WO2001030745A1 - Derives d'acide anthranilique utilises comme inhibiteurs de la cgmp-phosphodiesterase - Google Patents

Derives d'acide anthranilique utilises comme inhibiteurs de la cgmp-phosphodiesterase Download PDF

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WO2001030745A1
WO2001030745A1 PCT/JP2000/007308 JP0007308W WO0130745A1 WO 2001030745 A1 WO2001030745 A1 WO 2001030745A1 JP 0007308 W JP0007308 W JP 0007308W WO 0130745 A1 WO0130745 A1 WO 0130745A1
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group
cyano
optionally substituted
compound
nmr
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PCT/JP2000/007308
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English (en)
Inventor
Kozo Sawada
Akio Kuroda
Natsuko Kayakiri
Yasuharu Urano
Yuki Sawada
Tsuyoshi Mizutani
Teruo Oku
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Fujisawa Pharmaceutical Co., Ltd.
Oku, Noriko
Oku, Chikako
Oku, Tomohito
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Application filed by Fujisawa Pharmaceutical Co., Ltd., Oku, Noriko, Oku, Chikako, Oku, Tomohito filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to AU79516/00A priority Critical patent/AU7951600A/en
Publication of WO2001030745A1 publication Critical patent/WO2001030745A1/fr

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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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    • A61K31/275—Nitriles; Isonitriles
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by oxygen atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
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    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/59—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
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    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
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    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • This invention relates to novel anthranilic acid derivatives having pharmacological activity, to a process for their production, to a pharmaceutical composition containing the same, and to their use as a medicament.
  • cGMP cyclic guanosine-3',5'-monophosphate
  • cGMP-PDE 5 cyclic guanosine-3',5'-monophosphate phosphodiesterase
  • This invention relates to novel anthranilic acid derivatives, which have pharmacological activity such as inhibiting activity of cGMP-PDE, to a process for their production, to a pharmaceutical composition containing the same and to a use thereof.
  • an object of this invention is to provide the novel 0 anthranilic acid derivatives, which have an inhibitory activity of cGMP-
  • Another object of this invention is to provide a process for production of the anthranilic acid derivatives.
  • a further object of this invention is to provide a pharmaceutical 5 composition containing, as an active ingredient, the anthranilic acid derivatives.
  • Still further object of this invention is to provide a use of the anthranilic acid derivatives for treating or preventing various diseases.
  • the new anthranilic acid derivatives of this invention are represented by the following formula [I] :
  • R 1 is nitro group, amino group, cyano group, an acyl group, a halo (lower) alkyl group, sulfamoyl group, a carbamoyl group optionally substituted with lower alkyl, a halogen atom, a lower alkenyl group optionally substituted with protected carboxy, a lower alkane sulfonyl group, a saturated heterocyclic sulfonyl group optionally substituted with protected carboxy or an unsaturated heterocyclic group,
  • R 2 is hydrogen atom, hydroxy group, a lower alkoxy group, a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group or a heterocyclic group optionally substituted with lower alkyl,
  • A is a lower alkylene group
  • R 3 is an optionally substituted heterocyclic group or a group of the formula : -CR 4 R 5 R 6 , in which R 4 and R 5 are each independently a carbamoyl group or a lower alkyl group optionally substituted with one or more substituent(s) selected from the group consisting of hydroxy group and an amino group optionally substituted with acyl, protected carboxy, carbamoyl or lower alkylcarbamoyl, or R 4 and R 5 together with the carbon atom to which R 4 and R 5 are attached may form an optionally substituted carbocyclic group, and R 6 is hydrogen atom or a lower alkyl group.
  • the object compounds [I] or their salts can be prepared by the following processes:
  • a ring( ⁇ ) is a carbocyclic group
  • Y is cycloalkylidene
  • R 1 , R 2 , R 3 , R 4 , R 5 and A are the same as those defined in the above.
  • Process A Some of the starting materials are novel and can be prepared by the following processes: Process A
  • R is lower alkyl
  • R 1 , R 2 , R 3 and A are the same as those defined in the above.
  • lower is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise indicated.
  • Suitable lower alkyl groups and lower alkyl moieties in the terms of the lower alkanesulfonyl, lower alkylcarbamoyl, lower alkoxy, lower alkylthio and hydroxy (lower) alkyl groups may include straight or branched ones having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl or the like, more suitably the ones having 1 to 4 carbon atom(s) such as methyl, ethyl, propyl, isopropyl, butyl or isobutyl.
  • Suitable lower alkenyl groups may include straight or branched ones having 2 to 6 carbon atoms, such as ethenyl, propenyl [i.e., allyl or 1-propenyl], butenyl, isobutenyl, pentenyl, hexenyl or the like.
  • Suitable lower alkylene groups and lower alkylene moieties in the terms of the lower alkylenedioxy groups may include straight or branched ones having 1 to 6 carbon atom(s), such as methylene, methylmethylene, ethylene, methylethylene, tri ethylene, tetramethylene, 2-methyltrimethylene, pentamethylene, hexamethylene or the like, more suitably the ones having 1 to 3 carbon atom(s).
  • Suitable acyl groups and acyl moieties in the terms of the acyloxy groups may include aliphatic acyl groups such as lower alkanoyl groups [e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl or pivaloyl] and acyl groups containing an aromatic or heterocyclic ring such as aroyl groups [e.g., benzoyl, toluoyl, xyloyl or naphthoyl], ar (lower) alkanoyl groups [e.g., phenylacetyl or phenylpropionyl], ar (lower) alkoxycarbonyl groups [e.g., benzyloxycarbonyl or phenethyloxycarbonyl] , heterocyclic carbonyl groups [e.g., thenoyl or furoyl] and the like.
  • aroyl groups e.g
  • Suitable cycloalkyl groups and cycloalkyl moieties in the terms of the cycloalkylidene and cycloalkylidenedioxy groups may include the ones having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like.
  • Suitable aryl groups and aryl moieties in the terms of the aryloxy groups may be phenyl, naphthyl, indenyl, azulenyl, biphenylenyl, fiuorenyl, anthracenyl or the like, in which more preferable ones are phenyl or naphthyl.
  • the carbocyclic groups includes saturated and unsaturated carbocyclic groups.
  • Suitable saturated carbocyclic groups are the cycloalkyl groups as exemplified in the above.
  • Suitable unsaturated carbocyclic groups may include cycloalkenyl groups [e.g., cyclopentenyl, cyclohexenyl or cycloheptenyl], 2,3-dihydro-lH-indenyl, benzocyclohexyl and the like.
  • cycloalkenyl groups e.g., cyclopentenyl, cyclohexenyl or cycloheptenyl
  • 2,3-dihydro-lH-indenyl benzocyclohexyl and the like.
  • Suitable halogen atoms and halo moieties of halo (lower) alkyl groups may be fluorine, chlorine, bromine or iodine.
  • the heterocyclic groups include saturated and unsaturated heterocyclic groups.
  • Suitable unsaturated heterocyclic groups may include mono- or poly-cyclic groups containing at least one hetero atom selected from nitrogen, sulfur and oxygen atoms, such as
  • Suitable saturated heterocyclic groups may include monocyclic groups containing at least one hetero atom selected from nitrogen, sulfur and oxygen atoms, such as
  • Suitable substituents on the aryl groups in the terms of the optionally substituted aryl groups may be a lower alkyl group, a halo (lower) alkyl group, a lower alkylthio group, a halogen atom, hydroxy group, a lower alkylenedioxy group, cyano group, nitro group, carboxy group, a protected carboxy group, sulfamoyl group, an acyl group, an aryl group, an ar(lower)alkoxy group (e.g., benzyloxy, 4- methoxybenzyloxy, 4-nitrobenzyloxy, phenethyloxy, trityloxy, bis(methoxyphenyl)methoxy, 3,4-dimethoxybenzyloxy or 4-hydroxy-3,5- di-tert-butylbenzyloxy), an aryloxy group, a lower alkoxy group optionally substituted with lower alkoxy or cycloalkyl, an amino group
  • Suitable substituents on the heterocyclic groups in the terms of optionally substituted heterocyclic groups may be oxo group, an acyl group, a protected carboxy group, a lower alkanesulfonyl group, a sulfamoyl group optionally substituted with protected carboxy, an ar (lower) alkyl group [e.g., benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, trityl, bis(methoxyphenyl)methyl, 3,4-dimethoXybenzyl or 4- hydroxy-3,5-di-tert-butylbenzyl], a lower alkyl group optionally substituted with hydroxy or aryl, an ureido group optionally substituted with lower alkyl, a guanidino group optionally substituted with protected carboxy, an amidino group optionally substituted with protected carboxyl, or a carbamoyl group optionally substituted with lower al
  • Suitable substituents on the carbocyclic groups in the terms of optionally substituted carbocyclic groups may be a lower alkyl, a halogen atom, hydroxy group, a lower alkoxy group, a protected hydroxy group, carboxy group, a protected carboxy group, oxo group, an amidino group optionally substituted with protected carboxy, an ureido group optionally substituted with lower alkyl or aryl, a guanidino group optionally substituted with protected carboxy, an amino group optionally substituted with acyl, lower alkanesulfonyl or protected carboxy, a carbamoyl group optionally substituted with lower alkyl, a hydroxy (lower) alkyl group, a lower alkylenedioxy group optionally substituted with oxo or a cycloalkylidenedioxy group.
  • Suitable protected carboxy groups may include lower alkoxycarbonyl groups [e.g., methoxycarbonyl, ethoxycarbonyl or tert- butoxycarbonyl], halo (lower) alkoxycarbonyl groups [e.g., 2- iodomethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl], optionally substituted ar(lower) alkoxycarbonyl groups [e.g., benzyloxycarbonyl, trityloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4- nitrobenzyloxycarbonyl, phenethyloxycarbonyl, bis(methoxyphenyl)methoxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl or 4-hydroxy-3,5-di-tert-butylbenzyloxycarbonyl], aryloxycarbonyl groups [e.g., phenyloxycarbonyl, naphthyloxycarbonyl
  • Suitable protected hydroxy groups may include acyloxy groups, cyclo (lower) alkenyloxy groups [preferable examples are cyclo C3-C6 alkenyloxy groups such as cyclopentenyloxy or cyclohexenyloxy], ar (lower) alkoxy groups optionally substituted with one or more suitable substituent(s), trisubstituted silyloxy groups [e.g., trimethylsilyloxy or tert-butyldimethylsilyloxy], tetrahydropyranyloxy groups and the like.
  • Suitable halo (lower) alkyl groups may be fluoromethyl, iodomethyl, chloromethyl, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl or the like.
  • the carbamoyl group for R 1 may be substituted with lower alkyl
  • the lower alkenyl group for R 1 may be substituted with protected carboxy
  • the saturated heterocyclic sulfonyl group for R 1 may be substituted with protected carboxy
  • the heterocyclic group for R 2 may be substituted with lower alkyl.
  • Suitable pharmaceutically acceptable salts of the object compounds [I] are conventional non-toxic salts and include a salt with an alkali metal [e.g., sodium or potassium] and an alkaline earth metal [e.g., calcium or magnesium], an ammonia, an organic base [e.g., trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine or
  • N,N'-dibenzylethylenediamine an organic acid [e.g., formic acid, acetic acid, trifluoroacetic acid, maleic acid, tartaric acid, oxalic acid, methane sulfonic acid, benzenesulfonic acid or toluenesulfonic acid], an inorganic acid [e.g., hydrogen chloride, hydrogen bromide, sulfuric acid or phosphoric acid], an amino acid [e.g., arginine, aspartic acid or glutamic acid] or the like.
  • an organic acid e.g., formic acid, acetic acid, trifluoroacetic acid, maleic acid, tartaric acid, oxalic acid, methane sulfonic acid, benzenesulfonic acid or toluenesulfonic acid
  • an inorganic acid e.g., hydrogen chloride, hydrogen bromide, sulfuric acid or phosphoric acid
  • an amino acid
  • Preferred embodiments of the object compounds [I] are those of the formula [I] wherein:
  • R 1 is nitro group, amino group, cyano group, an acyl group, a halo (lower) alkyl group, sulfamoyl group, a carbamoyl group optionally substituted with lower alkyl, a halogen atom, a lower alkenyl group optionally substituted with protected carboxy, a lower alkane sulfonyl group, a saturated heterocyclic sulfonyl group optionally substituted with protected carboxy, or an unsaturated heterocyclic group which is 3 to 7-membered, preferably 5 or 6-membered heterocyclic group containing 1 to 4 nitrogen atoms, preferably, nitro group, amino group, cyano group, a halo(lower)alkyl group or a halogen atom;
  • R 2 is hydrogen atom, hydroxy group, a lower alkoxy group, a lower alkyl group, a cycloalkyl group, an aryl group optionally substituted with one
  • R 4 and R 5 together with the carbon atom to which R 4 and R 5 are attached may form a cycloalkyl group or a cycloalkenyl group, each of which may be substituted with one or more substituent(s) selected from the group consisting of a lower alkyl group, hydroxy group, a protected hydroxy group, a lower alkoxy group, an amino group optionally substituted with lower alkanoyl, an ureido group optionally substituted with lower alkyl, a lower alkylenedioxy group optionally substituted with oxo, a d a cycloalkylidenedioxy group, and
  • R 6 is hydrogen atom or a lower alkyl group, and their pro-drugs thereof, and salts thereof.
  • R 1 is nitro group, amino group, cyano group, a halo (lower) alkyl group or a halogen atom
  • R 2 is hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group optionally substituted with one or more substituent(s) selected from the group consisting of a halogen atom, cyano group, a lower alkyl group and a lower alkoxy group, or pyridyl group
  • A is a lower alkylene group and
  • R 3 is a saturated 3 to 7-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) or 1 to 2 oxygen atom(s) optionally substituted with one or more substituent(s) selected from the group consisting of carbamoyl group, sulfamoyl group, a protected carboxy group and a lower alkyl group optionally substituted with hydroxy, or a group of the formula : -CR 4 R 5 R 6 , in which R 4 and R 5 are each independently a carbamoyl group or a lower alkyl group optionally substituted with one or more substituent(s) selected from the group consisting of hydroxy group and an amino group optionally substituted with acyl, protected carboxy, carbamoyl or lower alkylcarbamoyl, or R 4 and R 5 together with the carbon atom to which R 4 and R 5 are attached may form a carbocyclic group optionally substituted with one or more substituent(s) selected from the group consisting of a lower
  • R 6 is hydrogen atom or a lower alkyl group, and their prodrugs, and salts thereof.
  • Still further preferred embodiments of the compounds [I] are those of the formula [I] wherein:
  • R 1 is nitro group, amino group, cyano group, a halo (lower) alkyl group or a halogen atom
  • R 2 is hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group optionally substituted with one or more substituent(s) selected from the group consisting of a halogen atom, cyano group, a lower alkyl group and a lower alkoxy group, or pyridyl group
  • A is a lower alkylene group
  • R 3 is a group of the formula : -CR 4 R 5 R 6 in which R 4 and R 5 together with the carbon atom to which R 4 and R 5 are attached may form a carbocyclic group substituted with one or more substituent(s) selected from the group consisting of a lower alkyl group, hydroxy group, a protected hydroxy group, a lower alkoxy group, an amino group optionally substituted with acyl, an ureido group optionally
  • R 1 is nitro group, amino group, cyano group, a halo (lower) alkyl group or a halogen atom,
  • R 2 is an aryl group substituted with one ore more substituent(s) selected from the group consisting of a halogen atom, cyano group, a lower alkyl group and a lower alkoxy group,
  • A is a lower alkylene group
  • R 3 is a saturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) or 1 to 2 oxygen atom(s) optionally substituted with one or more substituent(s) selected from the group consisting of carbamoyl group, sulfamoyl group, a protected carboxy group and a lower alkyl group optionally substituted with hydroxy, or a group of the formula : -CR 4 R 5 R 6 in which R 4 and R 5 are each independently a carbamoyl group or a lower alkyl group optionally substituted with one or more substituent(s) selected from the group consisting of hydroxy group and an amino group optionally substituted with acyl, protected carboxy, carbamoyl or lower alkylcarbamoyl, or
  • R 4 and R 5 together with the carbon atom to which R 4 and R 5 are attached may form a carbocyclic group optionally substituted with one or more substituent(s) selected from the group consisting of a lower alkyl group, hydroxy group, a protected hydroxy group, a lower-alkoxy group, an amino group optionally substituted with acyl, an ureido group optionally substituted with lower alkyl, a lower alkylenedioxy group optionally substituted with oxo, and a cycloalkylidenedioxy group, and R 6 is hydrogen atom or a lower alkyl group, and their pro-drugs thereof, and salts thereof.
  • substituent(s) selected from the group consisting of a lower alkyl group, hydroxy group, a protected hydroxy group, a lower-alkoxy group, an amino group optionally substituted with acyl, an ureido group optionally substituted with lower alkyl, a lower alkylenedioxy group optionally substituted
  • Still further preferred embodiments of the compounds [I] are those of the formula [I] wherein: R 1 is cyano group or a halo (lower) alkyl group,
  • R 2 is a phenyl group substituted with one or two substituent(s) selected from the group consisting of a halogen atom, cyano group and a lower alkoxy group, A is a lower alkylene group, and
  • R 3 is a group of the formula : -CR 4 R 5 R 6 in which
  • R 4 and R s together with the carbon atom to which R 4 and R 5 are attached may form a carbocyclic group substituted with one or two substituent(s) selected from the group consisting of hydroxy group, a lower alkoxy group and a lower alkanoylamino group, and R 6 is hydrogen atom, and a pro-drug thereof, and a salt thereof or R 1 is nitro group, amino group, cyano group, a halo (lower) alkyl group or a halogen atom,
  • R 2 is an aryl group substituted with cyano and optionally further substituted with halogen, cyano, lower alkyl or lower alkoxy
  • A is a lower alkylene group
  • R 3 is a saturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) or 1 to 2 oxygen atom(s) optionally substituted with one or more substituent(s) selected from the group consisting of carbamoyl group, sulfamoyl group, a protected carboxy group and a lower alkyl group optionally substituted with hydroxy, or a group of the formula : -CR 4 R 5 R 6 in which R 4 and R 5 are each independently a carbamoyl group or a lower alkyl group optionally substituted with one or more substituent(s) selected from the group consisting of hydroxy group and an amino group optionally substituted with acyl, protected carboxy, carbamoyl or lower alkylcarb
  • a compound [I] or its salt can be prepared by reacting a compound [II] or its salt with a compound [III] or its salt.
  • Suitable salts of the compounds [II] and [III] can be referred to the ones as exemplified for the compound [I].
  • This reaction is usually carried out in the presence of an inorganic or an organic base.
  • Suitable inorganic base may include an alkali metal [e.g., sodium or potassium], an alkali metal hydroxide [e.g., sodium hydroxide or potassium hydroxide], an alkali metal hydrogen carbonate [e.g., sodium hydrogen carbonate or potassium hydrogen carbonate], an alkali metal carbonate [e.g., sodium carbonate or potassium carbonate], an alkali earth metal carbonate [e.g., calcium carbonate], an alkali metal hydride [e.g., sodium hydride or potassium hydride] and the like.
  • an alkali metal e.g., sodium or potassium
  • an alkali metal hydroxide e.g., sodium hydroxide or potassium hydroxide
  • an alkali metal hydrogen carbonate e.g., sodium hydrogen carbonate or potassium hydrogen carbonate
  • an alkali metal carbonate e.g., sodium carbonate or potassium carbonate
  • an alkali earth metal carbonate e.g., calcium carbonate
  • Suitable organic base may include tri(lower)alkylamine [e.g., triethylamine or N,N-diisopropylethylamine], pyridine, alkyl lithiums [e.g., methyl lithium or butyl lithium], lithium diisopropylamide, lithium hexamethyldisilazido and the like.
  • tri(lower)alkylamine e.g., triethylamine or N,N-diisopropylethylamine
  • alkyl lithiums e.g., methyl lithium or butyl lithium
  • lithium diisopropylamide lithium hexamethyldisilazido and the like.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g., methanol, ethanol or isopropyl alcohol], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, pyridine, N,N-dimethylformamide or any other organic solvent which does not adversely affect the reaction, or a mixture thereof.
  • a conventional solvent such as water, alcohol [e.g., methanol, ethanol or isopropyl alcohol], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, pyridine, N,N-dimethylformamide or any other organic solvent which does not adversely affect the reaction, or a mixture thereof.
  • the reaction is preferably carried out at a temperature under cooling to warming.
  • the reaction temperature is not limited.
  • a compound [I] or its salt can be prepared by reacting a compound [IV] or its reactive derivative at the carboxy group or a salt thereof, with a compound [V] or its reactive derivative at the amino group or a salt thereof.
  • Suitable reactive derivatives at the carboxy group of the compound [IV] may include the acid chloride, azide, acid anhydride, activated amide, activated ester and the like.
  • Suitable acid anhydride may include anhydrides with an acid such as substituted phosphoric acid [e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid or halogenated phosphoric acid], dialkylphosphorous acid, sulfuric acid, thiosulfuric acid, alkanesulfonic acid [e.g., methanesulfonic acid or ethanesulfonic acid], alkanoic acid [e.g., pivalic acid, pentanoic acid or isopentanoic acid], aromatic carboxylic acid [e.g., benzoic acid, chlorobenzoic acid, fluorobenzoic acid or nitrobenzoic acid], or the like.
  • substituted phosphoric acid e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid or halogenated phosphoric acid
  • dialkylphosphorous acid
  • Suitable activated amide may include the imidazolylamide, 4- substituted imidazolylamide, dimethylpyrazolylamide, triazolylamide tetrazolylamide or the like.
  • 2,4-dinitrophenyl ester 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, methanesulfonylphenyl ester, phenyl thioester, p-nitrophenyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, 8-quinolyl thioester, an ester with a N-hydroxy compound [e.g., N,N-dimethylhydroxylamine, 1 -hydroxy- 2 H-pyridone, N- hydroxysuccinimide, N-hydroxybenzotriazole or N-hydroxyphthalimide] or the like.
  • N-hydroxy compound e.g., N,N-dimethylhydroxylamine, 1 -hydroxy- 2 H-pyridone, N- hydroxysuccinimide, N-hydroxybenzotriazo
  • Suitable reactive derivative at the amino group of the compound [V] may include Schiff s base type imino or its tautomeric enamine type isomer formed by the reaction of the compound [V] with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound [V] with a silylating reagent such as trimethylsilylchloride, N,O-bis(trimethylsilyl)acetamide, N- trimethylsilylacetamide or the like.
  • a silyl derivative formed by the reaction of the compound [V] with a silylating reagent such as trimethylsilylchloride, N,O-bis(trimethylsilyl)acetamide, N- trimethylsilylacetamide or the like.
  • Each reactive derivative of the compounds [IN] and [V] can optionally be selected from the above according to the kinds of the compounds [IV] and [V] to be used, respectively.
  • Suitable salts of the compounds [IV] and [V] and their reactive derivatives can be referred to the ones as exemplified for the compound [I].
  • the reaction is preferably carried out in the presence of a condensing agent.
  • Suitable condensing agent may include carbodumide [e.g., ⁇ , ⁇ - dicyclohexylcarbodiimide, N-cyclohexyl-N'-(4- diethylaminocyclohexyl)carbodiimide, N-ethyl-N'- (3- dimethylaminopropyl)carbodiimide, or hydrochloride thereof], diphenylphosphinic azide, diphenylphosphinic chloride, diethylphosphoryl cyanide, bis(2-oxo-3-oxazolidinyl)phosphinic chloride, N,N'-carbonyldiimidazole, 2-ethoxy-l-ethoxycarbonyl-l,2- dihydroquinoline, cyanuric chloride or the like.
  • carbodumide e.g., ⁇ , ⁇ - dicyclohexylcarbodiimide, N-cyclohexyl-N'-(4- die
  • the reaction may be also carried out in the presence of an organic or inorganic base such as an alkali metal carbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine or the like.
  • the reaction is usually carried out in a conventional solvent such as water, acetone, alcohol [e.g., methanol, ethanol or isopropyl alcohol], tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide or any other organic solvent which does not adversely affect the reaction, or a mixture thereof.
  • the reaction is preferably carried out at a temperature under cooling to warming. However, the reaction temperature is not limited.
  • a compound [I-l] or its salt can be prepared by reacting a compound [VI] or its salt with a ketone compound [VII] or its salt in the presence of an inorganic acid [e.g., sulfuric acid or hydrogen chloride] or an organic acid [e.g., acetic acid] and a reducing agent.
  • an inorganic acid e.g., sulfuric acid or hydrogen chloride
  • an organic acid e.g., acetic acid
  • Suitable salts of the compounds [VI] and [VII] can be referred to the ones as exemplified for the compound [I].
  • Suitable reducing agent may include sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, borane-pyridine complex and the like.
  • the reaction is usually carried out in a conventional solvent such as alcohol [e.g., methanol or ethanol], tetrahydrofuran, dioxane, toluene or any other organic solvent which does not adversely affect the reaction, or a mixture thereof.
  • a conventional solvent such as alcohol [e.g., methanol or ethanol], tetrahydrofuran, dioxane, toluene or any other organic solvent which does not adversely affect the reaction, or a mixture thereof.
  • the reaction is preferably carried out at a temperature under cooling to ambient temperature.
  • the reaction temperature is not limited.
  • the ketone compound[VII] its corresponding aldehyde may be used in this reaction.
  • a compound [1-3] or its salt can be prepared by subjecting a compound [1-2] to a hydrolysis reaction.
  • the hydrolysis is preferably carried out in the presence of an acid.
  • Suitable acid may include an organic acid [e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid or trifluoroacetic acid] or an inorganic acid [e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid].
  • organic acid e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid or trifluoroacetic acid
  • an inorganic acid e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid.
  • the reaction is usually carried out in a solvent such as water, an alcohol [e.g., methanol or ethanol], xylene, diethylene glycol monomethyl ether, methylene chloride, tetrahydrofuran, dioxane, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a solvent such as water, an alcohol [e.g., methanol or ethanol], xylene, diethylene glycol monomethyl ether, methylene chloride, tetrahydrofuran, dioxane, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a liquid acid can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • a compound [II] or its salt can be prepared by reacting a compound [VIII] or its reactive derivative at the carboxy group or a salt thereof, with a compound [V] or its reactive derivative at the amino group or a salt thereof.
  • Suitable reactive derivatives at the carboxy group of the compound [VIII] can be referred to the ones as exemplified for the compound [IV].
  • Suitable salts of the compound [VIII] and its reactive derivative can be referred to the ones as exemplified for the compound [I].
  • This reaction can be carried out in a similar manner to Process 2, and therefore, the reaction mode and reaction condition of this reaction are to be referred to those explained in Process 2.
  • a compound [IVa] or its salt can be prepared by reacting a compound [IX] or its salt with a compound [III] or its salt.
  • Suitable salts of the compound [IVa] can be referred to the ones as exemplified for the compound [I].
  • Suitable salts of the compound [IX] can be referred to the acid addition salts as exemplified for the compound [I].
  • Step 2 This reaction can be carried out in a similar manner to Process 1. and therefore, the reaction mode and reaction condition of this reaction are to be referred to those explained in Process 1. (Step 2)
  • a compound [IV] or its salt can be prepared by subjecting a compound [IVa] or its salt to hydrolysis reaction.
  • the hydrolysis is preferably carried out in the presence of a base or an acid.
  • Suitable base may be the same as those exemplified in Process 1.
  • Suitable acid may include an organic acid [e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid or trifluoroacetic acid] or an inorganic acid [e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid] .
  • organic acid e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid or trifluoroacetic acid
  • an inorganic acid e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid
  • the reaction is usually carried out in a solvent such as water, an alcohol [e.g., methanol or ethanol], xylene, diethylene glycol monomethyl ether, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which dose not adversely influence the reaction.
  • a solvent such as water, an alcohol [e.g., methanol or ethanol], xylene, diethylene glycol monomethyl ether, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which dose not adversely influence the reaction.
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • a compound [VI] or its salt can be prepared by reacting a compound [X] or its salt with a compound [V] or its reactive derivative at the amino group or a salt thereof.
  • Suitable salts of the compound [X] can be referred to the acid addition salts as exemplified for the compound [I].
  • This reaction is usually carried out in a conventional solvent such as acetone, tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N,N-dimethylformamide or any other organic solvent which does not adversely affect the reaction, or a mixture thereof.
  • the reaction is preferably carried out at a temperature under cooling to amibient temperature.
  • the reaction temperature is not limited.
  • the object compound [I] and the starting compounds can also be prepared by the methods of Examples mentioned below or similar manners thereto or conventional manners.
  • the compound obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, chromatography, reprecipitation or the like.
  • the compound [I] and the other compounds may include one or more stereoisomer(s) and geometrical isomer (s) due to asymmetric carbon atom(s) and double bond(s), and all of such isomer(s) and mixture thereof are included within the scope of this invention.
  • the compounds of the formula [I] may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
  • isomerization or rearrangement of the compounds [I] may occur by the effect of light, acid, base or the like, and the compounds obtained as the result of said isomerization or rearrangement are also included within the scope of the present invention.
  • the compound of the formula [I] and its salt can be in the form of a solvate, which is included within the scope of the present invention.
  • the solvate preferably includes a hydrate and an ethanolate.
  • a pharmaceutically acceptable salt of the compound [I] can be prepared by treating a compound [I] with an appropriate base or acid in accordance with the conventional method.
  • radiolabelled derivatives of compounds of formula [I] which are suitable for biological studies.
  • the compounds [I] and pharmaceutically acceptable salts thereof possess inhibitory activity of cGMP-PDE, especially PDE-V, relaxant activity of smooth muscle, bronchodilator activity, vasodilative activity, relaxant activity of the penile corpus cavernosum, inhibitory activity of smooth muscle cells proliferation, inhibitory activity of allergy, and so on.
  • the compounds [I] and pharmaceutically acceptable salts thereof are useful for the treatment and/or prevention of various diseases, such as angina, hypertension, pulmonary hypertension, congestive heart failure, glomerular diseases [e.g., diabetic glomerulosclerosis], renal tubulo-interstitial diseases [e.g., nephropathy induced by tacrolimus or cyclosporin], renal failure, atherosclerosis, conditions of reduced blood vessel patency [e.g., post- percutaneous transluminal coronary angioplasty], peripheral vascular disease, stroke, chronic reversible obstructive lung diseases [e.g., bronchitis, asthma [chronic asthma or allergic asthma]], allergic rhinitis, urticaria, glaucoma, diseases characterized by disorders of gut motility [e.g., irritable bowel syndrome], erectile dysfunction [e.g., organic erectile dysfunction or psychic erectile dysfunction], female sexual dysfunction, impotence, or diabetic complications [e
  • the compounds [I] and pharmaceutically acceptable salts thereof are also useful for the treatment and/or prevention of micturition disorder, incontinence or storage of urine disorder such as the ones ascribed to nerve regressive affection, inflammation, injury, neoplasm, diabetes mellitus, cerebral vascular accident, surgery, prostatomegaly, urethra relaxation incompetence or dysuria.
  • the compounds [I] and their salts of the present invention have much advantages, such as stronger activity, more suitable half-life, decreased adverse effect, or the like, compared to the known anthranilic acid derivatives having an inhibitory activity of cGMP-PDE, which are shown in the prior arts.
  • test Method cGMP-Phosphodiesterase (PDE) assay Human platelet cGMP-PDE was separated from other isozymes in human platelets by a modification of the method of Thompson et. al. [see Cyclic Nucleotide Phosphodiesterase (PDE), in Methods of Enzymatic analysis, Vol 4, pl27-234, 1984].
  • enzyme inhibition assays the test compounds were dissolved in DMSO and then diluted with assay buffer (50 mM Tris-HCl, 0.077 mg/ml dithiothreitol and 10 mg/ml snake venom, 1 mM EGTA, pH 8.0), at final concentrations ranging from 10 10 to lO 6 M.
  • Assays were performed at 0.1 ⁇ M substrate ([ 3 H]-cGMP) concentration, at 30 °C for 10 minutes using enzyme dilutions which gave 10-20% hydrolysis of substrate. Each assay was initiated by addition of substrate and terminated by addition of anion exchange resin (Dowex ® 1-X8, 250 mg/mg) followed by centrifugation for 10 minutes (3000 rpm, at 4 °C). Radioactivity of supernatant ( 3 H-GMP) was assayed by liquid scintillation counting.
  • anion exchange resin Dowex ® 1-X8, 250 mg/mg
  • the compounds [I] of the present invention have superior inhibitory activity against cGMP-PDE.
  • the compound [I] or its salt can be administered alone or in a form of a mixture, preferably, with a pharmaceutical vehicle or carrier.
  • the active ingredient of this invention can be used in a form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains a compound [I], as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for oral, parenteral such as intravenous, intramuscular, subcutaneous, intracavernous or intraarticular, external such as topical, intrarectal, transvaginal, inhalant, ophthalmic, nasal or hypoglossal applications.
  • parenteral such as intravenous, intramuscular, subcutaneous, intracavernous or intraarticular
  • external such as topical, intrarectal, transvaginal, inhalant, ophthalmic, nasal or hypoglossal applications.
  • the active ingredient may be compounded, for example, with the conventional non-toxic, pharmaceutically acceptable carriers or excipients for ointment, cream, plaster, tablets, pellets, capsules, suppositories, solution, emulsion, suspension, aerosols, pills, powders, syrups, injections, troches, cataplasms, aromatic waters, lotions, buccal tablets, sublingual tablets, nasal drops and any other form suitable for use.
  • the carriers which can be used are water, olive oil, saline, wax, glucose, lactose, gum acacia, gelatin, mannitol, starch paster, magnesium trisilicate, talc, corn starch, keratin, paraffin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations in solid, semisolid or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
  • the active compound is included in a pharmaceutical composition in an effective amount sufficient to produce the desired effect upon the process or condition of the diseases.
  • the active ingredient may be compounded into , for example, preparations for oral application, preparations for injection, preparations for external application, preparations for inhalation, preparations for application to mucous membranes [e.g., oral mucous membrane, fascia penis, facies urethralis penis, etc.].
  • mucous membranes e.g., oral mucous membrane, fascia penis, facies urethralis penis, etc.
  • Mammals which may be treated by the present invention include humans, livestock mammals such as cows, horses, etc., and domestic animals such as dogs, cats, rats, etc., preferably humans.
  • a daily dose of about 0.01- 1000 mg, preferably 0.1-500 mg and more preferably 0.5-100 mg of the active ingredient is generally given for treating the diseases, and an average single dose of about 0.2-0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg and 500 mg is generally administered.
  • Daily doses for chronic administration in humans will be in the range of about 0.3 mg/body to 1,000 mg/body.
  • N-Butyl-2-(cyclopentylamino)-5-nitrobenzamide (158 mg) was prepared from 2-(cyclopentylamino)-5-nitrobenzoic acid (150 mg) and butylamine (52.6 mg) in a similar manner to Example l-(3) as a yellow powder.
  • N-Cyclohexylmethyl-2-(cyclopentylamino)-5-nitrobenzamide (183 mg) was prepared from 2-(cyclopentylamino)-5-nitrobenzoic acid (150 mg) and aminomethylcyclohexane (81.4 mg) in a similar manner to
  • Example 8 2-(Cyclopentylamino)-5-nitro-N-(4-pyridylmethyl)benzamide (130 mg) was prepared from 2-(cyclopentylamino)-5-nitrobenzoic acid (100 mg) and 4-aminomethylpyridine (51.9 mg) in a similar manner to Example l-(3) as a yellow powder.
  • N-Benzyl-2-(cyclopentylammo)-5-nitrobenzamide (1.36 g) was prepared from 2-(cyclopentylamino)-5-nitrobenzoic acid (1.04 g) and benzyla ine (534 mg) in a similar manner to Example l-(3) as a yellow powder.
  • Example 10 2-Amino-iV-hexyl-5-nitrobenzamide (1.09 g) was obtained as an yellow powder from 5-nitroisatoic anhydride (1.00 g) and hexylamine
  • Methyl 5-cyano-2-cyclopentylaminobenzoate (438 mg) was prepared from methyl 2-amino-5-cyanobenzoate (500 mg) and cyclopentanone (716 mg), in a similar manner to Example 10- (2) as a colorless powder.
  • Example 12 2-Fluoro-N-hexyl-5-trifluoromethylbenzamide (604 mg) was prepared from 2-fluoro-5-trifluoromethylbenzoic acid (500 mg) and hexylamine (292 mg) in a similar manner to Example l-(3) as a colorless powder.
  • Example 14 A mixture of 5-bromoisatoic anhydride (1.0 g) and hexylamine (502 mg) in i ⁇ T,iV-dimethylformamide (10 ml) was stirred for 4 hours at 20°C. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by a silica gel column chromatography eluting with chloroform and recrystallization from a mixture of ethyl acetate and n-hexane to give 2- amino-5-bromo-N-hexylbenzamide (376 mg) as colorless crystals.
  • Example 15 (1) A mixture of (S)-2-benzyloxycarbonylamino- 1 ,4- bis(methanesulfonyloxy)butane (1.49 g) and 2-aminoethanol (2.3 g) was stirred for 2 hours at 40° C. The mixture was concentrated in vacuo, and the residue was partitioned between chloroform and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in v ⁇ cuo to give (S)-3-benzyloxycarbonylamino- l-(2- hydroxy ethyl) pyrrolidine (1.13 g) as an oil.
  • Example 16 N-(3-Chloro-4-methoxybenzyl)-2-fluoro-5-(trifluoromethyl)- benzamide (2.92 g) was obtained from 2-fluoro-5- (trifluoromethyl)benzoic acid (1.76 g) and 3-chloro-4- methoxybenzylamine (1.45 g) in a similar manner to Example l-(3).
  • N-(3-Chloro-4-methoxybenzyl)-2-[(S)- l-(2-hydroxyethyl)pyrrolidin- 3-ylamino]-5-trifluromethylbenzamide (41 mg) was prepared from N-(3- chloro-4-methoxybenzyl)-2-fluoro-5-trifluromethylbenzamide (150 mg) and (S)-3-an ⁇ ino-l-(2-hydroxyethyl)pyrrolidine diacetate (311 mg) in a similar manner to Example 15-(6) as an amorphous powder.
  • Example 17 (1) A solution of di- tert-butyl dicarbonate (5.44 g) in dioxane (10 ml) was added dropwise to a solution of (S)-3- benzyloxycarbonylaminopyrrolidine (3.66 g) in dioxane (10 ml) under cooling on an ice bath. The reaction mixture was stined at ambient temperature overnight, then the reaction was quenched by addition of 3-(N,N-dimethylamino)propylamine (5 ml). The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and 3.6% hydrochloric acid.
  • N-(3-Chloro-4-methoxybenzyl)-2-[(S)-2-hydroxy-l-(methoxycarbonyl- aminomethyl)ethylamino]-5-trifluoromethylbenzamide (107 mg) was prepared from N-(3-chloro-4-methoxybenzyl)-2-fluoro-5- trifluoromethylbenzamide (150 mg) and (S)-2-amino-3-
  • 5-cyano-N-(3,4-d nethoxybenzyl)-benzarnide (1.23 g) was prepared from 5-cyano-N-(3,4-cUmethoxybenzyl)-2-fluorobenzarnide (1 g) and (S)-2- arnino-3-(tert-butoxycarbonylamino)propanol (1.21 g) in a similar manner to Example 12-(2) as white crystals.
  • N-(3-Chloro-4-methoxybenzyl)-2-[(S)-l-(formamidomethyl)-2- hydroxyethylamino]-5-trifluoromethylbenzamide 72 mg was prepared from 2-[(S)- l-(aminomethyl)-2-hydroxyethylamino]-N-(3-chloro-4- methoxybenzyl)-5-trifluoromethylbenzamide (130 mg) in a similar manner to Example 23-(4) as an amorphous powder.
  • N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-fluorobenzamide (36.7 g) was prepared from 5-cyano-2-fluorobenzoic acid (20 g) and 3-chloro-4- methoxybenzylamine (21.2 g) in a similar manner to Example l-(3).
  • Example 28 5-Cyano-2-(t-2,t-3-dihydroxy-r- l-cyclopentylamino)-N-(3,4- dimethoxybenzyl)benzamide (104 mg) was prepared from 5-cyano-2- fluoro-N-(3,4-dimethoxybenzyl)benzamide (125 mg) and t-3-amino-r- l,c-2-cyclopentanediol (98 mg) in a similar manner to Example 12-(2).
  • Example 31 i ⁇ T-(3-Chloro-4-methoxybenzyl)-5-cyano-2-[( 1 S,2S)-2-hydroxy- cyclopentylaminojbenzamide (103 mg) was prepared from iV-(3-chloro- 4-methoxybenzyl)-5-cyano-2-fluorobenzamide (107 mg) and (lS,2S)-2- aminocyclopentanol (181 mg) in a similar manner to Example 12-(2).
  • Example 35 N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-(t-3,t-5-dihydroxy-r- 1- cyclohexylamino)benzamide (149 mg) was prepared from 7V-(3-chloro-4- methoxybenzyl)-5-cyano-2-fluorobenzamide (122 mg) and t-5-amino-r- l,c-3-cyclohexanediol (90 mg) in a similar manner to Example 12-(2).
  • N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-(t-3,t-4-dihydroxy-r-l- cyclopentylamino)benzamide (138 mg) was prepared from N-(3-chloro- 4-methoxybenzyl)-5-cyano-2-fluorobenzamide (125 mg) and t-4-amino- r-l,c-2-cyclopentanediol (69 mg) in a similar manner to Example 12-(2).
  • Example 38 To a solution of N-(3-chloro-4-methoxybenzyl)-5-cyano-2-(t-3,i-4- dihydroxy-r- l-cyclopentylamino)benzamide (88 mg) in 1,2- dichloroethane (5 ml) were added 2,6-di-tert-butyl-4-methylphenol (121 mg) and trimethyloxonium tetrafluoroborate (75 mg), and the mixture was refluxed for 3 hours. The resulting mixture was diluted with ethyl acetate and washed with an aqueous sodium bicarbonate and brine successively.
  • Example 40 5-Cyano-2-(t-3,t-4-dihydroxy-r-l-cyclopentylamino)-iV-(3,4- dimethoxybenzyljbenzamide (140 mg) was prepared from 5-cyano-2- fluoro-iV-(3,4-dimethoxybenzyl)benzamide (128 mg) and t-4-amino-r- l,c-2-cyclopentanediol (62 mg) in a similar manner to Example 12-(2).
  • N-(3-Chloro-4-methoxybenzyl)-2-(t-3 5-dihydroxy-r-l- cyclohexylarnino)-5-trifluorornethylbenzamide (56 mg) was prepared from N-(3-chloro-4-methoxybenzyl)-2-fluoro-5- trifluoromethylbenzamide (156 mg) and t-5-amino-r-l,c-3- cyclohexanediol (74 mg) in a similar manner to Example 12-(2).
  • Example 47 i ⁇ T-(3-Chloro-4-methoxybenzyl)-5-cyano-2-(c-3,c-5-dihydroxy-r- 1- cyclohexylamino)benzamide (55 mg) was prepared from N-(3-chloro-4- methoxybenzyl)-5-cyano-2-fluorobenzamide (98 mg) and c-5-amino-r- l,c-3-cyclohexanediol (48 mg) in a similar manner to Example 12-(2).
  • N-(3-Chloro-4-methoxybenzyl) -2-(c-3 , c-5-dihydroxy- r- 1 - cyclohexylamino)-5-trifluoromethylbenzamide 38 mg was prepared from N-(3-chloro-4-methoxybenzyl)-2-fluoro-5- trifluoromethylbenzamide ( 101 mg) and c-5-amino-r- l,c-3- cyclohexanediol (44 mg) in a similar manner to Example 12-(2).
  • N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-(c-3,c-4-dihydroxy-r-l- cyclopentylamino)benzamide (83 mg) was prepared from N-(3-chloro-4- methoxybenzyl)-5-cyano-2-fluorobenzamide (122 mg) and c-4-amino-r- l,c-2-cyclopentanediol (54 mg) in a similar manner to Example 12-(2).
  • N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-( 1 ,3-dioxan-5- ylamino)benzamide 25 mg was prepared from N-(3-chloro-4- methoxybenzyl)-5-cyano-2-fluorobenzamide (110 mg) and 5-amino-l,3- dioxane (43 mg) in a similar manner to Example 12-(2).
  • Example 53 To a solution of (li?,4S)-l-azido-4-(tert-butyldimethylsilyloxy)-2- cyclopentene (148 mg) in diethyl ether (3 ml) was added a IM solution of lithium aluminum hydride in tetrahydrofuran (0.74 ml), and the mixture was stined for 1 hour at 0°C. The resulting mixture was quenched with a diluted sodium hydroxide solution, filtered through a celite pad and washed with 10% aqueous solution of tetrahydrofuran.
  • N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-[(l J R,4S)-4-hydroxy-2- cyclopenten-l-ylamino]benzamide (77 mg) was prepared from N-(3- chloro-4-methoxybenzyl)-5-cyano-2-fluorobenzamide (96 mg) and (l J R,4S)-l-amino-4-(tert-butyldimethylsilyloxy)-2-cyclopentene (71 mg) in a similar manner to Examples 12-(2) and 44-(4).
  • Example 54 N-(3-Chloro-4-methoxybenzyl)-2-(t-3,t-4-dihydroxy-r- 1- cyclopentyla ⁇ ino)-5-trifluorornethylbenzarnide (149 mg) was prepared from i ⁇ T-(3-chloro-4-methoxybenzyl)-2-fluoro-5- trifluoromethylbenzamide (188 mg) and t-4-amino-r-l,c-2- cyclopentanediol (73 mg) in a similar manner to Example 12-(2). NMR (DMSO-d 6 , ⁇ ): 1.55 (2H, m), 2.12 (2H, m), 3.83 (3H, s), 3.94-4.08
  • Example 55 To a solution of ( 1 S,2R,4R ⁇ - 1 ,2-cyclohexylidenedioxy-4- cyclohexanol (1.62 g) and carbon tetrabromide (2.91 g) in dichloromethane (12 ml) was added triphenylphosphine (2.2 g), and the mixture was stined at ambient temperature for 1 hour. The solvent was evaporated in vacuo and the residue was diluted with ethyl acetate and washed successively with a sodium bicarbonate solution and brine.
  • N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-[(li?,3i?,4S)-3,4- cyclohexylidenedioxycyclohexylamino]benzamide 134 mg was prepared from N-(3-chloro-4-methoxybenzyl)-5-cyano-2-fluorobenzamide (140 mg) and (lS,2i?,4.R)-4-amino-l,2-cyclohexylidenedioxycyclohexane (102 mg) in a similar manner to Example 12-(2).
  • N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-[( 1 S,3R,4S)-3,4- dihydroxycyclohexylamino]benzamide (69 mg) was prepared from N-(3- chloro-4-methoxybenzyl)-5-cyano-2-[( 1 S,3i?,4S)-3,4-cyclohexylidene- dioxycyclohexylaminojbenzarnide (135 mg) in a similar manner to Example 55-(5).
  • Example 58 (1) i ⁇ r-(3-Chloro-4-methylbenzyl)-2-fluoro-5-nitrobenzamide (2.25 g) was prepared from 2-fluoro-5-nitrobenzoic acid (1.65 g) and 3-chloro-4- methylbenzylamine (1.46 g) in a similar manner to Example 66-(l) as a pale yellow powder.
  • Methyl 5-cyano-2-(tr ⁇ ns-4-hydroxycyclohexylamino)- benzoate (1.77 g) was prepared from methyl 5-cyano-2-fluorobenzoate (1.3 g) and tr ⁇ ns-4-aminocyclohexanol (1.25 g) in a similar manner to
  • Example 12-(2) as a yellow powder.
  • Example 62 7V-(3-Chloro-4-methoxybenzyl)-5-cyano-2-[(i?)- l-(hydroxymethyl)- propylaminojbenzamide (158 mg) was prepared from ⁇ T-(3-chloro-4- methoxybenzyl)-5-cyano-2-fluorobenzamide (150 mg) and (J- ⁇ -2-amino- 1-butanol (83.9 mg) in a similar manner to Example 12-(2) as a colorless powder.
  • NMR (DMSO-d 6 , ⁇ ): 0.89 (3H, t, J 7Hz), 1.35-1.54 (IH, br), 1.57- 1.76
  • Example 63 N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-[(S)- l-(hydroxymethyl)- propylamino]benzamide (150 mg) was prepared from N-(3-chloro-4- methoxybenzyl)-5-cyano-2-fluorobenzamide (150 mg) and (S)-2-amino- 1-butanol (83.9 mg) in a similar manner to Example 12-(2) as a colorless powder.
  • NMR (DMSO-d 6 , ⁇ ): 0.89 (3H, t, J 7Hz), 1.35-1.54 (IH, br), 1.57- 1.76
  • N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-(l,l-dimethyl-2-hydroxy- ethyljaminobenzamide (61.6 mg) was prepared from N-(3-chloro-4- methoxybenzyl)-5-cyano-2-fluorobenzamide (150 mg) and 2-amino-2- methyl- 1-propanol (126 mg) in a similar manner to Example 12-(2) as a colorless powder.
  • N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-(cis-4-hydroxycyclohexyl- aminojbenzamide (105 mg) was prepared from 5-cyano-2-(cis-4- hydroxycyclohexylamino)benzoic acid (80.0 mg) and 3-chloro-4- methoxybenzylamine (63.3 mg) in a similar manner to Example l-(3) as a colorless powder.
  • Example 12- (2) 1-propanol (47.1 mg) in a similar manner to Example 12- (2) as a colorless powder.
  • Example 67 N-(4-Chloro-3-methoxybenzyl)-5-cyano-2-[(S)- l-(hydroxymethyl)- propylaminojbenzamide (98.2 mg) was prepared from N-(4-chloro-3- methoxybenzyl)-5-cyano-2-fluorobenzamide (100 mg) and (S)-2-amino- 1-butanol (55.9 mg) in a similar manner to Example 12-(2) as a colorless powder.
  • ⁇ MR (DMSO-d 6 , ⁇ ): 0.88 (3H, t, J 7Hz), 1.38- 1.53 (IH, br), 1.58-1.75
  • Example 68 N-(4-Chloro-3-methoxybenzyl)-5-cyano-2-(l,l-dimethyl-2- hydroxyethylaminojbenzamide (71.9 mg) was prepared from N-(4- chloro-3-methoxybenzyl)-5-cyano-2-fluorobenzamide (150 mg) and 2- amino-2-methyl- 1-propanol (126 mg) in a similar manner to Example 12- (2) as a colorless powder.
  • NMR (DMSO-d 6 , ⁇ ): 1.28 (6H, s), 3.39 (2H, d, J 7Hz), 3.85 (3H, s), 4.41
  • N-(4-Chloro-3-methoxybenzyl)-5-cyano-2-(cis-4-hydroxycyclohexyl- aminojbenzamide (105 mg) was prepared from 5-cyano-2-(cis-4- hydroxycyclohexylamino)benzoic acid (80.0 mg) and 4-chloro-3- methoxybenzylamino (63.3 mg) in a similar manner to Example l-(3) as a colorless powder.
  • Example 79 (1) 5-Cyano-2-fluoro-N-(3-fluoro-4-methoxybenzyl)benzamide (2.48 g) was prepared from 5-cyano-2-fluorobenzoic acid (1.50 g) and 3-fluoro- 4-methoxybenzylamine ( 1.55 g) in a similar manner to Example l-(3) as a colorless powder.
  • Example 82 5-Cyano-N-(3-fluoro-4-methoxybenzyl)-2-[(S)- l-(hydroxymethyl)- propylaminojbenzamide (135 mg) was prepared from 5-cyano-2-fluoro- N-(3-fluoro-4-methoxybenzyl)benzamide (150 mg) and (S)-2-amino-l- butanol (88.5 mg) in a similar manner to Example 12- (2) as a colorless powder.
  • N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-[(lS,3S,4fl)-3,4- cyclohexylidenedioxycyclohexylaminojbenzamide 134 mg was prepared from N-(3-chloro-4-methoxybenzyl)-5-cyano-2-fluorobenzamide (100 mg) and (li?,2S,4S)-4-amino- l,2-cyclohexylidenedioxycyclohexane (66 mg) in a similar manner to Example 12-(2).
  • N-(3-Cyano-4-methoxybenzyl)-2-fluoro-5-(trifluoromethyl)- benzamide (1.5 g) was prepared from 2-fluoro-5-(trifluoromethyl)benzoic acid (1.2 g) and 3-cyano-4-methoxybenzylamine (1.0 g) in a similar manner to Example l-(3) as a white powder.
  • N-(3-Cyano-4-methoxybenzyl)-2-(t-3,t-5-dihydroxy-r- 1-cyclohexyl- amino)-5-trifluoromethylbenzamide 180 mg was prepared from N-(3- cyano-4-methoxybenzyl)-2-fluoro-5-trifluoromethylbenzamide (240 mg) and t-5-amino-r- l,c-3-cyclohexanediol (112 mg) in a similar manner to Example 12- (2).
  • N-(3-Cyano-4-methoxybenzyl)-2-[2-hydroxy-l-(hydroxymethyl)- ethylamino]-5-trifluoromethylbenzamide 180 mg was prepared from N-(3-cyano-4-methoxybenzyl)-2-fluoro-5-trifluoromethylbenzamide (172 mg) and 2-amino- 1 ,3-propanediol (133 mg) in a similar manner to Example 12-(2).
  • N-(3-Chloro-4-methoxybenzyl)-2-[(lS,3S,4 ⁇ )-3,4-cyclohexylidene- dioxycyclohexylamino]-5-trifluorornethylbenzam.ide (183 mg) was prepared from N-(3-chloro-4-methoxybenzyl)-2-fluoro-5- trifluoromethyl-benzamide (120 mg) and (li?,2S,4S)-4-amino-l,2- cyclohexylidenedioxy-cyclohexane (107 mg) in a similar manner to Example 12-(2).
  • N-(3-Chloro-4-methoxybenzyl)-2-[( 1 S,3S,4.R)-3,4-dihydroxycyclo- hexylamino]-5-trifluoromethylbenzamide (91 mg) was prepared from N- (3-chloro-4-methoxybenzyl)-2-[( 1 S,3S,4#)-3,4-cyclohexylidenedioxy- cyclohexylammo]-5-trifluoromethylbenzamide (148 mg) in a similar manner to Example 55-(5).
  • N-(3-Chloro-4-methoxybenzyl)-5-cyanol-2-[(l.R,3S,4.R)-3,4- dihydroxycyclohexylamino]benzamide (69 mg) was prepared from N-(3- chloro-4-methoxybenzyl)-5-cyano-2-fluorobenzamide (90 mg) and (li?,2S,4i?)-4- ⁇ mino- l,2-cyclohexanediol (41 mg) in a similar manner to Example 12-(2).
  • N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-(t-4-hydroxy-t-3-methoxy- r-l-cyclopentylamino)benzamide 38 mg was prepared from N-(3- chloro-4-methoxybenzyl)-5-cyano-2-fluorobenzamide (65 mg) and t-4- amino-c-2-methoxy-r-l-cyclopentanol (26 mg) in a similar manner to
  • N-(3-Chloro-4-methoxybenzyl)-2-[(li?,3i?,4S)-3,4-dihydroxycyclo- hexylamino]-5-trifluoromethylbenzamide (79 mg) was prepared from N- (3-chloro-4-methoxybenzyl)-2-fluoro-5-trifluoromethylbenzamide (122 mg) and (lS,2/?,4i? -4-amino-l,2-cyclohexanediol (49 mg) in a similar manner to Example 12- (2).
  • Example 98 N-(4-Chloro-3-methoxybenzyl)-5-cyano-2-[(li?,3i?,4S)-3,4- dihydroxycyclohexylamino]benzamide (104 mg) was prepared from N- (4-chloro-3-methoxybenzyl)-5-cyano-2-fluorobenzamide (122 mg) and (lS,2i?,4jR)-4-amino-l,2-cyclohexanediol (49 mg) in a similar manner to Example 12-(2).
  • N-(4-Chloro-3-methoxybenzyl)-5-cyano-2-(t-3,t-4-dihydroxy-r-l- cyclopentylamino) benzamide (97 mg) was prepared from iV-(4-chloro-3- methoxybenzyl)-5-cyano-2-fluorobenzamide (110 mg) and t-4-amino-r- l,c-2-cyclopentanediol (44 mg) in a similar manner to Example 12-(2).
  • Example 102 iV-(4-Chloro-3-methoxybenzyl)-5-cyano-2-(t-5-hydroxy-t-3-methoxy- r-l-cyclohexylamino)benzamide (66 mg) was prepared from N-(4-chloro- 3-methoxybenzyl)-5-cyano-2-fluorobenzamide (125 mg) and t-5-amino- c-3-methoxy-r-l -cyclohexanol (57 mg) in a similar manner to Example 12-(2).
  • N-(4-Chloro-3-methoxybenzyl)-5-cyano-2-(t-3,t-5-dihydroxy-r- l- cyclohexylamino) benzamide (59 mg) was prepared from N-(4-chloro-3- methoxybenzyl)-5-cyano-2-fluorobenzamide (125 mg) and t-5-amino-r- l,c-3-cyclohexanediol (57 mg) in a similar manner to Example 12-(2).
  • Example 105 ( 1 ) To a solution of benzyl N- ( t-3 , t-4-dihydroxy- r- 1 -cyclopentyl) - carbamate (134 mg) in 1,2-dichloroethane (3 ml) were added 2,6-di-tert- butyl-4-methylphenol (142 mg) and trimethyloxonium tetrafluoroborate (87 mg), and the mixture was refluxed for 1.5 hours. The resulting mixture was diluted with diethyl ether and washed successively with
  • N-(3-Chloro-4-methoxybenzyl)-5-cyano-2-[(l.R,3.R)-3- hydroxycyclo-pentylamino]benzamide (37 mg) was prepared from 2- [( li?,3i?)-3-(tert-butyldimethylsilyloxy)cyclopentylamino]-N-(3-chloro-4- methoxybenzyl)-5-cyanobenzamide (73 mg) in a similar manner to Example 44- (4).
  • N-(3-Chloro-4-methoxybenzyl)-2-[(S)-(2-hydroxy- l-methylethyl)- amino]-5-(trifluoromethyl)benzamide (109 mg) was prepared from N-(3- chloro-4-methoxybenzyl)-2-fluoro-5-(trifluoromethyl)benzamide ( 120 mg) and (S)-2-amino- 1-propanol (37 mg) in a similar manner to Example 12-(2) as an amorphous powder.
  • Example 110 N-(3-Cyano-4-methoxybenzyl)-2-[(i?)-(2-hydroxy- 1-methylethyl)- amino]-5-(trifluoromethyl)benzamide (75 mg) was prepared from N-(3- cyano-4-methoxybenzyl)-2-fluoro-5-(trifluoromethyl)benzamide ( 120 mg) and (R -2-aiaino- 1-propanol (38 mg) in a similar manner to Example 12-(2) as an amorphous powder.
  • N-(3-Cyano-4-methoxybenzyl)-2-[(S)-(2-hydroxy- l-methylethyl)- amino]-5-(trifluoromethyl)benzamide (97 mg) was prepared from N-(3- cyano-4-methoxybenzyl)-2-fluoro-5-(trifluoromethyl)benzamide (120 mg) and (S)-2-amino- 1-propanol (38 mg) in a similar manner to Example
  • N-(3-Chloro-4-methoxybenzyl)-2-(tr ⁇ ns-4-hydroxycyclohexyl- arnino)-5-(trifluoromethyl)benzaniide (187 mg) was prepared from N-(3- chloro-4-methoxybenzyl)-2-fluoro-5-(trifluoromethyl)benzamide (208 mg) and tr ⁇ ns-4-aminocyclohexanol (199 mg) in a similar manner to Example 12-(2).
  • N-(4-Chloro-3-methoxybenzyl)-2-(tr ⁇ ns-4-hydroxycyclohexyl- amino)-5-trifluoromethylbenzamide (282 mg) was prepared from N-(4- chloro-3-rnethoxybenzyl)-2-fluoro-5-trifluorornethylbenzamide (261 mg) and tr ⁇ ns-4-aminocyclohexanol (249 mg) in a similar manner to Example 12- (2).
  • N-(3-Cyano-4-methoxybenzyl)-2-(tr ⁇ n.s-4-hydroxycyclohexyl- amino)-5-(trifluoromethyl)benzamide (257 mg) was prepared from N-(3- cyano-4-methoxybenzyl)-2-fluoro-5-(trifluoromethyl)benzamide (250 mg) and tr ⁇ ns-4-aminocyclohexanol (123 mg) in a similar manner to
  • Example 12-(2) as a powder.

Abstract

La présente invention concerne un composé représenté par la formule (I): dans laquelle R1 désigne un groupe nitro, amino, ou cyano, un groupe halo(inférieur)alkyle, un atome d'halogène, etc., R2 représente un groupe aryle éventuellement substitué, A désigne un groupe alkylène inférieur, et R3 représente un groupe hétérocyclique éventuellement substitué, ou un groupe représenté par la formule: -CR?4R5R6, où R4 et R5¿ désignent chacun indépendamment un groupe carbamoyle éventuellement substitué ou une groupe alkyle inférieur éventuellement substitué, ou R4 et R5 peuvent former, avec l'atome de carbone auquel R4 et R5 sont fixés, un groupe carbocyclique éventuellement substitué, et R6 désigne un atome d'hydrogène ou un groupe alkyle inférieur, etc.. L'invention concerne également un promédicament et un sel acceptable dudit composé, ainsi que des procédés de préparation dudit composé, une composition pharmaceutique renfermant ledit composé, et une méthode destinée à la prévention et/ou au traitement de diverses maladies, notamment la dysérection.
PCT/JP2000/007308 1999-10-25 2000-10-19 Derives d'acide anthranilique utilises comme inhibiteurs de la cgmp-phosphodiesterase WO2001030745A1 (fr)

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US7514564B2 (en) 2001-01-12 2009-04-07 Amgen Inc. Substituted amine derivatives and methods of use
EP2311808A1 (fr) 2001-01-12 2011-04-20 Amgen Inc. Dérivés substitués d'alkylamine et procédés d'utilisation
US6878714B2 (en) 2001-01-12 2005-04-12 Amgen Inc. Substituted alkylamine derivatives and methods of use
EP1798230A1 (fr) * 2001-01-12 2007-06-20 Amgen Inc. Dérivés substitués d'alkylamine et procédés d'utilisation
US6995162B2 (en) 2001-01-12 2006-02-07 Amgen Inc. Substituted alkylamine derivatives and methods of use
US7102009B2 (en) 2001-01-12 2006-09-05 Amgen Inc. Substituted amine derivatives and methods of use
US7101868B2 (en) 2001-01-12 2006-09-05 Amgen Inc. Substituted arylamine derivatives and methods of use
WO2002066470A1 (fr) * 2001-01-12 2002-08-29 Amgen Inc. Derives d'alkylamine substitues et methodes d'utilisation
US8642624B2 (en) 2001-01-12 2014-02-04 Amgen Inc. Substituted alkylamine derivatives and methods of use
CZ303356B6 (cs) * 2001-01-12 2012-08-08 Amgen Inc. Substituovaný alkylaminový derivát a farmaceutická kompozice s jeho obsahem
US7105682B2 (en) 2001-01-12 2006-09-12 Amgen Inc. Substituted amine derivatives and methods of use
US7687643B2 (en) 2001-01-12 2010-03-30 Amgen Inc. Process for preparing 3,3-dimethylindolines
EP2311829A1 (fr) 2001-01-12 2011-04-20 Amgen Inc. Dérivés substitués d'alkylamine et procédés d'utilisation
US8058445B2 (en) 2001-01-12 2011-11-15 Amgen Inc. Substituted pyridinecarboxamides for the treatment of cancer
BG66160B1 (bg) * 2001-01-12 2011-09-30 Amgen Inc. Заместени алкиламинови производни и използването им
US7307088B2 (en) 2002-07-09 2007-12-11 Amgen Inc. Substituted anthranilic amide derivatives and methods of use
WO2004007458A1 (fr) 2002-07-17 2004-01-22 Amgen Inc. Derives substitues d'amide 2-alkylamine nicotinique et utilisations associees
JP2006022045A (ja) * 2004-07-08 2006-01-26 Kaneka Corp 光学活性１−ｔ−ブトキシカルボニル−３−アミノピロリジン塩の単離精製方法
US8247556B2 (en) 2005-10-21 2012-08-21 Amgen Inc. Method for preparing 6-substituted-7-aza-indoles
CN111825563A (zh) * 2020-07-01 2020-10-27 中国科学院福建物质结构研究所 一种β-高谷氨酸的制备方法

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