3.75 (4H, br m, piperazine), 5.93 (1H, s, CH), 6.85-6.91 (1H, m, PhH), 7.27-7.43 (3H, m, PhH and C4-H), 7.69 (1H, s, C7—H), 7.70-7.75 (1H, m, PhH)
    • EXAMPLE 27 5,6-dimethyl-2-(3-fluorophenyl)-3-(4-methyl-1-piperazinyl)-carbonyloxyisoindolin-1-one
  • A solution of 5,6-dimethyl-2-(3-fluorophenyl)-3-hydroxyisoindolin-1-one (83 mg, 0.31 mmol) in anhydrous dimethylformamide (3 ml) was added to a suspension of 65% sodium hydride (13 mg, 0.34 mmol) in anhydrous dimethylformamide (3 ml), and stirred at 25° C. for 35 minutes. Then, a solution of 1-chlorocarbonyl-4-methylpiperazine (50 mg, 0.31 mmol) in anhydrous dimethylformamide was added thereto, and stirred with heating at 70° C. for 5 hrs. The reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extracting with chloroform. The extract was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=20:1). The resulting crystals were washed with petroleum ether to give 21 mg of the title compound. melting point: 146-148° C.
  • 1H-NMR (CDCl3) δ: 2.38 (3H, s, CH3), 2.40 (3H, s, CH3), 2.73 (3H, s, NCH3), 3.01-3.14 (6H, m, piperazine), 3.18-3.24 (1H, m, piperazine), 3.32-3.38 (1H, m, piperazine), 6.43 (1H, s, CH), 6.85-6.91 (1H, m, PhH), 7.33-7.39 (1H, m, PhH), 7.36 (1H, s, C4—H), 7.66 (1H, s, C7-H), 7.66-7.76 (2H, m, PhH)
    • EXAMPLE 28 5,6-dimethyl-2-(3-fluorophenyl)-3-carboxymethyloxy-isoindolin-1-one [IUPAC name: 2-{[2-(3-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}acetic acid] (28-a) 5,6-dimethyl-2-(3-fluorophenyl)-3-ethoxycarbonyl-methyloxyisoindolin-1-one [IUPAC name: ethyl 2-{[2-(3-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}acetate]
  • To a solution of 5,6-dimethyl-2-(3-fluorophenyl)-3-hydroxyisoindolin-1-one (0.15 g, 0.55 mmol) in anhydrous tetrahydrofuran (5 ml) was added 60% sodium hydride (24 mg, 0.60 mmol), and stirred on ice for 10 minutes. Then, ethyl bromoacetate (67 ml, 0.60 mmol) was added thereto, and stirred at 25° C. overnight. The reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extracting with ethyl acetate. The extract was washed with saturated brine, dried, and concentrated under reduced pressure to give 0.19 g of 5,6-dimethyl-2-(3-fluorophenyl)-3-ethoxycarbonylmethyloxy-isoindolin-1-one [IUPAC name: ethyl 2-{[2-(3-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}-acetate].
  • 1H-NMR (CDCl3) δ: 1.17 (3H, t, CH2CH 3), 2.38 (3H, s, CH3), 2.40 (3H, s, CH3), 3.56 (1H, dd, CH2), 3.73 (1H, dd, CH2), 4.05-4.11 (2H, m, CH 2CH3), 6.52 (1H, s, CH), 6.87-6.95 (1H, m, PhH), 7.33-7.42 (1H, m, PhH), 7.43 (1H, s, C4—H), 7.63-7.82 (2H, m, PhH), 7.66 (1H, s, C7—H)
    • (28-b) 5,6-dimethyl-2-(3-fluorophenyl)-3-carboxymethyloxy-isoindolin-1-one [IUPAC name: 2-{[2-(3-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}acetic acid]
  • The product (0.19 g, 0.53 mmol) of above-mentioned (28-a) and 1N NaOH (0.59 ml) was stirred with heating in methanol (5 ml) at 100° C. The reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extracting with ethyl acetate. The water layer was acidified with concentrated hydrochloric acid, extracted with ethyl acetate. The extract was washed with water, followed by saturated NaCl solution, dried, and concentrated under reduced pressure to give 0.15 g of the title compound.
    • EXAMPLE 29 5,6-dimethyl-2-(3-fluorophenyl)-3-[2-(4-methyl-1-piperazinyl)-2-oxoethoxy]isoindolin-1-one
  • By using 0.15 g of 5,6-dimethyl-2-(3-fluorophenyl)-3-carboxymethyloxyisoindolin-1-one [IUPAC name: [2-{[2-(3-fluorophenyl)-5,6-dimethyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}acetic acid], 0.16 g of the title compound was obtained according to Example 3. melting point: 196-197° C.
  • 1H-NMR (CDCl3) δ: 2.15-2.37 (4H, m, piperazine), 2.25 (3H, s, NCH3), 2.38 (3H, s, CH3), 2.40 (3H, s, CH3), 3.01-3.15 (2H, m, piperazine), 3.36-3.46 (1H, m, piperazine), 3.54-3.64 (2H, m, piperazine and CH2), 3.80 (1H, dd, CH2), 6.58 (1H, s, CH), 6.88-6.93 (1H, m, PhH), 7.35-7.41 (1H, m, PhH), 7.43 (1H, s, C4—H), 7.63-7.77 (2H, m, PhH), 7.67 (1H, s, C7—H)
    • EXAMPLE 30 (+)-5,6-dimethyl-3-propoxycarbonylmethyl-2-(3-pyridyl)-isoindolin-1-one [IUPAC name: propyl (+)-2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetate] and (−)-5,6-dimethyl-3-propoxycarbonylmethyl-2-(3-pyridyl)-isoindolin-1-one [IUPAC name: propyl (−)-2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetate] (30-a) (+)-5,6-dimethyl-3-carboxymethyl-2-(3-pyridyl)-isoindolin-1-one [IUPAC name: (+)-2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetic acid] and (−)-5,6-dimethyl-3-carboxymethyl-2-(3-pyridyl)isoindolin-1-one [IUPAC name: (−)-2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetic acid]
  • Racemic 5,6-dimethyl-3-carboxymethyl-2-(3-pyridyl)-isoindolin-1-one [IUPAC name: 2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetic acid] was reacted with (−)-phenylethylamine to form a salt, and the salt was subjected to fractional recrystallization using ethanol. The resulting salt was treated with 1N hydrochloric acid to give (+)-5,6-dimethyl-3-carboxymethyl-2-(3-pyridyl)isoindolin-1-one [IUPAC name: (+)-2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetic acid] specific optical rotation [α]29 D=+ 108.6° (c=1.0, chloroform:methanol=1:1)
  • By using (+)-phenylethylamine, (−)-5,6-dimethyl-3-carboxymethyl-2-(3-pyridyl)isoindolin-1-one [IUPAC name: (−)-2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetic acid] was obtained according to the above-mentioned method.
  • specific optical rotation [α]29 D=−106.4° (c=1.0, chloroform:methanol=1:1)
    • (30-b) (+)-5,6-dimethyl-3-propoxycarbonylmethyl-2-(3-pyridyl)isoindolin-1-one [IUPAC name: propyl (+)-2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetate] and (−)-5,6-dimethyl-3-propoxycarbonylmethyl-2-(3-pyridyl)isoindolin-1-one [IUPAC name: propyl (−)-2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetate]
  • By using above-mentioned products of (+) isomer and (−) isomer respectively, optically active title compounds were obtained according to Example 8.
  • (+)-5,6-dimethyl-3-propoxycarbonylmethyl-2-(3-pyridyl)-isoindolin-1-one [IUPAC name: propyl (+)-2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetate] specific optical rotation [α]28 D=+106.3° (c=1.0, chloroform)
    (−)-5,6-dimethyl-3-propoxycarbonylmethyl-2-(3-pyridyl)-isoindolin-1-one [IUPAC name: propyl (−)-2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetate] specific optical rotation [α]29 D=−101.9° (c=1.0, chloroform)
    • EXAMPLE 31 Preparation for Injection (31-a) Hydrochloride (15 mg) of (−) isomer of the compound in Example 3 and sodium chloride (45.0 mg) were dissolved in distilled water for injection, and the total volume was made up to 5.0 ml. The aqueous solution was filtered under sterile conditions to give a transparent injectable solution. (31-b) Hydrochloride (15 mg) of (−) isomer of the compound in Example 3 and glucose (250.0 mg) were dissolved in distilled water for injection, and the total volume was made up to 5.0 ml. The aqueous solution was filtered under sterile conditions to give a transparent injectable solution. Pharmacological Test Example
  • The anesthetic effects of the compounds of the present invention were evaluated.
  • The compounds obtained in the above examples were used. Hydrochloride salt of the compound was dissolved in saline to give the test composition. Some compounds, of which hydrochloride salts were not water-soluble, were dissolved in water in the presence of solubilizer, hydroxypropyl-β-cyclodextrin.
  • The respective test composition was administrated to mice via the tail vein and the anesthetic effect was evaluated by occurrence and duration of loss of righting reflex. Results are shown in Table 9.
  • TABLE 9
    Compound No. Anesthetic activity
    Table 1 No. 2 +
    Table 1 No. 5 + +
    Table 2 No. 1 + + +
    Table 2 No. 2 + + +
    Table 2 No. 3 + +
    Table 2 No. 4 + +
    Table 2 No. 5 + +
    Table 2 No. 6 +
    Table 2 No. 7 + + +
    Table 2 No. 8 + + +
    Table 2 No. 12 + +
    Table 2 No. 13 + +
    Table 2 No. 15 +
    Table 2 No. 17 + + +
    Table 2 No. 20 + + +
    Table 2 No. 21 + +
    Table 2 No. 24 +
    Table 2 No. 28 + + +
    Table 2 No. 29 + + +
    Table 2 No. 31 + +
    Table 2 No. 33 + + +
    Table 2 No. 34 + +
    Table 2 No. 35 +
    Table 2 No. 36 + + +
    Table 2 No. 37 +
    Table 2 No. 38 + +
    Table 2 No. 39 + +
    Table 2 No. 40 + + +
    Table 2 No. 41 + +
    Table 2 No. 42 + + +
    Table 2 No. 44 + + +
    Table 2 No. 45(-) + +
    Table 2 No. 48 + +
    Table 2 No. 52 + + +
    Table 2 No. 53 + +
    Table 2 No. 55 + +
    Table 2 No. 56(-) + +
    Table 2 No. 60 +
    Table 2 No. 62 +
    Table 2 No. 63 +
    Table 2 No. 66 +
    Table 2 No. 67 +
    Table 2 No. 68 +
    Table 2 No. 87 + + +
    Table 3 No. 4 +
    Table 3 No. 6 + + +
    Table 3 No. 7 +
    Table 3 No. 14 + +
    Table 3 No. 15 +
    Table 3 No. 19 + +
    Table 3 No. 23 + +
    Table 3 No. 27 + +
    Table 3 No. 28(-) + +
    Table 3 No. 29(-) + +
    Table 3 No. 38 +
    Table 3 No. 39 + +
    Table 3 No. 49(-) + + +
    Table 3 No. 52(-) + +
    Table 3 No. 54(-) + +
    Table 3 No. 56(-) + + +
    Table 3 No. 57(-) + +
    Table 4 No. 2 + +
    Table 4 No. 5 + +
    Table 5 No. 2 +
    Table 5 No. 3 + +
    Table 5 No. 4 + + +
    Table 5 No. 5 + + +
    Table 5 No. 6 +
    Table 5 No. 7 + + +
    Table 5 No. 10 + +
    Table 6 No. 1 + +
    Table 6 No. 2 + +
    Table 6 No. 4 +
    Table 7 No. 1 + + +
    Table 8 No. 1 + + +
    Table 8 No. 3 + + +
    Table 8 No. 4 + + +
    Table 8 No. 5(-) + + +
    Propofol + + +
    ThiopentalSodium + +
  • Therapeutic index (T.I.) of the compound was determined. The HD50 value, the minimum dose at which at least 30 seconds loss of righting reflex were observed in 50% of the injected mice, and the LD50 value, the 50% lethal dose were determined. Then the T.I. of LD50/HD50 was obtained. Results are shown in Table 10. For the comparison purpose, the T.I. of clinically used intravenous anesthetics, propofol and thiopental sodium, which were disclosed in Japanese Patent Application Laid Open No. 50-154410, are shown in the table.
  • TABLE 10
    Figure US20090170835A1-20090702-C00458
    R2 L HD50 (mg/kg) LD50 (mg/kg) T.I. (mouse)
    racemic
    Figure US20090170835A1-20090702-C00459
    Figure US20090170835A1-20090702-C00460
         		6.92 92.00 13.29
    (+) 25.13 >120 >4.78
    (−) 1.90 64.69 34.05
    (−)
    Figure US20090170835A1-20090702-C00461
    Figure US20090170835A1-20090702-C00462
         		10.00 >120 >12.00
    (−)
    Figure US20090170835A1-20090702-C00463
    Figure US20090170835A1-20090702-C00464
         		12.61 >120 >9.52
    racemic
    Figure US20090170835A1-20090702-C00465
    Figure US20090170835A1-20090702-C00466
         		27.10 >100 >3.69
    (+) 75.35 >120 >1.59
    (−) 20.47 >120 >5.86
    (−)
    Figure US20090170835A1-20090702-C00467
    Figure US20090170835A1-20090702-C00468
         		23.07 >120 >5.20
    (−)
    Figure US20090170835A1-20090702-C00469
         		CH2CH2OCH2CH3 14.51 >120 >8.27
    (−)
    Figure US20090170835A1-20090702-C00470
         		CH2CH2OCH2CH2CH3 14.33 >120 >8.37
    (−)
    Figure US20090170835A1-20090702-C00471
         		2.17 120 55.30
    Propofol 13.5 56 4.14
    Thiopental Sodium 23.5 100 4.26
  • As shown in table 10, the 50% lethal dose (LD50) of the test compound is much higher than the HD50, which is an indicator of the anesthetic action, and the highest LD50 among the test compounds was more than 120 mg/kg (i.v.). This means that the anesthetic composition of the invention has a very wide safety margin. Propofol and thiopental sodium, most popular anesthetics, have significantly narrower safety margins.
  • Anesthesia induction time, the time from the complete injection of the compound (2×HD50) to loss of righting reflex, and after wake-up recovery time, the time from righting reflex was back to normal to the animal started to move spontaneously were determined. The results are shown in Table 11.
  • TABLE 11
    Figure US20090170835A1-20090702-C00472
    Anaesthetic after wake-up
    R2 L induction time recovery time
    (−)
    Figure US20090170835A1-20090702-C00473
    Figure US20090170835A1-20090702-C00474
         		0′00″ 6′44″
    (−)
    Figure US20090170835A1-20090702-C00475
    Figure US20090170835A1-20090702-C00476
         		0′23″ 4′24″
    racemic
    Figure US20090170835A1-20090702-C00477
    Figure US20090170835A1-20090702-C00478
         		0′13″ 3′32″
    (−)
    Figure US20090170835A1-20090702-C00479
    Figure US20090170835A1-20090702-C00480
         		0′02″ 1′08″
    Propofol 0′08″ 4′02″
  • As shown in table 11, the isoindoline derivatives of the invention can provide rapid induction and recovery from anesthesia.

Claims (13)

1. A compound represented by formula (I):
Figure US20090170835A1-20090702-C00481
wherein R1s are the same or different 2 groups, each of them is selected from the group consisting of C1-3 alkyl;
X is oxygen or sulfur;
R2 is selected from the group consisting of phenyl, benzyl, pyridyl, pyridylmethyl, pyrimidinyl, cyclohexyl, methylpiperazinyl, indanyl, 1,3-benzodioxolyl and naphthyl, all of which may optionally be substituted; provided that when R2 is phenyl, the 3- and 4-positions of the phenyl moiety are not substituted by alkoxy groups at the same time;
Figure US20090170835A1-20090702-P00003
represents a single bond or double bond; and
L is
Figure US20090170835A1-20090702-C00482
wherein W is oxygen or sulfur atom, A is a group represented by formula (J)
Figure US20090170835A1-20090702-C00483
wherein R3 is selected from the group consisting of hydrogen, linear or branched C1-8 alkyl, C1-3 alkyl substituted by at least one fluorine atoms, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexylmethyl, benzyl, 2-pyridyl and 2-pyrimidinyl groups,
n″ is an integer of 0-3; or
Figure US20090170835A1-20090702-C00484
wherein R3 is as defined above;
or a salt thereof.
2. The compound of claim 1, wherein R1s are selected from the group consisting of methyl and ethyl.
3. The compound of claim 2, wherein R1 is 5,6-dimethyl.
4. The compound of claim 1, wherein R2 is an optionally substituted phenyl or an optionally substituted pyridyl.
5. The compound of claim 1, which is represented by the formula
Figure US20090170835A1-20090702-C00485
wherein R2 is
Figure US20090170835A1-20090702-C00486
wherein R4 is selected from the group consisting of C1-5 alkyl, optionally substituted phenyl and optionally substituted benzyl, and L is
Figure US20090170835A1-20090702-C00487
6. An anesthetic composition for inducing sedative effect and anesthesia in a mammal, comprising an anesthetic effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
7. The composition of claim 6, which is for intravenous injection.
8. A method for inducing sedative effect and anesthesia in a mammal, comprising the step of administering an anesthetic effective amount of the compound of claim 1 to the subject in need of anesthesia.
9. The compound of claim 1, wherein L is
Figure US20090170835A1-20090702-C00488
wherein A, W and n″ are the same as those defined in claim 1.
10. The compound of claim 9, wherein R3 is methyl or isopropyl.
11. The compound of claim 9, which is represented by the formula:
Figure US20090170835A1-20090702-C00489
wherein R2 and L are selected from the following combinations:
R2 L
Figure US20090170835A1-20090702-C00490
Figure US20090170835A1-20090702-C00491
Figure US20090170835A1-20090702-C00492
Figure US20090170835A1-20090702-C00493
Figure US20090170835A1-20090702-C00494
Figure US20090170835A1-20090702-C00495
Figure US20090170835A1-20090702-C00496
Figure US20090170835A1-20090702-C00497
Figure US20090170835A1-20090702-C00498
Figure US20090170835A1-20090702-C00499
Figure US20090170835A1-20090702-C00500
Figure US20090170835A1-20090702-C00501
Figure US20090170835A1-20090702-C00502
Figure US20090170835A1-20090702-C00503
Figure US20090170835A1-20090702-C00504
Figure US20090170835A1-20090702-C00505
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 1, wherein L is
Figure US20090170835A1-20090702-C00506
wherein R3 is the same as that defined in claim 1.
13. The compound of claim 12, which is represented by the formula:
Figure US20090170835A1-20090702-C00507
wherein R2 and L are selected from the following combinations:
R2 L
Figure US20090170835A1-20090702-C00508
Figure US20090170835A1-20090702-C00509
Figure US20090170835A1-20090702-C00510
Figure US20090170835A1-20090702-C00511
or a pharmaceutically acceptable salt thereof.
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PL376890A1 (en) 2006-01-09
PT1566378E (en) 2012-11-29
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US20060052392A1 (en) 2006-03-09
TW200416218A (en) 2004-09-01

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