WO2010146881A1 - 置換されたイソキノリン誘導体 - Google Patents
置換されたイソキノリン誘導体 Download PDFInfo
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- WO2010146881A1 WO2010146881A1 PCT/JP2010/004101 JP2010004101W WO2010146881A1 WO 2010146881 A1 WO2010146881 A1 WO 2010146881A1 JP 2010004101 W JP2010004101 W JP 2010004101W WO 2010146881 A1 WO2010146881 A1 WO 2010146881A1
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- WIPO (PCT)
- Prior art keywords
- isoquinoline
- ylsulfonyl
- group
- methyl
- diazepan
- Prior art date
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- 0 CN(C*=C)S(c1ccc(cncc2)c2c1)(=O)=O Chemical compound CN(C*=C)S(c1ccc(cncc2)c2c1)(=O)=O 0.000 description 8
- KAACYWKSANINMR-GOSISDBHSA-N CC(C)(C)OC(N(CCCC1)C[C@@H](CF)N1Sc1ccc(cncc2)c2c1)=O Chemical compound CC(C)(C)OC(N(CCCC1)C[C@@H](CF)N1Sc1ccc(cncc2)c2c1)=O KAACYWKSANINMR-GOSISDBHSA-N 0.000 description 1
- IYWARLNEGAUUGO-UHFFFAOYSA-N CC(C)(C)OC(N(CCCO)CC(C)(C)NSc1ccc(cncc2)c2c1)=O Chemical compound CC(C)(C)OC(N(CCCO)CC(C)(C)NSc1ccc(cncc2)c2c1)=O IYWARLNEGAUUGO-UHFFFAOYSA-N 0.000 description 1
- OQGHRLCOQRKPPR-UHFFFAOYSA-N CC(C)(C)OC(NC(CC1)CCN1S(c(cc1)cc2c1cncc2)(=O)=O)=O Chemical compound CC(C)(C)OC(NC(CC1)CCN1S(c(cc1)cc2c1cncc2)(=O)=O)=O OQGHRLCOQRKPPR-UHFFFAOYSA-N 0.000 description 1
- SJUDBWLFTFYTNA-UHFFFAOYSA-N CC(C)(C)OC(NCC(N(CCC1)CCN1Sc(cc1)cc2c1cncc2)=O)=O Chemical compound CC(C)(C)OC(NCC(N(CCC1)CCN1Sc(cc1)cc2c1cncc2)=O)=O SJUDBWLFTFYTNA-UHFFFAOYSA-N 0.000 description 1
- LBGJFIHQPOGMQX-UHFFFAOYSA-N COC(C(CC1)CCN1Sc1ccc(cncc2)c2c1)=O Chemical compound COC(C(CC1)CCN1Sc1ccc(cncc2)c2c1)=O LBGJFIHQPOGMQX-UHFFFAOYSA-N 0.000 description 1
- BEYNCSUHCMELQC-AWEZNQCLSA-N C[C@@H](CN(CCCO[Si+](C)(C)C(C)(C)C)C(OC(C)(C)C)=O)N Chemical compound C[C@@H](CN(CCCO[Si+](C)(C)C(C)(C)C)C(OC(C)(C)C)=O)N BEYNCSUHCMELQC-AWEZNQCLSA-N 0.000 description 1
- DEKWBKSTKKCXSH-SNVBAGLBSA-N C[C@H](CCN(CCCO)C(OC(C)(C)C)=O)N Chemical compound C[C@H](CCN(CCCO)C(OC(C)(C)C)=O)N DEKWBKSTKKCXSH-SNVBAGLBSA-N 0.000 description 1
- IFGUUXVCLJXWPK-MRXNPFEDSA-N C[C@H](CN(CC=C)C(OC(C)(C)C)=O)N(CC=C)S(c(cccc1)c1[N+]([O-])=O)(=O)=O Chemical compound C[C@H](CN(CC=C)C(OC(C)(C)C)=O)N(CC=C)S(c(cccc1)c1[N+]([O-])=O)(=O)=O IFGUUXVCLJXWPK-MRXNPFEDSA-N 0.000 description 1
- YEEGABRJQANFPJ-OAHLLOKOSA-N C[C@H](CN(CCCC1)C(OC(C)(C)C)=O)N1Sc1ccc(cncc2)c2c1Br Chemical compound C[C@H](CN(CCCC1)C(OC(C)(C)C)=O)N1Sc1ccc(cncc2)c2c1Br YEEGABRJQANFPJ-OAHLLOKOSA-N 0.000 description 1
- NKIOSXRFVSDKIZ-CQSZACIVSA-N C[C@H](CN(CCCO[IH]S(C)(C)C(C)(C)C)C(OC(C)(C)C)=O)N Chemical compound C[C@H](CN(CCCO[IH]S(C)(C)C(C)(C)C)C(OC(C)(C)C)=O)N NKIOSXRFVSDKIZ-CQSZACIVSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Definitions
- the present invention relates to an isoquinoline-6-sulfonamide derivative useful for preventive treatment of diseases or disorders caused by glaucoma, cardiovascular diseases, neurodegeneration or nerve damage.
- Patent Document 1 a cannabinoid receptor antagonist
- Patent Document 2 a mitochondrial F1F0 ATPase inhibitor
- An object of the present invention is to provide a novel isoquinoline-6-sulfonamide derivative useful as a medicine.
- the present inventor has studied to introduce various substituents at the 6-position of the isoquinoline skeleton, and uses 6-chlorosulfonylisoquinoline as a key intermediate to produce a novel isoquinoline-6 represented by the following general formula (1).
- 6-chlorosulfonylisoquinoline as a key intermediate to produce a novel isoquinoline-6 represented by the following general formula (1).
- sulfonamide derivatives were synthesized.
- they have excellent intraocular pressure-lowering action, blood pressure-lowering action, nerve cell axon extension action, etc., resulting from glaucoma, cardiovascular disease, neurodegeneration or nerve damage It has been found that it is useful as an active ingredient for preventing or treating a disease or disorder.
- the present invention has the general formula (1)
- X and Y each independently represent a direct bond, NH, CH ⁇ CH, O or S
- R 1 and R 2 are each independently a hydrogen atom, halogen atom, cyano group, alkyl group, halogenoalkyl group, alkenyl group, alkoxy group, alkylthio group, hydroxy group, mercapto group, nitro group, aryl group, amino group or Represents an aminoalkylthio group
- R 3 and R 4 are each independently a hydrogen atom, alkyl group, alkenyl group, amino group, alkylamino group, dialkylamino group, aminoalkyl group, halogenoalkyl group, alkanoyl group, aminoalkanoyl group, alkylaminoalkanoyl group, Represents an alkoxycarbonyl group, a hydroxy group or a mercapto group, or R 3 and R 4 together form an alkylene group or an alkenylene group, and may be bridged between
- the present invention also provides a pharmaceutical composition containing the isoquinoline-6-sulfonamide derivative represented by the above general formula (1), a salt thereof or a solvate thereof.
- the present invention also provides an isoquinoline-6-sulfonamide derivative represented by the above general formula (1) and a salt thereof for preventing or treating glaucoma, cardiovascular disease, or a disease or disorder caused by neurodegeneration or nerve damage. Or a solvate thereof.
- the present invention provides a glaucoma, cardiovascular disease, or nerve characterized by administering an effective amount of the isoquinoline-6-sulfonamide derivative represented by the above general formula (1), a salt thereof or a solvate thereof.
- the present invention provides a preventive and therapeutic method for diseases or disorders caused by degeneration or nerve damage.
- the isoquinoline-6-sulfonamide derivative of the present invention has excellent intraocular pressure-lowering action, blood pressure-lowering action, vasodilatory action, nerve axon extension action, etc., and is suitable for glaucoma, cardiovascular disease, neurodegeneration or nerve damage. It is useful as an active ingredient for preventive treatment of diseases or disorders caused by it.
- X and Y each independently represent a direct bond, NH, CH ⁇ CH, O or S, and X is more preferably a direct bond or NH, and particularly preferably NH. Y is more preferably a direct bond, NH, CH ⁇ CH or O, and particularly preferably a direct bond, CH ⁇ CH or O.
- R 1 and R 2 are each independently a hydrogen atom, halogen atom, cyano group, alkyl group, halogenoalkyl group, alkenyl group, alkoxy group, alkylthio group, hydroxy group, mercapto group, nitro group, aryl group, amino group Or an aminoalkylthio group is shown.
- examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and among these, a fluorine atom, a chlorine atom, or a bromine atom is preferable.
- alkyl group examples include a linear, branched, or cyclic alkyl group having 1 to 8 carbon atoms (C 1-8 alkyl group), preferably an alkyl group having 1 to 6 carbon atoms, An alkyl group having a number of 1 to 3 is preferred. Specific examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, Examples thereof include an isohexyl group and a cyclopropyl group. Of these, those having 1 to 3 carbon atoms are preferable, and methyl group and ethyl group are particularly preferable.
- halogenoalkyl group a halogeno C 1-8 alkyl group is preferable, and a halogeno C 1-6 alkyl group is more preferable.
- Specific examples include chloromethyl group, fluoromethyl group, chloroethyl group, fluoroethyl group, trifluoromethyl group and the like.
- alkenyl group examples include linear or branched alkenyl groups having 2 to 8 carbon atoms (C 2-8 alkenyl groups), and alkenyl groups having 2 to 6 carbon atoms are preferable.
- Specific examples include vinyl group, allyl group, isopropenyl group, 2-methallyl group, 2-butenyl group, and 3-butenyl group. Of these, those having 2 to 4 carbon atoms are preferred.
- alkoxy group examples include a linear or branched alkoxy group having 1 to 8 carbon atoms (C 1-8 alkoxy group), and an alkoxy group having 1 to 6 carbon atoms is preferable. Specific examples include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, and tert-butoxy group.
- alkylthio group examples include a linear or branched alkylthio group having 1 to 8 carbon atoms (C 1-8 alkylthio group), and an alkylthio group having 1 to 6 carbon atoms is preferable. Specific examples include a methylthio group, an ethylthio group, an isopropylthio group, and an n-propylthio group.
- aryl group examples include a C 6-14 aryl group, and a phenyl group and a naphthyl group are preferable, and a phenyl group is more preferable.
- the aminoalkylthio group is preferably an amino-C 1-8 alkylthio group, and more preferably an amino-C 1-6 alkylthio group. Specific examples include aminomethylthio group, aminoethylthio group, aminopropylthio group and the like.
- R 1 and R 2 are each independently a hydrogen atom, halogen atom, C 1-8 alkyl group, nitro group, cyano group, halogeno C 1-8 alkyl group, phenyl group, C 2-8 alkenyl group, hydroxy It is preferably a group, an amino group or an amino C 1-8 alkylthio group. Further, each independently preferably a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group or a halogeno C 1-6 alkyl group. Further, each independently preferably a hydrogen atom, a halogen atom or a C 1-3 alkyl group.
- R 1 may be substituted at any of the 1-position, 3-position and 4-position of the isoquinoline skeleton.
- R 2 may be substituted at any of the 5-position, 7-position and 8-position of the isoquinoline skeleton.
- R 3 and R 4 are each independently a hydrogen atom, alkyl group, alkenyl group, amino group, alkylamino group, dialkylamino group, aminoalkyl group, halogenoalkyl group, alkanoyl group, aminoalkanoyl group, alkylaminoalkanoyl group , An alkoxycarbonyl group, a hydroxy group or a mercapto group, or R 3 and R 4 may be combined to form an alkylene group or an alkenylene group, and may be bridged between two carbons at an arbitrary position.
- alkyl group examples include those shown as examples of R 1 and R 2 .
- the alkylamino group is preferably a C 1-8 alkylamino group, and specific examples include a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, an n-butylamino group, an isobutylamino group, sec- Examples thereof include a butylamino group, an n-pentylamino group, and an n-hexylamino group.
- the dialkylamino group is preferably a di-C 1-8 alkylamino group, and specific examples include a dimethylamino group, a diethylamino group, a dipropylamino group, a dibutylamino group, and the like.
- the aminoalkyl group is preferably an amino C 1-8 alkyl group, and specific examples include an aminomethyl group, an aminoethyl group, an aminopropyl group, an aminobutyl group, and the like.
- alkanoyl group examples include a linear or branched alkanoyl group having 2 to 8 carbon atoms (C 2-8 alkanoyl group), and an alkanoyl group having 2 to 6 carbon atoms is preferable. Specific examples include an acetyl group, a propionyl group, and a butyryl group.
- the aminoalkanoyl group includes an amino-C 2-8 alkanoyl group, and an amino-C 2-6 alkanoyl group is preferable. Specific examples include aminoacetyl group, aminopropionyl group, aminobutyryl group and the like.
- alkylaminoalkanoyl group examples include a C 1-8 alkylamino C 2-8 alkanoyl group, and a C 1-4 alkylamino C 2-4 alkanoyl group is preferable. Specific examples thereof include a methylaminoacetyl group and a methylaminopropionyl group. Groups and the like.
- alkoxycarbonyl group examples include a C 1-8 alkoxycarbonyl group, and examples thereof include a methoxycarbonyl group and an ethoxycarbonyl group.
- R 3 and R 4 may be substituted at any position of the cyclic amino group in the general formula (1), but nitrogen on the carbon atom and when X and Y are NH or CH ⁇ CH Substitution on an atom or carbon atom is preferred, and substitution on a carbon atom is more preferred.
- Examples of the alkylene group formed by combining R 3 and R 4 include C 1-3 alkylene groups such as a methylene group, an ethylene group, and a trimethylene group (—CH 2 CH 2 CH 2 —). Group and ethylene group are preferred.
- Examples of the alkenylene group formed by combining R 3 and R 4 include C 2-4 alkenylene groups such as —CH ⁇ CH— and —CH 2 CH ⁇ CH—. These alkylene groups or alkenylene groups may be bridged between two carbons to any position on the nitrogen-containing saturated heterocyclic ring in formula (1).
- Such a bridge is preferably a bridge by a bridged C 1-3 alkylene group, that is, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —.
- R 3 and R 4 are each independently a hydrogen atom, C 1-8 alkyl group, C 2-8 alkenyl group, amino group, amino C 1-8 alkyl group, halogeno C 1-8 alkyl group, C 1 -8 alkylamino group, di-C 1-8 alkylamino group, C 2-8 alkanoyl group, amino C 2-8 alkanoyl group, C 1-8 alkoxycarbonyl group, hydroxy group or mercapto group, or R It is preferred that 3 and R 4 together form a bridged C 1-3 alkylene group.
- R 3 and R 4 are each independently a hydrogen atom, a C 1-8 alkyl group, an amino group, a C 1-8 alkylamino group, an amino C 1-8 alkyl group or a halogeno C 1-8 alkyl group. More preferably, R 3 and R 4 together form a bridged C 1-3 alkylene group. R 3 and R 4 are preferably a hydrogen atom, a C 1-6 alkyl group or a halogeno C 1-6 alkyl group.
- the substituent is a hydrogen atom, a C 1-8 alkyl group, C 2-8 An alkenyl group, a halogeno C 1-8 alkyl group, a C 2-8 alkanoyl group, an amino C 2-8 alkanoyl group, an amino C 1-8 alkyl group, a C 2-8 alkanoyl group or a C 1-8 alkoxycarbonyl group. It is preferable.
- L, m and n each represent a number of 1 to 4, but l and m are each independently preferably a number of 1 to 3.
- N is preferably a number from 2 to 3, and 2 is particularly preferred.
- nitrogen-containing heterocycle in the general formula (1) include, for example, pyrrolidino, imidazolidyl, piperidino, piperazino, morpholino, thiomorpholino, 1,4-diazepanyl, 1,4-diazocanyl, 1,4-diazononyl, 1,4-diazecanyl, 1,5-diazecanyl, tetrahydro-1,4-diazepinyl, hexahydro-1,4-diazosinyl, 1,4,7-oxadiazonanyl, 1,4,7-thiadiazonanyl, 1,4 7-triazonanyl, 3,6-diazabicyclo [3.2.2] nonan-3-yl, 3,6-diazabicyclo [3.2.1] octane-3-yl, 2,5-diazabicyclo [2.2. 1) heptan-2-yl or 2,5-diazabicyclo [2.2.2]
- the salt of the compound (1) of the present invention may be a pharmaceutically acceptable salt, and examples thereof include acid addition salts.
- salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, or acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid
- organic acid salts such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid and camphorsulfonic acid.
- the compound (1) of the present invention can be produced, for example, by the following method. Manufacturing method 1
- L 1 as a leaving group examples include residues of reactive derivatives of sulfonic acid described later.
- the protecting group used when X and Y are N include, for example, acyl groups such as formyl, acetyl and benzoyl, aralkyloxycarbonyl groups such as benzyloxycarbonyl, alkoxycarbonyl groups such as tert-butyloxycarbonyl, benzyl and the like The aralkyl group of can be mentioned.
- the amine represented by the general formula (3) is reacted with the sulfonic acid represented by the general formula (2) or a reactive derivative thereof in a suitable solvent, and if necessary, the protecting group is removed to obtain the compound (1).
- the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
- ethers such as tetrahydrofuran, dioxane and diethyl ether, hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as methylene chloride and chloroform, Aprotic solvents such as N, N-dimethylformamide and N, N-dimethylacetamide, pyridine, acetonitrile, or a mixture thereof can be used.
- sulfonic acid halide eg, sulfonic acid chloride, sulfonic acid bromide
- sulfonic acid anhydride e.g., N-sulfonyl imidazolide and the like
- a sulfonic acid halide is preferable.
- This reaction is preferably performed in the presence of a suitable base.
- bases include alkali metals such as alkali metal bicarbonates (eg, sodium bicarbonate), alkali metal carbonates (eg, potassium carbonate), alkali metal hydroxides (eg, sodium hydroxide, potassium hydroxide), Organic tertiary amines such as triethylamine and triethylenediamine can be used. If a basic solvent such as pyridine is used as the solvent, such a base is unnecessary and preferable.
- this reaction often proceeds at room temperature, but it can be carried out at ⁇ 78 to 150 ° C., preferably 0 to 120 ° C. with cooling or heating as necessary.
- the amount of the reactive derivative (2) used is preferably in the range of 1 to 10 times mol, more preferably 1 to 3 times mol for the amine (3).
- the amount of the base used is preferably in the range of 1 to 10 times mol, more preferably 1 to 3 times mol for the amine (3).
- the amount of the sulfonic acid or reactive derivative (2) used is equimolar or less, preferably in the range of 0.5 to 0.1-fold mol with respect to the amine (3).
- the reaction time varies depending on the raw materials used, solvent, reaction temperature and the like, but is usually 5 minutes to 70 hours. If necessary, the protecting group is then removed by methods known per se.
- R 8 and R 9 each independently represent a hydrogen atom, a halogen atom or a trifluoromethanesulfonyloxy group, and when either one is a hydrogen atom, the other represents a halogen atom or a trifluoromethanesulfonyloxy group.
- R 10 is the above definition of R 2 excluding a halogen atom
- R 11 is the above definition of R 1 excluding a halogen atom
- R 3 , R 4 , X, Y, l , M and n are the same as above.
- Halogen represented by R 8 and R 9 chlorine or bromine is preferable.
- Halogen represented by the general formula (1a) is a Grignard reagent corresponding to R 10 and R 11 or an organometallic reagent such as alkyl lithium, an alkali metal hydroxide (eg, sodium hydroxide, potassium hydroxide), sodium alcoholate
- Compound (1b) is prepared by treatment with an alkali such as sodium methylate (eg, sodium methylate) or potassium cyanide. This reaction can be carried out according to a known method. It can also be synthesized using a Suzuki-Miyaura coupling performed in the presence of a palladium catalyst.
- the compound (1d) in which the nitrogen-containing heterocycle in the general formula (1) is a cyclic diamino can also be produced as follows.
- L 2 represents a leaving group, and R 1 to R 4 , Y, 1, m, and n are the same as described above.
- L 2 as the leaving group may be a halogen such as chlorine or bromine or an acyloxy group such as acetyloxy, mesyloxy or tosyloxy.
- Compound (1d) is produced by reacting compound (1c) with an amine, guanidine or ammonia corresponding to X. This reaction can be performed according to a known method (Acta Chemica Scand., 45, 621 (1991)).
- R 12 represents a hydrogen atom or an amino-protecting group
- L 2 , R 1 to R 4 , Y, l, m, and n are the same as described above.
- Compound (1d) is produced by reacting compound (1e) with compound (1f) and, if necessary, treating with acid or alkali to remove the protecting group. This reaction can be performed according to a known method (Acta Chemica Scand., 45, 621 (1991)).
- Compound (1d) is obtained by subjecting compound (1g) to an intramolecular dehydration reaction (so-called Mitsunobu reaction) using an organophosphorus reagent such as triphenylphosphine and an azo reagent such as diethyl azodicarboxylate or diisopropyl azodicarboxylate. it can be obtained by removing the protecting group R 12.
- organophosphorus reagent such as triphenylphosphine
- an azo reagent such as diethyl azodicarboxylate or diisopropyl azodicarboxylate.
- R 12 represents a hydrogen atom or a protecting group of an amino group
- R 1 ⁇ R 4, Y , l, m, n, L 1, L 2 are as defined above.
- Compound (1h) is produced by reacting aminoalkyl alcohol and compound (2) in the same manner as in Production Method 1.
- the hydroxy group of compound (1h) is converted into halogen (eg, chlorine, bromine), acyloxy (eg, tosyloxy, methanesulfonyloxy, acetyloxy) by a method known per se, and then compound ( 1i) is manufactured.
- Step 3 Compound (1g) is produced by reacting compound (1i) and aminoalkyl alcohol in an appropriate solvent in the presence or absence of a base in the same manner as in Production Method 1.
- Compound (1g) can also be synthesized in one step by reacting compound (2) with the corresponding amino alcohol.
- Step 4 After protecting the secondary amino nitrogen atom of compound (1g) by a known method, if necessary, compound (1g) can be converted to compound (1j) according to a conventional method.
- Step 5 Compound (1j) is treated with a base in an appropriate solvent, and treated with an acid or alkali as necessary to remove the protecting group to produce compound (1d).
- an alkali such as sodium hydride, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or an organic tertiary amine such as triethylamine or triethylenediamine can be used.
- What was illustrated by the manufacturing method 1 as a reaction solvent is made to react on the same reaction conditions.
- Compound (1d) can also be synthesized by intramolecular dehydration reaction (so-called Mitsunobu reaction) and subsequent deprotection of R 12 according to production method 5.
- the hydroxyl group or amino group is protected with a commonly used protecting group, if necessary, and subjected to the above reaction, followed by a method known per se such as acid treatment, alkali treatment or catalytic reduction. Can be removed.
- a commonly used protecting group for example, benzyl, benzyloxycarbonyl, trifluoroacetyl can be used.
- the hydroxyl-protecting group methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, tetrahydropyranyl, tert-butyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl and the like can be used.
- Starting material (2) can be produced using commercially available 6-aminoisoquinoline (2d) or 6-bromoisoquinoline (2c). In addition, it can be synthesized by the following method.
- R 14 represents an alkyl group
- L 3 represents a leaving group such as a methanesulfonyl group or a toluenesulfonyl group.
- R 1 , R 2 and L 1 are the same as described above.
- R 13 may be formyl group, halomethyl group, halogen, or acyloxymethyl such as acetyloxymethyl, mesyloxymethyl, or tosyloxymethyl.
- a secondary amine can be synthesized by reductive amination and then reacted with a sulfonyl halide represented by a tosyl group or a mesyl group to synthesize a compound (2b).
- R 13 is a halomethyl group, halogen, or acyloxymethyl such as acetyloxymethyl, mesyloxymethyl, or tosyloxymethyl
- compound (2b) can be synthesized by a substitution reaction with an amine.
- Compound (2c) can be synthesized by reacting compound (2b) in the presence of a strong acid and a Lewis acid.
- the compound (2) can be synthesized from the compound (2c) using a known method.
- Some of the compounds of the present invention have an asymmetric carbon and have optical isomers. Any of these isomers and mixtures thereof are included in the present invention. Usually obtained in racemic form. These racemates have pharmacological activity as they are, but can be resolved into the respective isomers as desired.
- a mixture of isomers can be prepared by a known optical resolution method such as optically active carboxylic acid (eg, (+)-or ( ⁇ )-tartaric acid, (+)-or ( ⁇ )-malic acid) or optically active sulfone.
- a salt with an acid eg, (+)-camphorsulfonic acid
- the optical isomer can be obtained by using an optically active raw material compound (S configuration or R configuration).
- the compound of the present invention can form the aforementioned salt by a known method.
- the hydrochloride of the compound of the present invention can be obtained by dissolving the compound of the present invention in an alcohol solution or ethyl ether solution of hydrogen chloride.
- a solvate may be obtained by recrystallizing the compound of the present invention or a salt thereof from an appropriate solvent (including water). These solvates are also included in the present invention.
- a hydrate of the compound of the present invention may be obtained by recrystallizing the compound of the present invention from a hydrous alcohol.
- the compound of the present invention may take a crystalline polymorph. The crystal polymorph is also included in the present invention.
- the compound of the present invention thus produced can be obtained by a method known per se, for example, in the form of free base or acid addition salt, for example, concentration, liquid conversion, phase transfer, solvent extraction, crystallization, fractional distillation. It can be isolated and purified by chromatography.
- the compound of the present invention has an excellent intraocular pressure lowering action, blood pressure lowering action, vasodilatory action, nerve cell axon extension action, and motor function recovery action after spinal cord injury, as shown in Examples described later. Therefore, the compound of the present invention is useful as a therapeutic agent for diseases or disorders caused by glaucoma, cardiovascular diseases, neurodegeneration or nerve damage.
- the glaucoma of the present invention includes primary open angle glaucoma, normal pressure glaucoma, aqueous humor production hyperglaucoma, ocular hypertension, acute closed angle glaucoma, chronic closed angle glaucoma, mixed glaucoma, steroid glaucoma, pigment Examples include glaucoma, desquamation glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma, capsular glaucoma of the lens, and plateau iris syndrome (piateau iris syndrome).
- the cardiovascular diseases in the present invention include, but are not limited to, hypertension, arteriosclerosis, cerebral circulatory disorder, heart disease, and peripheral circulatory disorder. More specifically, as hypertension, essential hypertension, renal hypertension, renovascular hypertension, pregnancy-induced hypertension, endocrine hypertension, cardiovascular hypertension, neurological hypertension, iatrogenic hypertension, pulmonary hypertension Examples of arteriosclerosis include those in which lesions occur in main arteries such as coronary artery, abdominal aorta, renal artery, carotid artery, fundus artery, and cerebral artery.
- Cerebral circulation disorders include cerebral thrombosis, cerebral infarction, cerebral hemorrhage, transient cerebral ischemic attack, hypertensive encephalopathy, cerebral arteriosclerosis, subdural hematoma, epidural hematoma, subarachnoid hemorrhage, cerebral hypoxia, Examples include cerebral edema, encephalitis, brain abscess, head injury, psychosis, metabolic poisoning, drug addiction, transient respiratory arrest, deep anesthesia during surgery, and the like.
- Cardiac disease is congestive heart failure, acute myocardial infarction, old myocardial infarction, subendocardial infarction, right ventricular infarction, atypical myocardial infarction, ischemic cardiomyopathy, atypical angina, stable angina, effort Includes angina pectoris, coronary angina, post-infarct angina, unstable angina, arrhythmia, acute cardiac death, etc.
- Peripheral circulation disorders include arterial diseases such as Buerger's disease, obstructive arteriosclerosis, Raynaud's syndrome and venous thrombosis, venous diseases such as thrombophlebitis, blood hyperviscous syndrome, frostbite / frost wound, cold feeling due to coldness And sleep deprivation, wounds, cracks / reds, and hair loss.
- arterial diseases such as Buerger's disease, obstructive arteriosclerosis, Raynaud's syndrome and venous thrombosis
- venous diseases such as thrombophlebitis, blood hyperviscous syndrome, frostbite / frost wound, cold feeling due to coldness And sleep deprivation, wounds, cracks / reds, and hair loss.
- Diseases or disorders caused by neurodegeneration or nerve damage include diseases related to the central nervous system, such as dementia, Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitis Parkinson's syndrome, post encephalitis Parkinson's syndrome, fisting encephalitis, Guam Parkinson's syndrome-dementia complex disease, Pick's disease, cortical basal ganglia degeneration, spinocerebellar degeneration, frontotemporal dementia, Huntington's disease, AIDS-related dementia , Including but not limited to amyotrophic lateral sclerosis, multiple sclerosis and neurotrauma such as acute cerebral infarction, post-cerebral infarction dysfunction, cerebral hemorrhage, traumatic brain injury, spinal cord injury.
- diseases related to the central nervous system such as dementia, Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitis Parkinson's syndrome, post encephalitis
- diseases related to the peripheral nervous system include, but are not limited to, trigeminal nerve disorder, facial neuropathy, single neuropathy, polyneuropathy, diabetic neuropathy, and traumatic nerve palsy.
- diseases related to retinal nerve and optic nerve include, but are not limited to, glaucoma, age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy, retinal neuritis, optic neuritis, optic nerve tear, and traumatic optic neuropathy. .
- the compound of the present invention can be administered orally or parenterally.
- the dosage form include tablets, capsules, granules, powders, injections, eye drops and the like, and these can be used in combination with commonly used techniques.
- oral preparations such as tablets, capsules, granules, powders are lactose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, calcium carbonate, calcium hydrogen phosphate and other excipients, stearic acid, magnesium stearate , Lubricants such as talc, binders such as starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, disintegrants such as carboxymethylcellulose, low-substituted hydroxypropylmethylcellulose, calcium citrate, hydroxypropylmethylcellulose, macrogol, Coating agents such as silicone resins, stabilizers such as ethyl paraoxybenzoate and benzyl alcohol, and flavoring agents such as
- parenteral preparations such as injections and eye drops include, for example, isotonic agents such as glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol, phosphoric acid, phosphate, citric acid, glacial acetic acid, Buffers such as ⁇ -aminocaproic acid and trometamol, pH regulators such as hydrochloric acid, citric acid, phosphoric acid, glacial acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, polysorbate 80, polyoxyethylene-cured castor Oil 60, Macrogol 4000, Soybean lecithin, Solubilizing or dispersing agent such as polyoxyethylene (160) polyoxypropylene (30) glycol, cellulose polymer such as hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinyl Such as pyrrolidone Preservatives or preservatives such as stickers
- the pH is preferably set to 4.0 to 8.0, and the osmotic pressure ratio is preferably set to around 1.0.
- the dose of the compound of the present invention can be appropriately selected and used depending on symptoms, age, dosage form and the like.
- 0.01 to 1000 mg per day preferably 1 to 100 mg can be administered in one or several divided doses.
- those usually having a concentration of 0.0001% to 10% (w / v), preferably 0.01% to 5% (w / v) are administered once or divided into several times. be able to.
- the daily dose is in the range of 0.1 to 100 mg / human, preferably in the range of 1 to 30 mg / human.
- oral administration it is in the range of 1 to 1,000 mg / human, preferably in the range of 10 to 30 mg / human per day. In some cases, less than this may be sufficient, and vice versa. It can also be administered in 2 to 3 divided doses per day.
- Boc in the chemical structural formula represents a tert-butoxycarbonyl group.
- Reference compound 3 was synthesized using 6-bromo-8-fluoroisoquinoline (synthesized with reference to WO 2008/077753) according to the production method of reference compounds 1 and 2. The resulting dichloromethane solution was used in the next reaction without further purification.
- Reference compound 4 was synthesized using 6-amino-5-bromoisoquinoline (see Bioorg. Med. Chem. Lett. 13,1345 (2003)) according to the production method of Reference compound 2. The resulting dichloromethane solution was used in the next reaction without further purification.
- Reference compound 5 was synthesized using 6-bromo-7-fluoroisoquinoline (synthesized with reference to WO 2008/077753) according to the production method of reference compounds 1 and 2. The resulting dichloromethane solution was used in the next reaction without further purification.
- Reference compound 6 was synthesized using 6-bromo-5-nitroisoquinoline (see Bioorg. Med. Chem. Lett. 16,3150 (2006)) according to the production method of Reference compounds 1 and 2. The resulting dichloromethane solution was used in the next reaction without further purification.
- Reference Compounds 7 to 34 were synthesized according to WO2006 / 115244 and US2008 / 064681.
- the product (1.0 g) obtained in Step 1 was dissolved in ethyl acetate (10 mL), 10% palladium-carbon (300 mg) was added, and the mixture was stirred at 70 ° C. for 3 hours in a hydrogen atmosphere. After completion of the reaction, the temperature was returned to room temperature, dichloromethane (5 mL) was added, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in methanol. 10% palladium-carbon (200 mg) was again added thereto, and the mixture was stirred at 70 ° C. for 16 hours under a hydrogen atmosphere. It returned to room temperature, the dichloromethane (5 mL) was added, and cerite filtration was carried out.
- the product (3.00 g) obtained in Step 2 was dissolved in methanol (200 mL) -water (40 mL), potassium carbonate (10 g) was added, and the mixture was stirred at 80 ° C. for 30 hr. After completion of the reaction, the reaction solution was returned to room temperature and concentrated under reduced pressure. Methanol was added, and excess potassium carbonate precipitated was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (20 mL). The mixture was cooled to 0 ° C., triethylamine (2.10 mL) and benzyl chloroformate (2.55 g) were added, and the mixture was stirred at room temperature for 16 hours.
- Oxalyl chloride (5 mL) was dissolved in dichloromethane (30 mL), cooled to ⁇ 78 ° C., dimethyl sulfoxide (1.4 mL) was added, and the mixture was stirred for 10 minutes.
- a solution of 1.5 g of benzyl-1-hydroxy-2-methylpropan-2-ylcarbamate in 5 mL of dichloromethane was added dropwise and stirred for 10 minutes.
- 3.6 mL of triethylamine was added dropwise, stirred for 10 minutes, and then stirred for 1 hour and a half while gradually raising the temperature to ⁇ 10 degrees.
- Step 2 of Example 1 instead of 6- (4-tert-butoxycarbonylpiperazin-1-ylsulfonyl) isoquinoline, (R) -6- (3-tert-butoxycarbonylaminopyrrolidin-1-ylsulfonyl) isoquinoline To give compound 2 (67%).
- Step 2 of Example 1 instead of 6- (4-tert-butoxycarbonylpiperazin-1-ylsulfonyl) isoquinoline, 6- (4-tert-butoxycarbonyl-1,4-diazepan-1-ylsulfonyl) isoquinoline To give compound 3 (42%).
- Step 2 of Example 1 6- ⁇ 4- (tert-butoxycarbonylamino) piperidin-1-ylsulfonyl ⁇ isoquinoline is used instead of 6- (4-tert-butoxycarbonylpiperazin-1-ylsulfonyl) isoquinoline This gave compound 4 (31%).
- Step 2 of Example 1 instead of 6- (4-tert-butoxycarbonylpiperazin-1-ylsulfonyl) isoquinoline, 6- ⁇ (1S, 4S) -4-tert-butoxycarbonyl-2,5-diazabicyclo [ 2.2.1] Compound 7 was obtained by using heptan-2-ylsulfonyl ⁇ isoquinoline (95%).
- step 1 Synthesis of (R, Z) -6- (4-tert-butoxycarbonyl-2-methyl-2,3,4,5-tetrahydro-1,4-diazocin-1 (8H) -ylsulfonyl) isoquinoline
- Step 2 of Example 1 instead of 6- (4-tert-butoxycarbonylpiperazin-1-ylsulfonyl) isoquinoline, (R, Z) -6- (2-methyl-2,3,4,5-tetrahydro
- -1,4-diazocine-1 (8H) -ylsulfonyl) isoquinoline, the desired product was obtained as a white crystalline substance (81%).
- Step 2 of Example 1 compound 9 was obtained by using 6- (morpholin-1-ylsulfonyl) isoquinoline instead of 6- (4-tert-butoxycarbonylpiperazin-1-ylsulfonyl) isoquinoline ( 79%).
- Step 2 of Example 1 instead of 6- (4-tert-butoxycarbonylpiperazin-1-ylsulfonyl) isoquinoline, (S) -6- ⁇ 3- (N-methylamino) pyrrolidin-1-ylsulfonyl ⁇ Compound 10 was obtained by using isoquinoline (white crystalline material, 90%).
- Step 2 of Example 1 instead of 6- (4-tert-butoxycarbonylpiperazin-1-ylsulfonyl) isoquinoline, (S) -6- ⁇ 3- (N-butylamino) pyrrolidin-1-ylsulfonyl ⁇ Compound 11 was obtained by using isoquinoline (white crystalline material, 78%).
- Compound 13 was prepared according to the production method of Step 2 of Example 12 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized with (S) -6- (4-tert-butoxycarbonyl-2-methylpiperazin-1-ylsulfonyl) isoquinoline.
- Compound 14 was prepared according to the production method of Step 2 of Example 12 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized with (R) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazocan-1-ylsulfonyl) isoquinoline.
- Compound 15 was prepared according to the production method of Step 2 of Example 12, instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized with (S) -5-bromo-6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline.
- Compound 16 was prepared according to the production method of Step 2 of Example 12 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized using 6- (4-tert-butoxycarbonyl-3-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline.
- Compound 17 was prepared according to the production method of Step 2 of Example 12 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized using 6- (4-tert-butoxycarbonyl-7-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline.
- Compound 18 was prepared according to the production method of Step 2 of Example 12, instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized with (R) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline.
- Compound 19 was prepared according to the production method of Step 2 of Example 12, instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. It was synthesized using (R) -6- (4-tert-butoxycarbonyl-2-ethyl-1,4-diazepan-1-ylsulfonyl) isoquinoline.
- Compound 20 was prepared according to the production method of Step 2 of Example 12 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized with (R) -6- (4-tert-butoxycarbonyl-2-ethyl-1,4-diazocan-1-ylsulfonyl) isoquinoline.
- Compound 23 was prepared according to the production method of Step 2 of Example 12, instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized using (R) -5-bromo-6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazocan-1-ylsulfonyl) isoquinoline (white crystalline material, 64%).
- Compound 24 was prepared according to the production method of Step 2 of Example 12 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized with (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazocan-1-ylsulfonyl) isoquinoline (white crystalline material, 21%).
- Compound 25 was synthesized according to the production method of Step 3 of Example 22 using (R) -6- (2-methyl-1,4-diazepan-1-ylsulfonyl) -7-fluoroisoquinoline ( Pale yellow crystalline material, 82%).
- Compound 26 was prepared according to the production method of Step 2 of Example 12, instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized with (S) -6- (4-tert-butoxycarbonyl-2-fluoromethyl-1,4-diazepan-1-ylsulfonyl) isoquinoline (white crystalline material, 20%).
- Compound 27 was prepared according to the production method of Step 2 of Example 12 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized with (S) -6- (4-tert-butoxycarbonyl-2-fluoromethyl-1,4-diazocan-1-ylsulfonyl) isoquinoline (white crystalline material, 50%).
- Compound 28 was prepared according to the production method of Step 2 of Example 12 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized with (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazonan-1-ylsulfonyl) isoquinoline (white crystalline material, 42%).
- Compound 29 was prepared according to the production method of Step 2 of Example 12, instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized using (R) -5-bromo-6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline (white crystalline material, 14%).
- Step 2 of Example 22 synthesis was performed using (R) -6- ⁇ 2- (tert-butoxycarbonyl-4-hydroxy-3-methylbutylamino) ethylaminosulfonyl ⁇ isoquinoline (brown Oily substance, 52%).
- Compound 32 was synthesized according to the production method of Step 2 of Example 22 using (R) -6- ⁇ 2- (3-hydroxybutyl-tert-butoxycarbonylamino) ethylaminosulfonyl ⁇ isoquinoline. (White crystalline material, 50%).
- Compound 34 was prepared according to the production method of Step 2 of Example 12 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized using (R) -6- (7-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline (white crystalline material, 50%).
- Compound 35 was prepared according to the production method of Step 2 of Example 12, instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized using (2R, 7R) -6- (4-tert-butoxycarbonyl-2,7-dimethyl-1,4-diazepan-1-ylsulfonyl) isoquinoline (white crystalline material, 38%).
- Compound 36 was prepared according to the production method of Step 2 of Example 12 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized using (2S, 7R) -6- (4-tert-butoxycarbonyl-2,7-dimethyl-1,4-diazepan-1-ylsulfonyl) isoquinoline (white crystalline material, 57%).
- Compound 37 was prepared according to the production method of Step 2 of Example 12, instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized using (R) -6- (4-tert-butoxycarbonyl-8-methyl-1,4-diazocan-1-ylsulfonyl) isoquinoline (white crystalline material, 58%).
- Compound 38 was prepared according to the production method of Step 2 of Example 12 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized with (R) -6- (4-tert-butoxycarbonyl-2-methyl-1,5-diazocan-1-ylsulfonyl) isoquinoline (white crystalline material, 54%).
- Compound 39 was prepared according to the production method of Step 2 of Example 12 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized using (R) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazocan-1-ylsulfonyl) -5-nitroisoquinoline (white crystalline material, 74%).
- Compound 40 was prepared according to the production method of Step 2 of Example 12, instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized using (2R, 6R) -6- (4-tert-butoxycarbonyl-2,6-dimethylpiperazin-1-ylsulfonyl) isoquinoline (white crystalline material, 45%).
- Compound 43 was prepared according to the production method of Step 2 of Example 12, instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized using (R) -6- (7-tert-butoxycarbonyl-5-methyl-1,4,7-oxadiazonan-4-ylsulfonyl) isoquinoline (white crystalline material, 77%).
- Compound 44 was prepared according to the production method of Step 2 of Example 12 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized using (R) -6- (4,7-di-tert-butoxycarbonyl-2-methyl-1,4,7-triazonan-1-ylsulfonyl) isoquinoline (white crystalline material, 34%).
- Compound 45 was prepared according to the production method of Step 2 of Example 12, instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized using 6- (4-tert-butoxycarbonylglycyl-1,4-diazepan-1-ylsulfonyl) isoquinoline.
- Compound 46 was prepared according to the production method of Step 2 of Example 12, instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. It was synthesized using (S) -6- (4-tert-butoxycarbonylglycyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline.
- Compound 47 was prepared according to the production method of Step 2 of Example 12 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized using (R) -6- (4-tert-butoxycarbonylglycyl-2-methyl-1,4-diazocan-1-ylsulfonyl) isoquinoline (white crystalline material, 53%).
- Compound 48 was prepared according to the production method of Step 2 of Example 12 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized using (R) -6- (4-tert-butoxycarbonylsarcosyl-2-methyl-1,4-diazocan-1-ylsulfonyl) isoquinoline (white crystalline material, 53%).
- Compound 49 was prepared according to the production method of Step 2 of Example 12, instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized with (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) -5-methylisoquinoline (white crystalline material, 34%).
- Compound 50 was prepared according to the production method of Step 2 of Example 12, instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline.
- (S) -1- ⁇ 2- (tert-butoxycarbonylamino) ethylthio ⁇ -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline was synthesized. .
- Step 1 of Example 50 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline, (R)- Synthesized using 6- (4-tert-butoxycarbonyl-7-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline (colorless oil, 68%).
- Compound 51 was prepared according to the production method of Step 2 of Example 12 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline.
- (R) -1- ⁇ 2- (tert-butoxycarbonylamino) ethylthio ⁇ -6- (4-tert-butoxycarbonyl-7-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline was synthesized. (White crystalline material, 64%).
- Step 1 of Example 50 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline, (R)- Synthesized using 6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazocan-1-ylsulfonyl) isoquinoline (colorless oil, 56%).
- Compound 52 was prepared according to the production method of Step 2 of Example 12, instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline.
- (R) -1- ⁇ 2- (tert-butoxycarbonylamino) ethylthio ⁇ -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazocan-1-ylsulfonyl) isoquinoline was synthesized. (White crystalline material, 47%).
- Step 1 of Example 50 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline, 6- (4-tert-butoxy Synthesized using carbonyl-1,4-diazepan-1-ylsulfonyl) isoquinoline (colorless oil, 99%).
- 6- (4-tert-Butoxycarbonyl-1,4-diazepan-1-ylsulfonyl) isoquinoline 2-oxide 300 mL of methanol in 5 mL solution was stirred dropwise at 0 degree with 0.2 mL of triethylamine and 0.1 mL of ethyl chlorocarbonate added dropwise. And stirred at room temperature for 3 hours. After completion of the reaction, 20 mL of ethyl acetate was added to the residue obtained by evaporating the reaction solvent under reduced pressure, and the precipitated insoluble matter was removed by filtration.
- Compound 54 was prepared according to the production method of Step 2 of Example 12 instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized using 1-amino-6- (4-tert-butoxycarbonyl-1,4-diazepan-1-ylsulfonyl) isoquinoline (92%).
- Step 2 of Example 1 instead of 6- (4-tert-butoxycarbonylpiperazin-1-ylsulfonyl) isoquinoline, 1-nitrile-6- (4-tert-butoxycarbonyl-1,4-diazepan-1- Compound 55 was obtained by using (ylsulfonyl) isoquinoline.
- Compound 56 was prepared according to the production method of Step 2 of Example 12, instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline.
- (S) -6- (4-tert-butoxycarbonyl-2- (4-tert-butoxycarbonylaminobutyl) -1,4-diazepan-1-ylsulfonyl) isoquinoline was used for synthesis.
- Step 1 of Example 1 synthesis was performed using methyl isonipecotate instead of tert-butoxycarbonylpiperazine.
- Step 2 of Example 1 compound 57 was obtained by substituting 6- (4-methoxycarbonylpiperidin-1-ylsulfonyl) isoquinoline for 6- (4-tert-butoxycarbonylpiperazin-1-ylsulfonyl) isoquinoline.
- Step 1 of Example 1 synthesis was performed using (S) -3-hydroxypyrrolidine instead of tert-butoxycarbonylpiperazine.
- Step 2 of Example 1 by using (S) -6- (3-hydroxypyrrolidin-1-ylsulfonyl) isoquinoline instead of 6- (4-tert-butoxycarbonylpiperazin-1-ylsulfonyl) isoquinoline Compound 58 was obtained.
- Compound 56 was prepared according to the production method of Step 2 of Example 12, instead of (S) -6- (4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl) isoquinoline. Synthesized using 5-phenyl-6- (4-tert-butoxycarbonyl-1,4-diazepan-1-ylsulfonyl) isoquinoline.
- Evaluation example 1 of biological activity evaluation Blood pressure lowering action in rats of the compound of the present invention
- Example 18 was used as a test compound.
- test compound solution preparation of test compound solution
- the test compound was dissolved and diluted in physiological saline to prepare a test compound solution having a predetermined concentration.
- Test method The test drug was administered intraperitoneally to rats (6 rats per group) at a dose of 10 mg / kg, and blood pressure and pulse rate were measured over time using a non-invasive blood pressure measuring device BP-98A manufactured by Softron.
- Evaluation example 2 Blood pressure lowering effect of the compound of the present invention in spontaneously hypertensive rats
- the compound of the present invention was intraperitoneally administered to spontaneously hypertensive rats (SHR / Izm, sex: male, 4 to 6 mice per group) to evaluate the blood pressure lowering effect.
- Examples 32, 34, and 35 were used as test compounds.
- test compound solution preparation of test compound solution
- the test compound was dissolved and diluted in physiological saline to prepare a test compound solution having a predetermined concentration.
- Test method A test drug was administered intraperitoneally to animals (4-6 animals per group) at a dose of 10 mg / kg (30 mg / kg only in Example 34), and a non-invasive blood pressure measuring device BP-98A manufactured by Softron was used. Blood pressure and pulse rate were measured over time.
- the systolic blood pressure of the animals to which the compound of the present invention was administered was maximal compared to the pre-dose value, and Examples 34 and 35 were reduced by 30% or more.
- Example 32 was lowered by 16%.
- the pulse rate measured increased. This was considered to be a decrease in blood pressure due to vasodilation and an increase in pulse rate as a compensation. From these results, it was found that the compound of the present invention is useful as a therapeutic agent for cardiovascular diseases including hypertension.
- test compound solution Test compound dissolved in base (1.04 g sodium dihydrogen phosphate dihydrate, 0.5 g sodium chloride dissolved in purified water, adjusted to pH 7.0 with sodium hydroxide to a total volume of 100 mL) Then, a test compound solution having a concentration of 1% (W / V) was prepared.
- Test method Immediately before the test compound was administered to the rabbit, the intraocular pressure was measured using a Tonovet hand-held tonometer manufactured by Tiorato. The test compound solution was instilled into one eye and 0.04 mL of the base alone was instilled into the contralateral eye, and the intraocular pressure was similarly measured over time. The ratio of the intraocular pressure of the test compound solution-administered eye to the intraocular pressure of the base-administered eye was calculated as the degree of decrease.
- NG108-15 cells which are frequently used as nerve model cells, are cultured in the presence of the compound of the present invention, and the nerve axon stretching action is exhibited. evaluated. Examples 15 and 49 were used as test compounds.
- test compound solution A test compound was dissolved and diluted in dimethyl sulfoxide to prepare a test compound solution having a predetermined concentration.
- NG108-15 cells obtained from ATCC were cultured in Dulbecco's modified Eagle's medium containing 5% fetal calf serum and 1 ⁇ HAT (hypoxanthine, aminopterin, thymidine). Cells were seeded in a 24-well plate at 12,000 cells / well, and allowed to stand for 12 hours in an environment of 37 ° C., 5% CO 2 , and 95% air, followed by a final concentration of 10, 3, 1,. The test compound was added so that it might become 3 micromol / L. After 24 hours, the degree of nerve axon extension was observed under an inverted microscope.
- Example 14 was dissolved and diluted in physiological saline to prepare a test compound solution having a predetermined concentration.
- Test method According to the method described in the paper (Acta Neuropathol. 100, 13-22 (2000)), C57BL / 6Cr mice (female, body weight around 19 g, 6-8 mice per group) were inhaled by halothane inhalation, and the spinal cord at the 8th thoracic vertebra level The spinal cord injury model was created by pressing the stool with a 20 g weight for 5 minutes. The test compound was intraperitoneally administered at a dose of 3 mg / kg once a day for 7 days continuously from the day of surgery. 1, 4, 7, 10, and 14 days after the spinal cord injury model was created, the behavioral score described in J. Neurosurg. 93 (1 Suppl.), 94, 101 (2000) was partially corrected to score the degree of neuropathy. .
- the neuropathy score of each group was 41 points in the physiological saline-administered group, and 33 points in the test compound-administered group.
- the compound of the present invention showed an action to restore motor function after spinal cord injury. This indicates that the compound of the present invention is useful as a therapeutic agent for spinal cord injury.
Abstract
Description
R1及びR2はそれぞれ独立して水素原子、ハロゲン原子、シアノ基、アルキル基、ハロゲノアルキル基、アルケニル基、アルコキシ基、アルキルチオ基、ヒドロキシ基、メルカプト基、ニトロ基、アリール基、アミノ基又はアミノアルキルチオ基を示し;
R3及びR4はそれぞれ独立して水素原子、アルキル基、アルケニル基、アミノ基、アルキルアミノ基、ジアルキルアミノ基、アミノアルキル基、ハロゲノアルキル基、アルカノイル基、アミノアルカノイル基、アルキルアミノアルカノイル基、アルコキシカルボニル基、ヒドロキシ基又はメルカプト基を示すか、あるいはR3とR4が一緒になってアルキレン基又はアルケニレン基を形成し、任意の位置へ2つの炭素間で架橋していてもよく;
l、m及びnは1~4の数を示す。)
で表されるイソキノリン-6-スルホンアミド誘導体、その塩又はそれらの溶媒和物を提供するものである。
また本発明は、緑内障、循環器疾患、又は神経変性若しくは神経損傷に起因する疾患若しくは障害を予防又は治療するための上記一般式(1)で表されるイソキノリン-6-スルホンアミド誘導体、その塩又はそれらの溶媒和物を提供するものである。
さらに本発明は、上記一般式(1)で表されるイソキノリン-6-スルホンアミド誘導体、その塩又はそれらの溶媒和物の有効量を投与することを特徴とする緑内障、循環器疾患、又は神経変性若しくは神経損傷に起因する疾患若しくは障害の予防治療方法を提供するものである。
具体例としては、メチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、イソブチル基、sec-ブチル基、tert-ブチル基、n-ペンチル基、イソペンチル基、n-ヘキシル基、イソヘキシル基、シクロプロピル基を挙げることができる。なかでも炭素数1~3のものが好ましく、特にメチル基、エチル基が好ましい。
アルキルアミノ基としては、C1-8アルキルアミノ基が好ましく、具体例としてはメチルアミノ基、エチルアミノ基、n-プロピルアミノ基、イソプロピルアミノ基、n-ブチルアミノ基、イソブチルアミノ基、sec-ブチルアミノ基、n-ペンチルアミノ基、n-ヘキシルアミノ基等が挙げられる。ジアルキルアミノ基としては、ジ-C1-8アルキルアミノ基が好ましく、具体例としてはジメチルアミノ基、ジエチルアミノ基、ジプロピルアミノ基、ジブチルアミノ基等が挙げられる。アミノアルキル基としては、アミノC1-8アルキル基が好ましく、具体例としてはアミノメチル基、アミノエチル基、アミノプロピル基、アミノブチル基等が挙げられる。
また、R3及びR4としては、それぞれ独立して水素原子、C1-8アルキル基、アミノ基、C1-8アルキルアミノ基、アミノC1-8アルキル基又はハロゲノC1-8アルキル基であるか、あるいはR3とR4とが一緒になって架橋C1-3のアルキレン基を形成するのがより好ましい。
さらにR3及びR4は水素原子、C1-6アルキル基又はハロゲノC1-6アルキル基であるのが好ましい。
6-(ピペラジン-1-イルスルホニル)イソキノリン、
(R)-6-(3-アミノピロリジン-1-イルスルホニル)イソキノリン、
6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
6-(4-アミノピペリジン-1-イルスルホニル)イソキノリン、
5-ブロモ-6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
6-(1,4-ジアゼパン-1-イルスルホニル)-8-フルオロイソキノリン、
6-{(1S,4S)-2,5-ジアザビシクロ[2.2.1]ヘプタン-2-イルスルホニル}イソキノリン、
(R,Z)-6-(2-メチル-2,3,4,5-テトラヒドロ-1,4-ジアゾシン-1(8H)-イルスルホニル)イソキノリン、
6-(モルホリン-1-イルスルホニル)イソキノリン、
(S)-6-{3-(N-メチルアミノ)ピロリジン-1-イルスルホニル}イソキノリン、
(S)-6-{3-(N-ブチルアミノ)ピロリジン-1-イルスルホニル}イソキノリン、
(S)-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(S)-6-(2-メチルピペラジン-1-イルスルホニル)イソキノリン、
(R)-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
(S)-5-ブロモ-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
6-(3-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
6-(7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-6-(2-エチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-6-(2-エチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
6-(1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
6-(2,2-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-5-ブロモ-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
(S)-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
(R)-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)-7-フルオロイソキノリン、
(S)-6-(2-フルオロメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(S)-6-(2-フルオロメチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
(S)-6-(2-メチル-1,4-ジアゾナン-1-イルスルホニル)イソキノリン、
(R)-5-ブロモ-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-6-(6-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
(R)-6-(7-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
(S)-6-(7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-6-(2-メチル-1,4-ジアゾナン-1-イルスルホニル)イソキノリン、
(R)-6-(7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(2R,7R)-6-(2,7-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(2S, 7R)-6-(2, 7-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-6-(8-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
(R)-6-(2-メチル-1,5-ジアゾカン-1-イルスルホニル)イソキノリン、
(R)-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)-5-ニトロイソキノリン、
(2R, 6R)-6-(2, 6-ジメチルピペラジン-1-イルスルホニル)イソキノリン、
(2S, 7S)-6-(2, 7-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(S)-6-(2-メチル-1,5-ジアゾカン-1-イルスルホニル)イソキノリン、
(R)-6-(5-メチル-1,4, 7-オキサジアゾナン-4-イルスルホニル)イソキノリン、
(R)-6-(2-メチル-1,4,7-トリアゾナン-1-イルスルホニル)イソキノリン、
6-(4-グリシル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(S)-6-(4-グリシル-2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-6-(4-グリシル-2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
(R)-6-(4-サルコシル-2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
(S)-5-メチル-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(S)-1-(2-アミノエチルチオ)-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-1-(2-アミノエチルチオ)-6-(7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-1-(2-アミノエチルチオ)-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン-1(2H)-オン、
1-アミノ-6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
1-ニトリル-6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(S)-6-(2-(4-アミノブチル)-1、4-ジアゼピン-1-イルスルホニル)イソキノリン、
6-(4-メトキシカルボニルピペリジン-1-イルスルホニル)イソキノリン、
(S)-6-(3-ヒドロキシピロリジン-1-イルスルホニル)イソキノリン、
5-フェニル-6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン
から成る群より選択される化合物、その塩又はその溶媒和物。
製造法1
一般式(1a)で表されるハロゲン体をR10及びR11に対応するグリニヤール試薬若しくはアルキルリチウムなどの有機金属試薬、アルカリ金属水酸化物(例、水酸化ナトリウム、水酸化カリウム)、ナトリウムアルコラート(例、ナトリウムメチラート、ナトリウムエチラート)などのアルカリ、又はシアン化カリウムで処理することにより化合物(1b)を製造する。本反応は、公知の方法に準じて行うことができる。
またパラジウム触媒存在下に行なわれる鈴木―宮浦カップリングを用いても合成できる。
化合物(1c)をXに対応するアミン、グアニジン又はアンモニアと反応させることにより化合物(1d)を製造する。本反応は、公知の方法(Acta Chemica Scand., 45,621(1991))に準じて行うことができる。
化合物(1d)は、化合物(1g)をトリフェニルホスフィンなどの有機リン試薬とアゾジカルボン酸ジエチル又はアゾジカルボン酸ジイソプロピルなどのアゾ試薬を用いて分子内脱水反応(いわゆる光延反応)を行い、続いて保護基R12を除去することによって得ることができる。
(第2工程)化合物(1h)のヒドロキシ基をそれ自体公知の方法で、ハロゲン(例、塩素、臭素)、アシルオキシ(例、トシルオキシ、メタンスルホニルオキシ、アセチルオキシ)に変換して、その後化合物(1i)を製造する。
(第3工程)化合物(1i)とアミノアルキルアルコールを適当な溶媒中、塩基の存在又は不存在下で、製造法1と同様に反応させることにより、化合物(1g)を製造する。
また、化合物(1g)は、化合物(2)と対応するアミノアルコールを反応させることにより1工程で合成することも可能である。
(第4工程)化合物(1g)の2級アミノの窒素原子を必要に応じて、公知の方法で保護した後、常法に従い化合物(1g)を化合物(1j)に変換することができる。
(第5工程)化合物(1j)を適当な溶媒中、塩基で処理し、必要により酸又はアルカリ処理して保護基を除去して化合物(1d)を製造する。塩基としては、水素化ナトリウム、炭酸水素ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウムのようなアルカリ、トリエチルアミン、トリエチレンジアミン等の有機第3級アミンを用いることができる。反応溶媒として製造法1で例示したものを用い、同様の反応条件で反応させる。
また、化合物(1d)は製造法5に従い、分子内脱水反応(いわゆる光延反応)と続くR12の脱保護により合成することもできる。
式中R13はホルミル基、ハロメチル基、ハロゲン又はアセチルオキシメチル、メシルオキシメチル若しくはトシルオキシメチル等のアシルオキシメチルを挙げることができる。R13がホルミル基の場合、還元的アミノ化により2級アミンを合成し、その後トシル基やメシル基で代表されるスルホニルハライドと反応させることにより化合物(2b)を合成できる。R13がハロメチル基、ハロゲン又はアセチルオキシメチル、メシルオキシメチル若しくはトシルオキシメチル等のアシルオキシメチルの場合、アミンによる置換反応により化合物(2b)を合成できる。化合物(2b)を強酸、及びルイス酸存在下反応させることにより、化合物(2c)を合成できる。化合物(2c)から化合物(2)の合成は、公知の方法を用いて合成できる。
本発明化合物は、公知の方法により、前記した塩を形成させることができる。例えば、本発明化合物の塩酸塩は、本発明化合物を塩化水素のアルコール溶液又はエチルエーテル溶液に溶解することにより得ることができる。
本発明化合物は、結晶多形をとる場合がある。その結晶多形も本発明に含まれる。
より詳細には、高血圧症としては、本態性高血圧症、腎性高血圧症、腎血管性高血圧、妊娠誘発性高血圧、内分泌性高血圧、心臓血管性高血圧、神経性高血圧、医原生高血圧、肺高血圧症等が例示され、動脈硬化症としては、冠動脈・腹部大動脈・腎動脈・頚動脈・眼底動脈・脳動脈等全身主要動脈に病変が生じたものが例示される。脳循環障害としては、脳血栓、脳梗塞、脳出血、一過性脳虚血発作、高血圧性脳症、脳動脈硬化症、硬膜下血腫、硬膜外血腫、クモ膜下出血、脳低酸素症、脳浮腫、脳炎、脳膿瘍、頭部外傷、精神病、代謝中毒、薬物中毒、一過性の呼吸停止、手術時の深麻酔等が例示される。心臓病は、うっ血性心不全、急性心筋梗塞、陳旧性心筋梗塞、心内膜下梗塞、右室梗塞、非定型的心筋梗塞、虚血性心筋症、異型狭心症、安定狭心症、労作性狭心症、冠レン縮性狭心症、梗塞後狭心症、不安定狭心症、不整脈、急性心臓死等を含む。
末梢循環障害には、バージャー病、閉塞性動脈硬化症、レイノー症候群等の動脈疾患及び静脈血栓症、血栓性静脈炎等の静脈疾患、血液の過粘性症候群、凍傷・凍創、冷え性による冷感及び入眠障害、褥創、ひび・あかぎれ、脱毛が含まれる。
また、末梢神経系に関する疾患として、例えば、三叉神経障害、顔面神経障害、単ニューロパチー、多発性ニューロパチー、糖尿病性ニューロパチー、外傷性神経麻痺を含むがこれらに限定されない。
また、網膜神経及び視神経に関する疾患として例えば、緑内障、加齢黄斑変性症、網膜色素変性症、糖尿病性網膜症、網膜神経炎、視神経炎、視神経断裂、外傷性視神経症を含むがこれらに限定されない。
例えば、錠剤、カプセル剤、顆粒剤、散剤等の経口剤は、乳糖、マンニトール、デンプン、結晶セルロース、軽質無水ケイ酸、炭酸カルシウム、リン酸水素カルシウム等の賦形剤、ステアリン酸、ステアリン酸マグネシウム、タルク等の滑沢剤、デンプン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン等の結合剤、カルボキシメチルセルロース、低置換度ヒドロキシプロピルメチルセルロース、クエン酸カルシウム等の崩壊剤、ヒドロキシプロピルメチルセルロース、マクロゴール、シリコーン樹脂等のコーティング剤、パラオキシ安息香酸エチル、ベンジルアルコール等の安定化剤、甘味料、酸味料、香料等の矯味矯臭剤等を必要に応じて本発明化合物に組合わせて、調製することができる。
また、注射剤、点眼剤等の非経口剤は、例えば、グリセリン、プロピレングリコール、塩化ナトリウム、塩化カリウム、ソルビトール、マンニトール等の等張化剤、リン酸、リン酸塩、クエン酸、氷酢酸、ε-アミノカプロン酸、トロメタモール等の緩衝剤、塩酸、クエン酸、リン酸、氷酢酸、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム等のpH調節剤、ポリソルベート80、ポリオキシエチレン硬化ヒマシ油60、マクロゴール4000、精製大豆レシチン、ポリオキシエチレン(160)ポリオキシプロピレン(30)グリコール等の可溶化又は分散剤、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース等のセルロース系高分子、ポリビニルアルコール、ポリビニルピロリドン等の増粘剤、エデト酸、エデト酸ナトリウム等の安定化剤、汎用のソルビン酸、ソルビン酸カリウム、塩化ベンザルコニウム、塩化ベンゼトニウム、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル、クロロブタノール等の保存又は防腐剤、クロロブタノール、ベンジルアルコール、リドカイン等の無痛化剤を必要に応じて本発明化合物に組合わせて、調製することができる。
また、点眼剤であれば通常0.0001%~10%(w/v)、好ましくは0.01%~5%(w/v)の濃度のものを1回又は数回に分けて投与することができる。静脈内投与の場合、1日あたり、0.1~100mg/ヒトの範囲、好ましくは、1~30mg/ヒトの範囲である。経口投与の場合、1日あたり、1~1,000mg/ヒトの範囲、好ましくは、10~30mg/ヒトの範囲である。場合によっては、これ以下でも足りるし、また逆にこれ以上の用量を必要とすることもある。また、1日2~3回に分割して投与することもできる。
(参考例1)
6-アミノイソキノリン(参考化合物1)の合成
1H-NMRスペクトル (CDCl3, δ ppm): 5.54 (br s, 2H), 6.58 (s, 1H), 7.00 (d, J = 9.0 Hz, 1H ), 7.35 (d, J = 5.5 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 8.32 (d, J = 5.5 Hz, 1H), 8.98 (s, 1H)
6-クロロスルホニルイソキノリン(参考化合物2)の合成
6-クロロスルホニル-8-フルオロイソキノリン(参考化合物3)の合成
5-ブロモ-6-クロロスルホニルイソキノリン(参考化合物4)の合成
6-クロロスルホニル-7-フルオロイソキノリン(参考化合物5)の合成
6-クロロスルホニル-5-ニトロイソキノリン(参考化合物6)の合成
以下、参考化合物7~34は、WO2006/115244及びUS2008/064681に準じて合成した。
(R)-4-アミノ-N-(tert-ブトキシカルボニル)-N-(2-ヒドロキシエチル)ペンチルアミン(参考化合物35)の合成
N-[(R)-4-(ベンジルオキシ)-1-メチル-ブト-2-エニル]-トリフルオロアセトアミドの合成
1H-NMRスペクトル(CDCl3, δ ppm): 1.31 (d, J = 6.0 Hz, 1.5H), 1.33 (d, J = 6.0 Hz, 1.5H), 4.14 -4.16 (m, 2H), 4.52 (s, 2H), 4.58-4.63 (m, 0.5H), 4.77-4.79 (m, 0.5H), 5.46-5.50 (m, 0.5H), 5.75 -5.80 (m, 1.5H), 6.17 (br s, 0.5H), 6.43 (br s, 0.5H), 7.30-7.41 (m, 5H)
(R)-4-(トリフルオロアセチルアミノ)-1-ペンタノールの合成
1H-NMRスペクトル(CDCl3, δ ppm):1.24 (d, J = 6.0 Hz, 3H), 1.52 (dd, J = 5.0 Hz, 1H), 1.59 -1.69 (m, 4H), 3.69-3.72 (m, 2H), 4.05-4.08 (m, 1H), 6.59 (br s, 1H)
(R)-4-(ベンジルオキシカルボニルアミノ)-1-ペンタノールの合成
1H-NMRスペクトル(CDCl3, δ ppm):1.15 (d, J = 6.5 Hz, 3 H), 1.25-1.31 (m, 1H), 1.53-1.60 (m, 4H), 3.66-3.77 (m, 3H), 4.59-4.70 (m, 1H), 5.08 (s, 2H), 7.31-7.36 (m, 5H)
(R)-4-アミノ-N-(tert-ブトキシカルボニル)-N-(2-ヒドロキシエチル)ペンチルアミン(参考化合物35)の合成
1H-NMRスペクトル(CDCl3, δ ppm):1.07 (d, J = 6.0 Hz, 3 H), 1.27-1.31 (m, 2H), 1.46 (s, 9H), 1.58 (m, 1H), 1.78-1.85 (m, 4H), 2.88-2.91 (m, 1H), 3.20-3.25 (m, 2H), 3.35-3.40 (m, 2H), 3.70-3.75 (m, 2H)
(R、Z)-4-tert-ブトキシカルボニル-2-メチル-1、2,3,4,5、8-ヘキサヒドロ-1,4-ジアゾシン(参考化合物36)の合成
(R)-N-{1-(アリルアミノ)プロパン-2-イル}-2-ニトロベンゼンスルホンアミドの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.16 (d, J = 6.7 Hz, 3H), 2.60 (ddd, J = 26.7, 12.7, 6.0 Hz, 2H), 3.08 (d, J = 6.1 Hz, 2H), 3.50-3.52 (m, 1H), 5.03-5.07 (m, 3H), 5.72-5.75 (m, 1H), 6.21 (br s,1H), 7.73-7.74 (m, 3H), 8.16-8.18 (m, 1H)
(R)-N-[1-{アリル(tert-ブトキシカルボニル)アミノ}プロパン-2-イル]-2-ニトロベンゼンスルホンアミドの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.10 (d, J = 5.9 Hz, 3H), 1.43 (s, 9H), 3.13 (dd, J = 5.0, 14.0 Hz, 1H), 3.24-3.36 (m, 1H), 3.72 (s, 2H), 3.77-3.84 (m, 1H), 5.05-5.11 (m, 2H), 5.68 (br s, 1H), 5.86 (br s, 1H), 7.73 (s, 2H), 7.84 (s, 1H), 8.13 (d, J = 6.2 Hz, 1H)
(R)-N-アリル-N-[1-{アリル(tert-ブトキシカルボニル)アミノ}プロパン-2-イル]-2-ニトロベンゼンスルホンアミドの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.18 (d, J = 6.3 Hz, 3H), 1.45 (s, 9H), 3.20-3.43 (m, 2H), 3.69-3.83 (m, 2H), 3.99 (s, 2H), 4.25 (q, J = 6.4 Hz, 1H), 5.02-5.20 (m, 4H), 5.69-5.78 (m, 2H), 7.62-7.69 (m, 3H), 8.04 (s, 1H)
(R、Z)-4-tert-ブトキシカルボニル-2-メチル-1-(2-ニトロフェニルスルホニル)-1、2,3,4,5、8-ヘキサヒドロ-1,4-ジアゾシンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.07 (d, J = 4.6 Hz, 1.5H), 1.09 (d, J = 4.6 Hz, 1.5H), 1.47 (s, 9H), 3.47-3.65 (m, 1H), 3.80 (d, J = 18.9 Hz, 1H), 4.06-4.28 (m, 5H), 5.71 (s, 2H), 7.66-7.69 (m, 3H), 8.03 (s, 1H)
(R、Z)-4-tert-ブトキシカルボニル-2-メチル-1、2,3,4,5、8-ヘキサヒドロ-1,4-ジアゾシン(参考化合物36)の合成
1H-NMRスペクトル (CDCl3, δ ppm):1.04 (d, J = 3.1 Hz, 1.5H), 1.06 (d, J = 3.1 Hz, 1.5H), 1.46 (s, 9H), 1.78 (br s,1H), 2.82 (dd, J = 9.8, 13.4 Hz, 0.5H), 2.92 (dd, J = 9.8, 14.0 Hz, 0.5H), 3.10-3.16 (m, 1H), 3.30 (dd, J = 4.9, 15.9 Hz, 1H), 3.53-3.67 (m, 2H), 3.87 (d, J = 17.4 Hz, 0.5 H), 3.89 (d, J = 17.4 Hz, 0.5H), 4.16 (dd, J = 4.6, 17.4 Hz, 0.5H), 4.35 (dd, J = 3.4, 17.4 Hz, 0.5H), 5.60-5.76 (m, 2H)
2-アミノ-1-(tert-ブトキシカルボニル-3-ヒドロキシプロピルアミノ)-2-メチルプロパン(参考化合物37)の合成
ベンジル 1-ヒドロキシ2-メチルプロパン-2-イルカルバメートの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.28 (s, 6H), 1.51 (br s,1H), 3.60 (d, J = 6.0 Hz, 2H), 5.29 (s, 2H), 6.12 (s, 1H), 7.26-7.38 (m, 5H)
ベンジル 2-メチル-1-オキソプロパン-2-イルカルバメートの合成
この反応液に、トリエチルアミン3.6mLを滴下し、10分間攪拌した後、-10度まで徐々に昇温しつつ、1時間半攪拌した。反応終了後、反応液に水を加え、ジクロロメタン(30mL×2)で抽出し、抽出液を無水硫酸ナトリウムで乾燥した。ろ過を行い、ろ液を濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=1:2)で精製し、目的物960mgを白色固体として得た。(65%)
1H-NMRスペクトル (CDCl3, δ ppm):1.39 (s, 6H), 5.09 (s, 2H), 6.23 (br s, 1H), 7.28-7.40 (m, 5H), 9.43 (s, 1H)
2-(ベンジルオキシカルボニルアミノ)-1-(tert-ブトキシカルボニル-3-ヒドロキシプロピルアミノ)-2メチルプロパンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.33 (s, 6H), 1.46 (s, 9H), 1.60-1.79 (m, 3H), 3.29-3.63 (br m, 6H), 5.04 (s, 2H), 6.31 (br s, 1H), 7.27-7.37 (m, 5H)
2-アミノ-1-(tert-ブトキシカルボニル-3-ヒドロキシプロピルアミノ)-2-メチルプロパン(参考化合物37)の合成
1H-NMRスペクトル (CDCl3, δ ppm):1.15 (s, 6H), 1.47 (s, 9H), 1.75 (br s, 2H), 1.95 (br s, 3H), 3.12 (br s, 2H), 3.53 (br s, 4H)
6-(ピペラジン-1-イルスルホニル)イソキノリン二塩酸塩(化合物1)の合成
ステップ1
6-(4-tert-ブトキシカルボニルピペラジン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):2.42 (s,9H), 3.11 (d, J= 4.9 Hz, 4H), 3.40 (s, 4H), 7.56 (d, J= 9.2 Hz, 1H), 7.58 (d, J = 5.5 Hz, 1H), 7.83 (s, 1H), 7.93 (d, J= 8.5 Hz, 1H), 8.55 (d, J = 5.5 Hz, 1H), 9.24 (s, 1H)
6-(ピペラジン-1-イルスルホニル)イソキノリン二塩酸塩の合成
1H-NMRスペクトル (DMSO-d6, δppm):2.98 (d, J= 4.3 Hz, 4H), 3.39 (s, 4H), 4.33 (br s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 8.19 (s, 1H), 8.47 (d, J = 8.5 Hz, 1H), 8.50 (br s, 2H), 8.59 (s, 1H), 8.72 (dd, J = 5.5, 11.0 Hz, 1H), 9.58 (s, 1H)
融点:242度
(R)-6-(3-アミノピロリジン-1-イルスルホニル)イソキノリン二塩酸塩(化合物2)の合成
(R)-6-(3-tert-ブトキシカルボニルアミノピロリジン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.37 (s, 9H), 1.77-1.80 (m, 1H), 2.05-2.09 (m, 1H), 3.29 (s, 2H), 3.45-3.52 (m, 2H), 4.09-4.14 (m, 1H), 4.48 (s, 1H), 7.81 (d, J = 5.5 Hz, 1H), 7.96 (dd, J = 1.8, 8.5 Hz, 1H), 8.16 (d, J = 9.2 Hz, 1H), 8.38 (s, 1H), 8.71 (d, J = 5.5 Hz, 1H), 9.39 (s, 1H)
(R)-6-(3-アミノピロリジン-1-イルスルホニル)イソキノリン二塩酸塩(化合物2)の合成
1H-NMRスペクトル (DMSO-d6, δppm):1.83-1.85 (m, 1H), 2.03-2.06 (m, 1H), 3.25-3.28 (m, 1H), 3.31 (dd, J = 10.7, 4.0 Hz, 1H), 3.44 (dd, J = 7.0, 10.7 Hz, 1H), 3.50 (dd, J = 7.9, 16.5 Hz, 1H), 3.70 (s, 1H), 4.36 (br s, 2H), 8.11 (d, J = 5.5 Hz, 1H), 8.38 (d, J = 5.5 Hz, 1H), 8.54 (d, J = 8.5 Hz, 1H), 8.59 (br s, 1H), 8.63 (br s, 1H), 8.69 (s, 1H), 8.75 (d, J = 6.1 Hz, 1H), 9.73 (s, 1H)
融点:281度
6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物3)の合成
6-(4-tert-ブトキシカルボニル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.41 (s, 9H), 1.96-1.97 (m, 2H), 3.31-3.32 (m, 2H), 3.35-3.42 (m, 2H), 3.47-3.58 (m, 4H), 7.78 (d, J= 5.5 Hz, 1H), 7.89 (d, J = 8.5 HZ, 1H), 8.12 (d, J = 8.5 Hz, 1H), 8.34 (s, 1H), 8.68 (d, J = 5.5 Hz, 1H), 9.36 (s, 1H)
6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物3)の合成
1H-NMRスペクトル (D2O, δ ppm): 1.99-2.03 (m, 2H), 3.27 (t, J= 5.5 Hz, 2H), 3.30 (t, J = 5.2 Hz, 2H), 3.41 (t, J = 6.1 Hz, 2H), 3.60 (t, J = 5.5 Hz, 2H), 8.14-8.15 (m, 1H), 8.41-8.46 (m, 1H), 8.53 (d, J = 6.7 Hz, 2H), 8.66 (s, 1H), 9.65 (dd, J = 5.2, 8.2 Hz, 1H)
融点:204度
6-(4-アミノピペリジン-1-イルスルホニル)イソキノリン二塩酸塩(化合物4)の合成
6-{4-(tert-ブトキシカルボニルアミノ)ピペリジン-1-イルスルホニル}イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.40 (s, 9H), 1.48-1.53 (m, 2H), 2.00 (d, J = 12.2 Hz, 2H), 2.56 (t, J = 11.6 Hz, 2H), 3.40 (s, 1H), 3.80 (d, J = 10.4 Hz, 2H), 4.39 (s, 1H), 7.80 (d, J = 5.5 Hz, 1H), 7.88 (d, J= 8.5 Hz, 1H), 8.15 (d, J = 9.2 Hz, 1H), 8.32 (s, 1H), 8.71 (d, J= 5.5 Hz, 1H), 9.40 (s, 1H)
6-(4-アミノピペリジン-1-イルスルホニル)イソキノリン二塩酸塩(化合物4)の合成
1H-NMRスペクトル (DMSO-d6, δppm):1.54 (dd, J= 3.8, 11.7 Hz, 2H), 1.94 (d, J= 10.4 Hz, 2H), 2.49-2.52 (m, 2H), 3.01-3.03 (m, 1H), 3.74 (d, J = 12.8 Hz, 2H), 5.13 (bs s, 2H), 8.01 (dd, J = 1.2, 8.5 Hz, 1H), 8.02 (br s, 2H), 8.28 (d, J = 5.5 Hz, 1H), 8.49 (d, J = 9.2 Hz, 1H), 8.59 (s, 1H), 8.73 (d, J= 6.1 Hz, 1H), 9.66 (s, 1H)
融点:290度
5-ブロモ-6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物5)の合成
1H-NMRスペクトル (DMSO-d6, δppm):2.05 (t, J= 4.9 Hz, 2H), 3.19-3.25 (m, 4H), 3.50 (t, J = 6.1 Hz, 2H), 3.76 (t, J= 4.6 Hz, 2H), 4.96 (br s, 1H), 8.12 (br s, 2H), 8.20 (d, J = 8.5 Hz, 1H), 8.27 (d, J = 6.1 Hz, 1H), 8.40 (d, J = 8.5 Hz, 1H), 8.81 (d, J = 6.1 Hz, 1H), 9.61 (s, 1H)
融点:215度
6-(1,4-ジアゼパン-1-イルスルホニル)-8-フルオロイソキノリン二塩酸塩(化合物6)の合成
1H-NMRスペクトル (DMSO-d6, δppm): 1.96-2.00 (m, 2H), 3.15 (s, 2H), 3.20 (s, 2H), 3.41 (t, J = 5.8 Hz, 2H), 3.62 (t, J = 4.9 Hz, 2H), 4.52 (br s, 1H), 7.88 (dd, J = 1.2, 9.8 Hz, 1H), 8.22 (d, J = 5.5 Hz, 1H), 8.27 (br s, 2H), 8.45 (s, 1H), 8.82 (d, J = 5.5 Hz, 1H), 9.62 (s, 1H)
融点:208度
6-{(1S,4S)-2,5-ジアザビシクロ[2.2.1]ヘプタン-2-イルスルホニル}イソキノリン二塩酸塩(化合物7)の合成
6-{(1S,4S)-4-tert-ブトキシカルボニル-2,5-ジアザビシクロ[2.2.1]ヘプタン-2-イルスルホニル}イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.39-1.43 (m, 1H), 1.58 (s, 9H), 1.74 (m, 1H), 3.26-3.33 (m, 2H), 3.43-3.52 (m, 2H), 4.36 (s, 0.5 H), 4.47 (s, 0.5 H), 4.56 (s, 1H), 7.80 (s, 1H), 7.98 (d, J = 7.9 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 8.39 (s, 1H), 8.71 (br s, 1H), 9.40 (br s, 1H)
6-{(1S,4S)-2,5-ジアザビシクロ[2.2.1]ヘプタン-2-イルスルホニル}イソキノリン二塩酸塩(化合物7)の合成
1H-NMRスペクトル (D2O, δ ppm):1.38 (d, J = 11.6 Hz, 1H), 1.75 (d, J = 11.6 Hz, 1H), 3.28 (dd, J = 2.4, 11.6 Hz, 2H), 3.43 (td, J = 2.2, 10.8 Hz, 2H), 3.61 (d, J = 11.0 Hz, 1H), 4.34 (s, 1H), 8.21-8.23 (m, 1H), 8.44 (t, J = 5.5 Hz, 1H), 8.57 (d, J = 7.3 Hz, 2H), 8.72 (s, 1H), 9.67 (s, 1H)
融点:192度
(R,Z)-6-(2-メチル-2,3,4,5-テトラヒドロ-1,4-ジアゾシン-1(8H)-イルスルホニル)イソキノリン二塩酸塩(化合物8)の合成
(R,Z)-6-(4-tert-ブトキシカルボニル-2-メチル-2,3,4,5-テトラヒドロ-1,4-ジアゾシン-1(8H)-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.98 (d, J = 5.2 Hz, 1.5H), 1.00 (d, J = 5.2 Hz, 1.5Hz), 1.47 (s, 9H), 3.59 (m, 3H), 3.71 (d, J = 17.1 Hz, 1H), 4.07-4.14 (m, 1H), 4.22-4.29 (m, 2H), 5.61-5.70 (m, 1H), 5.76-5.81 (m, 1H), 7.78 (d, J = 5.5 Hz, 1H), 7.90 (dd, J = 1.8, 8.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.37 (s, 1H), 8.68 (d, J = 6.1 Hz, 1H), 9.36 (s, 1H)
(R,Z)-6-(2-メチル-2,3,4,5-テトラヒドロ-1,4-ジアゾシン-1(8H)-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.96 (d, J = 6.1 Hz, 3H), 2.59 (br s, 1H), 2.73 (dd, J = 2.4, 14.6 Hz, 1H), 3.04 (dd, J = 6.1, 14.6 Hz, 1H), 3.52 (dd, J = 4.3, 16.5 Hz, 1H), 3.78 (dd, J = 5.2, 16.2 Hz, 1H), 4.08-4.14 (m, 2H), 4.27 (dd, J = 5.5, 16.5 Hz, 1H), 5.53-5.57 (m, 1H), 5.83-5.88 (m, 1H), 7.78 (d, J = 5.5 Hz, 1H), 7.95 (dd, J = 1.2, 8.5 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.40 (s, 1H), 8.67 (d, J = 6.1 Hz, 1H), 9.35 (s, 1H)
(R,Z)-6-(2-メチル-2,3,4,5-テトラヒドロ-1,4-ジアゾシン-1(8H)-イルスルホニル)イソキノリン二塩酸塩(化合物8)の合成
1H-NMRスペクトル (D2O, δ ppm):0.71 (d, J = 6.7 Hz, 3H), 3.11 (dd, J = 3.1, 14.6 Hz, 1H), 3.21 (t, J = 13.4 Hz, 1H), 3.57 (dd, J = 8.9, 13.7 Hz, 1H), 3.84 (d, J = 20.1 Hz, 1H), 4.53 (m, 3H), 5.61 (d, J = 11.0 Hz, 1H), 6.07 (d, J = 11.0 Hz, 1H), 8.20 (t, J = 6.7 Hz, 1H), 8.38-8.44 (m, 1H), 8.54 (dd, J = 6.7, 14.6 Hz, 2H), 8.71 (s, 1H), 9.63 (d, J = 7.3 Hz, 1H)
[α]25 D-59.0(c=0.031,H2O)
6-(モルホリン-1-イルスルホニル)イソキノリン塩酸塩(化合物9)の合成
6-(モルホリン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):3.10 (t, J = 4.6 Hz, 4H), 3.76 (t, J = 4.6 Hz, 4H), 7.81 (d, J = 5.5 Hz, 1H), 7.89 (dd, J = 1.2, 8.5 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.33 (s, 1H), 8.71 (d, J = 5.5 Hz, 1H), 9.41 (s, 1H)
6-(モルホリン-1-イルスルホニル)イソキノリン塩酸塩(化合物9)の合成
1H-NMRスペクトル (D2O, δ ppm):3.08 (t, J = 4.6 Hz, 4H), 3.66 (t, J = 4.6 Hz, 4H), 8.14 (d, J = 8.5 Hz, 1H), 8.47 (d, J = 6.7 Hz, 1H), 8.57 (t, J = 7.0 Hz, 2H), 8.64 (s, 1H), 9.69 (s, 1H)
融点:202度
(S)-6-{3-(N-メチルアミノ)ピロリジン-1-イルスルホニル}イソキノリン二塩酸塩(化合物10)の合成
(S)-6-{3-(tert-ブトキシカルボニルアミノ)ピロリジン-1-イルスルホニル}イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.37 (s, 9H), 1.79 (br s, 1H), 2.06-2.09 (m, 1H), 3.26-3.33 (m, 2H), 3.44-3.52 (m, 2H), 4.10 (s, 1H), 4.49 (s, 1H), 7.82 (d, J = 4.3 Hz, 1H), 7.96 (dd, J = 1.2, 8.5 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.38 (s, 1H), 8.72 (s, 1H), 9.41 (s, 1H)
(S)-6-{3-(N-tert-ブトキシカルボニル-N-メチルアミノ)ピロリジン-1-イルスルホニル}イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.13 (s, 9H), 1.89-1.97 (m, 1H), 1.98-2.04 (m, 1H), 2.71 (s, 3H), 3.15 (s, 1H), 3.23 (t, J = 7.9 Hz, 1H), 3.40 (t, J = 8.5 Hz, 1H), 3.60 (s, 1H), 4.62 (br s, 1H), 7.81 (d, J = 6.1 Hz, 1H), 7.96 (dd, J = 1.2, 8.5 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.38 (s, 1H), 8.70 (d, J = 5.5 Hz, 1H), 9.39 (s, 1H)
(S)-6-{3-(N-メチルアミノ)ピロリジン-1-イルスルホニル}イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.57 (br s, 1H), 1.62-1.69 (m, 1H), 1.98-2.05 (m, 1H), 2.30 (s, 3H), 3.13 (dd, J = 4.6, 10.1 Hz, 1H), 3.16-3.20 (m, 1H), 3.35-3.40 (m, 1H), 3.42-3.46 (m, 1H), 3.48-3.52 (m, 1H), 7.80 (d, J = 5.5 Hz, 1H), 7.98 (dd, J = 1.2, 8.5 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 8.39 (s, 1H), 8.68 (d, J = 6.1 Hz, 1H), 9.37 (s, 1H)
(S)-6-{3-(N-メチルアミノ)ピロリジン-1-イルスルホニル}イソキノリン二塩酸塩(化合物10)の合成
1H-NMRスペクトル (D2O, δ ppm):1.97-2.03 (m, 1H), 2.13-2.21 (m, 1H), 2.60 (s, 3H), 3.18-3.24 (m, 1H), 3.44 (dd, J = 6.4, 11.3 Hz, 1H), 3.54-3.59 (m, 2H), 3.68-3.72 (m, 1H), 8.19 (dd, J = 2.1, 8.9 Hz, 1H), 8.45 (dd, J = 3.4, 6.4 Hz, 1H), 8.56 (d, J = 6.7 Hz, 2H), 8.69 (s, 1H), 9.67 (s, 1H)
融点:189度
[α]25 D+30.3(c=0.038,H2O)
(S)-6-{3-(N-ブチルアミノ)ピロリジン-1-イルスルホニル}イソキノリン二塩酸塩(化合物11)の合成
(S)-6-{3-(N-tert-ブトキシカルボニル-N-ブチルアミノ)ピロリジン-1-イルスルホニル}イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.87 (t, J = 7.3 Hz, 3H), 1.18-1.23 (m, 2H), 1.34 (s, 9H), 1.39-1.44 (m, 2H), 1.94-2.05 (m, 2H), 2.96-3.07 (m, 2H), 3.18-3.22 (m, 2H), 3.50 (t, J = 9.2 Hz, 1H), 3.55 (s, 1H), 4.27 (br s, 1H), 7.80 (d, J = 5.5 Hz, 1H), 7.97 (dd, J = 1.8, 8.5 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 8.38 (s, 1H), 8.70 (d, J = 6.1 Hz, 1H), 9.39 (s, 1H)
(S)-6-{3-(N-ブチルアミノ)ピロリジン-1-イルスルホニル}イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.81 (t, J = 7.0 Hz, 3H), 1.14-1.29 (m, 5H), 1.60-1.66 (m, 1H), 1.99-2.06 (m, 1H), 2.38-2.47 (m, 2H), 3.08 (dd, J = 4.9, 10.4 Hz, 1H), 3.23-3.27 (m, 1H), 3.36-3.45 (m, 2H), 3.52 (dd, J = 6.1, 10.4 Hz, 1H), 7.80 (d, J = 5.5 Hz, 1H), 7.98 (dd, J = 1.8, 8.5 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.39 (s, 1H), 8.69 (d, J = 5.5 Hz, 1H), 9.38 (s, 1H)
(S)-6-{3-(N-ブチルアミノ)ピロリジン-1-イルスルホニル}イソキノリン二塩酸塩(化合物11)の合成
1H-NMRスペクトル (D2O, δ ppm):0.76 (t, J = 7.3 Hz, 3H), 1.20-1.25 (m, 2H), 1.46-1.52 (m, 2H), 1.94-1.99 (m, 1H), 2.15-2.21 (m, 1H), 2.89-2.92 (m, 2H), 3.18-3.23 (m, 1H), 3.46-3.58 (m, 3H), 3.71-3.74 (m, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.54-8.59 (m, 3H), 8.70 (s, 1H), 9.70 (s, 1H)
融点:207度
[α]25 D+30.0(c=0.053,H2O)
(S)-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物12)の合成
(S)-6-(4-tert-ブトキシカルボニル-2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.12 (s, 1.5H), 1.13(s, 1.5H), 1.48 (m, 9H), 1.62 (s, 2H), 2.90 (m, 1H), 3.03-3.08 (m, 4H), 3.30-3.32 (m, 1H), 3.50 (s, 2H), 3.62 (s, 1H), 7.78 (d, J = 5.5 Hz, 1H), 7.94-7.96 (m, 1H), 8.11-8.12 (m, 1H), 8.41 (s, 1H), 8.69 (d, J = 3.7 Hz, 1H), 9.37 (s, 1H)
1H-NMRスペクトル (CDCl3, δ ppm):0.95 (d, J = 6.7 Hz, 1.5H), 0.99 (d, J = 6.7 Hz, 1.5H), 1.46 (s, 9H), 1.73-1.78 (m, 2H), 3.09-3.14 (m, 2H), 3.52-3.76 (m, 2H), 3.87 (m, 1H), 3.91 (m, 1H), 4.43 (dd, J= 6.7, 12.8 Hz, 1H), 7.79 (d, J= 5.5 Hz, 1H), 7.92 (t, J = 8.2 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.40 (s, 1H), 8.68 (s, 1H), 9.37 (s, 1H)
(S)-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩の合成
(1)(S)-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.99 (d, J = 6.7 Hz, 3H), 1.66-1.79 (m, 3H), 2.49 (dd, J= 8.5, 14.6 Hz, 1H), 2.65-2.69 (m, 1H), 3.01 (td, J = 4.1, 9.0 Hz, 1H), 3.16-3.20 (m, 2H), 3.85 (d, J = 15.9 Hz, 1H), 4.18 (dd, J = 6.4, 13.7 Hz, 1H), 7.78 (d, J = 5.5 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.45 (s, 1H), 8.67 (d, J = 5.5 Hz, 1H), 9.35 (s, 1H)
1H-NMRスペクトル (D2O, δ ppm):0.81 (d, J = 6.7 Hz, 3H), 1.99 (m, 2H), 3.00 (m, 2H), 3.30 (m, 1H), 3.41 (m, 1H), 3.55 (dd, J = 5.8, 14.3 Hz, 1H), 3.84 (m, 1H), 4.46 (m, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.48 (s, 1H), 8.54 (m, 2H), 8.72 (s, 1H), 9.67 (s, 1H)
融点:232度
[α]25 D+88.3(c=0.043,H2O)
(S)-6-(2-メチルピペラジン-1-イルスルホニル)イソキノリン二塩酸塩(化合物13)の合成
(S)-6-(4-tert-ブトキシカルボニル-2-メチルピペラジン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.95 (m, 3H), 1.40 (s, 9H), 2.00 (d, J = 12.2 Hz, 2H), 2.56 (t, J = 11.6 Hz, 2H), 3.80 (d, J = 10.4 Hz, 2H), 4.39 (s, 1H), 7.80 (d, J = 5.5 Hz, 1H), 7.88 (d, J= 8.5 Hz, 1H), 8.15 (d, J = 9.2 Hz, 1H), 8.43 (s, 1H), 8.71 (d, J= 5.5 Hz, 1H), 9.40 (s, 1H)
(S)-6-(2-メチルピペラジン-1-イルスルホニル)イソキノリン二塩酸塩(化合物13)の合成
1H-NMRスペクトル (D2O, δ ppm):1.07 (d, J = 7.3 Hz, 3H), 2.97 (td, J = 4.3, 12.8 Hz, 1H), 3.11 (dd, J = 4.3, 13.4 Hz, 1H), 3.20 (d, J = 13.4 Hz, 1H), 3.32 (d, J = 12.8 Hz, 1H), 3.42-3.48 (m, 1H), 3.96 (d, 15.3 Hz, 1H), 4.44 (t, J = 5.8 Hz, 1H), 8.17-8.20 (m, 1H), 8.41-8.46 (m, 1H), 8.56 (d, J = 7.3 Hz, 2H), 8.72 (s, 1H), 9.65-9.66 (m, 1H)
融点:229度
[α]25 D+39.7(c=0.045,H2O)
(R)-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物14)の合成
(R)-6-(4-tert-ブトキシカルボニル-2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.84 (d, J = 6.7 Hz, 1.5H), 0.88 (d, J = 6.7 Hz, 1.5H), 1.47 (s, 9H), 1.70-1.81 (m, 2H), 1.91 (s, 2H), 2.99-3.09 (m, 1H), 3.32-3.39 (m, 1H), 3.43-3.53 (m, 3H), 3.62 (td, J = 4.9, 9.8 Hz, 1H), 4.23-4.28 (m, 1H), 7.79 (d, J = 4.3 Hz, 1H), 7.92 (dd, J = 1.2, 8.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.38 (s, 1H), 8.68 (d, J = 5.5 Hz, 1H), 9.36 (s, 1H)
(R)-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物14)の合成
1H-NMRスペクトル (D2O, δ ppm):0.63 (d, J = 6.1 Hz, 3H), 1.76-2.01 (m, 4H), 3.19 (m, 4H), 3.41 (dd, J = 7.6, 13.7 Hz, 1H), 3.65 (d, J = 15.3 Hz, 1H), 4.36-4.41 (m, 1H), 8.26 (d, J = 9.2 Hz, 1H), 8.48 (d, J = 6.7 Hz, 1H), 8.56 (t, J = 8.2 Hz, 2H), 8.75 (s, 1H), 9.35 (s, 1H)
融点:197度
[α]24 D-60.8(c=0.046,H2O)
(S)-5-ブロモ-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物15)の合成
(S)-5-ブロモ-6-(4-tert-ブトキシカルボニル-2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.86 (d, J = 6.4 Hz, 1.5H), 0.90 (d, J = 6.4 Hz, 1.5H), 1.49 (d, J = 2.4 Hz, 9H), 1.83-1.94 (m, 2H), 3.17-3.29 (m, 4H), 3.64-3.71 (m, 2H), 4.29 (t, J = 6.1 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 8.21 (t, J = 4.6 Hz, 1H), 8.32 (dd, J = 8.5, 18.9 Hz, 1H), 8.75 (d, J = 4.3 Hz, 1H), 9.36 (s, 1H)
(S)-5-ブロモ-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物15)の合成
1H-NMRスペクトル (D2O, δ ppm):0.79 (d, J = 6.7 Hz, 3H), 2.03 (m, 2H), 3.11 (m, 2H), 3.41 (td, J = 4.3, 9.2 Hz, 1H), 3.50 (m, 2H), 4.04 (dt, J = 5.3, 10.4 Hz, 1H), 4.35 (m, 1H), 8.30 (d, J = 9.2 Hz, 1H), 8.36 (d, J = 9.2 Hz, 1H), 8.59 (d, J = 6.7 Hz, 1H), 8.62 (d, J = 6.7 Hz, 1H), 9.57 (s, 1H)
融点:251度
6-(3-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物16)の合成
6-(4-tert-ブトキシカルボニル-3-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.07 (d, J = 6.4 Hz, 1.5H), 1.12 (d, J = 6.4 Hz, 1.5H), 1.43 (s, 4.5H), 1.47 (s, 4.5H), 1.95 (br s, 2H), 2.78-2.88 (m, 2H), 3.77-3.94 (m, 3H), 4.32-4.47 (m, 1H), 4.94-4.95 (m, 1H), 7.79 (d, J = 6.1 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 8.11 (s, 1H), 8.37 (s, 1H), 8.68 (s, 1H), 9.36 (d, J = 4.9 Hz, 1H)
6-(3-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物16)の合成
1H-NMRスペクトル (D2O, δ ppm):1.24 (d, J = 6.7 Hz, 3H), 1.94-1.99 (m, 1H), 2.04-2.10 (m, 1H), 3.16-3.20 (m, 1H), 3.22-3.36 (m, 3H), 3.46-3.51 (m, 1H), 3.56-3.62 (m, 1H), 3.68 (m, 1H), 8.12 (dd, J = 1.5, 8.6 Hz, 1H), 8.38 (d, J = 6.7 Hz, 1H), 8.52 (dd, J = 7.9, 10.4 Hz, 2H), 8.64 (s, 1H), 9.62 (s, 1H)
融点:吸湿性により測定不可
6-(7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物17)の合成
6-(4-tert-ブトキシカルボニル-7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.97-1.11 (m, 3H), 1.40 (s, 9H), 1.54-1.73 (m, 2H), 2.56 (t, J = 9.4 Hz, 2H), 3.30 (br s, 2H), 3.78-3.85 (m, 2H), 4.39 (s, 1H), 7.80 (d, J = 5.5 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 8.14-8.16 (m, 2H), 8.71 (d, J = 5.5 Hz, 1H), 9.38 (s, 1H)
6-(7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物17)の合成
1H-NMRスペクトル (D2O, δ ppm):0.75 (d, J = 6.7 Hz, 3H), 1.63 (m, 2H), 2.26-2.33 (m, 1H), 3.02-3.08 (m, 2H), 3.35-3.42 (m, 2H), 3.95-3.97 (m, 1H), 4.17-4.21 (m, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.39 (d, J= 6.7 Hz, 1H), 8.52 (dd, J = 11.3, 7.6 Hz, 2H), 8.69 (s, 1H), 9.61 (s, 1H)
融点:84度(吸湿性のため、測定途中で潮解)
(R)-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物18)の合成
(R)-6-(4-tert-ブトキシカルボニル-2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.95 (d, J = 6.7 Hz, 1.5H), 0.99 (d, J = 6.7 Hz, 1.5H), 1.41 (s, 4.5H), 1.43 (s, 4.5H), 1.67-1.91 (m, 2H), 3.06-3.20 (m, 3H), 3.60-3.76 (m, 2H), 3.88 (d, J = 15.6 Hz, 0.5H), 3.89 (d, J = 15.6 Hz, 0.5H), 4.43 (td, J = 6.3, 12.8 Hz, 1H), 7.77 (d, J = 6.1 Hz, 1H), 7.91 (t, J= 8.9 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 8.39 (s, 1H), 8.67 (d, J= 5.5 Hz, 1H), 9.35 (s, 1H)
(R)-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物18)の合成
1H-NMRスペクトル (D2O, δ ppm):0.83 (d, J = 6.7 Hz, 3H), 1.97-2.09 (m, 2H), 3.00-3.03 (m, 2H), 3.31 (m, 1H), 3.43 (dt, J = 4.5, 9.2 Hz, 1H), 3.57 (dd, J = 6.1, 14.6 Hz, 1H), 3.86 (dt, J = 5.3, 9.9 Hz, 1H), 4.48 (dt, J = 5.0, 12.2 Hz, 1H), 8.24 (d, J = 9.2 Hz, 1H), 8.49 (d, J = 6.1 Hz, 1H), 8.56 (t, J = 7.3 Hz, 2H), 8.74 (s, 1H), 9.69 (s, 1H)
融点:224度
[α]24 D-84.3(c=0.043,H2O)
(R)-6-(2-エチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物19)の合成
(R)-6-(4-tert-ブトキシカルボニル-2-エチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.62-0.75 (m, 3H), 1.39-1.46 (m, 11H), 1.70-1.76 (m, 2H), 3.00-3.04 (m, 1H), 3.39-3.61 (m, 4H), 3.81-4.12 (m, 2H), 7.77 (d, J = 5.5 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H), 8.09 (d, J = 9.0 Hz, 1H), 8.39 (s, 1H), 8.67 (d, J = 5.5 Hz, 1H), 9.35 (s, 1H)
(R)-6-(2-エチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物19)の合成
1H-NMRスペクトル (DMSO-d6, δppm):0.57 (t, J = 7.2 H, 3H), 1.48-1.58 (m, 2H), 1.88-1.90 (m, 3H), 3.05-3.08 (m, 2H), 3.24-3.37 (m, 3H), 3.79-3.84 (m, 1H), 4.22-4.26 (m, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.31 (br s, 1H), 8.46(d, J = 8.5 Hz, 1H), 8.70 (s, 3H), 9.13 (br s, 1H), 9.49 (br s, 1H)
融点:199~200度
[α]26 D-35.0(c=0.049,H2O)
(R)-6-(2-エチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物20)の合成
(R)-6-(4-tert-ブトキシカルボニル-2-エチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.47-0.50 (m, 3H), 1.18-1.27 (m, 2H), 1.46 (s, 9H), 1.71-1.85 (m, 4H), 2.96-3.24 (m, 2H), 3.46-3.94 (m, 5H), 7.78 (d, J = 6.0 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.36 (s, 1H), 8.67 (d, J = 6.0 Hz, 1H), 9.35 (s, 1H)
(R)-6-(2-エチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物20)の合成
1H-NMRスペクトル (DMSO-d6, δppm):0.55 (t, J = 7.2 H, 3H), 1.13-1.21 (m, 1H), 1.36-142 (m, 1H), 1.60-1.84 (m, 4H), 3.06-3.17 (m, 4H),3.26-3.48 (m, 2H), 3.63-3.69 (m, 1H), 4.12-4.16 (m, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.57-8.59 (m, 4H), 8.81 (s, 1H), 9.18 (bs, 1H), 9.47 (br s, 1H)
融点:99~100度
[α]25 D-21.3(c=0.043,H2O)
6-(1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物21)の合成
6-(4-tert-ブトキシカルボニル-1,4-ジアゾカン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.46 (s, 9H), 1.57 (s, 4H), 1.61-1.67 (m, 2H), 3.24 (s, 2H), 3.28 (t, J= 7.0 Hz, 2H), 3.69 (t, J = 6.1 Hz, 2H), 7.80 (d, J = 6.1 Hz, 1H), 7.91 (dd, J = 1.8, 8.5 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 8.35 (s, 1H), 8.69 (d, J = 5.5 Hz, 1H), 9.38 (s, 1H)
6-(1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物21)の合成
1H-NMRスペクトル (D2O, δ ppm):1.92-1.95 (m, 2H), 2.04-2.08 (m, 2H), 3.05-3.10 (m, 2H), 3.38-3.40 (m, 4H), 3.70-3.74 (m, 2H), 8.11 (d, J= 8.5 Hz, 1H), 8.33-8.36 (m, 1H), 8.51 (d, J = 8.5 Hz, 1H), 8.54 (d, J= 6.7 Hz, 1H), 8.63 (s, 1H), 9.60 (s, 1H)
融点:吸湿性により測定不可
6-(2,2-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物22)の合成
6-{2-(tert-ブトキシカルボニル-3-ヒドロキシプロピルアミノ)-1,1-ジメチルエチルアミノスルホニル}イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.24 (s, 6H), 1.54 (s, 9H), 1.69-1.77 (m, 3H), 3.16-3.67 (br m, 6H), 5.92 (br s, 1H), 7.75 (d, J = 5.5 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.05 (br s, 1H), 8.40 (s, 1H), 8.65 (d, J = 5.3 Hz, 1H), 9.34 (s, 1H)
6-(2,2-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.51 (s, 6H), 1.54-1.65 (m, 2H),1.94 (br s, 1H), 2.80-2.85 (m, 4H), 3.60-3.66 (m, 2H), 7.77 (d, J = 6.1 Hz, 1H), 8.03 (dd, J = 1.8, 8.5 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.46 (s, 1H), 8.65 (d, J = 6.1 Hz, 1H), 9.34 (s, 1H)
6-(2,2-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物22)の合成
1H-NMRスペクトル (D2O, δ ppm):1.40 (s, 6H), 1.87-1.94 (m, 2H), 3.16 (t, J = 6.1 Hz, 2H), 3.30 (s, 2H), 3.75-3.80 (m, 2H), 8.21 (dd, J = 1.8, 8.6 Hz, 1H), 8.41 (d, J = 6.56 Hz, 1H), 8.5-8.59 (m, 2H), 8.73 (s, 1H), 9.64 (s, 1H)
(R)-5-ブロモ-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物23)の合成
(R)-5-ブロモ-6-(4-tert-ブトキシカルボニル-2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.89 (d, J = 6.4 Hz, 1.5H), 0.91 (d, J = 6.4 Hz, 1.5H), 1.48 (d, J = 8.5 Hz, 9H), 1.83-2.00 (m, 4H), 3.17-3.19 (m, 1H), 3.39-3.52 (m, 4H), 3.93-3.96 (m, 1H), 4.06-4.08 (m, 1H), 8.03 (t, J = 9.5 Hz, 1H), 8.22 (s, 1H), 8.30 (d, J = 8.5 Hz, 1H), 8.75 (d, J = 5.5 Hz, 1H), 9.36 (s, 1H)
(R)-5-ブロモ-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物23)の合成
1H-NMRスペクトル (D2O, δ ppm):0.70 (d, J = 6.8 Hz, 3H), 1.79-1.93 (m, 1H), 1.97-2.06 (m, 1H), 3.25 (d, J = 8.0 Hz, 2H), 3.27-3.30 (m, 1H), 3.36-3.42 (m, 1H), 3.49-3.54 (m,1H), 3.36-3.42 (m, 1H), 3.49-3.54 (m, 1H), 4.04 (dt, J = 4.5, 15.6 Hz, 1H), 4.17-4.25 (m, 1H), 8.40 (dd, J = 8.8, 13.7 Hz, 2H), 8.66 (dd, J = 6.9, 12.5 Hz, 2H), 9.63 (s, 1H)
融点:192度
(S)-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物24)の合成
(S)-6-(4-tert-ブトキシカルボニル-2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.84 (d, J = 6.7 Hz, 1.5H), 0.88 (d, J = 6.7 Hz, 1.5H), 1.47 (s, 9H), 1.70-1.81 (m, 2H), 1.91 (s, 2H), 2.99-3.09 (m, 1H), 3.32-3.39 (m, 1H), 3.43-3.56 (m, 3H), 3.62 (td, J = 4.9, 9.8 Hz, 1H), 4.14-4.28 (m, 1H), 7.79 (d, J = 4.3 Hz, 1H), 7.92 (dd, J = 1.2, 8.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.38 (s, 1H), 8.68 (d, J = 5.5 Hz, 1H), 9.37 (s, 1H)
(S)-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物24)の合成
1H-NMRスペクトル (D2O, δ ppm):0.68 (d, J = 7.1 Hz, 3H), 1.77-2.07 (m, 4H), 3.16-3.47 (m, 4H), 3.45 (ddd, J = 1.8, 7.9, 13.4 Hz, 1H), 3.69 (dt, J = 4.7, 15.2 Hz, 1H), 4.39-4.44 (m, 1H), 8.22 (d, J = 8.9 Hz, 1H), 8.36 (t, J = 5.1 Hz, 1H), 8.52 (d, J = 8.3 Hz, 1H), 8.58 (d, J = 6.3 Hz, 1H), 8.72 (s, 1H), 9.61 (s, 1H)
融点:182度
(R)-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)-7-フルオロイソキノリン二塩酸塩(化合物25)の合成
(R)-6-{2-(tert-ブトキシカルボニル-3-ヒドロキシプロピルアミノ)-1-メチルエチルアミノスルホニル}-7-フルオロイソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.13 (d, J = 5.7 Hz, 3H), 1.38 (s, 9H), 1.58 (s, 1H), 1.69 (s, 1H), 1.93 (br s, 1H), 3.03 (dd, J = 4.8, 14.5 Hz, 1H), 3.17-3.34 (m, 2H), 3.47 (s, 2H), 3.59-3.75 (m, 2H), 5.54 (br s, 1H), 7.74-7.77 (m, 2H), 8.47 (d, J = 7.0 Hz, 1H), 8.66 (s, 1H), 9.31 (s, 1H)
(R)-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)-7-フルオロイソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.96 (d, J = 6.7 Hz, 3H), 1.54-1.66 (m, 3H), 2.52-2.59 (m, 1H), 2.72-2.79 (m, 1H), 3.05-3.12 (m, 1H), 3.17-3.29 (m, 2H), 3.93-4.00 (m, 1H), 4.19-4.28 (m, 1H), 7.71 (d, J = 10 Hz, 1H), 7.76 (d, J = 5.5 Hz, 1H), 8.56 (d, J = 6.7 Hz, 1H), 8.65 (d, J = 5.5 Hz, 1H), 9.29 (s, 1H)
(R)-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)-7-フルオロイソキノリン二塩酸塩(化合物25)の合成
1H-NMRスペクトル (D2O, δ ppm):0.88 (d, J = 6.8 Hz, 3H), 2.05-2.09 (m, 2H), 3.09-3.17 (m, 2H), 3.45-3.50 (m, 2H), 3.56-3.60 (dd, J = 5.9, 14.7 Hz, 1H), 3.97-4.00 (dt, J = 4.3, 15.7 Hz, 1H), 4.42-4.50 (m, 1H), 8.26 (d, J = 9.8 Hz, 1H), 8.44 (d, J = 6.1 Hz, 1H), 8.59 (s, 1H), 8.80 (d, J = 6.7 Hz, 1H), 9.63 (s, 1H)
[α]24 D-91.3(c=0.048,H2O)
(S)-6-(2-フルオロメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物26)の合成
(S)-6-(4-tert-ブトキシカルボニル-2-フルオロメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル(CDCl3, δ ppm):1.47 (s, 9H), 1.65-1.78 (m, 2H), 3.03-3.26 (m, 2H), 3.42-3.47 (m, 1H), 3.68-3.81 (m, 3H), 3.91-4.00 (m, 1H), 4.35-4.53 (m, 2H), 7.78 (s, 1H), 7.93 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.40 (s, 1H), 8.67 (br s, 1H), 9.35 (br s, 1H)
(S)-6-(2-フルオロメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物26)の合成
1H-NMRスペクトル(D2O, δ ppm): 2.05-2.12 (m, 2H), 3.06-3.11 (m, 1H), 3.28-3.33 (m, 1H), 3.44-3.52 (m, 2H), 3.75-3.79 (m, 1H), 3.99-4.01 (m, 1H), 4.30-4.34 (m, 1H), 4.40-4.44 (m, 1H), 4.73-4.76 (m, 1H), 8.25 (d, J = 8.7 Hz, 1H), 8.44 (br s, 1H), 8.55 (d, J = 8.7 Hz, 1H), 8.64 (br s, 1H), 8.74 (s, 1H), 9.71 (br s, 1H)
(R)-6-(2-フルオロメチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物27)の合成
(S)-6-(4-tert-ブトキシカルボニル-2-フルオロメチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル(CDCl3, δ ppm):1.44 (s, 9H), 1.71-1.89 (m, 4H), 3.12-3.16 (m, 1H), 3.28-3.32 (m, 1H), 3.44-3.48 (m, 2H), 3.57-3.61 (m, 2H), 3.71-3.75 (m, 1H), 4.31-4.47 (m, 2H), 7.93 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.0 Hz, 2H), 8.37 (s, 1H), 8.67 (br s, 1H), 9.35 (br s, 1H)
(R)-6-(2-フルオロメチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物27)の合成
1H-NMRスペクトル(D2O, δ ppm): 1.59-1.60 (m, 1H), 1.78-1.80 (m, 2H), 1.87-1.97 (m, 1H), 3.10-3.17 (m, 2H), 3.30-3.33 (m, 2H), 3.69-3.72 (m, 2H), 4.26-4.30 (m, 1H), 4.35-4.39 (m, 1H), 4.55-4.65 (m, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.33(br s, 1H), 8.46 (d, J = 8.5 Hz, 1H), 8.56 (br s, 1H), 8.73 (s, 1H), 9.09 (br s, 1H)
[α]24 D-52.9(c=0.034,H2O)
(S)-6-(2-メチル-1,4-ジアゾナン-1-イルスルホニル)イソキノリン二塩酸塩(化合物28)の合成
(S)-6-(4-tert-ブトキシカルボニル-2-メチル-1,4-ジアゾナン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.92 (d, J = 7.1 Hz, 1.5H), 1.14 (d, J = 7.1 Hz, 1.5H), 1.59 (s, 9H), 1.68-1.77 (m, 2H), 1.80-1.88 (m, 3H), 1.89-1.98 (m, 1H), 3.14-3.21 (m, 1H), 3.33 (dd, J = 8.0, 15.3 Hz, 1H), 3.39-3.46 (m, 3H), 3.70 (s, 1H), 4.07-4.13 (m, 1H), 7.77 (d, J = 6.1 Hz, 1H), 7.93 (dd, J = 1.8, 8.2 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 8.35 (s, 1H), 8.67 (d, J = 6.1 Hz, 1H), 9.35 (s, 1H)
(S)-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物28)の合成
1H-NMRスペクトル (D2O, δ ppm):0.66 (d, J = 6.4 Hz, 3H), 1.73-1.84 (m, 4H), 1.87-2.02 (m, 2H), 3.16-3.24 (m, 4H), 3.43-3.49 (m, 2H), 4.44 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.45 (dd, J = 6.1, 11.1 Hz, 1H), 8.58 (d, J = 5.3 Hz, 1H), 8.61 (d, J = 5.9 Hz, 1H), 8.77 (s, 1H), 8.86 (s, 1H)
融点:吸湿性により測定不可
[α]24 D+36.9(c=0.021,H2O)
(R)-5-ブロモ-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物29)の合成
(R)-5-ブロモ-6-(4-tert-ブトキシカルボニル-2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.84 (d, J = 7.2 Hz, 1.5H), 0.94 (d, J = 6.5 Hz, 1.5H), 1.48 (s, 9H), 1.78-1.96 (m, 2H), 3.16-3.32 (m, 3H), 3.62-3.74 (m, 2H), 3.98-4.13 (m, 2H), 8.03 (d, J = 7.6 Hz, 1H), 8.21 (t, J = 4.7 Hz, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.74 (dd, J = 2.1, 6.3 Hz, 1H), 9.36 (s, 1H)
(R)-5-ブロモ-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物29)の合成
1H-NMRスペクトル (D2O, δ ppm):0.84 (d, J = 6.7 Hz, 3H), 2.04-2.09 (m, 2H), 3.11-3.18 (m, 2H), 3.45 (dt, J = 4.5, 13.7 Hz, 1H), 3.52-3.58 (m, 2H), 4.08 (dt, J = 4.7, 15.4 Hz, 1H), 4.34-4.39 (m, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.40 (d, J = 8.3 Hz, 1H), 8.64 (s, 2H), 9.60 (s, 1H)
融点:吸湿性のため測定不可
(R)-6-(6-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物30)の合成
(R)-6-[3-{(tert-ブトキシカルボニル-2-ヒドロキシエチルアミノ)メチル}ブチルアミノスルホニル]イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.83 (d, J = 6.5 Hz, 3H), 1.43 (s, 9H), 1.52-1.62 (m, 2H), 1.80-1.90 (br m, 2H), 2.80-3.53 (br m, 6H), 3.68-3.82 (br m, 2H), 6.14 (s, 1H), 7.79 (d, J = 5.5 Hz, 1H), 7.99 (d, J = 9.1 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.42 (s, 1H), 8.69 (d, J = 5.6 Hz, 1H), 9.34 (s, 1H)
(R)-6-(6-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.98 (d, J = 6.7 Hz, 3H), 1.61-1.70 (m, 2H), 1.95-2.09 (m, 2H), 2.77 (dd, J = 9.2, 13.5 Hz, 1H), 3.06-3.30 (m, 5H), 3.33-3.41 (m, 1H), 3.55-3.60 (m, 1H), 7.78 (d, J = 5.49 Hz, 1H), 7.90 (dd, J = 1,83, 8.55 Hz, 1H), 8.12 (d, J = 8.54 Hz, 1H), 8.33 (s, 1H), 8.68 (d, J = 6.1 Hz, 1H), 9.37 (s, 1H)
(R)-6-(6-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物30)の合成
1H-NMRスペクトル (D2O, δ ppm):0.99 (d, J = 6.6 Hz, 3H), 1.64-1.71 (m, 1H), 1.87-1.90 (m, 1H), 2.15 (br s, 1H), 3.10-3.15 (m, 2H), 3.30-3.44 (m, 4H), 3.50-3.57 (m, 1H), 3.61-3.66 (m, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.44 (d, J = 6.6 Hz, 1H), 8.56-8.59 (m, 2H), 8.68 (s, 1H), 9.67 (s, 1H)
[α]25 D+9.7(c=0.059,H2O)
(R)-6-(7-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物31)の合成
1H-NMRスペクトル (CDCl3, δ ppm):0.85 (d, J = 6.6 Hz, 3H), 1.45 (s, 9H), 1.49-1.66 (br m, 4H), 3.04-3.50 (m, 8H), 5.76 (br s, 1H), 7.78 (d, J = 5.5 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 8.12(d, J = 8.4 Hz, 1H), 8.40 (s, 1H), 8.68 (d, J = 5.7 Hz, 1H), 9.37 (s, 1H)
(R)-6-(7-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.95 (d, J = 6.6 Hz, 3H), 1.37-1.52 (br m,2H), 1.89-1.99 (br m, 2H), 2.91-3.20 (m, 6H), 3.24-3.32 (m, 1H), 3.39-3.46 (m, 1H), 7.79 (d, J = 5.5 Hz, 1H) 7.91 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 8.34 (s, 1H), 8.69 (d, J = 6.0 Hz, 1H), 9.37 (s, 1H)
(R)-6-(7-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物31)の合成
1H-NMRスペクトル (D2O, δ ppm):0.85 (d, J = 6.7 Hz, 3H), 1.61-1.70 (m, 1H), 1.92-2.06 (m, 2H), 2.92-2.99 (m, 1H), 3.19-3.26 (m, 1H), 3.26-3.34 (m, 2H), 3.35-3.43 (m, 2H), 3.44-3.51 (m, 1H), 3.60-3.68 (m, 1H), 8.17 (dd, J = 1.8, 9.2 Hz, 1H), 8.42 (d, J = 6.1 Hz, 1H), 8.53-8.58 (m, 2H), 8.67 (s, 1H), 9.66 (s, 1H)
[α]24 D+9.6(c=0.050,H2O)
(S)-6-(7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物32)の合成
(R)-6-{2-(3-ヒドロキシブチル-tert-ブトキシカルボニルアミノ)エチルアミノスルホニル}イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.15 (d, J = 7.3 Hz, 3H), 1.43 (s, 9H), 1.46-1.50 (m, 2H), 1.91 (br s, 1H), 3.02 (br s, 1H), 3.17 (s, 3H), 3.44 (br s, 1H), 3.69 (br s, 1H), 3.80 (s, 1H), 6.22 (br s, 1H), 7.79 (d, J = 6.6 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 8.13 (d, J = 7.3 Hz, 1H), 8.41 (s, 1H), 8.69 (d, J = 5.8 Hz, 1H), 9.36 (s, 1H)
(S)-6-(7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物32)の合成
1H-NMRスペクトル (D2O, δ ppm):0.80 (d, J = 6.1 Hz, 3H), 1.63-1.72 (m, 1H), 2.34 (dt, J = 7.1, 17.6 Hz, 1H), 3.04-3.15 (m, 2H), 3.39-3.47 (m, 3H), 4.00 (d, J = 16.9 Hz, 1H), 4.23 (dt, J = 6.3, 9.7 Hz, 1H), 8.22 (dd, J = 1.8, 8.5 Hz, 1H), 8.42 (d, J = 7.4 Hz, 1H), 8.54 (d, J = 9.0 Hz, 1H), 8.57 (d, J = 6.6 Hz, 1H), 8.73 (s, 1H), 9.64 (s, 1H)
融点:吸湿性のため測定不可
(R)-6-(2-メチル-1,4-ジアゾナン-1-イルスルホニル)イソキノリン二塩酸塩(化合物33)の合成
(R)-6-(4-tert-ブトキシカルボニル-2-メチル-1,4-ジアゾナン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.91 (d, J = 7.1 Hz, 1.5H), 1.13 (d, J = 7.1 Hz, 1.5H), 1.47 (s, 9H), 1.70-1.80 (m, 2H), 1.85 (br s, 3H), 1.93-1.98 (m, 1H), 3.20-3.27 (m, 1H), 3.37 (dd, J = 6.8, 15.3 Hz, 1H), 3.40-3.49 (m, 3H), 3.67 (s, 1H), 4.11 (br s, 1H), 7.78 (d, J = 6.1 Hz, 1H), 7.97 (dd, J = 1.8, 8.2 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.39 (s, 1H), 8.69 (d, J = 6.1 Hz, 1H), 9.36 (s, 1H)
(R)-6-(2-メチル-1,4-ジアゾナン-1-イルスルホニル)イソキノリン二塩酸塩(化合物33)の合成
1H-NMRスペクトル (D2O, δ ppm):0.63 (d, J = 4.7 Hz, 3H), 1.69-1.89 (m, 6H), 2.95-3.20 (m, 4H), 3.42-3.48 (m, 2H), 4.42 (br s, 1H), 8.24 (dd, J = 2.1, 8.9 Hz, 1H), 8.40 (dd, J = 3.0, 6.2 Hz, 1H), 8.57 (d, J = 8.3 Hz, 1H), 8.58 (d, J = 6.8 Hz, 1H), 8.73 (s, 1H), 9.63 (s, 1H)
融点:吸湿性により測定不可
(R)-6-(7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物34)の合成
(S)-6-{2-(3-ヒドロキシブチル-tert-ブトキシカルボニルアミノ)エチルアミノスルホニル}イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.27 (d, J = 7.3 Hz, 3H), 1.43 (s, 11H), 1.91 (br s, 1H), 3.02 (s, 1H), 3.17 (s, 1H), 3.50-3.63 (m, 4H), 3.80 (s, 1H), 6.20 (br s, 1H), 7.78 (d, J = 6.1 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 7.9 Hz, 1H), 8.41 (s, 1H), 8.68 (d, J = 5.5 Hz, 1H), 9.36 (s, 1H)
(R)-6-(7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.02 (d, J = 6.7 Hz, 3H), 1.70 (br s, 2H), 2.15-2.21 (m, 1H), 2.61 (dd, J = 9.2, 13.4 Hz, 1H), 2.91-2.95 (m, 3H), 3.12-3.17 (m, 1H), 3.87 (d, J = 15.3 Hz, 1H), 4.16-4.20 (m, 1H), 7.78 (d, J = 5.5 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.40 (s, 1H), 8.68 (d, J = 5.5 Hz, 1H), 9.35 (s, 1H)
(R)-6-(7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物34)の合成
1H-NMRスペクトル (D2O, δ ppm):0.78 (d, J = 6.1 Hz, 3H), 1.67 (dt, J =8.4, 19.1 Hz, 1H), 2.33 (dt, J = 7.5, 16.5 Hz, 1H), 3.03-3.13 (m, 2H), 3.41-3.44 (m, 3H), 3.98 (d, J = 17.1 Hz, 1H), 4.21-4.24 (m, 1H), 8.23 (dd, J = 1.8, 9.2 Hz, 1H), 8.46 (d, J = 6.1 Hz, 1H), 8.56 (d, J = 3.7 Hz, 1H), 8.57 (s, 1H), 8.74 (s, 1H), 9.68 (s, 1H)
融点:吸湿性のため測定不可
(2R,7R)-6-(2,7-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物35)の合成
(2R,7R)-6-(4-tert-ブトキシカルボニル-2,7-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.09-1.21 (m, 3H), 1.31-1.43 (m, 3H), 1.49 (s, 9H), 1.88-2.16 (br m, 2H), 3.36-3.79 (br m, 6H), 7.77 (d, J = 5.5 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 8.38 (s, 1H), 8.67 (d, J = 5.5 Hz, 1H), 9.34 (s, 1H)
6-{(2R,7R)-2,7-ジメチル-1,4-ジアゼパン-1-イルスルホニル}イソキノリン二塩酸塩(化合物35)の合成
1H-NMRスペクトル (D2O, δ ppm):0.93 (d, J = 6.7 Hz, 3H), 1.36 (d, J = 7.3 Hz, 3H), 1.71-1.82 (m, 1H), 2.28-2.37 (m, 1H), 3.18-3.32 (m, 2H), 3.39-3.49 (m, 2H), 3.83-3.92 (m, 1H), 4.21-4.32 (m, 1H), 8.15 (d, J = 9.0 Hz, 1H), 8.28 (d, J = 6.4 Hz, 1H), 8.45 (d, J = 9.4 Hz, 1H), 8.53 (d, J = 6.1 Hz, 1H), 8.64 (s, 1H), 9.53 (s, 1H)
[α]25 D-64.3(c=0.033,H2O)
(2S, 7R)-6-(2, 7-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物36)の合成
(2S, 7R)-6-(4-tert-ブトキシカルボニル-2, 7-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル(CDCl3, δ ppm): 1.20-1.35 (m, 6H), 1.44 (s, 9H), 1.80-1.83 (m, 1H), 2.04-2.05 (m, 1H), 3.15-3.20 (m, 1H), 3.42-3.46 (m, 3H), 4.35-4.39 (m, 1H), 4.47-4.50 (m, 1H), 7.82 (s, 1H), 7.93 (d, J = 9.0 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 8.41 (s, 1H), 8.69 (s, 1H), 9.36 (s, 1H)
(2S, 7R)-6-(2, 7-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物36)の合成
1H-NMRスペクトル(D2O, δ ppm): 1.10 (d, J = 6.5 Hz, 3H), 1.26 (d, J = 6.5 Hz, 3H), 1.89-1.96 (m, 1H), 2.25-2.28 (m, 1H), 2.99-3.04 (m, 1H), 3.11-3.14 (m, 1H), 3.27-3.31 (m, 1H), 3.34-3.38 (m, 1H), 4.40-4.42 (m, 1H), 4.50-4.52 (m, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.52 (br s, 1H), 8.56 (d, J = 8.5 Hz, 1H), 8.73-8.76 (m, 2H), 9.63 (s, 1H)
[α]25 D-22.5(c=0.030,H2O)
(R)-6-(8-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物37)の合成
(R)-6-(4-tert-ブトキシカルボニル-8-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル(CDCl3, δ ppm):0.65 (d, J = 6.0 Hz, 3 H), 1.45 (s, 9H), 1.48-1.66 (m, 4H), 3.07-3.13 (m, 1H), 3.18-3.23 (m, 1H), 3.30-3.37 (m, 1H), 3.50-3.52 (m, 1H), 3.72-3.76 (m, 1H), 4.08-4.14 (m, 2H), 7.78 (d, J = 5.5 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 8.38 (s, 1H), 8.68 (d, J = 5.5 Hz, 1H), 9.36 (br s, 1H)
(R)-6-(8-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩の合成
1H-NMRスペクトル(D2O, δ ppm):0.56 (d, J = 6.0 Hz, 3 H), 1.52-1.59 (m, 1H), 1.82-1.93 (m, 3H), 3.16-3.20 (m, 1H), 3.24-3.28 (m, 1H), 3.37-3.50 (m, 3H), 3.71-3.75 (m, 1H), 4.09-4.13 (m, 1H), 7.78 (d, J = 8.5 Hz, 1H), 8.37 (d, J = 6.5 Hz, 1H), 8.51 (d, J = 8.5 Hz, 1H), 8.54 (d, J = 6.0 Hz, 1H), 8.71 (s, 1H), 9.36 (s, 1H)
[α]25 D-95.3(c=0.035,H2O)
(R)-6-(2-メチル-1,5-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物38)の合成
(R)-6-(4-tert-ブトキシカルボニル-2-メチル-1,5-ジアゾカン-1-イルスルホニル)イソキノリンの合成
スペクトル(CDCl3, δ ppm):0.72 (d, J = 6.0 Hz, 3H), 1.45 (s, 9H), 1.80-1.86 (m, 1H), 1.93-1.98 (m, 2H), 2.15-2.17 (m, 1H), 2.82-2.95 (m, 3H), 3.17 -3.22 (m, 1H), 3.36-3.46 (m, 1H), 3.70-3.73 (m, 1H), 4.05-4.13 (m, 1H), 7.78 (d, J = 5.5 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 8.40 (s, 1H), 8.68 (d, J = 5.5 Hz, 1H), 9.37 (s, 1H)
(R)-6-(2-メチル-1,5-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物38)の合成
1H-NMRスペクトル(D2O, δ ppm):0.58 (d, J = 6.5 Hz, 3H), 1.87-1.99 (m, 3H), 2.10-2.20 (m, 1H), 3.13-3.17 (m, 2H), 3.29-3.30 (m, 3H), 3.64-3.69 (m, 1H), 4.11-4.15 (m, 1H), 8.18 (d, J = 6.0 Hz, 1H), 8.36 (d, J = 6.0 Hz, 1H), 8.49 (d, J = 9.5 Hz, 1H), 8.54 (br s, 1H), 8.68 (s, 1H), 9.61 (s, 1H)
[α]25 D-65.9(c=0.033,H2O)
(R)-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)-5-ニトロイソキノリン二塩酸塩(化合物39)の合成
(R)-6-(4-tert-ブトキシカルボニル-2-メチル-1,4-ジアゾカン-1-イルスルホニル)-5-ニトロイソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.86 (d, J = 6.7 Hz, 1.5H), 0.94 (d, J = 6.7 Hz, 1.5H), 1.48 (s, 9H), 1.74-1.80 (m, 2H), 1.90-2.00 (m, 2H), 3.14-3.23 (m, 1H), 3.39-3.51 (m, 4H), 3.90-3.95 (m, 1H), 4.06 (s, 1H), 8.03 (t, J = 7.0 Hz, 1H), 8.21 (d, J = 5.5 Hz, 1H), 8.31 (d, J = 8.5 Hz, 1H), 8.75 (d, J = 5.5 Hz, 1H), 9.36 (s, 1H)
(R)-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)-5-ニトロイソキノリン二塩酸塩(化合物39)の合成
1H-NMRスペクトル (D2O, δ ppm):0.68 (d, J = 6.1 Hz, 3H), 1.77-1.82 (m, 1H), 1.84-1.91 (m, 2H), 1.94-2.02 (m, 1H), 3.20-3.26 (m, 3H), 3.35-3.40 (m, 1H), 3.49 (dd, J = 5.8, 13.1 Hz, 1H), 4.02 (dd, J = 9.2, 15.9 Hz, 1H), 4.14-4.22 (m, 1H), 8.37-8.41 (m, 2H), 8.61-8.64 (m, 2H), 9.56-9.63 (m, 1H)
[α]25 D+65.9(c=0.064,H2O)
(2R, 6R)-6-(2, 6-ジメチルピペラジン-1-イルスルホニル)イソキノリン二塩酸塩(化合物40)の合成
(2R, 6R)-6-(4-tert-ブトキシカルボニル-2, 6-ジメチルピペラジン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル(CDCl3, δ ppm): 1.25 (s, 6H), 1.45 (s, 9H), 3.23 (br s, 1H), 3.45 (br s, 2H), 3.62 (br s, 1H), 4.07-4.17 (m, 2H), 7.77 (d, J = 6.0 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 9.5 Hz, 1H), 8.39 (s, 1H), 8.68 (d, J = 5.5 Hz, 1H), 9.35 (s, 1H)
(2R, 6R)-6-(2, 6-ジメチルピペラジン-1-イルスルホニル)イソキノリン二塩酸塩(化合物40)の合成
1H-NMRスペクトル(D2O, δ ppm): 1.23 (d, J = 7.0 Hz, 6H), 3.08-3.12 (m, 2H), 3.26-3.29 (m, 2H), 4.34 (br s, 2H), 8.17 (d, J = 8.0 Hz, 1H), 8.38 (d, J = 5.5 Hz, 1H), 8.50 (d, J = 8.5 Hz, 1H), 8.55 (br s, 1H), 8.70 (s, 1H), 9.36 (s, 1H)
[α]25 D-38.2(c=0.038,H2O)
(2S, 7S)-6-(2, 7-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物41)の合成
(2S, 7S)-6-(4-tert-ブトキシカルボニル-2, 7-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル(CDCl3, δ ppm): 1.12 (d, J = 6.0 Hz, 3H), 1.26 (d, J = 6.0 Hz, 3H), 1.48 (s, 9H), 1.62 (br s, 2H), 3.46-3.69 (m, 4H), 4.11-4.18 (m, 2H), 7.77 (d, J = 6.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.38 (s, 1H), 8.67 (d, J = 6.0 Hz, 1H), 9.34 (s, 1H)
(2S, 7S)-6-(2, 7-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物41)の合成
1H-NMRスペクトル(D2O, δ ppm): 0.90 (d, J = 6.5 Hz, 3H), 1.33 (d, J = 6.5 Hz, 3H), 1.70-1.78 (m, 1H), 2.26-2.32 (m, 1H), 3.18-3.27 (m, 2H), 3.38-3.44 (m, 2H), 3.82-3.84 (m, 1H), 4.19-4.23 (m, 1H), 8.04 (d, J = 8.5 Hz, 1H), 8.13 (br s, 1H), 8.31 (d, J = 8.5 Hz, 1H), 8.51 (m, 2H), 9.66 (s, 1H)
(S)-6-(2-メチル-1,5-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物42)の合成
(S)-6-(4-tert-ブトキシカルボニル-2-メチル-1,5-ジアゾカン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル(CDCl3, δ ppm): 0.72 (d, J = 7.0 Hz, 3H), 1.45 (s, 9H), 1.80-1.98 (m, 2H), 2.15-2.20 (m, 2H), 2.82-3.00 (m, 2H), 3.17-3.25 (m, 1H), 3.38-3.45 (m, 1H), 3.63-3.73 (m, 2H), 4.06-4.13 (m, 1H), 7.78 (d, J = 5.0 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 8.40 (s, 1H), 8.68 (d, J = 5.5 Hz, 1H), 9.37 (s, 1H)
(S)-6-(2-メチル-1,5-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物42)の合成
1H-NMRスペクトル(D2O, δ ppm): 0.59 (d, J = 6.0 Hz, 3H), 1.85-2.00 (m, 3H), 2.15-2.19 (m, 1H), 3.14-3.22 (m, 2H), 3.30-3.34 (m, 3H), 3.65-3.70 (m, 1H), 4.11-4.15 (m, 1H), 8.17 (d, J = 9.0 Hz, 1H), 8.34 (d, J = 5.5 Hz, 1H), 8.48 (d, J = 9.0 Hz, 1H), 8.54 (s, 1H), 8.67 (s, 1H), 9.62 (s, 1H)
[α]25 D+47.9(c=0.035,H2O)
(R)-6-(5-メチル-1,4, 7-オキサジアゾナン-4-イルスルホニル)イソキノリン二塩酸塩(化合物43)の合成
(R)-6-(7-tert-ブトキシカルボニル-5-メチル-1,4, 7-オキサジアゾナン-4-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル(CDCl3, δ ppm): 0.59 (d, J = 7.0 Hz, 3H), 1.51 (s, 9H), 3.03-3.18 (m, 3H), 3.33-3.39 (m, 2H), 3.50-3.53 (m, 1H), 3.81-3.98 (m, 3H), 4.07-4.14 (m, 1H), 4.69 (br s, 1H), 7.78 (d, J = 6.0 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.36 (s, 1H), 8.67 (d, J = 8.5 Hz, 1H), 9.36 (s, 1H)
(R)-6-(5-メチル-1,4, 7-オキサジアゾナン-4-イルスルホニル)イソキノリン二塩酸塩(化合物43)の合成
1H-NMRスペクトル(D2O, δ ppm): 0.58 (d, J = 7.0 Hz, 3H) , 3.17 (dd, J = 3.2, 14 Hz, 3H), 3.48-3.55 (m, 2H), 3.72-3.77 (m, 2H), 3.81-3.84 (m, 1H), 3.97 (d, J = 12.5 Hz, 1H), 4.12-4.17 (m, 1H), 4.45-4.55 (m, 1H), 8.22 (d, J = 8.5 Hz, 1H), 8.38 (d, J = 6.0 Hz, 1H), 8.52 (d, J = 8.5 Hz, 1H), 8.56 (d, J = 6.0 Hz, 1H), 8.72 (s, 1H), 9.36 (s, 1H)
[α]25 D-38.1(c=0.035,H2O)
(R)-6-(2-メチル-1,4,7-トリアゾナン-1-イルスルホニル)イソキノリン三塩酸塩(化合物44)の合成
(R)-6-(4、7-ジ-tert-ブトキシカルボニル-2-メチル-1,4,7-トリアゾナン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.52-0.67 (br m, 3H), 1.46 (dd, J = 8.2, 13.1 Hz, 9H), 1.56 (s, 9H), 3.06 (br s, 2H), 3.28-3.50 (m, 5H), 3.56 (d, J = 14.0 Hz, 1H), 3.84 (d, J = 11.6 Hz, 1H), 4.00 (d, J = 13.1 Hz, 1H), 4.73 (s, 1H), 7.80 (d, J = 5.5 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 8.13 (dd, J = 8.9, 13.1 Hz, 1H), 8.37 (d, J = 16.5 Hz, 1H), 8.69 (t, J = 6.1 Hz, 1H), 9.37 (d, J = 6.7 Hz, 1H)
(R)-6-(2-メチル-1,4,7-トリアゾナン-1-イルスルホニル)イソキノリン三塩酸塩(化合物44)の合成
1H-NMRスペクトル (D2O, δ ppm):0.60 (d, J = 4.9 Hz, 3H), 3.14 (t, J = 12.8 Hz, 1H), 3.40-3.51 (m, 4H), 3.63-3.68 (m, 2H), 3.71-3.77 (m, 2H), 3.84 (t, J = 11.6 Hz, 1H), 4.54-4.59 (m, 1H), 8.28 (d, J = 8.5 Hz, 1H), 8.48 (d, J = 6.7 Hz, 1H), 8.58 (d, J = 6.1 Hz, 1H), 8.61 (d, J = 8.5 Hz, 1H), 8.81 (s, 1H), 9.71 (s, 1H)
[α]25 D-59.0(c=0.040,H2O)
6-(4-グリシル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物45)の合成
6-(4-tert-ブトキシカルボニルグリシル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.42 (s, 9H), 2.02-2.04 (m, 2H), 2.56 (br s, 1H), 3.25-3.46 (m, 4H), 3.46-3.59 (m, 2H), 3.59-3.77 (m, 2H), 3.88-3.90 (m, 2H), 7.78 (d, J = 5.0 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H), 8.34 (s, 1H), 8.69 (d, J = 5.0 Hz, 1H), 9.37 (s, 1H)
6-(4-グリシル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物45)の合成
1H-NMRスペクトル (D2O, δ ppm):1.99-2.03 (m, 2H), 3.27 (t, J= 6.1 Hz, 2H), 3.30-3.31 (m, 2H), 3.46 (t, J = 6.1 Hz, 2H), 3.60 (t, J= 5.5 Hz, 2H), 4.01-4.05 (m, 2H), 8.14-8.15 (m, 1H), 8.41-8.46 (m, 1H), 8.53 (d, J = 6.7 Hz, 2H), 8.61 (s, 1H), 9.62-9.65 (m, 1H)
融点:吸湿性により測定不可
(S)-6-(4-グリシル-2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物46)の合成
(S)-6-(4-tert-ブトキシカルボニルグリシル-2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.12 (d, J = 7.0 Hz, 3H), 1.45 (s, 9H) 1.60-1.70 (m, 2H), 2.24 (br s, 1H), 2.79-2.84 (m, 1H), 3.02-3.21 (m, 3H), 3.51-3.53 (m, 1H), 3.80-3.83 (m, 1H), 4.11-4.15 (m, 2H), 4.45-4.53 (m, 1H), 7.78 (d, J = 5.5 Hz, 1H), 7.88 (d, J= 8.5 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 8.36 (s, 1H), 8.68 (d, J= 5.5 Hz, 1H), 9.33 (s, 1H)
(S)-6-(4-グリシル-2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩(化合物46)の合成
1H-NMRスペクトル (D2O, δ ppm):0.96 (d, J = 6.0 Hz, 3H), 1.75-1.90 (m, 2H), 3.23-3.31 (m, 5H), 3.50-3.57 (m, 2H), 4.05-4.40 (m, 2H), 7.98-8.28 (m, 2H), 8.41 (d, J = 7.5 Hz, 1H), 8.58 (s, 1H), 8.78 (s, 1H), 9.68 (s, 1H)
融点:190~191度
(R)-6-(4-グリシル-2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物47)の合成
(R)-6-(4-tert-ブトキシカルボニルグリシル-2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.85 (d, J = 6.7 Hz, 3H), 1.47 (s, 9H), 1.52 (m, 4H), 3.03-3.06 (m, 2H), 3.21-3.28 (m, 2H), 3.49 (ddd, J = 2.4, 7.9, 14.1 Hz, 1H), 3.65 (dd, J = 3.7, 17.1 Hz, 1H), 3.77-3.82 (m, 1H), 3.94-4.00 (m, 1H), 4.37-4.40 (m, 1H), 5.40 (s, 1H), 7.78 (d, J = 5.5 Hz, 1H), 7.89 (dd, J = 1.8, 8.5 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 8.36 (s, 1H), 8.68 (d, J = 5.5 Hz, 1H), 9.34 (s, 1H)
(R)-6-(4-グリシル-2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物47)の合成
1H-NMRスペクトル (D2O, δ ppm):0.62 (d, J = 6.8 Hz, 3H), 1.78-1.93 (m, 4H), 3.02 (dd, J = 11.2, 15.5 Hz, 1H), 3.07-3.13 (m, 1H), 3.20 (dd, J = 7.7, 14.7 Hz, 1H), 3.55-3.69 (m, 2H), 3.76 (dd, J = 5.6, 14.4 Hz, 1H), 3.97 (d, J = 16.6 Hz, 1H), 4.06 (d, J = 16.6 Hz, 1H), 4.29-4.36 (m, 1H), 8.20 (d, J = 8.2 Hz, 1H), 8.44 (d, J = 5.0 Hz, 1H), 8.55 (d, J = 8.8 Hz, 1H), 8.58 (d, J = 6.6 Hz, 1H), 8.68 (s, 1H), 9.66 (s, 1H)
[α]23 D-36.3(c=0.042,H2O)
(R)-6-(4-サルコシル-2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物48)の合成
(R)-6-(4-tert-ブトキシカルボニルサルコシル-2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.75 (d, J = 6.1 Hz, 3H), 1.46 (s, 9H), 1.63 (s, 1H), 1.72-1.86 (m, 2H), 2.09 (s, 1H), 2.42 (s, 3H), 3.01-3.08 (m, 2H), 3.13 (s, 1H), 3.33 (s, 1H), 3.59-3.73 (m, 2H), 3.80 (d, J = 14.0 Hz, 1H), 4.21 (s, 1H), 4.36 (s, 1H), 7.75 (d, J = 4.9 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 8.34 (s, 1H), 8.66 (s, 1H), 9.34 (s, 1H)
(R)-6-(4-サルコシル-2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン二塩酸塩(化合物48)の合成
1H-NMRスペクトル (D2O, δ ppm):0.57 (d, J = 6.7 Hz, 3H), 1.64-1.90 (m, 4H), 2.72 (s, 3H), 2.97 (t, J = 13.7 Hz, 1H), 3.03-3.18 (m, 2H), 3.51-3.62 (m, 2H), 3.73 (dd, J = 4.3, 14.0 Hz, 1H), 4.02 (d, J = 15.9 Hz, 1H), 4.11 (d, J = 16.5 Hz, 1H), 4.27-4.32 (m, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.45 (d, J = 6.7 Hz, 1H), 8.54 (d, J = 5.5 Hz, 2H), 8.66 (s, 1H), 9.60 (s, 1H)
[α]25 D-12.4(c=0.055,H2O)
(S)-5-メチル-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン(化合物49)の合成
(S)-6-(4-tert-ブトキシカルボニル-2-メチル-1,4-ジアゼパン-1-イルスルホニル)-5-メチルイソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.95 (d, J = 6.4 Hz, 1.5H), 0.99 (d, J = 6.4 Hz, 1.5H), 1.48 (s, 4.5H), 1.50 (s, 4.5H), 1.62 (s, 1H), 1.75-1.86 (m, 1H), 2.94 (s, 3H), 3.03-3.20 (m, 2H), 3.70-3.92 (m, 4H), 4.27 (d, J = 6.5 Hz, 0.5H), 4.28 (d, J = 6.5 Hz, 0.5H), 7.94 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 8.18 (t, J = 7.9 Hz, 1H), 8.67 (d, J = 6.1 Hz, 1H), 9.31 (s, 1H)
(S)-5-メチル-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン(化合物49)の合成
1H-NMRスペクトル (D2O, δ ppm):0.85 (d, J = 6.7 Hz, 3H), 2.03 (s, 2H), 2.94 (s, 3H), 3.07-3.13 (m, 2H), 3.43 (td, J = 4.7, 9.0 Hz, 1H), 3.48-3.55 (m, 2H), 3.88 (d, J = 4.4 Hz, 0.5H), 3.89 (d, J = 4.4 Hz, 0.5H), 4.31 (d, J = 5.4 Hz, 0.5H), 4.32 (d, J = 5.4 Hz, 0.5H), 8.20 (d, J = 9.2 Hz, 1H), 8.32 (d, J = 9.2 Hz, 1H), 8.53 (d, J = 6.7 Hz, 1H), 8.63 (d, J = 6.7 Hz, 1H), 9.59 (s, 1H)
融点:225度
(S)-1-(2-アミノエチルチオ)-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン三塩酸塩(化合物50)の合成
(S)-6-(4-tert-ブトキシカルボニル-2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン 2-オキシドの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.02 (d, J = 6.0 Hz, 3H), 1.43 (s, 9H), 1.50-1.60 (m, 2H), 3.04-3.11 (m, 3H), 3.68-3.92 (m, 3H), 4.35-4.45 (m, 1H), 7.75-7.81 (m, 2H), 7.89 (dd, J = 1.5, 7.0 Hz, 1H), 8.22 (dd, J = 1.5, 7.0 Hz, 1H), 8.31 (s, 1H), 8.78 (s, 1H)
(S)-1-{2-(tert-ブトキシカルボニルアミノ)エチルチオ}-6-(4-tert-ブトキシカルボニル-2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.88-0.98 (m, 3H), 1.39 (s, 9H), 1.45 (s, 9H), 1.67-1.72 (m, 2H), 3.08-3.15 (m, 3H), 3.50-3.54 (m, 4H), 3.60-3.68 (m, 2H), 3.81-3.92 (m, 2H), 4.38-4.42 (m, 1H), 7.43 (d, J = 5.5 Hz, 1H), 7.85 (d, J= 9.0 Hz, 1H), 8.27-8.29 (m, 2H), 8.38 (d, J = 5.5 Hz, 1H)
(S)-1-(2-アミノエチルチオ)-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン三塩酸塩(化合物50)の合成
1H-NMRスペクトル (D2O, δ ppm):0.96 (d, J = 7.0 Hz, 3H), 1.80-1.90 (m, 2H), 2.93-3.05 (m, 2H), 3.15-3.19 (m, 3H), 3.31-3.43 (m, 2H), 3.59 (t, J = 7.0 Hz, 2H), 3.68-3.71 (m, 1H), 4.40-4.45 (m, 1H), 7.87 (d, J = 6.0 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.30 (d, J = 8.5 Hz, 1H), 8.49 (d, J = 6.0 Hz, 1H), 8.62 (s, 1H)
融点:174~175度
[α]25 D+46.4(c=0.034,H2O)
(R)-1-(2-アミノエチルチオ)-6-(7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン三塩酸塩(化合物51)の合成
(R)-6-(4-tert-ブトキシカルボニル-7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン 2-オキシドの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.02 (d, J = 6.7 Hz, 3H), 1.44 (s, 9H), 1.62 (s, 1H), 2.12 (s, 1H), 3.18-3.33 (m, 3H), 3.62-3.93 (m, 3H), 4.21 (dd, J = 6.7, 13.4 Hz, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 8.23 (d, J = 7.3 Hz, 1H), 8.32 (s, 1H), 8.80 (s, 1H)
(R)-1-{2-(tert-ブトキシカルボニルアミノ)エチルチオ}-6-(4-tert-ブトキシカルボニル-7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.99 (d, J = 6.7 Hz, 3H), 1.28-1.29 (m, 1H), 1.43 (s, 18H), 2.11 (s, 1H), 3.18-3.28 (m, 2H), 3.53 (s, 4H), 3.71-3.78 (m, 2H), 3.85 (d, J = 11.0 Hz, 1H), 3.94 (s, 1H), 4.22 (s, 1H), 5.18 (s, 1H), 7.44 (d, J = 5.5 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 8.28 (s, 1H), 8.31 (d, J = 8.5 Hz, 1H), 8.40 (d, J = 5.5 Hz, 1H)
(R)-1-(2-アミノエチルチオ)-6-(7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン三塩酸塩(化合物51)の合成
1H-NMRスペクトル (D2O, δ ppm):0.76 (d, J = 6.7 Hz, 3H), 1.63 (dt, J = 8.4, 18.7 Hz, 1H), 2.29 (dt, J = 7.6, 12.3 Hz, 1H), 2.99-3.04 (m, 2H), 3.32 (t, J = 6.1 Hz, 2H), 3.35-3.40 (m, 3H), 3.55 (t, J = 6.1 Hz, 2H), 3.93 (d, J = 16.5 Hz, 1H), 4.14-4.16 (m, 1H), 7.61 (d, J = 5.5 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 8.32 (dd, J = 1.2, 5.5 Hz, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.41 (s, 1H)
融点:187度
[α]25 D-70.2(c=0.032,H2O)
(R)-1-(2-アミノエチルチオ)-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン三塩酸塩(化合物52)の合成
(R)-6-(4-tert-ブトキシカルボニル-2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン 2-オキシドの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.84 (d, J = 6.7 Hz, 1.5H), 0.94 (d, J = 6.7 Hz, 1.5H), 1.47 (s, 9H), 1.65-1.74 (m, 4H), 3.03-3.08 (m, 1H), 3.28-3.60 (m, 5H), 4.21-4.27 (m, 1H), 7.80 (dd, J = 7.9, 16.5 Hz, 2H), 7.91 (d, J = 8.5 Hz, 1H), 8.22 (d, J = 7.3 Hz, 1H), 8.30 (s, 1H), 8.80 (s, 1H)
(R)-1-{2-(tert-ブトキシカルボニルアミノ)エチルチオ}-6-(4-tert-ブトキシカルボニル-2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):0.84 (d, J = 6.7 Hz, 1.5H), 0.87 (d, J = 6.7 Hz, 1.5H), 1.42 (s, 9H), 1.46 (s, 9H), 1.66-1.75 (m, 2H), 1.87-2.01 (m, 2H), 2.97-3.07 (m, 1H), 3.35-3.58 (m, 8H), 4.21-4.35 (m, 2H), 5.19 (s, 1H), 7.45 (d, J = 5.5 Hz, 1H), 7.86 (d, J = 8.9 Hz, 1H), 8.27 (s, 1H), 8.30 (d, J = 8.5 Hz, 1H), 8.40 (d, J = 5.5 Hz, 1H)
(R)-1-(2-アミノエチルチオ)-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン三塩酸塩(化合物52)の合成
1H-NMRスペクトル (D2O, δ ppm):0.60 (d, J = 6.1 Hz, 3H), 1.71-1.73 (m, 1H), 1.79-1.89 (m, 2H), 1.96-2.00 (m, 1H), 3.13-3.21 (m, 4H), 3.32 (t, J = 6.1 Hz, 2H), 3.41 (dd, J = 7.3, 13.4 Hz, 1H), 3.56 (t, J = 6.1 Hz, 2H), 3.61-3.64 (m, 1H), 4.31-4.36 (m, 1H), 7.62 (d, J = 5.5 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 8.33-8.35 (m, 2H), 8.42 (s, 1H)
融点:209~213度
[α]23 D-35.9(c=0.040,H2O)
6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン-1(2H)-オン 二塩酸塩(化合物53)の合成
6-(4-tert-ブトキシカルボニル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン 2-オキシドの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.41 (s, 9H), 1.93-2.04 (m, 2H), 3.29-3.40 (m, 4H), 3.48-3.59 (m, 4H), 7.78 (d, J = 7.0 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 8.22 (d, J = 7.0 Hz, 1H), 8.27 (s, 1H), 8.78 (s, 1H)
6-(4-tert-ブトキシカルボニル-1,4-ジアゼパン-1-イルスルホニル)-1-メトキシイソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.41 (s, 9H), 1.94-1.96 (m, 2H), 3.29-3.37 (m, 4H), 3.47-3.57 (m, 4H), 4.15 (s, 3H), 7.30 (d, J = 6.0 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 6.0 Hz, 1H), 8.21 (s, 1H), 8.37 (d, J = 8.5 Hz, 1H)
6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン-1(2H)-オン(化合物53)の合成
1H-NMRスペクトル (DMSO-d6, δ ppm):1.95-1.99 (m, 2H), 2.01 (br s, 1H), 3.13-3.17 (m, 4H), 3.34-3.36 (m, 2H), 3.54-3.60 (m, 2H), 6.74 (d, J = 7.0 Hz, 1H), 7.32 (dd, J = 7.0 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 8.17 (s, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.65 (br s, 1H), 11.5 (s, 1H)
融点:266-267度
1-アミノ-6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩 (化合物54)の合成
1-アミノ-6-(4-tert-ブトキシカルボニル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.41 (s, 9H), 2.15-2.20 (m, 2H), 3.30-3.38 (m, 4H), 3.47-3.57 (m, 4H), 5.25 (s, 2H), 7.13 (d, J = 6.0 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 6.0 Hz, 1H), 8.18 (s, 1H)
1-アミノ-6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩 (化合物54)の合成
1H-NMRスペクトル (DMSO-d6, δ ppm):1.95-2.00 (m, 2H), 2.11 (br s, 1H), 3.15-3.18 (m, 4H), 3.36-3.41 (m, 2H), 3.55 (s, 2H), 3.60-3.64 (m, 2H), 7.40 (d, J = 7.0 Hz, 1H), 7.82 (d, J = 7.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 8.26 (br s, 2H), 8.47 (s, 1H), 8.86 (d, J = 8.0 Hz, 1H)
融点:214-215度
1-ニトリル-6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩 (化合物55)の合成
1-ニトリル-6-(4-tert-ブトキシカルボニル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.41 (s, 9H), 1.97 (br s, 2H), 3.38 (br s, 2H), 3.40 (br s, 2H), 3.50 (br s, 2H), 3.58 (br s, 2H), 8.03 (d, J = 6.0 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 8.45 (s, 1H), 8.49 (d, J = 9.0 Hz, 1H), 8.80 (d, J = 6.0 Hz, 1H)
1-ニトリル-6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩 (化合物55)の合成
1H-NMRスペクトル (D2O, δ ppm):2.11-2.13 (m, 2H), 3.36-3.42 (m, 4H), 3.48 (t. J = 6.0 Hz, 2H), 3.69 (t. J = 6.0 Hz, 2H), 8.11 (d, J = 8.5Hz, 1H), 8.27 (d, J = 6.0 Hz, 1H), 8.46 (d, J = 8.5Hz, 1H), 8.59 (s, 1H), 8.71 (d, J = 8.5 Hz, 1H)
(S)-6-{2-(4-アミノブチル)-1,4-ジアゼパン-1-イルスルホニル}イソキノリン三塩酸塩 (化合物56)の合成
(S)-6-{4-tert-ブトキシカルボニル-2-(4-tert-ブトキシカルボニルアミノブチル)-1,4-ジアゼパン-1-イルスルホニル}イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.11-1.27 (m, 2H), 1.35-1.37 (m, 2H), 1.46 (s, 9H), 1.40 (S, 9H), 1.70-2.05 (m, 4H), 2.87-3.03 (m, 3H), 3.30-3.65 (m, 4H), 3.81-3.88 (m, 1H), 4.09-4.21 (m, 1H), 4.60 (br s, 1H), 7.78 (d, J = 6.0 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.39 (s, 1H), 8.67 (d, J = 6.0 Hz, 1H), 9.35 (s, 1H)
(S)-6-{2-(4-アミノブチル)-1,4-ジアゼパン-1-イルスルホニル}イソキノリン三塩酸塩 (化合物56)の合成
1H-NMRスペクトル (D2O, δ ppm):1.04-1.14 (m, 2H), 1.31-1.48 (m, 3H), 1.56-1.61 (m, 1H), 1.83-1.93 (m, 2H), 2.48-2.50 (m, 2H), 3.03-3.07 (m, 2H), 3.25-3.32 (m, 3H), 3.75-3.80 (m, 1H), 4.30-4.32 (m, 1H), 7.90 (m, 2H), 8.17 (d, J = 8.5 Hz, 1H), 8.31 (s, 1H), 8.49 (d, J = 8.5 Hz, 1H), 8.72 (s, 1H)
融点:38~40度
[α]25 D-22.9(c=0.0483,H2O)
6-(4-メトキシカルボニルピペリジン-1-イルスルホニル)イソキノリン塩酸塩(化合物57)の合成
6-(4-メトキシカルボニルピペリジン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.80-1.87 (m, 2H), 1.96-2.00 (m, 2H), 2.27-2.31 (m, 1H), 2.61-2.66 (m, 2H), 3.64 (s, 3H), 3.69-3.72 (m, 2H),7.78 (d, J = 6.0 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.31 (s, 1H), 8.69 (d, J = 6.0 Hz, 1H), 9.38 (s, 1H)
6-(4-メトキシカルボニルピペリジン-1-イルスルホニル)イソキノリン塩酸塩の合成
1H-NMRスペクトル (D2O, δ ppm):1.61-1.69 (m, 2H), 1.94-1.97 (m, 2H), 2.39-2.43 (m, 1H), 2.68-2.73 (m, 2H), 3.60 (s, 3H), 3.74-3.77 (m, 2H),8.23 (d, J = 7.8 Hz, 1H), 8.58 (d, J = 7.8 Hz, 1H), 8.65-8.67 (m, 2H), 8.73 (s, 1H), 9.79 (s, 1H)
(S)-6-(3-ヒドロキシピロリジン-1-イルスルホニル)イソキノリン塩酸塩(化合物58)の合成
(S)-6-(3-ヒドロキシピロリジン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.95-2.01 (m, 2H), 3.34-3.43 (m, 1H), 3.44-3.55 (m, 3H), 4.42 (br s 1H), 7.78 (d, J = 5.5 Hz, 1H), 7.98 (d, J = 9.0 Hz, 1H), 8.11 (d, J = 9.0 Hz, 1H), 8.38 (s, 1H), 8.65 (d, J = 5.5 Hz, 1H), 9.32 (s, 1H)
(S)-6-(3-ヒドロキシピロリジン-1-イルスルホニル)イソキノリン塩酸塩の合成
1H-NMRスペクトル (D2O, δ ppm):1.63-1.76 (m, 2H), 3.14 (d, J = 11.0 Hz, 1H), 3.26-3.40 (m, 3H), 4.13-4.14 (m, 1H), 8.14 (d, J = 9.0 Hz, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.54 (d, J = 9.0 Hz, 1H), 8.69 (s, 1H), 8.76 (br s, 1H), 9.80 (br s, 1H)
5-フェニル-6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩 (化合物59)の合成
5-フェニル-6-(4-tert-ブトキシカルボニル-1,4-ジアゼパン-1-イルスルホニル)イソキノリンの合成
1H-NMRスペクトル (CDCl3, δ ppm):1.43 (s, 9H), 1.75-1.79 (m, 2H), 2.66-2.77 (m, 4H), 3.35-3.46 (m, 4H), 7.12 (d, J = 6.0 Hz, 1H), 7.31-7.32 (m, 2H), 7.53-7.54 (m, 3H), 8.12 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.47 (d, J = 6.0 Hz, 1H),9.36 (s, 1H)
5-フェニル-6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン二塩酸塩 (化合物59)の合成
1H-NMRスペクトル (D2O, δ ppm):1.85-1.90 (m, 2H), 2.95-2.99 (m, 4H), 3.09-3.11 (m, 2H), 3.20-3.24 (m, 2H), 7.33-7.35 (m, 2H), 7.50-7.54 (m, 3H), 7.70 (d, J = 6.0 Hz, 1H), 8.37 (d, J = 8.5 Hz, 1H), 8.49 (d, J = 8.5Hz, 1H), 8.83 (d, J = 6.0 Hz, 1H),9.35 (s, 1H)
評価例1
本発明化合物のラットにおける血圧降下作用
ラット(SD、性別:雄性、1群6匹)に本発明化合物を腹腔内投与した際の血圧降下作用を評価した。被験化合物としては実施例18を使用した。
被験化合物を生理食塩水に溶解、希釈し、所定の濃度の被験化合物溶液を調製した。
ラット(1群6匹)に被験薬物を10mg/kgの用量で腹腔内に投与し、ソフトロン社製非観血血圧測定装置BP-98Aを用いて血圧と脈拍数を経時的に測定した。
本発明化合物を投与した動物の収縮期血圧は投与前値に比較して最大30%以上降下し、本発明化合物は優れた血圧降下作用を有することが明らかとなった。また同時に測定した脈拍数は増加し、これは血管拡張による血圧降下が生じその代償としての脈拍数増加と認められた。これらの結果から、本発明化合物は高血圧症を始めとする循環器疾患の治療剤として有用であることがわかった。
本発明化合物の高血圧自然発症ラットにおける血圧降下作用
高血圧自然発症ラット(SHR/Izm、性別:雄性、1群4~6匹)に本発明化合物を腹腔内投与し血圧降下作用を評価した。被験化合物としては実施例32、34、35を使用した。
被験化合物を生理食塩水に溶解、希釈し、所定の濃度の被験化合物溶液を調製した。
動物(1群4~6匹)に被験薬物を10mg/kg(実施例34のみ30mg/kg)の用量で腹腔内に投与し、ソフトロン社製非観血血圧測定装置BP-98Aを用いて血圧と脈拍数を経時的に測定した。
本発明化合物を投与した動物の収縮期血圧は投与前値に比較して最大で実施例34及び35は30%以上降下させた。実施例32は16%降下させた。このように本発明化合物は優れた血圧降下作用を有することが明らかとなった。また同時に測定した脈拍数は増加していた。これは、血管拡張による血圧降下が生じ、その代償としての脈拍数増加と認められた。これらの結果から、本発明化合物は高血圧症を始めとする循環器疾患の治療剤として有用であることがわかった。
本発明化合物のウサギにおける眼圧降下作用
ウサギ(ニュージーランド白色、性別:雄性、一群3~7)に本発明化合物を投与した際の眼圧降下作用を評価した。
被験化合物を基剤(リン酸二水素ナトリウム二水和物1.04g、塩化ナトリウム0.5gを精製水に溶解し水酸化ナトリウムでpHを7.0に調製し全量を100mLにした)に溶解し、1%(W/V)の濃度の被験化合物溶液を調製した。
ウサギに被験化合物投与直前にティオラト社製トノベット手持眼圧計を用いて眼圧を測定した。片眼に被験化合物溶液を、対側眼に基剤のみをそれぞれ0.04mL点眼し、同様に眼圧を経時的に測定した。基剤投与眼の眼圧に対する被験化合物溶液投与眼の眼圧の割合を降下度として算出した。
各被験化合物の最大降下度を表1に示した。表1に示したように、本発明化合物はいずれも優れた眼圧降下作用を示した。このことから、本発明化合物は緑内障治療薬として有用であることがわかった。
神経細胞軸索伸展作用
本発明化合物の神経変性疾患治療剤としての有用性を調べるため、神経モデル細胞として多用されるNG108-15細胞を本発明化合物存在下で培養し、神経軸索伸展作用を評価した。被験化合物としては実施例15及び49を使用した。
被験化合物をジメチルスルホキシドに溶解、希釈し、所定の濃度の被験化合物溶液を調製した。
NG108-15細胞(ATCCより入手)は、5%ウシ胎児血清及び1×HAT(ヒポキサンチン、アミノプテリン、チミジン)を含有するダルベッコ変法イーグル培地で培養した。24ウェルプレートに12,000細胞/ウェルとなるように細胞を撒き、37℃、5%CO2、95%空気の環境下12時間の静置培養後、終濃度10,3,1,0.3μmol/Lとなるように被験化合物を添加した。その後24時間後に倒立顕微鏡下で神経軸索伸展の程度を観察した。
化合物添加培養液で培養したNG108-15細胞では化合物無添加で培養した細胞と比較して顕著な軸索伸展が認められた。本発明化合物は神経細胞の軸索伸展作用を有することがわかった。
本発明化合物のマウス脊髄損傷モデルにおける運動機能回復作用
本発明化合物の脊髄損傷治療剤としての有用性を調べるため、マウスの脊髄損傷モデルを作成し、脊髄損傷後の運動機能の回復作用を検討した。
被験化合物として実施例14を生理食塩水に溶解、希釈し、所定の濃度の被験化合物溶液を調製した。
論文(Acta Neuropathol. 100, 13-22(2000))に記載の方法に従い、C57BL/6Crマウス(雌、体重19g前後、1群6~8匹)をハロタン吸入麻酔し、第8胸椎レベルの脊髄を20gの重りで5分間圧迫することによって脊髄損傷モデルを作製した。被験化合物は手術日から連続して1日1回7日間3mg/kgの用量を腹腔内に投与した。脊髄損傷モデル作製後1,4,7,10,14日後に、J. Neurosurg. 93(1 Suppl.), 94,101(2000)に記載の行動スコアを一部修正して神経障害の程度を評点した。行動スコアの詳細は次の通りである。
オープン-フィールド移動行動(0~42点)
つま先の拡がり(0~5点)
接地反応(0~5点)
引っ込め反応(伸展刺激、痛み刺激、加圧刺激に対する反応それぞれで0-5点)
正姿勢反応(0~5点)
このスコアによれば正常動物は0点、最も重篤な障害を持つ動物は72点となる。
術後14日目における各群の神経障害のスコアは、生理食塩水投与群が41点であったのに対し、被験化合物投与群は33点であった。本発明化合物は脊髄損傷後の運動機能の回復作用を示した。このことから本発明化合物は脊髄損傷の治療薬として有用であることがわかった。
Claims (10)
- 一般式(1)
R1及びR2はそれぞれ独立して水素原子、ハロゲン原子、シアノ基、アルキル基、ハロゲノアルキル基、アルケニル基、アルコキシ基、アルキルチオ基、ヒドロキシ基、メルカプト基、ニトロ基、アリール基、アミノ基又はアミノアルキルチオ基を示し;
R3及びR4はそれぞれ独立して水素原子、アルキル基、アルケニル基、アミノ基、アルキルアミノ基、ジアルキルアミノ基、アミノアルキル基、ハロゲノアルキル基、アルカノイル基、アミノアルカノイル基、アルキルアミノアルカノイル基、アルコキシカルボニル基、ヒドロキシ基又はメルカプト基を示すか、あるいはR3とR4が一緒になってアルキレン基又はアルケニレン基を形成し、任意の位置へ2つの炭素間で架橋していてもよく;
l、m及びnは1~4の数を示す。)
で表されるイソキノリン-6-スルホンアミド誘導体、その塩又はそれらの溶媒和物。 - 一般式(1)において、
X、Yがそれぞれ独立して直接結合、NH、CH=CH、O又はSであり;R1及びR2がそれぞれ独立して水素原子、ハロゲン原子、シアノ基、C1-8アルキル基、ハロゲノC1-8アルキル基、C2-8アルケニル基、C1-8アルコキシ基、C1-8アルキルチオ基、ヒドロキシ基、メルカプト基、ニトロ基、フェニル基、アミノ基又はアミノC1-8アルキルチオ基であり;R3及びR4がそれぞれ独立して水素原子、C1-8アルキル基、C2-8アルケニル基、アミノ基、アミノC1-8アルキル基、ハロゲノC1-8アルキル基、C1-8アルキルアミノ基、ジ-C1-8アルキルアミノ基、C2-8アルカノイル基、アミノC2-8アルカノイル基、C1-8アルコキシカルボニル基、ヒドロキシ基、又はメルカプト基であるか、あるいはR3とR4が一緒になって架橋C1-3のアルキレン基又はアルケニレン基を形成し;l及びmがそれぞれ独立して1~3であり;nが2~3である請求項1記載のイソキノリン-6-スルホンアミド誘導体、その塩又はそれらの溶媒和物。 - 一般式(1)において、
Xが直接結合又はNHであり;Yが直接結合、NH、CH=CH、又はOであり;R1及びR2がそれぞれ独立して水素原子、ハロゲン原子、C1-8アルキル基、ニトロ基、シアノ基、ヒドロキシ基、ハロゲノC1-8アルキル基、フェニル基、又はアミノC1-8アルキルチオ基であり;R3及びR4が水素原子、C1-8アルキル基、アミノ基、C1-8アルキルアミノ基、アミノC1-8アルキル基又はハロゲノC1-8アルキル基、アミノC1-8アルカノイル基又はC1-8アルキルアミノ基又はC1-8アルカノイル基であるか、あるいはR3とR4が一緒になって架橋C1-3のアルキレン基を形成し;l及びmがそれぞれ独立して1~3であり;nが2~3である請求項1又は2記載のイソキノリン-6-スルホンアミド誘導体、その塩又はそれらの溶媒和物。 - 一般式(1)において、
Xが直接結合又はNHであり;Yが直接結合、NH、CH=CH、又はOであり;R1及びR2がそれぞれ独立して水素原子、ハロゲン原子、ニトロ基、アミノアルキルチオ基、C1-6アルキル基、ハロゲノC1-6アルキル基であり;R3及びR4が水素原子、C1-6アルキル基又はハロゲノC1-6アルキル基、アミノ基、C1-8アルキルアミノ基、アミノC1-8アルカノイル基であるか、あるいはR3とR4が一緒になって架橋C1-3のアルキレン基を形成し;l及びmがそれぞれ独立して1~3であり;nが2~3である請求項1~3のいずれか1項記載のイソキノリン-6-スルホンアミド誘導体、その塩又はそれらの溶媒和物。 - 一般式(1)において、
Xが直接結合又はNHであり;Yが直接結合、CH=CH、又はOであり;R1及びR2がそれぞれ独立して水素原子、ハロゲン原子、アミノアルキルチオ基、C1-6アルキル基であり;R3及びR4が水素原子、C1-6アルキル基、ハロゲノC1-6アルキル基、又はアミノ基であるか、あるいはR3とR4が一緒になって架橋C1-3のアルキレン基を形成し;l及びmがそれぞれ独立して1~3であり;nが2~3である請求項1~4のいずれか1項記載のイソキノリン-6-スルホンアミド誘導体、その塩又はそれらの溶媒和物。 - 6-(ピペラジン-1-イルスルホニル)イソキノリン、
(R)-6-(3-アミノピロリジン-1-イルスルホニル)イソキノリン、
6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
6-(4-アミノピペリジン-1-イルスルホニル)イソキノリン、
5-ブロモ-6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
6-(1,4-ジアゼパン-1-イルスルホニル)-8-フルオロイソキノリン、
6-{(1S,4S)-2,5-ジアザビシクロ[2.2.1]ヘプタン-2-イルスルホニル}イソキノリン、
(R、Z)-6-(2-メチル-2,3,4,5-テトラヒドロ-1,4-ジアゾシン-1(8H)-イルスルホニル)イソキノリン、
6-(モルホリン-1-イルスルホニル)イソキノリン、
(S)-6-{3-(N-メチルアミノ)ピロリジン-1-イルスルホニル}イソキノリン、
(S)-6-{3-(N-ブチルアミノ)ピロリジン-1-イルスルホニル}イソキノリン、
(S)-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(S)-6-(2-メチルピペラジン-1-イルスルホニル)イソキノリン、
(R)-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
(S)-5-ブロモ-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
6-(3-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
6-(7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-6-(2-エチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-6-(2-エチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
6-(1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
6-(2,2-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-5-ブロモ-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
(S)-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
(R)-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)-7-フルオロイソキノリン、
(S)-6-(2-フルオロメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(S)-6-(2-フルオロメチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
(S)-6-(2-メチル-1,4-ジアゾナン-1-イルスルホニル)イソキノリン、
(R)-5-ブロモ-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-6-(6-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
(R)-6-(7-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
(S)-6-(7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-6-(2-メチル-1,4-ジアゾナン-1-イルスルホニル)イソキノリン、
(R)-6-(7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(2R,7R)-6-(2,7-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(2S, 7R)-6-(2, 7-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-6-(8-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
(R)-6-(2-メチル-1,5-ジアゾカン-1-イルスルホニル)イソキノリン、
(R)-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)-5-ニトロイソキノリン、
(2R, 6R)-6-(2, 6-ジメチルピペラジン-1-イルスルホニル)イソキノリン、
(2S, 7S)-6-(2, 7-ジメチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(S)-6-(2-メチル-1,5-ジアゾカン-1-イルスルホニル)イソキノリン、
(R)-6-(5-メチル-1,4, 7-オキサジアゾナン-4-イルスルホニル)イソキノリン、
(R)-6-(2-メチル-1,4,7-トリアゾナン-1-イルスルホニル)イソキノリン、
6-(4-グリシル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(S)-6-(4-グリシル-2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-6-(4-グリシル-2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
(R)-6-(4-サルコシル-2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
(S)-5-メチル-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(S)-1-(2-アミノエチルチオ)-6-(2-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-1-(2-アミノエチルチオ)-6-(7-メチル-1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(R)-1-(2-アミノエチルチオ)-6-(2-メチル-1,4-ジアゾカン-1-イルスルホニル)イソキノリン、
6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン-1(2H)-オン、
1-アミノ-6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
1-ニトリル-6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン、
(S)-6-(2-(4-アミノブチル)-1、4-ジアゼピン-1-イルスルホニル)イソキノリン、
6-(4-メトキシカルボニルピペリジン-1-イルスルホニル)イソキノリン、
(S)-6-(3-ヒドロキシピロリジン-1-イルスルホニル)イソキノリン、
5-フェニル-6-(1,4-ジアゼパン-1-イルスルホニル)イソキノリン
から成る群より選択される化合物、その塩又はその溶媒和物。 - 請求項1~6のいずれか1項記載の化合物を含有する医薬組成物。
- 緑内障、循環器疾患、又は神経変性若しくは神経損傷に起因する疾患若しくは障害の予防治療薬である請求項1~6のいずれか1項記載の医薬組成物。
- 緑内障、循環器疾患、又は神経変性若しくは神経損傷に起因する疾患若しくは障害を予防又は治療するための請求項1~6のいずれか1項記載の化合物。
- 請求項1~6のいずれか1項記載の化合物の有効量を投与することを特徴とする緑内障、循環器疾患、又は神経変性若しくは神経損傷に起因する疾患若しくは障害の予防治療方法。
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AU2010261206A AU2010261206B2 (en) | 2009-06-19 | 2010-06-18 | Substituted isoquinoline derivative |
JP2011519583A JP4915010B2 (ja) | 2009-06-19 | 2010-06-18 | 置換されたイソキノリン誘導体 |
KR1020117028931A KR101732907B1 (ko) | 2009-06-19 | 2010-06-18 | 치환된 이소퀴놀린 유도체 |
US13/265,246 US8951997B2 (en) | 2009-06-19 | 2010-06-18 | Substituted isoquinoline derivative |
DK10789260.6T DK2444395T3 (en) | 2009-06-19 | 2010-06-18 | substituted isoquinoline |
NZ596615A NZ596615A (en) | 2009-06-19 | 2010-06-18 | Substituted isoquinoline derivative |
MX2011013857A MX2011013857A (es) | 2009-06-19 | 2010-06-18 | Derivado sustituido de isoquinolina. |
ES10789260.6T ES2560603T3 (es) | 2009-06-19 | 2010-06-18 | Derivado de isoquinolina sustituida |
CA2764124A CA2764124C (en) | 2009-06-19 | 2010-06-18 | Substituted isoquinoline derivative |
EA201171328A EA019523B1 (ru) | 2009-06-19 | 2010-06-18 | Производное замещенного изохинолина, содержащая его фармацевтическая композиция и применение для лечения заболеваний |
EP10789260.6A EP2444395B1 (en) | 2009-06-19 | 2010-06-18 | Substituted isoquinoline derivative |
BRPI1011683A BRPI1011683B8 (pt) | 2009-06-19 | 2010-06-18 | derivados de isoquinolina substituída, suas composições farmacêuticas e seus usos |
PL10789260T PL2444395T3 (pl) | 2009-06-19 | 2010-06-18 | Podstawiona pochodna izochinoliny |
CN201080023516.8A CN102448941B (zh) | 2009-06-19 | 2010-06-18 | 取代的异喹啉衍生物 |
HRP20160096TT HRP20160096T1 (hr) | 2009-06-19 | 2016-01-28 | Supstituirani derivati izokinolina |
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KR (1) | KR101732907B1 (ja) |
CN (1) | CN102448941B (ja) |
AU (1) | AU2010261206B2 (ja) |
BR (1) | BRPI1011683B8 (ja) |
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CY (1) | CY1117157T1 (ja) |
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2010
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Also Published As
Publication number | Publication date |
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CY1117157T1 (el) | 2017-04-05 |
EP2444395A4 (en) | 2012-11-28 |
PL2444395T3 (pl) | 2016-06-30 |
CN102448941B (zh) | 2016-04-06 |
MX2011013857A (es) | 2012-01-30 |
ES2560603T3 (es) | 2016-02-22 |
AU2010261206B2 (en) | 2015-10-08 |
EP2444395B1 (en) | 2016-01-06 |
AU2010261206A1 (en) | 2011-12-15 |
EA019523B1 (ru) | 2014-04-30 |
BRPI1011683A2 (pt) | 2016-03-22 |
HUE028684T2 (en) | 2016-12-28 |
NZ596615A (en) | 2013-07-26 |
TW201100385A (en) | 2011-01-01 |
EA201171328A1 (ru) | 2012-05-30 |
KR101732907B1 (ko) | 2017-05-08 |
CN102448941A (zh) | 2012-05-09 |
BRPI1011683B8 (pt) | 2021-05-25 |
US20120035159A1 (en) | 2012-02-09 |
TWI527798B (zh) | 2016-04-01 |
JPWO2010146881A1 (ja) | 2012-12-06 |
HRP20160096T1 (hr) | 2016-02-26 |
DK2444395T3 (en) | 2016-03-14 |
JP4915010B2 (ja) | 2012-04-11 |
EP2444395A1 (en) | 2012-04-25 |
CA2764124C (en) | 2016-12-13 |
US8951997B2 (en) | 2015-02-10 |
KR20120069609A (ko) | 2012-06-28 |
CA2764124A1 (en) | 2010-12-23 |
BRPI1011683B1 (pt) | 2020-10-20 |
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