AU3135497A - Diarylalkyl cyclic diamine derivatives as chemokine receptor antagonists - Google Patents
Diarylalkyl cyclic diamine derivatives as chemokine receptor antagonistsInfo
- Publication number
- AU3135497A AU3135497A AU31354/97A AU3135497A AU3135497A AU 3135497 A AU3135497 A AU 3135497A AU 31354/97 A AU31354/97 A AU 31354/97A AU 3135497 A AU3135497 A AU 3135497A AU 3135497 A AU3135497 A AU 3135497A
- Authority
- AU
- Australia
- Prior art keywords
- group
- groups
- formula
- mmol
- lower alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 cyclic diamine Chemical class 0.000 title claims description 90
- 229940122444 Chemokine receptor antagonist Drugs 0.000 title description 5
- 239000002559 chemokine receptor antagonist Substances 0.000 title description 5
- 238000000034 method Methods 0.000 claims description 331
- 150000001875 compounds Chemical class 0.000 claims description 315
- 125000000217 alkyl group Chemical group 0.000 claims description 114
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 109
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 76
- 125000003545 alkoxy group Chemical group 0.000 claims description 75
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 57
- 125000005843 halogen group Chemical group 0.000 claims description 55
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 47
- 125000001424 substituent group Chemical group 0.000 claims description 46
- 125000006828 (C2-C7) alkoxycarbonyl group Chemical group 0.000 claims description 30
- 102000019034 Chemokines Human genes 0.000 claims description 23
- 108010012236 Chemokines Proteins 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 22
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 22
- 125000004434 sulfur atom Chemical group 0.000 claims description 22
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 230000027455 binding Effects 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- 125000000304 alkynyl group Chemical group 0.000 claims description 14
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 14
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 10
- 125000004423 acyloxy group Chemical group 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 7
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 7
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 7
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 7
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000005879 dioxolanyl group Chemical group 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 5
- 108090001007 Interleukin-8 Proteins 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 2
- 102100021943 C-C motif chemokine 2 Human genes 0.000 claims 1
- 101710155857 C-C motif chemokine 2 Proteins 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 239000004615 ingredient Substances 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 165
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 157
- 230000029936 alkylation Effects 0.000 description 103
- 238000005804 alkylation reaction Methods 0.000 description 103
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 91
- 239000000243 solution Substances 0.000 description 88
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 67
- 239000000203 mixture Substances 0.000 description 67
- 238000002360 preparation method Methods 0.000 description 58
- 235000019439 ethyl acetate Nutrition 0.000 description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 52
- 210000004027 cell Anatomy 0.000 description 43
- 239000002904 solvent Substances 0.000 description 43
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- AHIKLYNQHAYCCS-UHFFFAOYSA-N 1-(3,3-diphenylpropyl)-1,4-diazepane Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)CCN1CCCNCC1 AHIKLYNQHAYCCS-UHFFFAOYSA-N 0.000 description 38
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 38
- 230000008878 coupling Effects 0.000 description 38
- 238000010168 coupling process Methods 0.000 description 38
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- 239000011541 reaction mixture Substances 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 21
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- 229910052708 sodium Inorganic materials 0.000 description 21
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- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- 101000897480 Homo sapiens C-C motif chemokine 2 Proteins 0.000 description 15
- 239000000284 extract Substances 0.000 description 15
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 15
- INVWQYARYKVFDV-UHFFFAOYSA-M sodium;2-[4-(3,3-diphenylpropyl)-1,4-diazepan-1-yl]acetate Chemical compound [Na+].C1CN(CC(=O)[O-])CCCN1CCC(C=1C=CC=CC=1)C1=CC=CC=C1 INVWQYARYKVFDV-UHFFFAOYSA-M 0.000 description 15
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
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- JTWRGDRPTHSBPF-UHFFFAOYSA-N 3-[3-(1,4-diazepan-1-yl)-1-hydroxy-1-phenylpropyl]phenol Chemical compound OC1=CC=CC(C(O)(CCN2CCNCCC2)C=2C=CC=CC=2)=C1 JTWRGDRPTHSBPF-UHFFFAOYSA-N 0.000 description 12
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- OKOKLFDSNLVNII-UHFFFAOYSA-N 2-[4-(3,3-diphenylpropyl)-1,4-diazepan-1-yl]acetic acid Chemical compound C1CN(CC(=O)O)CCCN1CCC(C=1C=CC=CC=1)C1=CC=CC=C1 OKOKLFDSNLVNII-UHFFFAOYSA-N 0.000 description 11
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
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- 102000005962 receptors Human genes 0.000 description 11
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
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- KFUSANSHCADHNJ-UHFFFAOYSA-N pyridine-3-carbohydrazide Chemical compound NNC(=O)C1=CC=CN=C1 KFUSANSHCADHNJ-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
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- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- OSWULUXZFOQIRU-UHFFFAOYSA-N tert-butyl 2-aminoacetate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)CN OSWULUXZFOQIRU-UHFFFAOYSA-N 0.000 description 1
- OVOZPKQGQWRHNP-UHFFFAOYSA-N tert-butyl 4-(3-methylsulfonyloxy-1-phenylpropyl)benzoate Chemical compound C1=CC(C(=O)OC(C)(C)C)=CC=C1C(CCOS(C)(=O)=O)C1=CC=CC=C1 OVOZPKQGQWRHNP-UHFFFAOYSA-N 0.000 description 1
- FRTNOMNLMDBVMB-UHFFFAOYSA-N tert-butyl 4-(3-oxo-3-phenylpropyl)-1,4-diazepane-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCCN1CCC(=O)C1=CC=CC=C1 FRTNOMNLMDBVMB-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- SOGBOGBTIKMGFS-UHFFFAOYSA-N thiophene-2-carbohydrazide Chemical compound NNC(=O)C1=CC=CS1 SOGBOGBTIKMGFS-UHFFFAOYSA-N 0.000 description 1
- VNNLHYZDXIBHKZ-UHFFFAOYSA-N thiophene-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CS1 VNNLHYZDXIBHKZ-UHFFFAOYSA-N 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940093609 tricaprylin Drugs 0.000 description 1
- VOITXYVAKOUIBA-UHFFFAOYSA-N triethylaluminium Chemical compound CC[Al](CC)CC VOITXYVAKOUIBA-UHFFFAOYSA-N 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Pharmacology & Pharmacy (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrane Compounds (AREA)
- Furan Compounds (AREA)
- Indole Compounds (AREA)
- Quinoline Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pyridine Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Hydrogenated Pyridines (AREA)
Description
SPECIFICATION
DIARYLALKYLCYCLICDIAMINEDERIVATIVESASCHEMOKINERECEPTORANTAGONISTS
Technical field
This invention relates to novel diarylalkyl cyclic diamine derivatives.
This invention also relates to chemokine receptor antagonists that may be effective as a therapeutic agent and/or preventive agent for diseases such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, glomerulonephritis, multiple sclerosis, pulmonary fibrosiε, and myocarditis, in which tissue infiltration of blood monocytes and lymphocytes plays a major role in the initiation, progression or maintenance of the disease.
Background Technology
Chemokines are a group of inflammatory/immunomodulatory polypeptide factors produced bylymphatic tissues andbyactivated macrophages and leukocytes at inflammatory sites; they have a molecular weight of 6-15 kD, contain four cysteine residues, are basic andhave heparin binding activity. The chemokines can be classified into two subfamilies, the CXC chemokines and CC chemokines, by the common location of the four cysteine residues and by the differences in the chromosomal locations of the genes encoding them. For example IL-8 (abbreviation for interleukin-8 is a CXC chemokine, while the CC chemokines include MlP-lα/β (abbreviation formacrophage inflammatory protein-lα/β). MCP-1 (abbreviation formonocyte chemotactic protein-1), and RANTES (abbreviation for regulated on activation, normal T-cell expressed and secreted cytokine). There also exists a chemokine called lymphotactin, which does not fall into either chemokine subfamily. These chemokines promote cell migration, increase the expression of cellular adhesion molecules such as integrins, andpromote cellular adhesion, and are thought to be the protein factors intimately involved in the adhesion and infiltration of leukocytes into the pathogenic sites in such as inflammatory tissues (for references, see for example, Michiel, D., Biotechnology, 1993, 11, 739; Oppenheim, J.J.. et al.. Annual Review of Immunology, 1991, 9, 617-648; Schall, T.J., Cytokine, 1991.3.165-183; Springer, T.A., Cell, 1994, 76, 301-314; Furie, M.B. , American Journal of Pathology. 1995,
146, 1287-1301; Kelner, G.S. , et al. , Science, 1994, 266, 1395-1399).
Forexample, MlP-lαinduces cellmigration andcauses atransient increase in intracellular calcium ion concentration levels, an increase in the expression ofintegrins, adhesionmolecules. anddegranulation ofmonocytes andlymphocytes, and inhibits bone marrow stem cell proliferation (See for example, Wolpe, S.D., et al.. Journal of Experimental Medicine, 1988, 167, 570-581; Wolpe, S.D., et al., Faseb Journal, 1989, 3. 2565-2573; Taub, D.D. , et al.. Science, 1993, 260, 355-358; Schall. T.J., et al. , Journal of Experimental Medicine. 1993, 177. 1821-1825; Neote. K. , et al.. Cell, 1993, 72, 415-425; Vaddi. K. , et al.. The Journal of Immunology. 1994, 153, 4721-4732).
With respect to the activity of MlP-lα in vivo and its role in the pathogenesis of disease, it has been reported that it is a pyrogen in rabbits (see for example Davatelis, G. , et al.. Science, 1989, 243, 1066-1068); that MlP-lα injection into mouse foot pads results in an inflammatory reaction such as infiltration by neutrophils and mononuclear cells (see for example Alam, R. , et al.. The Journal of Immunology, 1994, 152. 1298-1303); that MlP-lα neutralizing antibody has an inhibitory effect or a therapeutic effect in animal models of granuloma, multiple sclerosis and idiopathic pulmonary fibrosis (see for example Lukacε, N.W. , et al.. Journal of Experimental Medicine, 1993, 177, 1551-1559; Kaprus, W.J., etal.. The Journal of Immunology, 1995, 155, 5003-5010; Smith. R.E.. et al.. The Journal of Immunology, 1994, 153, 4704-4712); and that coxsackie virus induced myocarditis is inhibited in mice with a disrupted MlP-lα gene (see for example Cook. D.N. et al.. Science, 1995, 269, 1583-1585). These studies indicate that MlP-lαis deeply involved in the local attraction of various subtypes of leukocytes and the initiation, progression and maintenance of resulting inflammatory response.
MCP-1 (also known as MCAF (abbreviation for macrophage chemotactic and activating factor) or JE) is a chemokine produced bymacrophages. smooth muscle cells, fibroblasts, and vascular endothelial cells and causes cell migration and cell adhesion of monocytes, memory T cells, and natural killer cells, as well asmediating histamine release bybasophils (For reference, see for example, Rollins. B.J. , et al. , Proc. Natl. Acad. Sci. USA, 1988, 85.3738-3742; Matsushima, K.. et al.. Journal of Experimental Medicine, 1989. 169, 1485-1490; Yoshimura, T. et al.. Febs Letters. 1989. 244, 487-493; Rollins, B.J. et al.. Blood, 1991. 78. 1112-1116; Carr, M.W. , et al., Proc. Natl. Acad. Sci. USA, 1994, 91,
3652-3656; Jiang, Y.. et al., American Journal of Physiology, 1994, 267, C1112-C1118; Allavena, P., et al. , European Journal of Immunology. 1994, 24, 3233-3236; Alam, R., et al.. The Journal of Clinical Investigation. 1992, 89, 723-728). In addition, highexpression ofMCP-1 has been reported indiseases where accumulation of monocyte/macrophage and/or T cells is thought to be important in the initiation orprogression of diseases , such as atherosclerosis, restenosis due to endothelial injury following angioplasty, rheumatoid arthritis, glomerulonephritiε, pulmonary fibrosis, asthma and psoriasis (for reference, see for example, Firestein, G.S. et al.. Arthritis and Rheumatism, 1990, 33, 768-773; Nikolic-Peterson , D.J.. et al.. Kidney International. 1994, 45, enlarged ed., 45, S79-S82; Thomas, P.D. , etal., American Review of Respiratory Disease, 1987. 135. 747-760; Ross, R. , Nature, 1993, 362, 801-809; Cooper. K.D. , et al.. The Journal of Investigative Dermatology, 1994, 102, 128-137; Sousa, A.R., et al., American Journal of Respiratory Cell AndMolecular Biology, 1994). Furthermore, anti-MCP-1 antibody has been reported to inhibit delayed type hypersensitivity and hepatitis (for reference, see for example Rand, M.L. , et al., American Journal of Pathology, 1996, 148, 855-864; Wada, T. , et al., Faseb Journal, 1996, 10, 1418-1425).
These data indicate that chemokines such as MlP-lα and MCP-1 attract monocytes and lymphocytes to disease sites and mediate their activation and thus are thought to be intimately involved in the initiation, progression and maintenance of diseases deeply involving monocytes and lymphocytes, such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, glomerulonephritiε, multiple sclerosis, pulmonary fibrosis and myocarditis.
Therefore, drugs which inhibit the action of chemokines on target cells may be effective as a therapeutic and/or preventive drug in diseases such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, glomerulonephritis, multiple sclerosis, pulmonary fibrosis, and myocarditis.
Genes encoding receptors of specific chemokines have been cloned, and it is now known that these receptors are G protein-coupled seven-transmembrane receptors present on various leukocyte populations (for reference, see for example. Holmes, W.E. , et al.. Science 1991, 253, 1278-1280; Murphy P.M.. et al.. Science, 253, 1280-1283; Neote, K. et al.. Cell, 1993, 72, 415-425; Charo, I.F.. et al.. Proc. Natl. Acad. Sci. USA, 1994. 91, 2752-2756; Yamagami, S.,
et al., Biochem. Biophys. Res. Commun., 1994, 202. 1156-1162; Combadier , C, et al.. The Journal of Biological Chemistry. 1995. 270, 16491-16494, Power, C.A., et al., J. Biol. Chem., 1995, 270, 19495-19500; Samson, M. , et al. , Biochemistry, 1996, 35, 3362-3367; Murphy. P.M., Annual Review of Immunology, 1994. 12. 592-633). Therefore, compounds which inhibit the binding of chemokines such as MlP-lα and/or MCP-1 to these receptors, that is, chemokine receptor antagonists, may be useful as drugs which inhibit the action of chemokines such as MlP-lα and/or MCP-1 on the target cells, but there are no drugs known to have such effects. Cyclic diamine derivatives containing diarylalkyl groups are known to have muscarine receptor antagonistic activity (JP09-020758, Kokai) and may be useful as a drug in the treatment of substance abuse disorders (W09320821), may potentiate the effect of anti-cancer drugs by the inhibition of P-glycoproteins (JP03-101662, Kokai; EP363212). has calcium antagonistic activity ((a) DE3831993, (b) W09013539, (c) JP63-280081, Kokai; EP289227, (d) JP62-167762, Kokai; DE3600390), have activity on the central nervous system and inhibits hypermotility (W08807528), have antiaggression, antipsychotic, antidepressant and, analgesic effect (JP57-500828, Kokai), has coronary vasodilating activity (JP51-098281, Kokai), has anti-lipidemia effect and promotes vascular blood flow (JP49-093379, Kokai; EP42366), have coronary vasodilating activity and anti-reserpine activity (Aritomi, J., et al.. Yakugaku Zasshi , 1971, 91. 972-979); have anti-serotonin and anti-histamine activity (JP45-031193, Kokoku); and have central nervous system depressant activity (Vadodaria, D.J., et al., J. Med. Chem., 1969, 12, 860-865). However, these compounds differ from the novel compounds of the present invention and these compounds have not been known to interfere with binding of chemokines to the target cells.
Disclosure of the Invention
Therefore, it is an object of the present invention to discover small molecule drugs which inhibit the binding of liβmokines such as MlP-lα and/or MCP-1 to their receptors on the target cells
It is another object of the present invention to establish amethod to inhibit the binding to the receptors on the target cells and/or effects on target cells of chemokines such as MIP-1 α and/or MCP-1.
It is an additional object of the present invention to propose a method for the treatment of diseases for which the binding of chemokines such as MlP-lα and/or MCP-1 to the receptor on the target cell is one of the causes.
As a result of their intensive studies, the present inventors discovered that a cyclic diamine derivative having a diarylalkyl group or its pharmacologically acceptable acid adduct has an excellent activity to inhibit the binding of chemokines such as MlP-lα and/or MCP-1 and the like to the receptor of a target cell, which has led to the completion of this invention.
That is, the present invention provides a cyclic diamine derivative or its pharmacologically acceptable acid adduct (Invention 1), represented by the formula [I] below:
[wherein R1 and R2 are identical to or different from each other representing a phenyl group or an aromatic heterocyclic group having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms, in which the phenyl or aromatic heterocyclic group may be substituted by any number of halogen atoms, hydroxy groups, Cι-C„ lower alkyl groups, CJ-CJ lower alkoxy groups, phenyl groups, benzyl groups, phenoxy groups, methylenedioxy groups, Ci-Cj hydroxyalkyl groups, carboxy groups. C2-C7 alkoxycarbonyl groups, C2-C7 alkanoylamino groups, dioxolanyl grpoups, or by group represented by the formula: -NR5Rβ. or else may be condensed with a benzene ring to form a condensed ring, furthermore above substituents for the phenyl or aromatic heterocyclic group and the condenced ring condenced with abenzene ring are optionally substituted by any substituents independently selected from halogen atoms, hydroxy groups, or C^Cs lower alkoxy groups , and R5 and R6may be identical to or different from each other representing hydrogen atoms , Cj-Cg lower alkyl groups , or C2-C6 lower alkenyl groups;
R3 represents a hydrogen atom, hydroxy group, cyano group, C1-Ct lower alkoxy group or C2-C7 lower alkanoyloxy group; j represents an integer of 0-3; k represents 2 or 3 ;
R* is a group represented by :
1) Formula: -AJ-R7 (in the formula, R7 represents a phenyl group which may be substituted by any number of the same or different {halogen atoms, hydroxy groups, amino groups, Cj-Cj lower alkyl groups, Cι-C6 lower alkoxy groups, cyano groups, nitro groups, trifluoromethyl groups, C2-C7 alkoxycarbonyl groups, C2-C7 alkanoyl groups. Ci-C6 alkylsulfonyl groups, trifluoromethylsulfonyl groups, phenylsulfonyl groups {which may be substituted with ahydroxy group}, 1-pyrrolylsulfonyl groups, Cj-Ct hydroxyalkylsulfonyl groups, Cj-Ce alkanoylamino groups, or a group represented by the formula: -CONR'R9} in which R* and R9, identical to or different from each other, represent hydrogen atoms or Cι~C6 lower alkyl groups; A1 is a group represented by the formula: -(CH2)m- or a group represented by formula: - (CH2)P-G-(CH2)_- in which G represents G1 or G2; G1 represents -O-. -CO-, -Sθ2-, -CO-0-, -CONH-. -NHCO-, -NHCONH-, or -NH-S02-; G2 represents -(C=NH)NH-S02- , -CO-NH-NH-CO-, -CO-NH-NH-CO-NR10-, -CO-NH-CH2-CO- , -CO-NH-NH-Sθ2- , or -CO- N(CH2-CO-OCH3)-NH-CO- ; R10 represents a hydrogen atom or a phenyl group; m is an integer of 0-3; p is an integer of 1-3; q represents 0 or 1);
2) Formula: -A2-Ru
(wherein A2 represents -CO- or -Sθ2-; R11 represents:
a) A phenyl group which may be substituted by any number of the same or different {halogen atoms,
lower alkyl groups, Cj-C6 lower alkoxy groups, groups represented by formula -CH2-NR12R13 or groups represented by the formula:
b) An aromatic monocyclic heterocyclic group having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms, and optionally substituted with any of the same or different number of {halogen atoms. C^ C6 lower alkyl groups. C,-C( lower alkoxy groups} , or
c) A group represented by the formula: -CH 2-NR15R",
where R12, R13, R14 and R15. identical or different groups, represent hydrogen atoms or Ci-C,, lower alkyl groups and R16 represents {a phenyl group or a phenylalkyl group}, which may be substituted by any number of the same or different halogen atoms, C^Ce lower alkyl group, or Cj-C, lower alkoxy group);
3) Formula: -(CH2)„-R17
(in the formula, R17 is a group which may be substituted at any possible sites by any number of the same or different {halogen atoms, hydroxy groups, Cx-C6 lower alkyl groups, or Cj-Cj lower alkoxy groups}, representing
ahydrogen atom, cyano group, C2-C7 alkoxycarbonyl group, CJ-CJ hydroxyalkyl group, Cj-Cβ lower alkynyl group, C3-C6 cycloalkyl group, C3-C7 alkenoyl group, a group represented by the formula: -(CH0H)CH20Rlβ, a group represented by the formula: -CO-NH-NH-CO-OR 19, a group represented by the formula :
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula :
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula
a group represented by the formula:
a group represented by the formula:
in which n represents an integer of 1-4; Rlβ is Cj-C3 lower alkyl group. C2-C6 lower alkenyl group, or C2-C6 lower alkynyl group and R19 represents a Cj-Cj lower
alkyl group);
4) Formula: -(CH2)r-A3-R20
(wherein r represents an integer of 0-3; A3 represents a single bond, -CO-, -CO-NH-NH-CO- , -CO-NH-NH-CO-NH- , -CO-NH-CH2-CO-, -CO-NH-NH-S02-, -(CH0H)-CH2-, or -(CH0H)-CH20CH2-; R2C represents an aromatic heterocyclic group containing 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms in which the aromatic heterocyclic group may be substituted by any number of the same or different {halogen atoms, Cj-Ct lower alkyl groups, Cx-C6 lower alkoxy groups, or pyrrolyl groups} or may be condensed with a benzene ring to form a condensed ring ); or
5 ) Formula: -CH 2-CO-NR21R22
(wherein R21 represents a hydrogen atom or
lower alkyl group; R22 represents a hydrogen atom, C^Cj lower alkyl group, a group represented by the formula:
a group represented by the formula:
O
— CH — C-R26 (CH2)t-R25 . r or R21 and R22 may be taken together with the nitrogen to form a 4 to 7-membered saturated heterocycles. which may contain an oxygen atom, sulfur atom, or another nitrogen atom; where s represents 0 or 1; t represents an integer of 0-2; R" represents a hydrogen atom, hydroxy group, phenyl group, Cj-C6 lower alkyl group, or Ci-C8 lower alkoxy group; R24 represents a hydrogen atom or phenyl group which may be substituted by hydroxy group; R25 represents a hydrogen atom, phenyl group {which may be substituted by hydroxy group}, C2-C7 alkoxycarbonyl group. Cl- C6 lower alkyl group, C,-C6 alkylthio group, or 3-indolyl group; and R26 represents a hydroxy group, amino group, Ci-Cj lower alkoxy group, or phenylalkyloxy group);
Excepting that if R3 is a hydrogen atom, then, j is not 0, substituent for R7 is not hydroxy, C^C,; lower alkyl or Cj-C6 lower alkoxy; G1 is not -0- or
-CO-; its substituents, if R11 is a phenyl group, are not C,-C6 lower alkyl group;
R17 is not a hydrogen atom, C2-C7 alkoxycarbonyl group, or Cj-C6 hydroxyalkyl group;
r is not 0 and A3 is not a single bond or -CO- .
Furthermore, if R3 represents a hydrogen atom and k represents 2, R7 is not unsubstituted ; m is not 0 and R11 is not a substituted or unsubstituted phenyl group.
If R3 is a cyano group, R7 is not unsubstituted, and the substituent groups for R7 are not halogen atom, Cj-C6 lower alkyl group or C!-C6 lower alkoxy group. ]
The present invention provides a method of inhibiting the binding of chemokines to the receptor of a target cell and/or a method to inhibit its action onto a target cell using a pharmacological formulation containing as an active ingredient, a cyclic diamine derivative or its pharmacologically acceptable acid adduct (Invention 2) represented by the formula [II] below:
[wherein R1 and R2 are identical to or different from each other representing a phenyl group or an aromatic heterocyclic group having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms, in which the phenyl or aromatic heterocyclic group may be substituted by any number of halogen atoms, hydroxy groups, C^C, lower alkyl groups, CJ-CJ lower alkoxy groups , phenyl groups, benzyl groups, phenoxy groups, methylenedioxy groups, Cj-C, hydroxyalkyl groups, carboxy groups, C2-C7 alkoxycarbonyl groups, C2-C7 alkanoylamino groups, dioxolanyl grpoups. or by group represented by the formula: -NRSR', or else may be condensed with a benzene ring to form a condensed ring, furthermore above substituents for the phenyl or aromatic heterocyclic group and the condenced ring condenced with a benzene ring are optionally substituted by any ssubstituents independently selected from halogen atoms, hydroxy groups, orCi-Cj lower alkoxy groups , and Rs and R6 may be identical to or different from each other representing hydrogen atoms , C,-C6 lower alkyl groups , or C2-C6 lower alkenyl groups;
R3 represents a hydrogen atom, hydroxy group, cyano group, Cj-Cj lower alkoxy group or C2-C7 lower alkanoyloxy group;
j represents an integer of 0-3; k represents 2 or 3 ;
R4 is a group represented by :
1) Formula: -A'-R7
(in the formula, R7 represents a phenyl group which may be substituted by any number of the same or different {halogen atoms, hydroxy groups, amino groups, Ci-C,; lower alkyl groups, C^C,, lower alkoxy groups, cyano groups, nitro groups, trifluoromethyl groups, C2-C7 alkoxycarbonyl groups, C2-C7 alkanoyl groups, C^C* alkylsulfonyl groups, trifluoromethylsulfonyl groups, phenylsulfonyl groups {which may be substituted with a hydroxy group} , 1-pyrrolylsulfonyl groups, C,-C6 hydroxyalkylsulfonyl groups, Cj-C6 alkanoylamino groups, or a group represented by the formula: -CONR'R9} in which Rβ and R9. identical to or different from each other, represent hydrogen atoms or CJ-CJ lower alkyl groups; A1 is a group represented by the formula: -(CH2)m- or a group represented by formula: - (CH2)p-G-(CH2),j- in which G represents G1 or G2; G1 represents -O-, -CO-, -Sθ2-, -CO-0-, -CONH-, -NHC0-, -NHCONH-, or -NH-S02-; G2 represents -(C=NH)NH-S02-. -CO-NH-NH-CO- , -CO-NH-NH-CO-NR10-, -CO-NH-CH2-CO- , -CO-NH-NH-Sθ2- , or -CO- N(CH2-CO-OCH3)-NH-CO- ; R1D represents a hydrogen atom or a phenyl group; m is an integer of 0-3; p is an integer of 1-3; q represents 0 or 1);
2) Formula: -A2-Rn
(wherein A2 represents -CO- or -S02-; Ru represents:
a) A phenyl group which may be substituted by any number of the same or different {halogen atoms, Cj-C6 lower alkyl groups, CJ-CJ lower alkoxy groups, groups represented by formula -CH2-NR12R13 or groups represented by the formula:
b) An aromatic monocyclic heterocyclic group having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms . and optionally substituted with any of the same or different number of {halogen atoms, Cx- C6 lower alkyl groups, C^C, lower alkoxy groups} , or
c) A group represented by the formula: -CH 2-NR15R16,
where R12, R13, R14 and R15, identical or different groups, represent hydrogen atoms or Cx-C6 lower alkyl groups and R16 represents {a phenyl group or a phenylalkyl group}, which may be substituted by any number of the same or different halogen atoms, Cx-C6 lower alkyl group, or C^C, lower alkoxy group);
3) Formula: -(CH2)„-R17
(in the formula, R17 is a group which may be substituted at any possible sites by any number of the same or different {halogen atoms, hydroxy groups, C!-C6 lower alkyl groups, or Ci-C6 lower alkoxy groups}, representing
ahydrogen atom, cyano group, C2-C7alkoxycarbonyl group,
group, Cj-C6 lower alkynyl group, C3-C6 cycloalkyl group, C3-C7 alkenoyl group, a group represented by the formula: -(CHOH)CH20Rlβ, a group represented by the formula: -CO-NH-NH-CO-OR19. a group represented by the formula :
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula :
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
in which n represents an integer of 1-4; Rlβ is C^C^ lower alkyl group, C2-C6 lower alkenyl group, or C2-C6 lower alkynyl group and R1' represents a Ci-C6 lower
alkyl group) ;
4) Formula: -(CH2)r-A3-R20
(wherein r represents an integer of 0-3; A3 represents a single bond, -CO- . -CO-NH-NH-CO-, -CO-NH-NH-CO-NH- , -CO-NH-CH2-CO- , -CO-NH-NH- Sθ2-, -(CHOH)-CH2-, or -(CHOH)-CH2OCH2-; R20 represents an aromatic heterocyclic group containing 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms in which the aromatic heterocyclic group may be substituted by any number of the same or different {halogen atoms, Cj-C6 lower alkyl groups, Cj-Cs lower alkoxy groups, or pyrrolyl groups} or may be condensed with a benzene ring to form a condensed ring ) ;
5 ) Formula: -CH2-CO-NR21R22
(wherein R21 represents a hydrogen atom or Cj-C,; lower alkyl group; R22 represents a hydrogen atom, Cj-C6 lower alkyl group, a group represented by the formula:
—CH—CHOH (CH2)S-R23 ;or a group represented by the formula:
O
1 1 OR
— CH — C-R26 (CH2)t-R25 . or R21 and R22 may be taken together with the nitrogen to form a 4 to 7-membered saturated heterocycles, which may contain an oxygen atom, sulfur atom, or another nitrogen atom; where s represents 0 or 1; t represents an integer of 0-2; R23 represents a hydrogen atom, hydroxy group, phenyl group, C^Cs lower alkyl group, or Ci-Cj lower alkoxy group; R24 represents a hydrogen atom or phenyl group which may be substituted by hydroxy group; R25 represents a hydrogen atom, phenyl group {which may be substituted by hydroxy group}. C2-C7 alkoxycarbonyl group, C^ C6 lower alkyl group, Cj-Cs alkylthio group, or 3-indolyl group; and R26 represents a hydroxy group, amino group, Cj-Cj lower alkoxy group, or phenylalkyloxy group);
6) A hydrogen atom, Ci-C6 alkanoyl group, or C2-C7 alkoxycarbonyl group.]
Here, the compounds represented by the above formula [II] have activities to inhibit the binding of chemokines such as MIP-lα and/or MCP-1 and the like
to the receptor of a target cell and activities to inhibit physiological activities of cells caused by chemokines such as MlP-lα and/or MCP-1 and the like.
Preferred Embodiments of the Invention
(1) On Invention 1
In the above formula [I], R1 and R2 are identical to or different from each other representing a phenyl group or an aromatic heterocyclic group having
1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms, in which the phenyl or aromatic heterocyclic group may be substituted by any number of halogen atoms, hydroxy groups, Ci-C, lower alkyl groups, Ci-Cj lower alkoxy groups , phenyl groups, benzyl groups, phenoxy groups. methylenedioxy groups, Cι-C6 hydroxyalkyl groups, carboxy groups, C2-C7 alkoxycarbonyl groups,
CJ-CJ alkanoylamino groups, dioxolanyl grpoups, or by group represented by the formula: -NR5R6, or else may be condensed with a benzene ring to form a condensed ring. Unsubstituted aromatic heterocyclic groups having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms are specifically, for example, thienyl, furyl. pyrrolyl, imidazolyl, oxazolyl. isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazinyl, triazolyl. oxadiazolyl, thiadiazolyl group and the like, preferably including thienyl, furyl, pyrrolyl, and pyridyl groups.
The halogen atom as substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2 include fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, suitably including fluorine atoms and chlorine atoms. The Ci-C, lower alkyl groups mean Cj-C, straight-chain or branched alkyl groups such as methyl, ethyl, n-propyl, n-butyl. n-pentyl, n-hexyl. n-heptyl, n-octyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, 2-mβthylpentyl, 1-ethylbutyl, and the like, suitably specifically including, methyl, ethyl, and isopropyl groups. The Cι-Cβ lower alkoxy groups mean groups consisting of Cι-C6 part of the aforementioned C^C,, lower alkyl groups and oxy groups, specifically, for example, methoxy group and ethoxy group. The Cι-C6 hydroxyalkyl groups are groups in which Cι-C6 part of the aforementioned Cj-C, lower alkyl groups are substituted at their anypositions by a hydroxy group, preferably and specifically for example, hydroxymethyl group, 2-hydroxyethyl
group, and the like. The C2-C7 alkoxycarbonyl groups mean the aforementioned Cj-C6 lower alkoxy groups and carbonyl groups, preferably specifically for example, a methoxycarbonyl group and ethoxycarbonyl group. The C2-C7 lower alkanoylamino groups mean C2-C7 lower straight-chain or branched alkanoylamino groups such as acetylamino , propanoylamino, butanoylamino, pentanoylamino, hexanoylamino, heptanoylamino, isobutyrylamino, 3-methylbutanoylamino, 2- methy1butanoylamino, pivaloylamino, 4-methylpentanoylamino, 3,3- dimethylbutanoylamino, 5-methylhexanoylamino group, and the like, where the preferred and specific example includes an acetylamino group. Condensed rings obtained by condensation with a benzene ring mean a ring obtained by the condensation with a benzene ring of a phenyl group or an aromatic monocyclic heterocyclic ring having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms, at any possible sites, suitably and specifically for example, naphthyl, indolyl. benzofuranyl, benzothienyl, quinolyl group, indolyl group, benzimidazolyl group.
R5 and R6 represent each independently hydrogen atoms , Ci-C6 lower alkyl groups, or C2-C6 lower alkenyl groups. The Cι-C6 lower alkyl groups are the same as defined for the aforementioned Cι-C6 part of the CJ-CJ lower alkyl groups as substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given for the preferred specific examples. The C2-C6 lower alkenyl groups are for example, C2-Cβ straight-chain or branched alkenyl groups such as vinyl, allyl, 2-butenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 4-methyl-3-pentenyl, and the like, where preferred specific examples include allyl, 2-butenyl, and 3-butenyl group.
Furthermore above substituents for the phenyl or aromatic heterocyclic group and the condenced ring condenced with a benzene ring in R1 and R2 are optionally substituted by any ssubstituents independently selected from halogen atoms, hydroxy groups, or Cι-C6 lower alkoxy groups. The halogen atoms and Cι-C6 lower alkoxy groups are the same as defined for the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, and the same examples can be listed as preferred specific examples .
R3 in the above formula [I] represents a hydrogen atom, hydroxy group, cyano group, Cj-Cg lower alkoxy group, or C2-C7 lower alkanoyloxy group. The
lower alkoxy groups are the same as defined for the Cι~C6 lower alkoxy groups
in the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given for their preferred specific examples. The C2-C7 lower alkanoyloxy groups mean C2-C7 lower εtraight-chain or branched alkanoyloxy groups such as acetyloxy, propanoyloxy, butanoyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, isobutyryloxy, 3- methylbutanoyloxy, 2-methylbutanoyloxy, pivaloyloxy, 4-methylpentanoyloxy, 3,3-dimethylbutanoyloxy, 5-methylhexanoyloxy group, and the like, where the preferred and specific example includes an acetyloxy group. Preferred specific examples for R3 include a hydrogen atom and hydroxy group.
In the above formula [I] , j represents an integer of 0-3. If R3 represents a hydrogen atom, j is not 0. It is particularly preferred for j to be 2.
k in the above formula [I] represents 2 or 3; it is particularly preferred to use a homopiperazine derivative in which k is 3.
R* in the above formula [I] represents a group represented by:
1) Formula: -A^R7. 2) Formula: -A2-Ru.
3) Formula: -(CH2)n-R17.
4) Formula: -(CH2)r-A3-R20. or
5) Formula: -(CH2)-CO-NR21R22.
Here -CO- represents a carbonyl group. It is particularly preferred for R4 to be represented by formula 1): -A 1-R7 or formula 4): -(CH 2)r-A3-R20.
R7 represents a phenyl group which may be substituted by any number of the same or different {halogen atoms, hydroxy groups, amino groups, Ci-C6 lower alkyl groups, Ci-C6 lower alkoxy groups, cyano groups, nitro groups, trifluoromethyl groups, C2-C7 alkoxycarbonyl groups, C2-C7 alkanoyl groups, Ci-C3 alkylsulfonyl groups, trifluoromethylsulfonyl groups, phenylsulfonyl groups {which may be substituted with a hydroxy group}, 1-pyrrolylsulfonyl groups, Cι-C6 hydroxyalkylsulfonyl groups, Cι-C6 alkanoylamino groups, or a group represented by the formula: -CONR*R9}. However, if R3 represents a hydrogen atom, the substituent for a phenyl in R7 is not a hydroxy. Cι-C{ lower alkyl, or Cj-C6 lower alkoxy; if R3 is a hydrogen atom and k=2, R7 is not an unsubstituted phenyl group;
if R3 represents a cyano group, R7 is not unsubstituted and the substituent for a phenyl in R7 is not a halogen atom. Ci-C3 lower alkyl, or Cι-C6 lower alkoxy group.
The halogen atoms. Cι~Cβ lower alkyl groups, Cι-C6 lower alkoxy groups, C2-C7 alkoxycarbonyl groups , and C2-C7 alkanoylamino groups as substituents for a phenyl in R7 are the same as defined for the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, and the same examples can be listed as preferred specific examples. The C2-C7 lower alkanoyl groups mean C2-C7 lower straight-chain or branched alkanoyl groups such as acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl. isobutyryl, 3- methylbutanoyl, 2-methylbutanoyl , pivaloyl, 4-methylpentanoyl, 3,3- dimethylbutanoyl. 5-methylhexanoyl group, and the like, where the preferred and specific example includes an acetyl group. The Cι-C6 alkylsulfonyl groups mean those consisting of the aforementioned Ci-C6 part of the Ci-C, lower alkyl groups and sulfonyl groups, preferably and specifically, for example, a methylsulfonyl group. The phenylsulfonyl groups may be substituted with a hydroxy group at any position. The Cj-C, hydroxyalkylsulfonyl groups mean those consisting of the aforementioned Cι-C6 hydroxyalkyl groups and sulfonyl groups, preferably and specifically, for example, a (2-hydroxyethyl) sulfonyl group. R8 and R9, the same or different groups, represent hydrogen atoms or Cι-C6 lower alkyl groups. The Cι-Ct lower alkyl groups as Rβ and R9 are the same as defined for the aforementioned Cj-C, part of the Ci-C, lower alkyl groups as substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, and the same examples are listed for their preferred specific examples.
A1 is a group represented by the formula: -(CH2)m- or a group represented by formula: -(CH2)p-G-(CH2)q- in which G represents Gl or G2; G1 represents -0-, -CO-, -Sθ2-. -CO-0-, -CONH-, -NHCO-, -NHCONH-, or -NH-S02-; G2 represents - (C=NH)NH-S02-, -CO-NH-NH-CO-, -CO-NH-NH-CO-NR10-, -CO-NH-CH2-CO- , -CO-NH-NH- Sθ2- , or -CO-N(CH2-CO-OCH3)-NH-CO- ; R10 represents a hydrogen atom or a phenyl group; m is an integer of 0-3; p is an integer of 1-3; g represents 0 or 1); however, if R3 is a hydrogen atom, G1 is not -O- or -CO- ; if R3 represents a hydrogen atom and if k=2, m is not 0. In the above formula, -CO- means a carbonyl group and -Sθ2- means a sulfonyl group. Preferred A1 groups are specifically, for example, those represented by the formula -(CH2)„-, with m being preferably 1. Preferred A1 groups are also specifically, for example, -(CH2)p-CO-NH-NH-CO-
(CH2)q-, -{CH2)p-CO-NH-NH-CO-NH-(CH2)q-, -(CH2)p-CO-NH-CH2-CO-(CH2)q-: with p being preferably 1.
A2 represents -CO- (carbonyl group) or -Sθ2- (sulfonyl group).
R11 represents:
a) A phenyl group which may be substituted by any number of the same or different {halogen atoms, Cι-C6 lower alkyl groups, CJ-CJ lower alkoxy groups, groups represented by formula -CH2-NR12R13 or groups represented by the formula:
b) An aromatic monocyclic heterocyclic group having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms, and optionally substituted with any of the same or different number of {halogen atoms, C1- C6 lower alkyl groups, Cj-C, lower alkoxy groups} , or
c) A group represented by the formula: -CH 2-NR15R16.
However if R3 represents a hydrogen atom, the substituent group for a phenyl group in R11 is not a CJ-CJ lower alkoxy group; if R3 represents a hydrogen atom and k is 2, R11 is not a substituted or unsubstituted phenyl group. The halogen atoms, Cι-C6 lower alkyl groups, or Cι-C6 lower alkoxy groups as substituents for the groups in Ru are the same as defined for the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, and the same examples can be given as preferred specific examples.
Specific examples for R11 in which the aromatic monocyclic heterocyclic group is unsubstituted can be the same specific examples for the aromatic heterocyclic groups with no substituents in R1 and R2. Preferred examples specifically include a pyridyl group.
R12, R13, R14 and R15 represent each independently hydrogen atoms or Ci-C6 lower alkyl groups. The Cι-Cβ lower alkyl groups are of the same definition for the aforementioned Cι-C6 part of the Ci-C, lower alkyl groups as substituents
for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be listed as preferred specific examples.
R16 represents a {phenyl group or phenylalkyl group} which may be substituted by any number of the same or different {halogen atoms, Cj-C6 lower alkyl groups, or Cι-C6 lower alkoxy group}. The halogen atom, Cj-C6 lower alkyl group or Cx-C6 lower alkoxy group as substituents are the same as defined for the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given as preferred specific examples. The phenylalkyl group means a group consisting of a phenyl group and a Cι~C6 alkylene group, preferably and specifically for example, a benzyl group.
R17 is a group which may be substituted at any possible sites by any number of the same or different {halogen atoms, hydroxy groups, Cι-C6 lower alkyl groups, or Ci-Cj lower alkoxy groups}, representing
ahydrogen atom, cyano group. C2-C7 alkoxycarbonyl group, Cι-Cβhydroxyalkyl group, CJ-CJ lower alkynyl group, C3-C6 cycloalkyl group, C2-C7 alkenoyl group, a group represented by the formula: -(CHOH)CH2θRlβ, a group represented by the formula: -CO-NH-NH-CO-OR19, a group represented by the formula :
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula
a group represented by the formula:
o
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
If, however, R3 represents a hydrogen atom, R17 is not a hydrogen atom, C2-C7 alkoxycarbonyl group, or Ci-C, hydroxyalkyl group. R17 may be bonded at any possible site to an alkylene group -(CH2)n-. The C2-C7 alkoxycarbonyl and Cj-C, hydroxyalkyl groups are the same as defined for the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples may be given as preferred specific examples. The Cx-C6 lower alkynyl group means a C2-C6 straight-chain or branched alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 4-pentynyl, 5-hexynyl, 1- methyl-4-pentynyl group, and the like, preferably and specifically, for example, ethynyl group and 1-propynyl group. The C3-C6 cycloalkyl groups mean cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups and the like. The C3-C7 lower alkenoyl group means a C3-C7 straight-chain or branched alkenoyl groups such as propenoyl, 2-metylpropenoyl, 2-buenoyl, 3-butenoyl, 2-methyl-3-butenoyl, 3-methyl-2-butenoyl, 2-pentenoyl, 4-pentenoyl, 2- methyl-2-pentenoyl, 2,2-dimethyl-4-pentenoyl, 2-hexenoyl, 3-hexenoyl, 6- heptenoyl . and the like, preferably and specifically, for example propenoyl and 2-metylpropenoyl group .
The halogen atom. Cj-C, lower alkyl group or Cj-C6 lower alkoxy groups as substituents for R17 are the same as defined forthe aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, and the same examples can be given as preferred specific examples.
R18 represents a Cj-C, lower alkyl group, C2-C6 lower alkenyl group, or C2-C6 lower alkynyl group. The C^C, lower alkyl groups are the same as defined for the aforementioned Cj-C, part of the Ci-C, lower alkyl groups as substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given as preferred specific examples. The C2-C, lower alkenyl groups are the same as the C2-C, lower alkenyl groups in the aforementioned Rs and R6, where the preferred examples are specifically allyl, 2-butenyl, and 3-butenyl group. The C2-C6 lower alkynyl groups are the same as the C2-C6 lower alkynyl groups in the aforementioned R17 where the preferred examples are specifically 2-propynyl group and 3-butynyl group.
R19 represents a Cj-C6 lower alkyl group. Here, the Cι-C6 lower alkyl group is the same as defined for the aforementioned Cj-C, part of the Cj-C, lower alkyl groups as substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given as preferred specific examples.
n is an integer of 1-4. It is particularly preferred for the n to be 1 or 2.
A3 represents a single bond, -CO-, -CO-NH-NH-CO-, -CO-NH-NH-CO-NH-.
-CO-NH-CH2-CO-, -CO-NH-NH-S02- , -(CHOH)-CH2- , or -(CHOH)-CH2OCH2- . However, if R3 represents ahydrogen atom. A3 is not a single bond. Here, -CO- means a carbonyl group and -Sθ2- means a sulfonyl group. A3 is preferably a single bond or - CO-NH-NH-CO-.
R20 represents an aromatic heterocyclic group containing 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, and/or nitrogen atoms in which the aromatic heterocyclic group may be substituted by any number of the same or different {halogen atoms, Cj-C, lower alkyl groups. Cj-C, lower alkoxy groups, or pyrrolyl groups} or may be condensed with a benzene ring to form a condensed ring. As to specific examples in which the aromatic monocyclic heterocyclic group R20 has no substitution, the same specific example can be given as in the cases with no substituents on the aromatic heterocyclic rings in R1 and R2; preferred examples are spec ifically a pyridyl group and is oxazolyl group.
The halogen atom, C^C, lower alkyl group, or C^C, lower alkoxy group as substituents for the aromatic heterocyclic group in R20 are the same as defined for the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given as suitable specific examples. The condensed ring obtained by condensation with a benzene ring in R20 is the same as defined for the condenced ring in R ' and R2, where the same examples can be given as suitable specific examples.
r is an integer of 0-3. However, if R3 represents a hydrogen atom, r is not 0. In particular, it is preferred for r to be 1.
R21 represents a hydrogen atom or Ci-C6 lower alkyl group, R22 represents
hydrogen atom, Ci-C6 lower alkyl group , a group represented by the formula :
a group represented by the formula:
O — CH — C-R26 (CH 2),-R25 . or may be taken together with the nitrogen to form a 4 to 7-membered saturated heterocycles, which may contain an oxygen atom, sulfur atom, or another nitrogen atom. The Cj-C, lower alkyl groups in R21 and R22 are the same as defined for the aforementioned Cx-C6 part of the Cι-C„ lower alkyl groups as substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given for the preferred specific examples. Saturated heterocyclic rings consisting of R21 ,R22, and the nitrogen include azetidine, pyrrolidine, piperidine, perhydroazepine, morpholine. thiamorpholine, piperazine, homopiperazine, and the like; preferred specific examples include piperidine, morpholine, and thiamorpholine.
s represents 0 or 1 and t represents an integer of 0-2.
R23 represents a hydrogen atom, hydroxy group, phenyl group, Cj-C, lower alkyl group, or Cι-C€ lower alkoxy group. The C^C, lower alkyl group and Cj-C, lower alkoxy groups as R23 are the same as defined for the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given for the preferred specific examples .
R24 represents a hydrogen atom or phenyl group, where the phenyl group may be substituted by hydroxy group at any position.
R25 represents a hydrogen atom, pi ayl group, C2-C7 alkoxycarbonyl group, Ci-C, lower alkyl group, C X-Ct alkylthic roup, or 3-indolyl group, where the phenyl group may be substituted by hydroxy group at any position. The C2-C7 alkoxycarbonyl group and Cj-C, lower alkyl group as R25 are the same as defined for the aforementioned substituents for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given for the
preferred specific examples . The Cj-C, alkylthio group as R25 means a group consisting of thio group and Cj-C, part of the aforementioned Cj-C, lower alkyl groups for substituent in R1 and R2, specifically, for example, methylthio group and ethylthio group.
R26 represents a hydroxy group, amino group, Ci-C, lower alkoxy group, or phenylalkyloxy group. The Cj-C, lower alkoxy group is the same as defined for the aforementioned Cj-C6 lower alkoxy group as substituent for a phenyl group or an aromatic heterocyclic group in R1 and R2, where the same examples can be given for the preferred specific examples . The phenylalkyl group means a group consisting of a phenyl group, a Cι-C6 alkylene group, and a oxy group, preferably and specifically for example, a benzyl oxy group.
(2) On Invention 2
R1, R2, R3, j, and k in the above formula [II] are as the same as defined in the respective terms for the above formula [I) and the same examples can be listed for their preferred specific examples. R* in the above formula [II] includes R4 defined in the respective terms for the above formula [I] , where the same examples can be listed for their preferred specific examples, and furthermore R4 in the above formula [II] represents a hydrogen atom, Cj-C, alkanoyl group, or C2-C7 alkoxycarbonyl group. However, the above formula [II] does not involve the same limitations as made in the above formula [I] with respect to cases where R3 represents a hydrogen atom, where R3 represents a hydrogen atom and k represents 2, and where R 3 represents cyano group.
The cyclic diamine derivative represented by the formula [II] above or its pharmacologically acceptable acid adduct can be used to prepare a chemokine receptor antagonist preparation of the present invention by formulating the therapeutically required amount and a carrier and/or diluent into a pharmaceutical composition. Thus, the cyclic diamine derivative shown by the above formula [II] or its pharmacologically acceptable acid adduct can be administered orally or by parenterally , for example, intravenously, subcutaneously, intramuscularly, percutaneously or intrarectally.
The oral administration can be accomplished in the form of tablets, pills, granules, powder, solution, suspension, capsules, etc.
The tablets for example can be prepared using a vehicle such as lactose, starch and crystallized cellulose; binder such as carboxymethylcellulose, methylcellulose, and polyvinylpyrrolidone; disintegrator such as sodium alginate, sodium bicarbonate and sodium lauryl sulfate, etc.
Pills, powder and granule preparations can be prepared by a standard method using the vehicles mentioned above. Solution or suspension can be prepared by a standard method using glycerin ester such as tricaprylin and triacetin oralcohols such as ethanol. Capsules canbemade bycharging granules, powder or solution in gelatin, etc.
Subcutaneous, intramuscular or intravenous preparations can be prepared as an injection using aqueous or nonaqueous solution. Aqueous solution for example may include isotonic sodium chloride solution. Nonaqueous solutions may include for example, propyleneglycol, polyethyleneglycol, olive oil, ethyl oleate, etc.. and optionally, one can add antiseptics and stabilizers. For injection, one can be sterilized by filtration through a bacterial filter or combination of disinfectant .
Percutaneous administration may be in the form of an ointment or cream, and ointment can be prepared in the standard manner using fatty oils such as castor oil and olive oil. or Vaseline, while creams can be made using fatty oils or emulsifying agent such as diethyleneglycol and sorbitan esters of fatty acid.
For intrarectal administration, one can use standard suppositories using gelatin soft capsules , etc.
The cyclic diamine derivative of the present invention or its pharmacologically acceptable acid adduct is administered at a dose that varies depending on the type of disease, route of administration, age and sex of patient, and severity of disease, but is likely to be 1-500 mg/day in an average adult.
(3) Matter common throughout Invention 1 and Invention 2
Preferred specific examples for the cyclic diamine derivatives in the
above formula [I] or formula [II] include compounds having each substituent as shown in the following Tables 1.1 - 1.25.
Table 1.1 - Table 1.25
Table 1.2
Table 1.4
Table 1.6
Table 1.7
Table 1.8
Table 1.9
T
Table 1.11
Table 1.12
Table 1.13
Table 1.14
Table 1.15
Table 1.16
Table 1.17
Table 1.18
Table 1.19
Table 1.20
Table 1.21
Table 1.22
Table 1.23
Table 1.24
Table 1.25
The present invention can also use acid adducts of the cyclic diamine derivatives where such acids include, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, and the like, as well as organic acids such as citric acid, malic acid, tartaric acid, fumaric acid, methanesulfonic acid, trifluoroacetic acid, and the like.
The present invention may use racemates and all possible optically active forms of the cyclic diamine derivatives represented by the above formula [I] or [II].
Compounds represented by the above general formula [I] and/or [II] can be synthesized by any of the general preparations given below.
(Preparation 1)
A preparation which call for treating one equivalent of a cyclic diamine derivative represented by the formula [III] below :
[where R1, R2, R3, j, and k are as defined respectively in the above formula [I] or [II]] with 0.1-10 equivalents of a compound represented by the formula [IV] below:
R4 [IV]
[wherein R4 is the same as defined for the R4 in the above formula [I] or [II];
X1 is a halogen atom, alkylsulfonyloxy group, or arylsulfonyloxy group. R4 is not a group represented by the formula: -A2-Rn in where A2 and Ru are the same as defined respectively in the above formula [I] or [II] ], either in absence or presence of solvent; alternatively treating 1 equivalent of a cyclic diamine given by the formula
[V] below:
[where R4 and k are the same as defined respectively in the above formula [I] or [II]], with 0.1-10 equivalents of a compound represented by the formula [VI] below:
[where R1, R2, R3, and j are the same as defined respectively in the above formula [I] or [II]; X1 represents a halogen atom, alkylsulfonyloxy, or arylsulfonyloxy group] either in the absence or presence of solvent.
Such reactions can be more smoothly run if a base is present. The base which may be used includes inorganic salts such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate. and the like, or amines such as triethylamine, diisopropylethylamine, andpyridine, and the like. In addition, the reactions in these preparations can also be promoted by iodide such as potassium iodide, sodium iodide, or the like.
X1 in the above formulas [IV] and [VI] represents a halogen atom, alkylsulfonyloxy, or arylsulfonyloxy group. Such halogen atoms include preferably chlorine, bromine, and iodine atoms. Suitable specific examples for the alkylsulfonyloxy groups include methylsulfonyloxy and trifluoromethylsulfonyloxy group and the like. A preferred specific example for the arylsulfonyloxy group includes a tosyloxy group.
(Preparation 2)
A preparation which calls for treating 1 equivalent of a cyclic diamine derivative represented by the above formula [III] with 0.1-10 equivalents of a carboxylic acid, sulfonic acid represented by the formula [VII] below:
HO-A2-Ru [VII]
[where R11 and A2 are the same as defined respectively in the above formulas [I] or [II]], or its reactive derivative, either in the absence or presence of solvent.
The reactive derivatives for the carboxylic acids or sulfonic acids in the above formula [VII] include highly reactive carboxylic or sulfonic acid derivatives, which are usually used in synthetic organic chemistry, such as acid halides, acid anhydrides, mixed acid anhydrides. If esters are used, the reaction can be run smoothly by activating the cyclic diamine derivative represented by the above general formula [III], for example, by using triethylaluminum.
Such reactions can be more smoothly run by using suitable amounts of a dehydrating agent such as molecular sieve, condensing agents such as dicyclohexylcarbodiimide, N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide, carbonyldiimidazole. and the like, or bases similar to those used in the above preparation 1.
(Preparation 3)
A preparation which calls for treating 1 equivalent of a cyclic diamine represented by the above formula [III], with 0.1-10 equivalents of an aldehyde represented by the formula [VIII] below :
R27-(CH2).-CHO [VIII]
[where in the formula R27 represents either R7, R17, or R20 of the above formula [I] or [II] ; z represents an integer of 0-3] « either in the absence or the presence of solvent under reductive conditions, orelse treating 1 equivalent of acompound represented by the above formula [V] with 0.1-10 equivalents of an aldehyde represented by the formula [IX] below :
[where in the formula R1, R2, R3, and j are the same as defined respectively in the above formulas [I] or [II] ] , either in the absence or the presence of solvent under reductive conditions.
Such reactions are in general called reductive amination reactions and such reductive conditions may be generated by catalytic hydrogenation using a catalyst containing a metal such as palladium, platinum, nickel, rhodium, or the like, using complex hydrides such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydrlde, sodium triacetoxyborohydride, and the like, boranes, or electrolytic reduction, and the like.
(Preparation 4)
A preparation which calls for treating 1 equivalent of a cyclic diamine derivative represented by the formula [X] below:
[where in the formula j. k, and R4 are the same as defined respectively for the above formula [I] or [II] and R2β represents a Cj-C6 lower alkyl group] or 1 equivalent of a cyclic diamine derivative represented by the formula [XI] below:
[XI]
[where R1, j, k, and R4 are the same as defined respectively for the above formula [I] or [II]], with 0.1-10 equivalents of an organometallic reagent represented by the formula [XII] below:
R2'-M [XII]
[wherein the formula R2' is the same as defined for the R1 and R2 in the above formula [I] or [II]; M is a metal atom or its halide or complex] in the presence of solvent.
The organometallic reagents used in such preparations may be those suitably selected organometallic reagents known to cause a nucleophilic reaction toward esters and/or ketones in general in synthetic organic chemistry, such as Grignard reagents (M = MgX2), organolithium reagents (M = Li), organocerium reagents (M = CeX2 2) (X2 represents a halogen atom). These organometallic reagents may be prepared by known methods from the corresponding halides. The halldes preferably include chlorides, bromides, iodides.
If the substrates submitted to each of the above preparations contains a substituent which reacts under each reaction condition in general in synthetic organic chemistry or is thought to adversely affect the reaction, that functional group can be protected by a known suitable protecting group followed by the reaction of the above preparations and deprotection using a known procedure to obtain the desired compound.
Each of the above preparations may use solvents for the reaction such as halogenated hydrocarbons such as dichloromethane, chloroform, or the like, aromatic hydrocarbons such as benzene, toluene, and the like, ethers such as diethyl ether, tetrahydrofuran, or the like, esters such as ethyl acetate, aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile, and the like, alcohols such asmethanol, ethanol, isopropyl alcohol, and the like.
The reaction temperature in either of the preparations should be in the range of -78 - +150 _C. preferably 0_C - 100 _C. After completion of the reaction, the usual isolation and purification operations such as concentration, extraction, recrystallization, chromatography, and the like may be used . to isolate the desired cyclic diamine derivatives represented by the above formula [I] or [II]. These can be converted into pharmacologically acceptable acid adducts by the usual method.
Potential Industrial Utilities
The chemokine receptor antagonist, which contain the cyclic diamine derivative or its pharmacologically acceptable acid adducts of this invention, which inhibits chemokines such as MlP-lα and/or MCP-1 and the like from action
on target cells, are useful as therapeutic agents and/or preventive preparation for diseases such as atherosclerosis, rheumatic arthritis, psoriasis, asthma, ulcerative colitis, glomerulonephritis, multiple sclerosis, pulmonary fibrosis, myocarditis, and the like, in which tissue infiltration of blood monocytes, lymphocytes, and the like plays a major role in the initiation, progression, and maintenance of the disease.
Examples
The present invention is now specifically described by the following examples. However, the present invention is not limited to these compounds described in these examples. Compound numbers in these examples represent numbers attached to these compounds listed as suitable specific examples in
Tables 1.1 - 1.18.
Example 1: Synthesis of 1-(3.3-Diphenylpropyl)-4-(4- nitrobenzyDhomoplperazine (Compound No. 23).
A mixture of 120 mg of homopiperazine, 206 mg of homopiperazine dihydrochloride, and 3 mL of ethanol was heated to 70 _C to prepare a solution. 375 mg of sodium iodide and 287 mg of 3,3-diphenylpropyl methanesulfonate were added sequentially to the solution and the mixture was stirred at 70 _C for 14 hours. The mixture was allowed to cool to room temperature and the ethanol was removed under reduced pressure, followed by adding 20 mL of 2N aqueous sodium hydroxide solution and extracting with 20 mL x 2 of ethyl acetate. The organic layers were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate. filtered, and concentrated to give 1-(3,3-diphenylpropyl)homo piperazine.
The resulting 1-(3,3-dlphenylpropyl )homopiperazine was dissolved in 3 mL of acetonitrile followed by adding 213 mg of 4-nitrobenzyl bromide and 144 mg of potassium carbonate. The mixture was stirred at 70 _C for 14 hours and allowed to cool to room temperature and the solvent was removed under reduced pressure. 20 mL of aqueous 2N sodium hydroxide was added and the mixture was extracted with 20 mL x 2 of ethyl acetate. The organic layers were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated, andpurified bycolumn chromatography (silica gel, ethyl acetate) to obtain 255 mg of the titled compound. This was treated with a hydrogen chloride solution in ether and the solvent was removed under reduced pressure; and the residue was dried to obtain the hydrochloride salt of the titled compound.
Compound No.23 (Free Base) had the following *H NMR (CDC13.270 MHz) δ (ppm) : 1.73-1.82 (m, 2 H) , 2.16-2.25 (m. 2 H), 2.40-2.46 (m, 2 H) , 2.64-2.71 (m, 8 H) , 3.71 (s, 2 H), 4.01 (t, J = 7.6 Hz, 1 H). 7.13-7.19 (m, 2 H) , 7.19-7.31 (m, 8
H ) , 7 . 50 ( d , J = 8. 6 Hz , 2 H ) , 8 . 16 ( d, J = 8.6 Hz , 2 H ) .
Example 2: Preparation of l-Benzyl-4- (3,3- diphenylpropyl)homopiperazine (Compound No. 15). A mixture of 101 mg of homopiperazine, 175 mg of homopiperazine dihydrochloride, 3 mL of ethanol was heated to 70 _C into a solution. 0.115 mL of benzyl chloride was added and the mixture was stirred at 70 _C for 3 hours. After cooling to room temperature, ethanol was removed under reduced pressure, and 20 mL of aqueous 2N sodium hydroxide solution was added to the solution, which was extracted with 20 mL x 2 of ethyl acetate. The organic layers were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 1- benzylhomopiperazine.
The resulting benzylhomopiperazine was dissolved in 3 mL of ethanol, to which were added 296 mg of 3,3-diphenylpropyl methanesulfonate and 136 mg of potassium carbonate. The mixture was stirred at 70 _C for 15 hours and it was cooled to room temperature and the solvent was removed under reduced pressure . 20 mL of aqueous 2N sodium hydroxide was added and the solution was extracted with 20 mL x 2 of ethyl acetate. The organic layers were combined and washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate) to obtain 135 mg of the titled compound. This was treated with a hydrogen chloride solution in ether followed by removing the solvent under reduced pressure anddrying to give the hydrochloride salt of the titled compound.
Compound No.15 (free base) had the following λE NMR (CDC13, 270 MHz) δ (ppm) : 1.71-1.81 (m, 2 H), 2.16-2.25 (m. 2 H), 2.39-2.45 (m, 2 H) , 2.64-2.73 (m, 8 H) . 3.62 (s, 2 H), 4.01 (t. J = 7.9 Hz. 1 H) . 7.12-7.34 (m, 15 H) .
Example 3: Preparation of l-Benzoyl-4-( 3,3- dlphenylpropyl )homopiperazine (Compound No. 199).
A mixture of 126 mg of homopiperazine, 218 mg of homopiperazine dihydrochloride, 3 mL of ethanol was heated to 70 _C into a solution. 378 mg of sodium iodide and 289 mg of 3,3-diphenylpropyl methanesulfonate were added sequentially to the solution and the solution was stirred at 70 _C for 15 hours.
After the solution was cooled to room temperature, the ethanol was removed under
reduced pressure followed by adding 20 mL of aqueous 2N sodium hydroxide and extracting with 20 mL x 2 of ethyl acetate. The organic layers were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give l-(3,3- diphenylpropyl)homopiperazine .
The resulting 1-(3,3-diphenylpropyl )homopiperazine was dissolved in 3 mL of dichloromethane, followed by adding 107 mg of trlethylamine and 140 mg of benzoyl chloride. After the mixture was stirred at room temperature for 6 hours, it was mixed with 20 mL of aqueous 2N sodium hydroxide and extracted with 20 mL x 2 of ethyl acetate. The organic layers were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, hexane/ethyl acetate 4:6) to obtain 249 mg of the titled compound. This was treated with a hydrogen chloride solution in ether and the solvent was removed under reduced pressure and the residue was dried to give the hydrochloride salt of the titled compound.
Compound No.199 (free base) had the following *H NMR (CDC13.270 MHz) δ (ppm) : 1.69-1.79 (m, 1 H) , 1.90-1.99 (m, 1 H) , 2.12-2.28 (m. 2 H), 2.35-2.48 (m. 2 H).
2.54-2.61 (m. 2 H) . 2.64-2.69 (m, I H), 2.75-2.80 (m. 1 H) . 3.39-3.46 (m, 2 H).
3.73-3.78 (m, 2 H), 3.96-4.06 (m, I H). 7.13-7.31 (m, 10 H), 7.35-7.39 (m, 5
H).
Example 4: Preparation of l-[4-(Dimethylamlnoαιethyl) benzoyl]-4-
(3,3-diphenylpropyl)homopiperazine (Compound No. 202).
The same method as that of Example 1 was used to obtain l-(3,3- diphenylpropyl)homopiperazine .
The resulting l-(3,3-diphenylpropyl)homopiperazine was dissolved in 3 mL of toluene under argon, followed by adding 0.65 mL of a 15% trimethylaluminum solution in hexane. The mixture was stirred at room temperature for 15 minutes, mixed with 187 mg of methyl 4-(dimethylaminomethyl) benzoate, stirred at 60 _C for 22 hours. The mixture was cooled to room temperature, mixed with 2N hydrochloric acid, and stirred. 20 mL of aqueous 2N sodium hydroxide was added and the mixture was extracted with 20 mL x 2 of ethyl acetate. The organic layers were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated, andpurified by column
chromatography (silica gel, ethyl acetate/methanol 6:4) to obtain 234 mg of the titled compound. This was treated with a hydrogen chloride solution in ether, the solvent was removed under reduced pressure and the residue was dried to give the hydrochloride salt of the titled compound.
Compound No.202 (free base) had the following XH NMR (CDC13, 270 MHz) δ (ppm) :
1.65-1.80 (m, IH).1.89-2.01 (m. IH), 2.12-2.29 (m, 2H), 2.24 (s, 6 H) , 2.35-2.48
(m, 2 H), 2.52-2.60 (m, 2 H), 2.60-2.70 (m, 1 H), 2.74-2.79 (m, 1 H), 3.40-
3.48 (m. 2 H). 3.43 (s, 2 H). 3.32-3.77 (m. 2 H). 3.96-4.06 (m. 1 H), 7.16- 7.52 (m, 14 H).
Example 5: Preparation of l-(3,3-Diphenylpropyl )-4-(2- quinolylmethyDbomopiperazine (Compound No. 237).
The same method as that of Example 1 was used to obtain l-(3,3- diphenylpropyl)homopiperazine .
The resulting 1-(3,3-diphenylpropyl)homopiperazine was dissolved in 3 mL of ethanol, mixed with 228 mg of 2-(chloromethyl)quinoline hydrochloride and 141 mg of potassium carbonate, and stirred at 70 _C for 14 hours. The mixture was cooled to room temperature and the ethanol was removed under reduced pressure, 20 mL of aqueous 2N sodium hydroxide was added and the mixture was extracted with 20 mL x 2 of ethyl acetate. The organic layers were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography (silica gel. ethyl acetate/methanol 95:5) , to obtain 109 mg of the titled compound. This was treatedwith ahydrogen chloride solution in ether andthe solvent was removed under reduced pressure and the residue was dried to give the hydrochloride salt of the titled compound.
Compound No.237 (free base) had the following *H NMR (CDC13, 270 MHz) δ (ppm) : 1.76-1.86 (m, 2 H). 2.18-2.27 (m. 2 H) . 2.42-2.49 (m, 2 H) , 2.68-2.82 (m, 8 H),
3.96 (s, 2 H), 4.02 (t. J = 7.6 Hz, 1 H) . 7.12-7.31 (m. 1 H). 7.50 (dd, j = 7.9,
7.9 Hz. 1 H). 7.65-7.72 (m. 2 H), 7.79 (d, J = 7.9 Hz. 1 H) , 8.05 (d, J = 8.3
Hz, 1 H). 8.11 (d. J = 8.6 Hz, 1 H) .
Example 6: Preparation of 1-(3,3-Diphenylpropyl )-4-{7-mβthoxy-2 H- chromene-2-one-4-ylmethyl )homopiperazine (Compound No. 206).
The same method as that of Example 5 was used except for the use of 70
mg of 4-(bromomethyl)-7-methoxy-2 H-chromene-2-one to give 303 mg of the titled compound, and except for the use of ethanol/chloroform as the solvent for the reaction. Furthermore, the same method as that of Example 5 was used to obtain the hydrochloride salt of the titled compound.
Compound No.206 (free base) had the following *H NMR (CDC13, 270 MHz) δ (ppm) : 1.75-1.85 (m, 2 H), 2.16-2.25 (m, 2 H) , 2.39-2.45 (m, 2 H) . 2.62-2.79 (m, 8 H), 3.72 (s, 2 H). 3.87 (s, 3 H). 4.02 (t, J = 7.6 Hz, 1 H) , 6.36 (s. 1 H). 6.80-6.85 (m, 2 H), 7.12-7.31 (m, 10 H), 7.75 (d, J = 9.6 Hz, 1 H) .
Example 7: Preparation of l-(2-Benzimldazolylmethyl)-4- (3,3- diphenylpropyl)homopiperazine (Compound No. 207).
The same method as that of Example 5 was used except for the use of 165 mg of 2-(chloromethyl)benzimidazole and 16 mg of sodium iodide to promote the reaction to give 91 mg of the titled compound. Furthermore, the same method as that of Example 5 was used to obtain the hydrochloride salt of the titled compound.
Compound No.207 (free base) had the following *H NMR (CDC13, 270 MHz) δ (ppm) : 1.70-1.82 (m, 2 H). 2.19-2.29 (m. 2 H) . 2.43-2.50 (m, 2 H) , 2.65-2.73 (m, 4 H), 2.76-2.81 (m, 4 H). 3.96 (s, 2 H) , 3.99 (t, J = 7.6 Hz. 1 H), 7.14-7.31 (m, 14 H). 7.60-7.85 (m, 1 H).
Example 8: Preparation of l-(2,2-Diphenylethyl)-4-[ 4-
(methylsulfonyl)benzyl]homoplperazine (Compound No. 6).
A mixture of 120 mg of homopiperazine, 216 mg of homopiperazine dihydrochloride salt, 3 mL of ethanol was heated to 70 _C into a solution. To this solution were added sequentially 383 mg of sodium iodide and 250 mg of 4-(methylsulfonyl)benzyl bromide, followed by stirring at 70 _C for 14 hours. After the solution was cooled to room temperature, ethanol was removed under reduced pressure and 20mL of aqueous 2N sodium hydroxide was added and themixture was extracted with 20 mL x 2 of ethyl acetate. The organic layers were combined, washed with 20 mL of aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 176 mg of l-[4- (methylsulfonyl)benzyljhomopiperazine .
The resulting l-[4-(methylsulfonyl)benzyl]homopiperazine was dissolved in 5 mL of dichloromethane, followed by adding 223 mg of diphenylacetaldehyde and 217 mg of sodium triacetoxyborohydride. After the mixture was stirred at room temperature for 16 hours, it was mixed with 30 mL of aqueous saturated sodium hydrogencarbonate, and extracted with 30 mL x 2 of ethyl acetate. The organic layers were combined, washed with 30 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate) to obtain 173 mg of the titled compound. This was treated with a hydrogen chloride solution in ether and the solvent was removed under reduced pressure, the residue was dried to give the hydrochloride salt of the titled compound.
Compound No.6 (free base) had the following *H NMR (CDC13, 270 MHz) δ (ppm) : 1.64-1.77 (m. 2 H). 2.51-2.64 (m. 4 H), 2.67-2.83 (m, 4 H), 3.04 (S, 3 H), 3.15 (d, J = 7.6 Hz, 2 H). 3.61 (s. 2 H), 4.14 (t, J = 7.6 Hz. 1 H). 7.13-7.35 (m, 10 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.84 (d, J = 8.2 Hz, 2 H) .
Example 9: Preparation of 1-(3-Hydroxy-3,3-diphenylpropyl)-4-(4- σhlorobβnzyl )homopiperazine (Compound No. 107). A solution of 54 mg of methyl 3-[4-(4-chlorobenzyl) homopiperazinyl] propionate in 10 mL of ether was mixed with under nitrogen, 4 mL of 1 M phenyl magnesium bromide. The mixture was stirred at room temperature for 30 minutes, mixed with aqueous saturated ammonium chloride and the mixture was extracted with 50 mL of ethyl acetate. The extract was washed with 50 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate/methanol 9:1) to give 65 mg of the titled compound. This was treated with a hydrogen chloride solution in ether and the solvent was removed under reduced pressure and the residue was dried to give the hydrochloride salt of the titled compound.
Compound 107 (free base) had the following *H NMR (CDC13, 270 MHz) δ (ppm) : 1.77-1.86 (m. 2 H) . 2.36-2.40 (m, 2 H) , 2.54-2.71 (m, 10 H), 3.58 (s. 2 H) , 7.15-7.20 (m, 2 H), 7.26-7.32 (m, 8 H) , 7.44-7.48 (m, 4 H).
Example 10: Preparation of l-(3,3-Diphenylpropyl)-4-{4- oarbamoylbenzyl)homopiperazine (Compound No. 55).
A 20 mL solution of 175 mg of compound No. 30 in 20 mL of t-butyl alcohol was mixed with 570 mg of ground potassium hydroxide and the mixture was refluxed for 2.5 hours. The solution was cooled to room temperature and mixed with 50 mL of water and 100 mL of ethyl acetate. The organic layer was separated and the aqueous layer was extracted with 50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate/methanol 4:1) to give 91 mg of the titled compound. This was treated with a hydrogen chloride solution in ether and the solvent was removed under reduced pressure and the residue was dried to give the hydrochloride salt of the titled compound.
Compound No.55 (free base) had the following *H NMR (CDC13, 270 MHz) δ (ppm) : 0.86-0.91 (m, I H), 1.23-1.28 (m, 2 H), 1.73-1.82 (m. 2 H) . 2.18-2.26 (m. 2 H) , 2.42-2.47 (m, 2 H) , 2.65-2.73 (m, 6H), 3.67 (s, 2H).5.6-6.2 (brs.2H), 7.13-7.30 (m, 10 H), 7.41 (d . 2 H, J = 8.25 Hz). 7.75 (d. 2 H, J = 8.25 Hz).
Example 11: Preparation of 1-[3,3-Di(2-furyl)-3-hydroxypropyl ]-4- [4-(methyl8ulfonyl)benzyl]homopiperazine (Compound No. 129).
To a solution of 2-furyl lithium prepared in 50 mL of THF using 3 mL of furan and 2 mL of 1.63 Mn-butyllithium was added dropwise at 0 *C, a 10 mL solution in THF of 99 mg of methyl 3-[4-{4-
(methylsulfonyl)benzyl}homopiperazinyl] propionate. After stirring at 0 *C for
1 hour, themixture wasmixed with 50mLof an aqueous saturated ammonium chloride, and extracted with 50 mL x 2 of ethyl acetate. The extracts were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate) to give 62 mg of the titled compound.
Compound No.129 had the following XH NMR (CDC13.270 MHz) δ (ppm) : 1.80-1.89
(m. 2 H), 2.32-2.36 (m, 2 H). 2.56-2.60 (m, 2 H). 2.74-2.78 (m, 2 H). 2.66- 2.70 (m. 6 H), 3.05 (ε, 3 H), 3.70 (s, 2 H) , 6.30-6.34 (m, 4 H), 7.36-7.37 (m,
2 H), 7.55 (d. 2 H J = 8.25 Hz). 7.86 (d. 2 H. J = 8.25 Hz).
Example 12: Preparation of 1-[3,3-Bis(4-hydroxyphenyl)-3- hydroxypropyl]-4-[4-(methylsulfonyl)benzyl ]homopiperazine (Compound No.119). To a 2.0 mL anhydrous THF solution of 120 mg of methyl 3-[4-(4- chlorobenzyl) homopiperazinyl]propionate was added under nitrogen, 2.0 mL solution in THF of 1.5 mmol of 4-( tert-butyldimethylsilyloxy)phenyl magnesium
bromide. The mixture was stirred at room temperature for 30 minutes and an aqueous saturated ammonium chloride solution was added and the mixture was extracted with 20 mL x 3 of ethyl acetate. The extracts were washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, hexane/ethyl acetate 1:1) to give 33 mg of a silyl protected form of the titled compound. The resulting oily product was dissolved in 3 mL of THF and mixed with 0.8 mL of a IN THF solution of tributylammonium fluoride. The mixture was stirred at room temperature for 4 hours, mixed with aqueous saturated ammonium chloride and extracted with 20 mL x 3 of ethyl acetate. The extracts were washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 5 mg of the titled compound.
Compound No. 119 had the following *H NMR (CDC13, 270 MHz) δ (ppm) : 1.81-1.94 (m. 2 H), 2.35 (broad s. 3 H) , 2.55-2.82 (m, 1 H) , 3.08 (s. 3 H) , 3.70 (s, 2 H). 6.67 (d. J = 8.6 Hz, 4 H). 7.14 (d, J = 8.9 Hz, 4 H), 7.48 (d, J = 8.3 Hz, 2 H), 7.81 (d, J = 8.3 Hz, 2 H) .
Example 13: Preparation of l-[3-Hydroxy-3-(l-mβthyl-2-pyrrolyl) -3- phenylpropyl 3-4-[4-(methylsulfonyl )benzyl]homopiperazine (Compound No. 136).
1.0 mL of an anhydrous THF solution of 121 mg of methyl 3-[4-{4- (methylsulfonyl)benzyl}homo piperazinyl]propionate was added under nitrogen to 6 mL of a THF solution of 1.5 mmol of 1-methyl-2-pyrrolylcerium dichloride at -78 *C. After stirring at -78 "C for 3 hours, the mixture was mixed with 20 mL of water and it was filtered from insoluble matter using Celite, followed by extracting the filtrate with 30 mL x 2 of ethyl acetate. The extracts were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate, ethyl acetate/methanol 10:1) to give 7 mg of the titled compound.
Compound No. 136 had the following *H NMR (CDC13. 270 MHz) δ (ppm) : 7.88 (d. J = 8.4 Hz, 2 H), 7.56 (d, J = 8.4 Hz. 2 H) , 7.32-7.16 (m, 5 H). 6.48-6.47 (m, I H), 6.22-6.20 (m, I H), 6.06-6.04 (m, 1 H), 3.72 (s, 2 H). 3.26 (s. 3H). 3.06 (s, 3 H), 2.87-2.39 (m. 11 H) . 2.05-1.83 (m, 3 H) .
Example 14: Preparation of 1-[3,3-Biβ(l-methyl-2-pyrrolyl)-3-
hydroxypropyl]-4-[4-(methylsulfonyl )benzyl]homopiperazine (Compound No.127).
2.0 mL of an anhydrous THF solution of 160 mg of l-[4- (methylsulfonyl )benzyl]-4-(3-oxo-3-phenylpropyl)homopiperazine was added under nitrogen at -78 °C to a 3 mL THF solution of 0.8 mmol of l-methyl-2- pyrrolylcerium dichloride. The mixture was stirred at -78 *C for 3 hours and then it was mixed with 20 mL of water and filtered from insolubles. using Celite; the filtrate was extracted with 30 mL x 2 of ethyl acetate. The extracts were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, hexane/ethyl acetate 1:3, ethyl acetate) to give 18 mg of the titled compound.
Compound No. 127 had the following *H NMR (CDC13, 270 MHz) δ (ppm) : 7.88 (d, J = 8.3 Hz, 2 H), 7.56 (d, J = 8.3 Hz. 2 H). 6.50-6.48 (m. 2 H). 6.24-6.22 (m. 2 H), 6.03-6.00 (m, 2 H), 3.71 (s, 2 H), 3.21 (s, 6 H), 3.05 (s, 3 H). 2.8- 2.62 (m. 10 H), 2.36-2.32 (m. 2 H), 1.88-1.83 (m. 2 H).
Example 15: Preparation of l-(3.5-Difluorophenyl)-3-hydroxy-3-(3- hydroxyphenyl)propyl -4-[4-(methylsulfonyl )benzyl]homopiperazine (Compound No. 138).
To 1.0 mL anhydrous THF solution of 263 mg of l-[4- (methylsulfonyl)benzyl] -4-[3-oxo-3-{3-(tert- butyldimethylsilyloxy)phenyl}propyl]homopiperazine was added 3 mL of a THF solution of 2.5 mmol of 3,5-difluorophenylmagnesium bromide under nitrogen at 0 *C. The mixture was stirred at room temperature for 3 hours, and aqueous saturated ammonium chloride was added and the mixture was extracted with 40 mL x 2 with ethyl acetate. The extracts were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate, ethyl acetate/methanol 10:1) to obtain 11 mg of a silyl protected form of the titled compound.
The resulting oil was dissolved in 5 mL of THF and mixed with 0.07 mL of a THF solution of 1 M tetrabutylammonium fluoride. The mixture was stirred at room temperature for 30 minutes and mixed with 20 mL of water and extracted with 30 mLx 3 of ethyl acetate. The extracts were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate) to give 11 mg of the titled compound.
Compound No. 138 had the following lH NMR (CDC13, 270 MHz) δ (ppm) : 7.88 (d, J = 8.3 Hz, 2 H), 7.54 (d. J = 8.3 Hz, 2 H), 7.18 (t, J = 7.9 Hz, 1 H), 7.02-6.93 (m, 4 H). 6.70-6.58 (m, 1 H), 3.68 (s, 2 H), 3.06 (s, 3 H), 2.72-2.60 (m, 10 H) , 2.33-2.28 (m, 2 H), 1.85-1.76 (m, 2 H).
Example 16: Preparation of 1-[3-(4-Hydroxyphenyl)-3-phenyl propyl]- 4-[4-(methylsulfonyl )benzyl]homopiperazine (Compound No. 42).
5.0 mL solution in dichloromethane of 33 mg of l-[3-{4- methoxyphenyl)3-phenyl propyl]-4-[4-(methylsulfonyl )benzyl]homopiperazine was cooled under nitrogen to -78 *C, followed by adding 0.022 mL of boron tribromide. The mixture was gradually allowed to rise to room temperature, at which temperature the mixture was stirred for 3 hours, followed by adding 3 mL of an aqueous saturated sodium hydrogencarbonate solution and extracting with a 50 mL x 2 of ethyl acetate. The extracts were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate/methanol 9:1) to obtain 12 mg of the titled compound. This was treated with a hydrogen chloride solution in ether and the solvent was removed under reduced pressure and residue was dried to give the hydrochloride salt of the titled compound.
Compound No. 42 (free base) had the following XH NMR (CDC13, 270 MHz) δ (ppm): 1.75-1.8 (m, 2 H). 2.15-2.3 (m, 2 H). 2.4-2.9 (m, 10 H), 3.04 (s, 3 H), 3.68 (s. 2 H), 3.82 (t. J = 7.5 Hz. 1 H), 6.59 (d, J = 8.6 Hz. 2 H). 7.1-7.3 (m, 5 H), 7.51 (d. J - 8.2 Hz. 2 H). 7.86 (d. J - 8.2 Hz, 2 H).
Example 17: Preparation of 1-[3-Hydroxy-3-(3-methylanιinophβnyl)-3- phenylpropyl]-4-[4-(methylsulfonyl )benzyl]homopiperazine (Compound No. 146) .
To a solution of 34 mg of compound No. 143 in 1.2 mL of acetonitrile and
0.3 mL of water was added 14 mg of RhCl(PPh3)3. and the mixture was stirred at 100 _C for 2 days. After the mixture was allowed to cool to room temperature . evaporation of acetonitrile and column chromatography (silica gel, ethyl acetate) gave 9.0 mg of the titled compound.
Compound No. 146 had the following *H NMR (CDC13. 270 MHz) δ (ppm): 1.79-1.91 (m, 2H). 2.34-2.41 (m, 2 H), 2.55-2.75 (m. 11 H) , 2.80 (s, 3 H). 3.05
(s, 3 H). 3.70 (ε. 2 H) . 5.40 (broad s, 1 H), 6.39-6.44 (m, 1 H), 6.70-6.80 (m.
2 H). 7.05-7.20 (m, 2 H). 7.21-7.31 (m. 3 H). 7.41-7.48 (m, 2 H). 7.55 (d, J
= 8 . 1 Hz , 2 H) , 7 .78 (d, J = 8. 1 Hz , 2 H) .
Example 18: Preparation of l-[3-(3-Aoetylaminophenyl)-3-hydroxy-3- phenylpropyl]-4-[4-(methylsulfonyl )benzyl]homopiperazine (Compound No. 162). To a solution of 352 mg of compound No. 159 in 5 mL of dichloromethane was added 190 μL of trlethylamine and 130 μL of acetic anhydride. The mixture was stirred at room temperature for 2 hours. 3 mL of water was added and the mixture was extracted with dichloromethane. The extract was concentrated and purified by column chromatography (silica gel, ethyl acetate/methanol 7:3) to give 224 mg of the titled compound as a white solid .
Compound No. 162 had the following lH NMR (CDC13, 270 MHz) δ (ppm): 7.88 (d. J = 8.3 Hz. 2 H). 7.57-7.45 (m, 5 H), 7.22-7.16 (m. 6 H). 3.70 (s, 2 H). 3.05 (s, 3 H), 2.73-2.60 (m, 10 H). 2.40-2.37 (m, 2 H).1.88-1.81 (m. 2 H) .
Examples 19-151.
The compounds of this invention were synthesized pursuant to methods of Example 1, 2, 3. 4, 5, 6, 7, 9. 11, 12, 14, 15, or 16, using the corresponding reactant respectively. The *H NMR data, yields, and synthetic methods are summarized in Table 2.
■- Table 2 (Φ4 pages)—
Table 2
Table 2 (continued)
Table 2 (continued)
Table 2 (continued)
Table 2 (continued)
4
Table 2 (continued)
-4
Table 2 (continued)
Table 2 (continued)
Table 2 (continued)
Table 2 (continued)
10
Table 2 (continued)
1 1
Table 2 (continued)
1 2
Table 2 (continued)
00
1 3
Table 2 (continued)
00
14
Table 2 (continued)
0
15
Table 2 (continued)
00
16
Table 2 (continued)
(a) 2-(Trimethylsilyl)ethoxymethyl group was used as protective group.
17
Table 2 (continued)
30
-4
(a) 2-(Trimethylsilyl)ethoxymethyl group was used as protective group.
(b) Compound No.160 was obtained as the by-product in preparation of compound No.156.
Table 2 (continued)
19
Table 2 (continued)
20
Table 2 (continued)
21
Table 2 (continued)
22
General Alkylation Procedure of l-(3-Hydroxy-3,3- diphenylpropyl)homopiperazine for Examples 152-162.
A solution of 1-(3-hydroxy-3,3-diphenylpropyl)homopiperazine (0.12 mmol) in 0.5 mL of acetonitrile was treated with alkylating reagent (0.10 mmol) and potassium carbonate (0.15 mmol) and the reaction mixture was heated to 50 °C for 5 h. Polystyrene-linked benzyl isocyanate resin (0.65 mmol/g, 0.05 mmol) and dichloromethane (0.5 mL) was added and the mixture was stirred at room temperature for 1 h. The mixture was filtered and washed with dichloromethane (0.5 mL). The filtrate and washing were combined, and the solvent was removed under reduced pressure to afford the N,W-dialkylated material.
Example 152: Compound No. 174 (65 mg) was prepared by above general alkylation procedure. ESI/MS m/e 493.0 (M*+H, C29H36N2θ3S) .
Example 153: Compound No. 175 (51 mg) was prepared by above general alkylation procedure. ESI/MS m/e 507.5 (M*+H, C30H3βN2θ3S) .
Example 154: Compound No. 176 (48 mg) was prepared by above general alkylation procedure. ESI/MS m/e 507.5 (M*+H, C30H3βN2θ3S) .
Example 155: Compound No. 177 (51 mg) was prepared by above general alkylation procedure. ESI/MS m/e 521.5 (M*+H. C31H40N203S) .
Example 156: Compound No. 178 (56 mg) was prepared by above general alkylation procedure. ESI/MS m/e 541.5 (M*+H, C32H36N2θ3S) .
Example 157: Compound No. 179 (41 mg) was prepared by above general alkylation procedure. ESI/MS m/e 479.0 (M'+l, C2,H34N2θ3S) .
Example 158: Compound No. 180 (42 mg) was prepared by above general alkylation procedure. ESI/MS m/e 493.0 (M*+l, C„H36N2θ3S) .
Example 159: Compound No. 181 (42 mg) was prepared by above general alkylation procedure. ESI/MS m/e 507.5 (M++l, C30H3βN2θ3S) .
Example 160 : Compound No . 182 ( 53 mg) was prepared by above general alkylation procedure . ESI/MS m/e 507 .5 (M*+l , C30H3βN2θ3S) .
Example 161: Compound No. 183 (40 mg) was prepared by above general alkylation procedure. ESI/MS m/e 521.5 (M++l, C31H40N2O3S) .
Example 162: Compound No. 184 (52 mg) was prepared by above general alkylation procedure. ESI/MS m/e 541.5 (M*+l, C33H36N203S) .
Preparation of l-(3,3-Diphenylpropyl)homopiperazine .
A suspension of homopiperazine (2.9 g, 28.9 mmol) and homopiperazine dihydrochloride (5.0 g, 28.9 mmol) in EtOH was heated to 70 • C for 2 h, at which point a homogeneous solution of monohydrochloride salt (2.5 equiv) was obtained.
The reaction mixture was treated with 3,3-diphenylpropyl methanesulfonate (6.7 g, 23.1 mmol. 1 equiv) and Nal (8.65 g, 57.7 mmol, 2.5 equiv) and heated to reflux for 16 h. The reaction mixture was cooled to 25 * C and the solvent was removed in vacuo. The crude product was partitioned between 2N aqueous NaOH (100 mL) and EtOAc (100 mL), and the aqueous layer was extracted with EtOAc (3 x 50 mL).
The combined organic phase was washed with saturated aqueous NaCl (1 x 100 mL), dried (MgS04) and concentrated. Chromatography (Si02, 4 x 20 cm, 10% CH30H-
5% Et3N-CH2Cl2) afforded the monoalkylated product (6.44 g, 6.79 g theoretical, 95%) as an amber oil.
General Alkylation of 1-(3,3-Diphenylpropyl)homopiperazine forExamples 163-194.
A solution of l-(3,3-diphenylpropyl)homopiperazine (132 mg, 0.449 mmol) was treated with alkylating reagent (0.492 mmol, 1.1 equiv) and Et3N (75 mL.
0.54 mmol, 1.2 equiv) and the reaction mixture was heated to 70 * C for 16 h.
The solvent was removed under vacuum. Chromatography (Siθ2, 2 x 20 cm, 20%
CH3OH-EtOAc) afforded the N.iV-dialkylated material (10-95%).
Chromatography Methods.
HPLC analyses was performed with following methods. 1. Methods A and B. Column
Method A: Micra Analytical Column (4.6 mm x 3.3 cm) Method B: Monitor C18 column (50 mm x 4.6 mm) Buffer for methods A and B
Buffer A: 0.05% TFA in H20
Buffer B: 0.035% TFA in 10% H 2θ/CH3CN Gradient 1 (10-11 min)
1% Buffer B for 0.5 min
1 to 31% Buffer B in 5.0 min 31% to 51% Buffer B in 2.0 min
51% Buffer B for 0.5 min
51% to 1% Buffer B in 0.5 min
1% Buffer B Hold Gradient 2 (4 min) 10% Buffer B for 0.5 min
61% Buffer B in 1.8 min
91% Buffer B in 1.5 min
91% Buffer B for 0.8 min
91% to 10% Buffer B in 0.4 min 10% Buffer B Hold
2. Method C Column
C18 column 4.6 mm Gradient
1% Buffer B for 3 min 1% to 61% Buffer B in 20 min 61% Buffer B For 4 min 61% to 1% Buffer B in 1 min 1% Buffer B for 5 min - hold
Example 163: Compound No. 265 (82 mg, 39%) was prepared from 1-
(3,3-diphenylpropyl)homopiperazine (151.7 mg, 0.513 mmol) and N, N- diethylacetamide (78 mL, 0.567 mmol, 1.1 equiv) employing general alkylation procedure. RPLC tR = 4.93 min (90%), 220 nm (Method A); ESI/MS m/e 408.4 (M*+H.
C26H37N3θ).
Example 164: Compound No. 210 (53 mg, 34%) was prepared from 1- (3,3-diphenylpropyl)homopiperazine (131 mg, 0.446 mmol) and l-bromo-2-butyne (42 mL, 0.479 mmol, 1.1 equiv) employing general alkylation procedure. RPLC tR = 18.18 min (>90%), 220 nm (Method C); ESI/MS m/e 347.2 (M++H. C24H30N2).
Example 165: Compound No. 211 (102 mg, 75%) was prepared from 1-
(3.3-diphenylpropyl)homopiperazine (115 mg, 0.391 mmol) and
(bromomethyl) cyclopropane (42 mL, 0.433 mmol, 1.1 equiv) employing general alkylation procedure. RPLC tR = 17.91 min (>95%), 220 nm (Method C); ESI/MS m/e 349.4 (M4+H, C24H32N2).
Example 166: Compound No. 266 (150 mg, 95%) was prepared from 1- (3,3-diphenylpropyl)homopiperazine (132 mg, 0.449 mmol) and 2-bromoacetamide (68 mg. 0.492 mmol, 1.1 equiv) employing general alkylation procedure. RPLC t„ = 6.10 min (90%), 220 nm (Method A); ESI/MS m/e 352.2 (M*+H, C22H„N3θ) .
Example 167: Compound No. 212 (21 mg, 9%) was prepared from l-(3,3- diphenylpropyl)homopiperazine (151 mg, 0.513 mmol) and 7-acetoxy-4-
(bromomethyl)coumarin (168 mg, 0.565 mmol, 1.1 equiv) employing general alkylation procedure. RPLC tR = 5.73 min (>90%), 220 nm (Method A); ESI/MS m/e
469.4 (M*+H, C30H32N2O3).
Example 168: Compound No. 213 (164 mg, 94%) was prepared from 1-
(3,3-diphenylpropyl)homopiperazine (136.6 mg. 0.465 mmol) and 5- bromovaleronitrile (60 mL, 0.511 mmol, 1.1 equiv) employing general alkylation procedure. RPLC tR = 17.75 min (>90%), 220 nm (Method C); ESI/MS m/e 376.4 (M'+H,
C2«H33N3) .
Example 169: Compound No. 70 (132 mg, 89%) was prepared from 1- (3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and 2-chloro-N-
(2.6-diethylphenyl)acetamide (70 mg, 0.310 mmol. 0.9 equiv) employing general alkylation procedure. RPLC tR = 6.97 min (88%). 220 nm (Method A); ESI/MS m/e
484.4 (M'+H, C32H41N30).
Example 170: Compound No. 214 (49 mg, 42%) was prepared from 1-
(3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and 3- bromopropionitrile (31 mL, 0.374 mmol, 1.1 equiv) employing general alkylation procedure. RPLC tR = 4.36 min (>90%), 220 nm (Method A); ESI/MS m/e 348.2 (M*+H, CJ3H„N3).
Example 171: Compound No. 215 (71 mg, 58%) was prepared from 1- (3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and 4-
bromobutyronitrile (37 mL, 0.374 mmol, 1.1 equiv) employing general alkylation procedure. RPLC t„ = 3.91 min (86%), 220 nm (Method A); ESI/MS m/e 362.2 (M*+H, C24H31N3).
Example 172: Compound No. 267 (31 mg, 24%) was prepared from 1- (3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and N- ethylchloroaσetamide (45 mg, 0.374 mmol, 1.1 equiv) employing general alkylation procedure. RPLC t„ = 4.07 min (91%), 220 nm (Method A); ESI/MS m/e 380.4 (M*+H, C24H33N3θ) .
Example 173: Compound No. 204 (29 mg, 17%) was prepared from 1-
(3,3-diphenylpropyl)homopiperazine (105.4 mg, 0.359 mmol) and methyl 2-[3-
(2-chloroethyl) ureido]benzoate (llOmg, 0.394 mmol, 1.1 equiv) employing general alkylation procedure. RPLC tR = 4.95 min (>95%), 220 nm (Method A); ESI/MS m/e 483.4 (M*+H, C30H33N4O2).
Example 174: Compound No. 216 (79 mg, 36%) was prepared from 1- (3,3-diphenylpropyl)homopiperazine (136.7 mg, 0.465 mmol) and Maybridge SPB03660 (108.8 mg, 0.511 mmol, 1.1 equiv) employing general alkylation procedure. RPLC tR = 5.83 min (>90%), 220 nm (Method A); ESI/MS m/e 471.4 (M'+H, C2,H34N4θ2).
Example 175: Compound No. 246 (59 mg, 33%) was prepared from 1- (3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and Maybridge GK02253 (87 mg, 0.374 mmol) employing general alkylation procedure. RPLC tR = 5.11 min (>95%), 220 nm (Method A); ESI/MS m/e 491.4 (M++H, C2,H34N4θ2S) .
Example 176: Compound No. 217 (66 mg, 58%) was prepared from 1- (3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and bromoacetonitrile (26 mL, 0.374 mmol) employing general alkylation procedure. RPLC tR = 5.21 min (>95%), 220 nm; ESI/MS m/e 334.4 (M*+H, C22H27N3).
Example 177: Compound No. 71 (59 mg. 33%) was prepared from l-(3.3- diphenylpropyl)homopiperazine (100 mg. 0.340 mmol) and Maybridge CD08063 (100 mg. 0.374 mmol, 1.1 equiv) employing general alkylation procedure. RPLC tR = 6.23 min (>85%), 220 nm (Method A); ESI/MS m/e 525.2 (M*+H. C2,H33C1N402S) .
Example 178: Compound No. 247 (35 mg, 22%) was prepared from 1-
(3.3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and Maybridge SEW03081 (63 mg, 0.374 mmol) employing general alkylation procedure. RPLC tR = 6.20 min (90%), 220 nm (Method A) ; ESI/MS m/e 427.4 (M*+H, C22H27C1N4S) .
Example 179: Compound No. 74 (42 mg, 23%) was prepared from l-(3.3- diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and Maybridge S52956 (85 mg, 0.374 mmol) employing general alkylation procedure. RPLC tR = 21 min (90%), 220 nm (Method A); ESI/MS m/e 486.4 (M'+H, C31H39N3θ2) .
Example 180: Compound No. 248 (105 mg, 41%) was prepared from 1-
(3,3-diphenylpropyl)homopiperazine (133.5 mg, 0.454 mmol) and Maybridge GK1350 (149 mg, 0.500 mmol, 1.1 equiv) employing general alkylation procedure. RPLC tR = 6.60 min (>90%). 220 nm (Method A); ESI/MS m/e 556.4 (M*+H, C32H37N5θ2S) .
Example 181: Compound No. 249 (80 mg, 34%) was prepared from 1-
(3.3-diphenylpropyl)homopiperazine (126.7 mg, 0.430 mmol) and Maybridge RF00404 (134 mg, 0.474 mmol, 1.1 equiv) employing general alkylation procedure. RPLC t„ = 5.96 min (>90%), 220 nm (Method A); ESI/MS m/e 540.4 (M*+H, C2βH31Cl2N502) .
Example 182: Compound No. 219 (69 mg, 38%) was prepared from 1-
(3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and Maybridge S07335 (117 mg, 0.408 mmol. 1.2 equiv) employing general alkylation procedure. RPLC tR = 4.68 min (>95%), 220 nm (Method A); ESI/MS m/e 526.4 hydrolysis product (M*+H, C36H37N302).
Example 183: Compound No. 269 (20 mg, 13%) was prepared from 1- (3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and Maybridge CD07922 (67 mg, 0.374 mmol. 1.1 equiv) employing general alkylation procedure. RPLC tR = 4.65 min (90%). 220 nm (Method A); ESI/MS m/e 438.3 (M*+H. C26H3tN3OS).
Example 184: Compound No. 250 (24 mg, 19%) was prepared from 1- (3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and Maybridge SEW00285 (89 mg) employing general alkylation procedure. RPLC tR = 4.70 min (>90%), 220 nm (Method A); ESI/MS m/e 377.3 (M*+H, C23H2βN4θ) .
Example 185: Compound No. 220 (67 mg, 63%) was prepared from 1- (3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and propargyl bromide
(38 mg, 0.32 mmol) and potassium iodide (0.037 g, 0.22 mmol) employing general alkylation procedure. TLC Rt = 0.29 (10% CH30H-CH2C12); RPLC tR = 4.21 min (>85%), 220 nm (Method A); ESI/MS m/e 333.3 (M++H, C23H3βN2).
Example 186: Compound No. 221 (51 mg, 32%) was prepared from 1- (3.3-diphenylpropyl)homopiperazine (100 mg, 0.34 mmol) and l-(3- chloropropyl)-l,3-dihydro-2 H-benzimidazol-2-one (85 mg, 0.408 mmol) employing general alkylation procedure. RPLCtR= 4.70min(>97%), 220nm(MethodB); ESI/MS m/e 469.3 (M++H, C30H36N4O) .
Example 187: Compound No. 222 was synthesized from l-(3,3- diphenylpropyl)homopiperazine (200 mg. 0.680 mmol) and 2-( tert - butyldiphenylsilyl)-3-bromo-2-methyl-l-propanol (125 mg. 0.32 mmol) employing general alkylation procedure. Rt 0.53 (10% CH30H-CH2C12) . The purified intermediate was dissolved in anhydrous THF and treated with tert-butylammonium fluoride (0.35 mL, 0.35 mmol, 1.1 equiv). The reaction mixture was stirred at 25 *C for 2 h and concentrated. Chromatography (Siθ2, 40 g, 20% CH3OH-EtOAc) afforded the desired product (30 mg, 30%, two steps). TLC Rt 0.17 (conditions); 4.16 min (>85%), 220 nm (Method B); ESI/MS m/e 367.3 (M*+H, C24H34N2θ) .
Example 188: Compound No. 75 (91 mg, 65%) was prepared from l-(3,3- diphenylpropyl)homopiperazine (100 mg, 0.339 mmol) and α-bromo-o-tolunitrile (80 mg, 0.406 mmol) employing general alkylation procedure. RPLC tR = 6.52 min (>98%). 220 nm (Method B); ESI/MS m/e 410.3 (M*+H. C2βH31N3).
Example 189: Compound No. 76 (63 mg. 37%) was prepared from l-(3,3- diphenylpropyl)homopiperazine (100 mg, 0.339 mmol) and 2-bromoacetamido-4- nitrophenol (111 mg, 0.406 mmol) employing general alkylation procedure. RPLC tR - 6.55 min (>98%). 220 nm (Method B); ESI/MS m/e 489.3 (M'+H, C2,H32N4θ4).
Example 190: Compound No. 77 (103 mg, 61%) was prepared from 1-
(3,3-diphenylpropyl)homopiperazine (100 mg, 0.339 mmol) and ethyl 4-(2- chloroacetamido) benzoate (98 mg, 0.406 mmol) employing general alkylation procedure. RPLC tR = 6.52 min (>98%), 220 nm (Method B); ESI/MS m/e 500.3 (M*+H, C31H37N4θ3).
Example 191: Compound No. 223 (84 mg, 49%) was prepared from 1-
(3,3-diphenylpropyl)homopiperazine (100 mg, 0.339 mmol) and l-(3- chloropropyl) theobromine (104 mg. 0.406 mmol) employing general alkylation procedure. RPLC t„ = 5.25 min (>98%), 220 nm (Method B); ESI/MS m/e 515.3 (M*+H. C30H3βN6θ2).
Example 192: Compound No. 80 (81 mg, 47%) was prepared from l-(3,3- diphenylpropyl)homopiperazine (100 mg, 0.339 mmol) and 4-nitrobenzyl bromoacetate (111 mg, 0.406 mmol) employing general alkylation procedure. RPLC tR = 7.35 min (>98%), 220 nm (Method B); ESI/MS m/e 488.3 (M*+H. C29H33N304).
Example 193: Compound No. 81 (139 mg, 92%) was prepared from 1- (3.3-diphenylpropyl)homopiperazine (100 mg, 0.339 mmol) and 2-hydroxy-5- nitrobenzyl bromide (90 mg, 0.406 mmol) employing general alkylation procedure. 5.90 min (>95%). 220 nm (Method B); ESI/MS m/e 446.3 (M*+H, C27H31N3θ3).
Example 194: Compound No. 268 (34 mg, 25%) was prepared from 1-
(3.3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and N-
(chloroacetyl)isopropylamine (51 mg, 0.374 mmol) employing general alkylation procedure. RPLC tR = 5.47 min (>90%). 220 nm (Method B) ; ESI/MS m/e 394.4 (M*+H. C25H35N3θ) .
General Epoxide Opening with l-(3,3-Diphenylpropyl)homopiperazine for Examples 195-197.
A solution of l-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) in CH3CN (1.8 mL) was treated with epoxide (0.374 mmol, 1.1 equiv) and
(71 mL, 0.41 mmol. 1.2 equiv), and the reaction mixture was heated to 70 • C for
16 h. The solvent was removed under reduced pressure. Chromatography (Si02,
2 x 20 cm. 20% CH3OH-EtOAc) afforded the N,N-dialkylated material (23-83%).
Example 195: Compound No. 218 (114 mg, 83%) was prepared from 1- (3,3-diphenylpropyl)homopiperazine (100 mg, 0.340 mmol) and Maybridge NRB00767 (42 mg, 0.375 mmol) employing general epoxide opening procedure. RPLC tR = 3.77 min (>85%), 220 nm (Method A); ESI/MS m/e 407.4 (M*+H. C27H36N202) .
Example 196: Compound No. 253 (35 mg, 23%) was prepared from 1-
(3,3-diphenylpropyl)homopiperazine (100 mg, 0.339 mmol) and furfuryl glycidyl ether (63 mg, 0.406 mmol) employing general epoxide opening procedure. RPLC
tR = 5.70 min (>98%). 220 nm (Method B); ESI/MS m/e 449.3 (M'+H, C2βH36N4θ3) .
Example 197: Compound No. 225 (69 mg, 70%) was prepared from l-(3,3- diphenylpropyl )homopiperazine (40.3 mg, 0.137 mmol) and N-(2,3- epoxypropyl)phthalimide (42.6 mg.0.150 mmol) employing general epoxide opening procedure. TLC Rf = 0.40 (10% CH30H-CH2C12); RPLC tR = 5.96 min (>85%), 220 nm
(Method B-10 min); ESI/MS m/e 498.3 (M*+H, C3lH35N3θ3) .
Preparation of ιV,N-Diethyl-(l-homopiperazlnyl) acetamide. Acetyl chloride (3.90 mL, 54.9 mmol) was dissolved in EtOH (166 mL) and the mixture was stirred for 30 min at 25 *C. A solution of homopiperazine (5.0 g, 50 mmol, 1 equiv) in EtOH (20 mL) was added to the reaction mixture in one portion. The flask was fitted with a reflux condenser with a CaCl2 drying tube and the reaction mixture was heated to reflux for 1 h. N,N- Diethylchloroacetamide (3.37 g, 0.5 equiv) was added and the reaction was heated to reflux for an additional 16 h. The reaction mixture was allowed to cool and the solvent was removed in vacuo. The product was partitioned between EtOAc (150 mL) and saturated aqueous NaHC03 (100 mL) . The aqueous phase was extracted with EtOAc (1 x 100 mL) . The combined organic phase was dried (Na2S04) , filtered and concentrated to yield the symmetrically dialkylated material (0.950 g, 17%). The aqueous phase was basiσified with 1 M NaOH (100 mL) and was extracted CH2C12 (1 x 150 mL, 2 x 100 mL). The combined organic phase was dried (Na2S04) , filtered and concentrated to afford the pure monoalkylated homopiperazine (2.4 g, 45%).
Preparation of 1-(4-Cyanobenzyl )homopiperazine .
To a solution of homopiperazine (9.2 g, 92 mmol, 2 equiv), in EtOH (115 mL) was added 1 M HCl-EtOH (92 mL) dropwise over 1 h. The suspension was heated to 70 •C for 1 h at which point a homogeneous solution of monohydrochloride salt was obtained, α-Bromo-p-tolunitrile (9.0 g, 46 mmol, 1 equiv) was added and the reaction mixture was heated to reflux for 5 h. After cooling, the solvent was removed by rotary evaporation and the residue was partitioned between CH2C12 (100 mL) and 2N aqueous KOH (100 mL) . The acueous layer was extracted with CH2C12 (5 x 50 mL) and the combined organic phase was washed with saturated aqueous NaCl (1 x 150 mL) and dried (MgS04). Chromatography (Siθ2, 4 x 20 cm. 20% CH3OH - 5% Et3N-CH2Cl2) afforded the desired monoalkylated material (6.78 g, 10.1 g theoretical, 67%) as an amber oil.
Preparation of 1-[4-(Methylsulfonyl )benzyl]homopiperazine . To a 2-neck, 2-L round bottom flask containing anhydrous EtOH (800 mL) and equipped with a mechanical stirrer and condenser was added acetyl chloride (20.2 mL. 0.267 mol. 1.1 equiv). The solution was stirred for 0.5 h and homopiperazine (24.3 g, 0.243 mol) was added. The mixture was heated to reflux for 2 h. The reaction mixture was cooled to 25 *C, 4-(methylsulfonyl )benzyl chloride (25 g, 0.122 mol, 0.5 equiv) was added and the reaction mixture heated to reflux for 16 h. The reaction mixture was cooled to 25 * C and the solvent was removed under vacuum. The residue was diluted with EtOAc (500 mL) and waε washed with 2N KOH (2 x 500 mL). The aqueous layer was extracted with EtOAc (1 x 500 mL). The organic phase was combined, washed with 2N KOH (1 x 300 mL), dried (MgS04) and concentrated. The crude solid was washed with hot EtOAc to yield pure desired product (8.03 g, 32.7 g theoretical, 25%) as an off-white solid. TLC J?j 0.04 (10% CH30H-CH2C12); *H NMR (CDC13, 300 MHz) δ 9.82 (br s, 1 H). 7.92 (d. J = 8.0 Hz, 2 H), 7.60 (d. J = 7.7 Hz. 2 H). 3.80 (br s. 2 H). 3.36 (br m. 2 H), 3.07 (s. 3 H). 2.93 (br s, 2 H), 2.80 (br ε. 2 H), 2.12 (br m, 2 H)
Preparation of l-(4-Picolyl)homopiperazine . A solution of acetyl chloride (6.34 mL, 0.084 mol, 4 equiv) dissolved in anhydrous EtOH (50 mL) was stirred for 0.5 h and added to a solution of homopiperazine (10.4 g, 0.1 mol, 5 equiv) in EtOH (250 mL). The reaction mixture was heated to reflux for 1 h, cooled to 25 *C and a solution of 4-picolyl chloride hydrochloride 93.44 g, 0.021 mol) inEtOH (40mL) was added. Thereaction mixture was heated to reflux for 16 h, cooled to 25 •C and the solvent was removed under vacuum. The residue was diluted with CH2C12 (300 mL) and was washed with 2N KOH (1 x 300 mL). The aqueous layer was extracted with CH2C12 (1 x 300 mL) and the organic phase was washed with 2N KOH (150 mL). dried (MgS04) and concentrated. Chromatography (Siθ2. 5% H20-5% NH4OH-iPrOH) afforded the desired product (2.88 g, 4.01 g theoretical, 72%) as a yellow oil. TLC Rt 0.45 (5% H20-5% N^OH^PrOH): *H NMR (CDC13. 300 MHz) δ 8.77 (d. J = 5.9 Hz, 2 H) , 7.53 (d, J = 5.7 Hz, 2 H) , 3.91 (s. 2 H). 3.19 (m. 4 H), 2.92 (m, 4 H). 2.04 (m, 2 H) .
Preparation of l-(4-Chlorobenzyl )homopiperazine . Acetyl chloride (11.7 mL. 0.165 mol) was added to anhydrous EtOH (500 mL) and the mixture was stirred for 30 min at 25 "C. Homopiperazine (15.0 g, 0.150 mol) was added and the mixture was heated to reflux for 4 h. 4-Chlorobenzyl
chloride (13.96 g, 0.087 mol) was added and the reaction mixture was heated to reflux for 16 h before concentrating. The residue was dissolved in EtOAc (500 mL) and washed with IN aqueous KOH (50 mL). The aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were dried (MgS04), filtered and concentrated in vacuo. Chromatography (double separation, Si02. 20 x 7 cm, ^PrOH-H^-NH^H, 80:12:6 to 70:20:10 gradient elution) afforded the desired product (10.6 g, 53.4%) and the dialkylated homopiperazine (2.36 g, 16.5%). GC/MS m/e 224 (M\ C12H17N2C1) .10 % CH30H-CH2C12) ; RPLC tR - 5.96 min (>85%) , 220 nm (Mm (Method B); ESI/MS m/e 498.3 (M4+H, C31H35N3θ3).
Preparation of l-(4-Methyl-2-thienyl)-2-(l- homopipβrazinylaσetyl)hydrazinβ. l-( tert-butyloxycarbonyl)homopiperazine (1.0 g, 5.0 mmol) in CH3CN (25 mL) was treated with Maybridge GK 02253 (1.2 g. 5.0 mmol) and ^r^Et (1.04 mL, 6.0 mmol, 1.2 equiv). The reaction mixture was heated to 70 _C for 16 h. After cooling, the solvent was removed under reduced pressure and the residue was purified by chromatography (Siθ2, 4 x 20 cm, 5% CH3OH-CH2Cl2) to afford the Boc-protected monoalkylated material as a white foam (1.33 g, 67%). RPLC t„ = 5.20 min (>98%), 220 nm (Method B); ESI/MS m/e 397.0 (M*+H. C18H3βN4θ4S) . The product (1.1 g, 2.8 mmol) was dissolved in 3 M HC1-CH30H (14 mL) and stirred at 25 _C for 30 min. The solvent was removed by rotary evaporation and the deprotected homopiperazine HCl salt waε dissolved in tBuOH-H20 (3:1. 25 mL). Dowex Anion exchange resin was added until pH = 9. The resin was removed by filtration and evaporation afforded the pure mono-alkylated product (703 mg, 86%). RPLC tR = 0.78 min (>98%). 220 nm (Method B); ESI/MS m/e 297.1 (M*+H, C14H30N4O2S).
General Alkylation with 4-Bromo-2,2-diphβnylbutyronitrilβ for Examples 198-203. Monosubstituted homopiperazine (100 mg, 0.468 mmol. 1.0 equiv) in CH3CN
(3 mL) was treated sequentially with 4-bromo-2,2-diphenylbutyronitrile (168 mg. 0.561 mmol, 1.2 equiv) followed by
(60 mg. 0.468 mmol, 1.2 equiv). The reaction mixture was heated to 70 * C with stirring for 16 h. The mixture was allowed to cool and the solvent was removed in vacuo. The product was purified by chromatography (Siθ2. 3 x 5 cm. 20% CH3OH-EtOAc) to afford the desired dialkylated material (4B mg, 24%).
Example 198: Compound No. 264 (48 mg, 24%) was prepared from N, N- diethyl-(l-homopiperazinyl) acetamide (100 mg, 0.468 mmol) and 4-bromo-2,2- diphenylbutyronitrile (168 mg, 0.561 mmol) employing general alkylation procedure. TLC Rt = 0.30 (20% CH3OH-EtOAc) ; RPLC tR = 4.58 min (>98%), 220 nm (Method B); ESI/MS m/e 433.3 (M*+H. C27H36N4θ) .
Example 199: Compound No. 233 (225 mg, 73%) was prepared from l-(4- picolyl)homopiperazine (200 mg, 1.05 mmol) and 4-bromo-2,2- diphenylbutyronitrile (225 mg, 0.75 mmol) employing general alkylation procedure. TLC Rf = 0.33 (10% CH30H-CH2C12); RPLC tR = 4.27 min (>85%), 220 nm (Method B); ESI/MS m/e 411.3 (M*+H, C27H30N4).
Example 200: Compound No. 2 (155 mg, 52%) was prepared from l-(4- cyanobenzyl )homopiperazine (150 mg, 0.684 mmol) and 4-bromo-2,2- diphenylbutyronitrile (226 mg, 0.752 mmol, 1.1 equiv) employing general alkylation procedure. RPLC tR = 4.93 min (85.1%), 220 nm (Method B); ESI/MS m/e
435.3 (M*+H, C29H30N4).
Example 201: Compound No. 3 (16 mg, 12%) was prepared from l-(4- chlorobenzyl )homopiperazine (68 mg, 0.30 mmol) and 4-bromo-2,2- diphenylbutyronitrile (100 mg, 0.33 mmol) employing general alkylation procedure. TLC Rt «- 0.32 (5% CH30H-CH2C12); RPLC tR = 5.27 min (>85%). 220 nm (Method A); ESI/MS m/e 444.3 (M*+H, C20H30C1N2).
Example 202: Compound No. 4 (251 mg, 69%) was prepared from l-[4-
(methylsulfonyl )benzyl]homopiperazine (200 mg, 0.75 mmol) and 4-bromo-2.2- diphenylbutyronitrile (270 mg, 0.9 mmol) employing general alkylation procedure. TLC Rt - 0.53 (10% CH30H-CH2C12); RPLC tR = 4.73 min (>85%), 220 nm (Method A); ESI/MS m/e 488.3 (M*+H, C„H33N2θ2S) .
Example 203: Compound No. 234 (9 mg, 5%) was prepared from l-(4- methyl-2-thienyl)-2-(l-homopiperazinylacetyl)hydrazine (95 mg. 0.32 mmol) and 4-bromo-2,2-diphenylbutyronitrile (96 mg, 0.32 mmol) employing general alkylation procedure . RPLC tR = 6.03 min (>90%) , 220 nm (Method B-10 min) ; ESI/MS m/e 516.3 (M*+H, C„H33N5θ2S) .
Preparation of l-(4-Cyanobenzyl )piperazine .
To a solution of piperazine (5.17 g, 60 mmol, 2 equiv) in EtOH (40 mL) was added 1 M HCl-EtOH (60 mL) dropwise over 1 h and the suspension was heated to 70 •C for 1 h. α-Bromo-p-tolunitrile (5.88 g, 30 mmol, 1 equiv) was added and the reaction was heated to reflux for 16 h. After cooling the solvent was removed by rotary evaporation and the residue was partitioned between CH2C12 (70 mL) and 2N aqueous KOH (70 mL) and the combined organic phase was washed with saturated aqueous NaCl (100 mL) and dried (MgS04). Chromatography (Si02, 20% CH3OH-5% Et3N-CH2Cl2) afforded the monoalkylated material (2.6 g, 6.0 g theoretical, 43%) as an amber oil.
General Alkylation of 1-(4-Cyanobenzyl)piperazine for Examples 204 and 205.
A solution of 1-(4-cyanobenzyl )piperazine (150 mg, 0.745 mmol) was treated with alkylating reagent (0.745 mmol, 1 equiv) and iPr2NEt (156 mL, 0.894 mmol, 1.2 equiv). The reaction mixture was heated to 70 *C and stirred by vortex for 16 h. After cooling, the reaction mixture was subjected directly to chromatography (Siθ2, 3-7% CH3OH-CH2Cl2, gradient elution) to afford the desired N,N-dialkylated piperazine (11-77%).
Example 204: Compound No. 9 (142 mg. 48%) was prepared from l-(4- cyanobenzyl )piperazine (150 mg, 0.745 mmol) and 3,3-diphenylpropyl methanesulfonate (216 mg, 0.745 mmol, 1 equiv) employing general alkylation procedure. RPLC t„ = 6.47 min (>95%), 220 nm (Method B); ESI/MS m/e 396.2 (M*+H. C27H2,N3).
Example 205: Compound No. 1 (166 mg, 53%) was prepared from l-(4- cyanobenzyl )homopiperazine (150 mg, 0.745 mmol) and 4-bromo-2,2- diphenylbutyronitrile (224 mg. 0.745 mmol) employing general alkylation procedure. RPLC t„ = 6.82 min <>95%), 220 nm (Method B); ESI/MS m/e 422.3 (M*+H, C2βH2,N4).
General Preparation of Hydrazide Alkylating Agents .
The hydrazide starting material (7.93 mmol) was dissolved in CH3CN (20 mL) and treated with chloroacetyl chloride (0.95 mL, 11.93 mmol, 1.5 equiv) and Et3N (1.11 mL, 7.96 mmol. 1.02 equiv). The mixture was stirred at 25 βC for 16 h and concentrated. The residue was dissolved in EtOAc (300 mL). washed with
IN aqueous HCl (10 mL) saturated aqueous NaCl (20 mL). dried (MgS04) , and
concentrated in vacuo. The desired compound was isolated by trituration with EtOAc, followed by washing with hexane or chromatography (Si02) . General alkylation procedure for Example 163-194 was then used to afford the desired homopiperazine analogs.
Example 206: l-Benzoyl-2-(chloroacetyl)hydrazine (850 mg, 54%) was prepared from benzhydrazide (1.00 g, 7.34 mmol) and chloroacetyl chloride (0.58 mL, 7.34 mmol, 1 equiv) using general procedure. Compound No. 78 (300 mg, 51%) was prepared from 1-(3,3-diphenylpropyl) homopiperazine (100 mg, 0.34 mmol) and l-benzoyl-2-(chloroacetyl)hydrazine (80 mg, 0.38 mmol) employing general alkylation procedure. TLC Rt = 0.44 (10% CH30H-CH2C12); RPLC tR = 5.85 min (>85%), 220 nm (Method B); ESI/MS m/e 471.3 (M*+H, C29H34N4θ2).
Example 207: l-(Chloroacetyl)-2-(phenylacetyl)hydrazine (1.24 g, 82%) was prepared from phenylacetohydrazide (1.00 g, 6.66 mmol) and chloroacetyl chloride (0.53 mL. 6.66 mmol, 1 equiv) using general procedure. Compound No. 79 (71 mg, 43%) was prepared from l-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.34 mmol) and l-{chloroacetyl)-2-(phenylacetyl)hydrazine (85 mg, 0.38 mmol) employing general alkylation procedure. TLC Rf = 0.40 (10% CH30H-CH2C12); RPLC tR = 6.02 min (>85%), 220 nm (Method B); ESI/MS m/e 485.5 (M*+H, C30H36N4O2).
Example 208: l-(2-Furoyl)-2-(chloroacetylJhydrazine (1.21 g, 75%) was prepared from 2-furoic acid hydrazide (1.06 g, 7.93 mmol) and chloroacetyl chloride (0.95 mL, 11.9 mmol, 1.5 equiv) using general procedure. Compound No. 251 (63 mg, 40%) was prepared from l-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.34 mmol) and l-(2-furoyl)-2-(chloroacetyl)hydrazine (76 mg, 0.38 mmol) employing general alkylation procedure. TLC J?f = 0.42 (10% CH30H-CH2C12) ; RPLC tR = 5.60 min (>85%), 220 nm (Method B); ESI/MS m/e 461.3 (M*+H, C27H32N403).
Example 209: l-(2-Thlophenecarbonyl)-2-(chloroacetylJhydrazine (1.14 g, 74%) was prepared from 2-thiophenecarbohydrazide (1.00 g, 7.03 mmol) and chloroacetyl chloride (0.86 mL. 10.6 mmol, 1.5 equiv) using general procedure. Compound No. 252 (88 mg, 54%) was prepared from l-(3,3- diphenylpropyl)homopiperazine (100 mg, 0.34 mmol) and l-(2- Thiophenecarbonyl )-2-(chloroacetyl)hydrazine (82 mg, 0.38 mmol) employing general alkylation procedure. TLC Rf = 0.47 (10% CH30H-CH2C12) ; RPLC tR = 5.92 min (>85%), 220 nm (Method B); ESI/MS m/e 477.3 (M*+H, C27H32N402S) .
Example 210: 1-(Diphenylcarbamoy1)-4-(2-chloroacetyl)semicarbazide (1.30 g, 65%) was prepared from 4,4-diphenylsemicarbazide (1.5 g, 6.60 mmol) and chloroacetyl chloride (0.79 mL, 9.92 mmol, 1.5 equiv) using general procedure. Compound No. 297 (46 mg, 24%) was prepared from l-(3,3- diphenylpropyl )homopiperazine (100 mg, 0.34 mmol) and 1- (diphenylcarbamoyl)-4-(2-chloroacetyl)semicarbazide (114 mg, 0.38 mmol) employing general alkylation procedure. TLC Rt -0.44 (10% CH30H-CH2C12) ; RPLC tR = 6.55 min (>85%). 220 nm (Method B); ESI/MS m/e 562.5 (M*+H, C35H39N502).
Example 211: 1-(Phenylcarbamoyl)-4-(2-chloroacetyl)semicarbazide (1.19 g, 67%) was prepared from 4-phenylsemicarbazide (1.00 g, 6.62 mmol) and chloroacetyl chloride (0.79 mL, 9.92 mmol) using general procedure. Compound No. 82 (33 mg, 20%) was prepared from 1-(3,3-diphenylpropyl )homopiperazine (100 mg, 0.34 mmol) and l-(phenylcarbamoyl)-4-(2-chloroacetyl)semicarbazide (85 mg, 0.37 mmol) employing general alkylation procedure. TLC Rt = 0.41 (10% CH3OH-CH2Cl2); RPLC t„ = 5.96 min (>85%), 220 nm (Method B); ESI/MS m/e 486.4 (M*+H. C29H35Ns02).
Example 212: 1-(Ethylcarbamoyl)-2-(chloroacetyl)hydrazine (1.31 g,
76%) was prepared from ethyl carbazate (1.00 g, 9.61 mmol) and chloroacetyl chloride (1.15 mL, 10.16 mmol, 1 equiv) using general procedure. Compound No. 224 (81 mg, 54%) was prepared from 1-(3,3-diphenylpropy1 )homopiperazine (100 mg, 0.34 mmol) and l-(ethylcarbamoyl)-2-(chloroacetyl)hydrazine (68 mg, 0.37 mmol) employing general alkylation procedure. TLC Rt -0.44 (10% CH30H-CH2C12); RPLC tR - 5.91 min (>85%), 220 nm (Method B); ESI/MS m/e 439.3 (M*+H, C34H36N403).
Example 213: 1-(4-Nitrobenzoyl)-2-(chloroacetyl)hydrazine was prepared from 4-nitrobenzhydrazide (1.00 g, 5.52 mmol) and chloroacetyl chloride (0.66 mL, 8.29 mmol) using general procedure. Trituration from EtOAc gave the hydrazine i- quantitative yield, which was used without further purification. Compound o. 86 (56 mg, 32%) was prepared from l-(3,3- diphenylpropyl )homopiperazine (100 mg, 0.34 mmol) and 1-(4-nitrobenzoyl)-2- (chloroacetyl)hydrazine (96 mg, 0.37 mmol) employing general alkylation procedure. TLC Rf =0.46 (10% CH3OH-CH2Cl2); RPLC tR = 5.56 min (>85%). 220 nm (Method A); ESI/MS m/e 516.3 (M*+H. C29H33N5θ4).
Example 214: 1-(Toluoyl)-2-(chloroacetyl)hydrazine was prepared from 4-toluic hydrazide (1.00 g, 6.66 mmol) and chloroacetyl chloride (0.80 mL, 9.99 mmol) using general procedure. Trituration from EtOAc gave the hydrazine in quantitative yield, which was used without further purification. Compound No. 87 (61 mg, 37%) was prepared from 1-(3,3-diphenylpropyl )homopiperazine (100 mg, 0.34 mmol) and 1-(toluoyl)-2-(chloroacetyl)hydrazine (74 mg, 0.37 mmol) employing general alkylation procedure. TLC J?£ = 0.44 (10% CH30H-CH2C12) ; RPLC tR = 5.51 min (>85%). 220 nm (Method A); ESI/MS m/e 485.4 (MVH, C30H36N4θ2) .
Example 215: l-(4-Hydroxybenzoyl)-2-(chloroacetyl)hydrazine was prepared from 4-hydroxybenzhydrazide (1.00 g, 6.57 mmol) and chloroacetyl chloride (0.79 mL, 9.92 mmol) using general procedure. Trituration from EtOAc gave the hydrazine in quantitative yield, which was used without further purification. Compound No. 89 (71 mg, 43%) waε prepared from l-(3,3- diphenylpropyl )homopiperazine (100 mg, 0.34 mmol) and l-(4-hydroxy benzoyl)-2-(chloroacetyl)hydrazine (85 mg, 0.37 mmol) employing general alkylation procedure . RPLC tR = 6.21 min (>85%) , 220 nm (Method B-10 min); ESI/MS m/e 487.3 (M*+H, C29H34N403) .
Example 216: 1-(2-Nitrobenzoyl)-2-(chloroacetyl)hydrazine (0.579 g,
41%) was prepared from 2-nitrobenzhydrazide (1.00 g, 5.52 mmol) and chloroacetyl chloride (0.66 mL, 8.83 mmol) using general procedure. Compound No. 90 (82 mg, 47%) was prepared from l-(3,3-diphenylpropyl )homopiperazine (100 mg, 0.34 mmol) and l-(2-nitro benzoyl)-2-(chloroacetyl)hydrazine (96 mg, 0.37 mmol) employing general alkylation procedure. TLC Rf =0.40 (10% CH30H-CH2C12); RPLC tR = 6.04 min (>85%). 220 nm (Method B); ESI/MS m/e 516.1 (M++H. C„H33N5θ4).
Example 217: l-(4-Methoxybenzoyl)-2-(chloroacetyl)hydrazine (1.783 g, 54%) was prepared from 4-methoxybenzhydrazide (1.00 g, 6.00 mmol) and chloroacetyl chloride (0.72 mL. 9.00 mmol) using general procedure. Compound No. 92 (63 mg, 51%) was prepared from 1-(3.3-diphenylpropyl )homopiperazine (100 mg, 0.34 mmol) and l-(4-methoxy benzoyl)-2-(chloroacetyl)hydrazine (91 mg. 0.37 mmol) employing general alkylation procedure. TLC Rt - 0.52 (10% CH30H-CH2C12) ; RPLC tR = 5.46 min (>85%). 220 nm (Method A); ESI/MS m/e 501.1 (M*+H, C30H36N403) .
Example 218: 1-(Nicotinoyl)-2-(chloroacetyl)hydrazine (1.29 g, 83%) waε prepared from nicotinohydrazide (1.00 g, 7.29 mmol) and chloroacetyl chloride
(0.87 mL, 10.94 mmol) using general procedure. Compound No. 254 (100 mg, 66%) was prepared from 1-(3,3-diphenylpropyl )homopiperazine (100 mg, 0.34 mmol) and 1-(nicotinoyl)-2-(chloroacetyl)hydrazine (87 mg, 0.41 mmol) employing general alkylation procedure. TLC Rc =0.12 (10% CH30H-CH2C12) ; RPLC tR = 5.61 min (93%), 220 nm (Method B); ESI/MS m/e 472.3 (M*+H, C2βH33N502) .
Example 219: l-(2-Benzo[b]thiophenecarbonyl)-2-
(chloroacetyl)hydrazine (0.578 g, 94%) was prepared from (2- benzo[b]thiophenecarbonyl)hydrazine (0.50 g, 2.60 mmol) and chloroacetyl chloride (0.31 mL, 3.90 mmol) using general procedure. Compound No. 255 (73 mg, 41%) was prepared from 1-(3,3-diphenylpropyl )homopiperazine (100 mg. 0.34 mmol) and 1-(2-benzo[b]thiophenecarbonyl)-2- (chloroacetyl)hydrazine (88 mg, 0.37 mmol) employing general alkylation procedure. TLC Rt =0.26 (10% CH30H- CH2C12); RPLC tR = 6.96 min (>85%). 220 nm (Method B); ESI/MS m/e 527.3 (M*+H, C31H34N4θ2S).
Example 220: 1-(4-Bromobenzoyl)-2-(chloroacetyl)hydrazine (0.886 g, 73%) was prepared from 4-bromobenzhydrazide (1.00 g, 4.64 mmol) and chloroacetyl chloride (0.55 mL, 6.90 mmol) using general procedure. Compound No. 98 (143 mg. 76%) was prepared from l-(3,3-diphenylpropyl)homopiperazine (100 mg, 0.34 mmol) and l-(4-bromobenzoyl)-2-(chloroacetyl)hydrazine (98 mg, 0.37 mmol) employing general alkylation procedure. TLC Rt =0.50 (10% CH30H-CH2C12) ; RPLC t„ = 6.76 min (>85%), 220 nm (Method B); ESI/MS m/e 551.0 (M4+H, C29H33N402Br) .
Preparation of Sodium (4-(3,3-Dlphenylpropyl)homopiperazine-l- yl]acetate. l-(3,3-Diphenylpropyl)homopiperazine (2.0 g. 6.79 mmol) was dissolved in CH3CN (60 mL) and treated with methyl bromoacetate (1.56 g, 10.18 mmol) and Et3N (1.42 mL, 10.18 mmol). The mixture was refluxed for 18 h and subsequently concentrated in vacuo. The residue waε subjected to flash silica gel column chromatography (eluent: CH2Cl2/Me0H, 96/4, v/v) to give Methyl [4-(3,3- diphenylpropyl)homopiperazine-1-yl]acetate (1.93 g) in 78% yield. TLC Rf = 0.53 (10% CH30H-CH2C12); RPLC tR = 4.71 min (>85%), 220 nm (Method A); ESI/MS m/e 367.1 (M*+H, C23H30N202). Methyl [4-(3,3-diphenylpropyl)homopiperazine-l-yl)acetate (0.327 g, 0.89 mmol) was dissolved in a mixture of dioxane (3.1 mL). MeOH (1.1 mL) and 4N NaOH (0.22 mL). After stirring for 30 min, 5 more drops of 4N NaOH were added
and stirring was continued until hydrolysis of the methyl ester was complete. The mixture was concentrated in vacuo and the residue subjected to flash silica gel column chromatography (eluent: CH2Cl2/MeOH, 1/1, v/v) to give sodium [4- (3,3-diphenylpropyl)homopiperazine-l-yl]acetate (0.278 g) in 88% yield. TLC Re = 0.22 (10% CH30H-CH2C12); RPLC tR = 1.98 min (>85%), 220 nm (Method B); ESI/MS m/e 353.3 (M*+H, C22H2,N2θ2).
General Procedure for Coupling to Sodium [4-(3,3- Diphenylpropyl)homopiperazine-1-yl]acetate for Examples 221-253. sodium (4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol) was suspended in dry CH2C12 (1 mL) and HOBt (12 mg, 0.089 mmol) and the amine, hydrazide or amino acid (0.88 mmol) were added. After cooling the mixture to 0 _C. EDCI (30 mg, 0.10 mmol) was added, the pH adjusted to 7-8 with Et3N and the mixture was stirred for 15 min at 0 _C and 16 h at rt. Concentration invacuo of themixture gave aresidue whichwas not worked upbut purified directly by HPLC.
Example 221: Compound No. 270 (55.6 mg, 70%) waε prepared from sodium sodium [4-(3,3-diphenylpropyl)homopiperazine-l-yl]acetate (53.6mg, 0.15 mmol) and dihexylamine (39 mL, 0.167 mmol) employing general coupling procedure. TLC
Rt =0.46 (10% CH30H-CH2C12); RPLC tR = 8.27 min (>85%). 220 nm (Method B); ESI/MS m/e 520.6 (M*+H, C34H53N30) .
Example 222: Compound No. 83 (30 mg, 39%) was prepared sodium sodium [4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (60.2 mg. 0.17 mmol) and benzylhydrazine dihydrochloride (40 mg, 0.205 mmol) employing general coupling procedure. TLC Rt =0.39 (10% CH30H-CH2C12) ; RPLC tR = 6.16 min (>85%). 220 nm
(Method B); ESI/MS m/e 457.3 (M4+H, C„H36N40) .
Example 223: Methyl 2-benzoylhydrazinoacetate (0.418 g, 27%) was prepared from benzhydrazide (l.OOg, 7.34 mmol) and methyl bromoacetate (0.76 mL. 80.3 mmol) employing general procedure. Compound No. 84 (37 mg, 44%) was prepared from sodium [4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (56mg. 0.158 mmol) and methyl 2-benzoylhydrazinoacetate (36 mg. 0.17 mmol) employing general coupling procedure. TLC Rt =0.49 (10% CH30H-CH2C12); RPLC tR = 6.21 min (>85%), 220 nm (Method B); ESI/MS m/e 543.1 (M*+H. C32H„N404) .
Example 224: Compound No. 85 (59 mg, 75%) was prepared from sodium
[4-(3,3-diphenylpropyl)homopiperazine-l-yl]aσetate (62 mg, 0.166 mmol) and
2-aminoacetophenone hydrochloride (33 mg, 0.195 mmol) employing general coupling procedure. TLC Rt =0.40 (10% CH30H-CH2C12); RPLC tR = 5.51 min (>85%), 220 nm (Method A); ESI/MS m/e 470.3 (M*+H, C30H3SN302) .
Example 225: Compound No. 88 (41 mg, 58%) was prepared from sodium
[4-(3,3-diphenylpropyl)homoplperazine-l-yl]acetate (50 mg, 0.14 mmol) and
4-chlorobenzhydrazide (27 mg. 0.156 mmol) employing general coupling procedure . RPLC tR = 5.71min (>85%). 220 nm (Method A); ESI/MS m/e 505.2 (M*+H, C2,H33N402C1) .
Example 226: Compound No. 91 (55 mg, 68%) was prepared from sodium
[4-(3.3-diphenylpropyl)homopiperazine-l-yl]acetate (60 mg, 0.16 mmol) and
2-amino-4 ' -mβthoxyacetophenone hydrochloride (36 mg, 0.176 mmol) employing general coupling procedure. TLC Rt =0.55 (10% CH3OH-CH2Cl2) ; RPLC tR = 6.50 min
(>85%), 220 nm (Method B); ESI/MS m/e 500.2 (M*+H, C31H37N303).
Example 227: Compound No. 271 (51 mg, 73%) was prepared from sodium
[4-(3,3-diphenylpropyl)homopiperazlne-l-yl]acetate (60 mg, 0.16 mmol) and dipropylamine (24 mL, 0.176 mmol) employing general coupling procedure. TLC
Rt =0.56 (10% CH30H-CH2C12); RPLC tR = 5.51 min (>85%), 220 nm (Method A); ESI/MS m/e 436.3 (M*+H. C2βH41N3θ) .
Example 228: Compound No. 186 (34 mg, 23%) was prepared from sodium [4-(3,3-diphenylpropyl)homoplperazine-1-yl]acetate (100 mg, 0.267 mmol) and bβnzenesulfonohydrazide (54 mg, 0.31 mmol) employing general coupling procedure.
TLC Rt =0.47 (10% CH3OH-CH2Cl2); RPLC tR = 6.31 min (87%), 220 nm (Method B);
ESI/MS m/e 507.5 (MN-H, C2,H34N403S) .
Example 229: Compound No. 93 (79 mg, 81%) was prepared from sodium [4-(3,3-diphenylpropyl)homopiperazine-l-yl]acetate (75 mg, 0.20 mmol) and 4-aminobenzhydrazide (34 mg, 0.22 mmol) employing general coupling procedure. TLC Rc =0.26 (10% CH30H-CH2C12); RPLC tR = 5.61 min (>85%), 220 nm (Method B) ; ESI/MS m/e 486.3 (M*+H, C29H35N502).
Example 230: Compound No. 94 (24.4 mg, 17%) was prepared from sodium [4-(3,3-diphenylpropyl)homopiperazine-l-yl]acetate (100 mg, 0.267 mmol) and
4-methoxybenzeneεulfonohydrazide (59.4 mg. 0.29 mmol) employing general coupling procedure. TLC Rt =0.45 (10% CH30H-CH2C12) ; RPLC tR = 6.71 min (>85%), 220 nm (Method B); ESI/MS m/e 537.3 (M*+H, C29H36N404S) .
Example 231: Compound No. 95 (27.9 mg, 20%) was prepared from sodium [4-(3,3-diphenylpropyl)homopiperazine-l-yl]acetate (100 mg, 0.267 mmol) and p-toluenesulfonohydrazide (55 mg, 0.295 mmol) employing general coupling procedure. TLC Rt =0.52 (10% CH30H-CH2C12) ; RPLC tR = 6.91 min (>85%), 220 nm (Method B); ESI/MS m/e 521.3 (M*+H, C29H36N403S) .
Example 232: Compound No. 272 (34 mg, 65%) was prepared from sodium
[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol) and glycine methyl ester hydrochloride (10.6 mg, 0.084 mmol) employing general coupling procedure. TLC Rt =0.42 (10% CH30H-CH2C12) ; RPLC tR = 6.96 min (>85%). 220 nm (Method B); ESI/MS m/e 424.3 (M*+H, C25H33N303).
Example 233: Compound No. 273 (37 mg, 72%) was prepared from sodium
[4-(3,3-diphenylpropyl)homopiperazine-l-yl]acetate (30 mg, 0.08 mmol) and glycinamide hydrochloride (9.3 mg, 0.084 mmol) employing general coupling procedure. TLC Rf =0.32 (10% CH30H-CH2C12); RPLC tR = 5.76 min (>85%), 220 nm
(Method B); ESI/MS m/e 409.3 (M++H, C24H32N402).
Example 234: Compound No. 274 (24 mg, 47%) was prepared sodium [4- (3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol) and glycine tert-butyl ester hydrochloride (14.1 mg, 0.084 mmol) employing general coupling procedure. This compoundwas purified bydiluting withCH2C12, washing with NaHC03, brine, drying (MgS04), filtering and evaporating off the solvent in vacuo. Final purification by silica gel column chromatography. TLC Rt = 0.41 (10% CH3OH- CH2C12); RPLC tR = 6.56 min (>85%), 220 nm (Method B); ESI/MS m/e 466.5 (M*+H. C2βH39N3θ3).
Example 235: Compound No. 275 (26.9 mg, 43%) was prepared from sodium
[4-(3,3-diphenylpropyl)homopiperazine-l-yl]acetate (30 mg, 0.08 mmol) and
(D)-(-)-2-phenylglycinol (13.2 mg, 0.096 mmol) employing general coupling procedure. TLC Rt =0.42 (10% CH30H-CH2C12); RPLC tR = 6.21 min (>85%), 220 nm
(Method B); ESI/MS m/e 472.0 (M++H, C30H37N3O2).
Example 236: Compound No. 226 (27.0 mg, 43%) was prepared from sodium
[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol) and
(lS,2R)-(-)-cis-l-amino-2-indanol (14.3 mg, 0.096 mmol) employing general coupling procedure. TLC J7f =0.42 (10% CH30H-CH2C12) ; RPLC tR = 6.36 min (>85%), 220 nm (Method B); ESI/MS m/e 484.0 (M'+H, C31H37N302).
Example 237: Compound No. 276 (24.9 mg, 20%) was prepared from sodium
[4-(3,3-diphenylpropyl)homopiperazine-l-yl]acetate (30 mg, 0.08 mmol) and (IR.
2S)-(+)-cis-l-amino-2-indanol (14.3 mg. 0.096 mmol) employing general coupling procedure. TLC Rf = 0.42 (10% CH3OH-CH2Cl2); RPLC tR = 6.26 min (>85%), 220 nm
(Method B); ESI/MS m/e 484.0 (M*+H, C31H37N302).
Example 238: Compound No. 277 (29.9 mg, 43%) was prepared sodium
[4-(3.3-diphenylpropyl)homoplperazine-l-yl]acetate (30 mg, 0.08 mmol) and dl-octopamine hydrochloride (18.2 mg, 0.096 mmol) employing general coupling procedure. TLC Rf =0.24 (10% CH30H-CH2C12) ; RPLC tR = 5.76 min (95%), 220 nm
(Method B); ESI/MS m/e 488.0 (M*+H. C30H37N302).
Example 239: Compound No. 278 (28.3 mg, 43%) was prepared from sodium [4-{3,3-diphenylpropyl)homopiperazine-l-yl]acetate (30 mg, 0.08 mmol) and dl-norphenylephrine hydrochloride (18.2 mg, 0.38 mmol) employing general coupling procedure. TLC Rt =0.24 (10% CH30H-CH2C12) ; RPLC tR = 5.91 min (>85%),
220 nm (Method B); ESI/MS m/e 488.0 (M*+H, C30H37N3O3).
Example 240: Compound No. 279 (27.7 mg, 43%) was prepared from sodium [4-(3.3-diphenylpropyl)homopiperazine-l-yl]acetate (30 mg, 0.08 mmol) and (lS,2S)-(+)-2-amino-3-methoxy-l-phenyl-l-propanol (17.4 mg, 0.096 mmol) employing general coupling procedure. TLC Rt =0.46 (10% CH30H-CH2C12); RPLC tR = 6.36 min (>85%). 220 nm (Method B); ESI/MS m/e 516.0 (M*+H, C32H41N3θ3).
Example 241: Compound No. 280 (29.9 mg, 43%) was prepared from sodium [4-(3,3-diphenylpropyl)homopiperazine-l-yl]acetate (30 mg, 0.08 mmol) and norephedrine hydrochloride (18.0 mg, 0.096 mmol) employing general coupling procedure. TLC Rf =0.46 (10% CH30H-CH2C12); RPLC t„ = 6.06 min (>85%), 220 nm (Method B); ESI/MS m/e 486.3 (M*+H, C31H39N302) .
Example 242: Compound No. 281 (22.4 mg, 20%) was prepared from sodium
[4-(3.3-diphenylpropyl)homopiperazine-l-yl]acetate (30 mg, 0.08 mmol) and 2-amino-l-phenylethanol (16.2 mg, 0.118 mmol) employing general coupling procedure. TLC Rt = 0.53 (10% CH30H-CH2C12) ; RPLC rR = 6.11 min (>85%), 220 nm (Method B); ESI/MS m/e 472.3 (M'+H, C30H37N302).
Example 243: Compound No. 298 (26.9 mg, 43%) was prepared from sodium
[4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol) and
2-amino-l,3-propanediol (11.0 mg, 0.121 mmol) employing general coupling procedure. TLC Rt =0.16 (10% CH30H-CH2C12) ; RPLC tR = 5.51 min (>85%), 220 nm (Method B); ESI/MS m/e 426.0 (M*+H. C25H35N3θ3).
Example 244: Compound No. 282 (26.9 mg, 43%) was prepared from sodium
[4-(3,3-diphenylpropyl)homopiperazine-l-yl]acetate (30 mg, 0.08 mmol) and
L-phenylalaninol (17.8 mg, 0.118 mmol) employing general coupling procedure. TLC Rt =0.53 (10% CH30H-CH2C12); RPLC tR = 6.31 min (>85%), 220 nm (Method B);
ESI/MS m/e 486.3 (M*+H, C31H39N3θ2).
Example 245: Compound No. 283 (27.0 mg, 46%) was prepared from sodium
[4-(3,3-diphenylpropyl)homopiperazine-l-yl]acetate (30 mg, 0.08 mmol) and DL-phenylalaninamide hydrochloride (19.3 mg. 0.096 mmol) employing general coupling procedure. TLC Rt =0.25 (10% CH30H-CH2C12) ; RPLC tR = 2.16 min (>85%),
220 nm (Method B); ESI/MS m/e 499.4 (M*+H, C31H38N4θ2).
Example 246: Compound No. 284 (24 mg, 42%) was prepared from sodium (4-(3.3-diphenylpropyl)homopiperazine-l-yl]acetate (30 mg, 0.08 mmol) and
DL-aspartic acid dimethyl ester hydrochloride (19.0 mg. 0.096 mmol) employing general coupling procedure. TLC Rf =0.46 (10% CH30H-CH2C12); RPLC tR = 2.16 min
(>85%). 220 nm (Method B-); ESI/MS m/e 496.4 (M*+H. C2,H37N305) .
Example 247: Compound No. 285 (32.4 mg, 49%) was prepared from sodium
[4-(3.3-diphenylpropyl)homopiperazine-l-yl]acetate (30 mg, 0.08 mmol) and DL-phenylalanine benzyl ester p-toluenesulfonic acid salt (34.3 mg, 0.08 mmol) employing general coupling procedure. TLC Rt =0.53 (10% CH30H-CH2C12) ; RPLC tR = 2.53 min (>85%) , 220 nm (Method B) ; ESI/MS m/e 590.6 (M*+H, C3,H43N3θ3).
Example 248: Compound No. 286 (22.5 mg, 40%) was prepared from sodium [4-(3.3-diphenylpropyl)homopiperazine-1-yl]acetate (30 mg, 0.08 mmol) and
DL-leucine methyl ester hydrochloride (17.5 mg, 0.096 mmol) employing general coupling procedure. TLC Rt =0.53 (10% CH30H-CH2C12) ; RPLC tR = 2.21 min (>85%), 220 nm (Method B); ESI/MS m/e 480.5 (M*+H, C29H41N3θ3).
Example 249: Compound No. 287 (23 mg, 20%) was prepared from sodium [4-(3,3-diphenylpropyl)homopiperazine-l-yl]acetate (30 mg. 0.08 mmol) and DL-tyrosine methyl ester hydrochloride (22.3.0 mg, 0.096 mmol) employing general coupling procedure. RPLC tR = 2.01 min (>85%), 220 nm (Method B); ESI/MS m/e 530.2 (M*+H, C32H3,N304).
Example 250: Compound No. 288 (23.8 mg, 43%) was prepared from sodium
[4-(3,3-diphenylpropyl)homopiperazine-l-yl)acetate (30 mg, 0.08 mmol) and
DL-methionine methyl ester hydrochloride (19.2 mg, 0.096 mmol) employing general coupling procedure. RPLC tR = 2.01 min (>85%), 220 nm (Method B); ESI/MS m/e 498.2 (M*+H, C2,H„N303S).
Example 251: Compound No. 289 (21.6 mg, 30%) was prepared from sodium
[4-(3,3-dlphenylpropyl)homopiperazine-l-yl]acetate (30 mg. 0.08 mmol) and
DL-Tryptophan methyl ester hydrochloride (24.5 mg.0.096 mmol) employing general coupling procedure. RPLC t„ = 2.27 min (>85%), 220 nm (Method B); ESI/MS m/e
553 . 4 (M*+H , C34H40N403 ) .
Example 252: Compound No. 299 (20.9 mg, 43%) was prepared from sodium
[4-(3,3-diphenylpropyl)homopiperazine-l-yl]acetate (30 mg, 0.08 mmol) and (lS,2R)-(+)-2-amino-1.2-diphβnylβthanol (20.5 mg. 0.096 mmol) employing general coupling procedure. RPLC tR = 2.12 min (>85%). 220 nm (Method B); ESI/MS m/e 548.4 (M*+H. C3βH41N302).
Example 253: Compound No. 291 (23.8 mg, 41%) was prepared from sodium [4-(3,3-diphenylpropyl)homopiperazine-l-yl]acetate (30 mg. 0.08 mmol) and
DL-methionine methyl ester hydrochloride (19.2 mg, 0.096 mmol) employing general coupling procedure. RPLC tR = 2.21 min (>85%), 220 nm (Method B); ESI/MS m/e
484 .4 (M*+H , C27H37N303S ) .
Preparation of [4-(3,3-Diphenylpropyl)-1- homopiperazinyl]aoetohydrazlde.
Methyl [4-(3,3-diphenylpropyl)-1-homopiperazinyl]acetate (0.607 g.
1.66 mmol) was dissolved in ethanol (20 mL) and hydrazine hydrate (1 mL) was added. The mixture was refluxed for 19 h and subsequently concentrated in vacuo. The residue waε taken up in EtOAc, washed with brine, dried (MgSOJ and concentrated in vacuo to afford the title compound as an oil (0.547 g) in 90% yield. TLC Rt = 0.35 (10% CH30H-CH2C12); RPLC tR = 1.93 min (>85%), 220 nm (Method B); ESI/MS m/e 367.1 (M*+H, C22H30N40).
General Coupling Procedure for [4-(3.3-Diphenylpropyl)-l- homopiperazinyljaσetohydrazide for Examples 254-256. [4-(3,3-Diphenylpropyl)-l-homopiperazinyl]acetohydrazide (60.5 mg,
0.165 mmol) was dissolved in dry CH2C12 (2 mL) and CH3CN (0.5 mL). Pyridine (19 mL. 0.23 mmol) and the sulfonyl chloride (0.195 mmol) were added and the mixture was stirred at room temperature for 16 h. After concentration of the mixture in vacuo. flash silica gel column chromatography was used to isolate the desired product.
Example 254: Compound No. 96 (69 mg, 70%) was prepared from [4-
(3.3-Diphenylpropyl)-l-homopipβrazinyl]acetohydrazide (65 mg, 0.177 mmol) and iV-acetylεulfanilyl chloride (46 mg. 0.195 mmol) employing general coupling procedure. TLC R£ = 0.35 (10% CH30H-CH2C12); RPLC tR = 6.36 min (>85%). 220 nm
(Method B); ESI/MS m/e 564.3 (M*+H, C30H37N504S) .
Example 255: Compound No. 97 (63.5 mg, 71%) waε prepared from [4-
(3,3-Diphenylpropyl)-1-homopiperazinylJacetohydrazide (60.5 mg, 0.165 mmol) and 4-chlorobenzenesulfonyl chloride (38.3 mg, 0.181 mmol) employing general coupling procedure. RPLC tR ■ 7.01 min (>85%), 220 nm (Method B); ESI/MS m/e
541.3 (M'+H, CIβH33N403SCl) .
Example 256: Compound No. 256 (40 mg, 53%) was prepared from [4- (3,3-Diphenylpropyl)-1-homopiperazinylJacetohydrazide (55 mg, 0.15 mmol) and
2-thiophenesulfonyl chloride (30 mg, 0.164 mmol) employing general coupling procedure. RPLC tR = 6.61 min (>85%). 220 nm (Method B); ESI/MS m/e 513.3 (M*+H,
C26H32N403S2).
Example 257: Compound No. 99 (55 mg, 64%) was prepared by dissolving [4-(3,3-Diphenylpropyl)-l-homopiperazinylJacetohydrazide (51 mg, 0.139 mmol) in dry CH2C12 (2 mL) and adding HOBt (21 mg, 0.155 mmol) and 4-
(methylsulfonyl)benzoic acid (29 mg, 0.146 mmol). This mixture was cooled (0 _C) and treated with EDCI (45 mg, 0.151 mmol) followed by Et3N such that the pH was around 8. After stirring for 16 h at room temperature, the mixture was diluted with CH2C12, washed with saturated NaHC03. brine, dried (MgS04), filtered and concentrated in vacuo. The residue was applied to silica gel column chromatography (eluent: gradient of 96/4 to 94/6 CH2Cl2/MeOH, v/v) to afford the desired compound. TLC Rf =0.45 (10% CH30H-CH2C12) ; RPLC t„ = 6.06 min (>85%), 220 nm (Method B); ESI/MS m/e 549.3 (M*+H, C30H36N4O4S) .
Example 258: Compound No. 100 (45 mg, 64%) was prepared by dissolving
[4-(3,3-Diphenylpropyl)-l-homopiperazinyl]acetohydrazide (49 mg, 0.134 mmol) in dry CH2C12 (2 mL) and adding HOBt (20 mg, 0.148 mmol) and 4-acetylbenzoic acid (23 mg, 0.14 mmol). This mixture was cooled (0 _C) and treated with EDCI (44 mg, 0.148 mmol) followed by Et3N such that the pH was around 8. After stirring for 16 h at room temperature, the mixture was diluted with CH2C12, washed with saturated NaHC03, brine, dried (MgS04), filtered and concentrated in vacuo. The residue was applied to silica gel column chromatography (eluent: gradient of 96/4 to 94/6 CH2Cl2/MeOH. v/v) to afford the desired compound. TLC Rf =0.46 (10% CH30H-CH2C12); RPLC tR = 6.26 min (>85%), 220 nm (Method B); ESI/MS m/e 513.3 (M++H, C31H36N403).
Example 259: Compound No. 290 (6.6 mg, 64%) was prepared by treatment of Compound No. 286 (10.5 mg, 0.015 mmol) with 0.44 mL of 0.25 N LiOH (MeOH/H20. 3/1, v/v) at room temperature for 16 h. After acidifying the reaction mixture with TFA and evaporating off the solvents, the residue was purified using a small C-18 column (eluent: water followed by MeOH). RPLC tR = 2.28 min (>85%), 220 nm (Method B); ESI/MS m/e 466.4 (M*+H. C2βH39N303).
Example 260: Compound No. 292 (6.0 mg, 64%) was prepared by treatment of Compound No. 289 (9.6 mg, 0.0123 mmol) with 0.35 mL of 0.25 N LiOH (MeOH/H20, 3/1, v/v) at room temperature for 16 h. After acidifying the reaction mixtu ^ with TFA and evaporating off the solvents, the residue was purified using a snu C-18 column (eluent: water followed by MeOH). RPLC tR = 2.41 min (>85%), 2-J nm (Method B); ESI/MS m/e 539.3 (M*+H, C33H3βN403) .
Example 261: Preparation of Compound No. 69.
A solution of 1-[4-(methylsulfonyl )benzyl]homopiperazine (314 mg, 1.17
mmol) in CH3CN (50 mL) was treated sequentially with 3-[4-(tert- butoxycarbonyl)phenyl]-3- phenylpropyl methanesulfonate (456 mg, 1.17 mmol, 1 equiv) and Na2C03 (124 mg, 1.17 mmol, 1 equiv). The reaction mixture was heated to 70 'C for 16 h, cooled to 25 *C, filtered and concentrated. Chromatography (Si02, 2 x 20 cm, 5% CH30H-CH2C12) afforded the desired material (346 mg, 53%) RPLC tR = 7.63 min <>90%), 220 nm (Method A); ESI/MS m/e 563.2 (M*+H, C33H42N204S) .
Example 262: Preparation of Compound No. 72 and 73.
A solution of compound No. 69 (278 mg. 0.494 mmol) in CH30H (2 mL) was treated with a 1.0 M solution of HCl-Et20 (5 mL) and stirred at 25 *C for 1 h.
Concentration and chromatography (Si02. 2 x 20 cm. 5% CH30H-CH2C12 to CH3OH, gradient elution) afforded the compound No. 72 (132 mg, 51%) and compound No.
73 (88 mg, 35%). Compound No. 72: RPLC tR = 4.78 min (>90%), 220 nm (Method A);
ESI/MS m/e 521.2 (M*+H. C30H36N2O4S) . For compound No.73: RPLC t„ = 4.08min (>95%), 220 nm (Method A); ESI/MS m/e 507.2 (M*+H, C29H34N204S) .
Example 263: Preparation of 1-( tert-Butyloxycarbonyl)-4-[3-hydroxy- 3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 294) .
1. A solution of di-tert-butyl dicarbonate (25 g, 115 mmol. ) in CH2C12 (100 mL) was added over a period of 20 min to a solution of homopiperazine (57 g,
5.0 equiv) in CH2C12 (200 mL). The reaction mixture was stirred at room temperature for 3 days. H20 (150 mL) was added to the reaction mixture and the mixture was extracted with CH2C12 (2 x 100 mL). The combined extracts were washed with brine and dried over MgS04. The solvent was removed under reduced pressure to afford an oil which was purified by simple distillation to give l-( tert-butyloxycarbonyl)homopiperazine: 13.68 g, 59% yield, colorless oil; The purity waε determined by GC/MS (95%), m/e 200.1 (M *. C10H20N202).
2. 3-Chloropropiophenone (7.14 g, 24.4 mmol). K2C03 (8.79 g, 1.50 equiv) and KI (1.41 mg, 0.2 equiv) were added to a solution of the purified l-(tert- butyloxycarbonyl)homopiperazine (8.486 g, 42.4 mmol) in CH3CN (60 mL). The reaction mixture was stirred at 70 *C for 17 h and then AσOEt (200 mL) was added to the cooled mixture. The precipitated solid was removed by filtration and washed with AcOEt (50 mL). The combined filtrate was evaporated to afford an oil which was purified by column chromatography (Si02, 0%-20% CH3CN/AcOEt) to give 1-( tert-Butyloxycarbonyl)-4-(3-phenyl-3-oxopropy1)homopiperazine : 11.27 g, 80% yield, pale yellow oil; *H NMR (CDC13, 300 MHz) δ 1.40-1.65 (m, 9 H) ,
1.80-1.95 (m, 2 H), 2.65-2.85 (m. 4 H) , 3.01 (t, 2 H, J = 6.9 Hz), 3.19 (t, 2 H, J = 6.9 Hz), .3.35-3.55 (m, 4 H), 7.47 (t, 2 H. J = 7,7 Hz), 7.55-7.65 (m, 1 H), 7.90-8.02 (m, 2 H). The purity waε determined by RPLC/MS (Method B). RPLC tR = 5.53 min (95%), 220 nm; ESI/MS m/e 333.4 (M'+H, C19H29N203).
3. A solution of 3-( tert-butyldimethylsilyloxy)phenylmagnesium bromide [prepared from 3-( tert-butyldimethylεilyloxyjbromobenzene (28.5 g, 99.2 mmol) and magnesium turnings (2.30 g, 94.5 mmol) in Et20 (65 mL) ] was added at 0 _C to a solution of the purified 1-( tert-Butyloxycarbonyl)-4-(3-phenyl-3- oxopropyl)homopiperazine (11.25 g. 33.8 mmol) in dry THF (150 mL). The mixture was warmed to room temperature with stirring and the stirring was continued for 3 h. Saturated aqueous NH4C1 (300 mL) was added to the reaction mixture, the mixture was stirred for 15 min and extracted with AcOEt (3 x 150 mL) . The combined extracts were washed with brine and dried over MgS04. The solvent waε removed under reduced preεsure to afford an oil (31.00 g) which was purified by column chromatography (Si02, 3%-25% AcOEt/hexane) to give l-(tert- butyloxycarbonyl)-4-[3-{3-( tert-butyldimethylsilyloxy)phenyl}-3-hydroxy-3- phenylpropyl]homopiperazine : 9.00 g, 49% yield, pale yellow oil; *H NMR (CDC13, 300 MHz) δ 0.00 (s. 6 H), 0.81 (s, 9 H). 1.32 (s, 9 H), 1.4-1.5 (m. 2 H), 1.7-1.8 (m, 2 H). 2.2-2.3 (m. 2 H) . 2.4-2.55 (m, 4 H). 3.25-3.45 (m, 4 H) , 6.50-6.56 (m, 1 H), 6.80-6.92 (m. 2 H) , 6.99-7.10 (m. 2 H). 7.11-7.20 (m. 2 H) , 7.28- 7.34 (m, 2 H). The purity was determined by RPLC/MS (Method A). RPLC tR = 7.13 min (>95%). 220 nm; ESI/MS m/e 541.3 (M*+H, C31H49N202Si) .
4. A solution of tetrabutylammonium fluoride (1.0 M solution in THF. 4.0 mL, 4.0 mmol, 1.03 equiv) was added to a solution of the purified l-(tert- butyloxycarbonyl)-4-[3-{3-( tert-butyldimethylsilyloxy)phenyl}-3-hydroxy-3- phenylpropyl]homopiperazine (2.11 g, 3.90 mmol) in THF (35 mL). The mixture waε stirred at room temperature for 30 min. H20 (100 mL) was added to the reaction mixture and the mixture was extracted with AcOEt (3 x 100 mL). The combined extracts were washed with brine and dried over MgS04. The solvent was removed under reduced pressure to afford an oil (3.11 g) which waε purified by column chromatography (Si02. 50% AcOEt/hexane) to give 1-( tert-butyloxycarbonyl)- 4-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (compound No. 294): 1.381 g, 83% yield, colorless oil; lH NMR (CDC13, 300 MHz) δ 1.47 (s, 3 H), 1.50 (s, 6 H). 1.9-2.1 (m, 2 H) , 2.45-2.9 (m, 8 H) . 3.3-3.8 (m, 4 H), 6.7-7.0 (m. 2 H), 7.05-7.28 (m, 2 H). 7.3-7.38 (m. 2 H) , 7.42-7.50 (m, 2 H) . The purity
was determined by RPLC/MS (Method A). RPLC tR = 5.30 min (>95%). 220 nm; ESI/MS m/e 427.3 (M*+H, C25H35N204) .
Example 264: Preparation of l-[3-Hydroxy-3-(3-hydroxyphenyl)-3- phenylpropyl]homopiperazine (Compound No. 295) . p-Toluenesulfonic acid monohydrate (1.90 g, 10.0 mmol, 4.0 equiv) waε added to a solution of the purified l-( tert-butyloxycarbonyl)-4-[3-hydroxy- 3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 294, 1.066 g, 2.50 mmol) in CH3CN (15 mL) . The reaction mixture was stirred at room temperature for 2.0 h and then. H20 (50 mL) and CH3OH (20 mL) were added. Anion exchange resin (11.5 g, DOWEX 1x2-200, washed with aqueous NaOH) was added and the mixture was gently agitated at room temperature for 5 min. The resin was removed by filtration and washed with CH3OH (300 mL). The combined filtrate was evaporated to afford an oil (1.35 g) which was purified by column chromatography (Si02, 5%->10% CH30H, 5% TEA/CH2C12) to give l-[3-hydroxy-3-(3-hydroxyphenyl)-3- phenylpropyl]homopiperazine (Compound No. 295): 657 mg, 81% yield, colorlesε oil; XH NMR (CDC13, 300 MHz) δ 1.8 - 2.0 (m. 2 H) , 2.35-2.45 (m, 2 H). 2.55- 2.80 (m, 6H). 3.0-3.15 (m, 4H), 6.68-6.75 (m, 1 H) , 6.82-6.88 (m. IH). 7.10-7.38 (m, 5 H). 7.42-7.52 (m. 2 H) . The purity waε determined by RPLC/MS (Method B) . RPLC tR = 4.27 min (>99%). 220 nm; ESI/MS m/e 327.3 (M*+H. C20H27N2O2).
Example 265: General Alkylation of l-[3-Hydroxy-3-(3- hydroxyphenyl)-3-phenylpropyl]homopiperazine (Preparation of Compound No. 185). l-Benzoyl-2-(chloroacetyl)hydrazlne (60 mg. 0.281 mmol, 1.2 equiv) and
Et3N (118 mg, 1.17 mmol, 5.0 equiv) were added to a solution of l-[3- hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 100 mg, 0.306 mmol) in CH3CN (2.0 mL). The reaction mixture was stirred at 60-70 *C for 13 h. The solvent was evaporated to afford an oil which was purified by column chromatography (Si02, 10% CH30H/CH2C12) to give Compound No. 185: 71 mg.46% yield, colorless oil; ^NMR (CD3OD.300 MHz) δ 1.85-2.00 (m.2H).2.45-2.55 (m, 2 H). 2.65-2.75 (m. 2 H) , 2.78-3.00 (m, 8 H). 3.36 (s, 2 H) . 6.62-6.65 (m. 1 H). 6.90-6.98 (m, 2 H), 7.10-7.35 (m, 4 H). 7.40-7.65 (m, 5 H), 7.88 (d. 2 H, J = 5.4 Hz). The purity was determined by RPLC/MS (Method B) . RPLC tR = 5.08 min (>98%), 220 nm; ESI/MS m/e 503.2 (M*+H. C2,H35N404).
Example 266: Compound No. 259, di-TFA salt (54.B mg, 15%) was prepared
from 1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 158 mg, 0.486 mmol) and Maybridge GK02253 (136 mg, 1.2 equiv) employing general alkylation procedure. The product was purified by preparative RPLC. RPLC tR = 4.60 min (>98%), 220 nm (Method A); ESI/MS m/e 523.2 <M*+H, C2,H35N404S).
Example 267: Compound No. 227 (20 mg, 35%) was prepared from l-[3- hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295,
36 mg, 0.11 mmol) and W-(3-bromopropyl)phthalimide (32 mg, 1.1 equiv) employing general alkylation procedure. RPLC tB = 5.23 min (98%), 220 nm (Method B); ESI/MS m/e 514.3 (M*+H. C31H36N304) .
Example 268: Compound No. 227260 (105 mg, 67%) was prepared from 1- [3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 100 mg, 0.306 mmol) and l-(chloroacetyl)-2-(2-thiophenecarbonl)hydrazine (61 mg, 1.2 equiv) employing general alkylation procedure. RPLC tR = 4.95 min (>98%). 220 nm (Method B); ESI/MS m/e 509.2 (M*+H. C27H33N404S) .
Example 269: Compound No. 261 (94 mg, 53%) was prepared from l-[3- hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295,
100 mg, 0.306 mmol) and Maybridge RF00404 (79 mg, 1.2 equiv) employing general alkylation procedure. RPLC tR = 5.52 min (>98%), 220 nm (Method B); ESI/MS m/e
572.2 (M++H, C2,H32C12NS04).
Example 270: Compound No. 293 (65 mg, 48%) was prepared from l-[3- hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295. 100 mg, 0.306 mmol) and N,N-diethylacetamide (150 mg, 4.3 equiv) employing general alkylation procedure. RPLC tR= 4.68 min (89%), 220 nm (Method B); ESI/MS m/e 440.2 (M*+H, C26H38N303).
Example 271: Compound No. 228 (97 mg, 63%) was prepared from l-[3~ hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 100 mg, 0.306 mmol) and l-(3-chloropropyl)-l,3-dihydro-2 H-benzimidazol-2-one (230 mg, 4.6 equiv) employing general alkylation procedure. tR= 4.98 min (>95%), 220 nm (Method B); ESI/MS m/e 501.1 (M*+H, C36H37N403) .
Example 272: Compound No. 229 (60 mg, 63%) was prepared from l-[3-
hydroxy-3-{3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 59 mg, 0.182 mmol) and 4-bromo-2-butenyl phenyl sulfone (50 mg, 1.0 equiv) employing general alkylation procedure. RPLC tR= 5.20 min (>95%). 220 nm (Method B); ESI/MS m/e 521.3 (M*+H, C30H37N2O„S) .
Example 273: Compound No. 262 di-TFA salt (88 mg, 48%) waε prepared from 1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 80 mg, 0.245 mmol) and 1-(chloroacetyl)-2-(5- methylthiophenecarbonl)hydrazine (68 mg, 1.2 equiv) employing general alkylation procedure. The Product waε purified by preparative RPLC. RPLC tR = 5.23 min (>98%). 220 nm (Method B); ESI/MS m/e 523.3 (M*+H. C2βH3SN404S) .
Example 274: Compound No. 187 di-TFA εalt (19 mg, 9.5%) was prepared from 1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 80 mg, 0.245 mmol) and Salor S2,688-4 (88 mg, 1.2 equiv) employing general alkylation procedure. The Product was purified bypreparative RPLC. RPLC tR = 5.22 min (>85%), 220 nm (Method B); ESI/MS m/e 589.0 (M*+H, C33H37N206S).
Example 275: Compound No. 189 (26 mg, 42%) was prepared from l-[3- hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295. 40 mg, 0.123 mmol) and W-(phenacyl)chloroacetamide (32 mg, 1.2 equiv) employing general alkylation procedure. RPLC t„= 5.73 min (>98%). 220 nm (Method B); ESI/MS m/e 502.3 (M*+H, C30H36N3O4).
Preparation of 1-[4-(Bromomethyl)benzenesulfonyl]pyrrole. NaH (60% dispersion inmineral oil, 40mg, 1.0 mmol) was added toa solution of pyrrole (67 mg, 1.0 mmol) in THF (2.0 mL) and the mixture was stirred at room temperature for 5 min. Then 4-(bromomethyl)benzenesulfonyl chloride (269 mg, 1.0 mmol) was added to the mixture. After stirring at room temperature for additional 10 min, brine (15 mL) was added and the mixture was extracted with AcOEt (40 mL x 2). The combined extracts were dried over MgS04. The solvent was removed under reduced pressure to afford an oil which was purified by column chromatography (Si02, 10% AcOEt/hexane) to give l-[4- (bromomethyl)benzenesulfonyl]pyrrole: 46 mg, 15% yield, colorlesε oil. The purity was determined by GC/MS (>95%). m/e 299 (M\ CnH10N02BrS) .
Example 276: Compound No. 190 (27 mg, 40%) was prepared from l-[3- hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295,
40 mg. 0.123 mmol) and 1-[4-(bromomethyl)benzenesulfonyl]pyrrole (46 mg. 1.24 equiv) employing general alkylation procedure. RPLC tR = 5.85 min (>98%), 220 nm (Method B); ESI/MS m/e 546.3 (M'+H. C31H36N304S) .
Example 277: Compound No. 191 (39 mg, 61%) was prepared from l-[3- hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295,
40 mg, 0.123 mmol) and 1-(chloroacetyl)-2-(4-hydroxybenzoyl)hydrazine (28 mg, 1.0 equiv) employing general alkylation procedure. RPLC tR = 4.72 min (>95%),
220 nm (Method B); ESI/MS m/e 519.3 (M*+H. C29H35N405).
Example 278: Compound No. 194 di-TFA salt (39 mg, 42%) was prepared from 1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 40 mg, 0.123 mmol) and l-(chloroacetyl)-2-(4-chlorobenzoyl)hydrazine (31 mg, 1.0 equiv) employing general alkylation procedure. The Product was purified by preparative RPLC. RPLC tR = 5.48 min (>95%), 220 nm (Method B); ESI/MS m/e 537.0 (M++H, C29H34C1N405).
Example 279: Compound No. 195 di-TFA salt (30 mg, 33%) was prepared from
1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 40 mg, 0.123 mmol) and 1-chloroacetyl-4-phenylsemicarbazide (28 mg, 1.0 equiv) employing general alkylation procedure. The Product was purified by preparative RPLC. RPLC t„ = 5.18 min (>95%). 220 nm (Method B); ESI/MS m/e 518.3 (M*+H. C29H36N504).
Example 280: Compound No. 231 di-TFA salt (29 mg, 42%) was prepared from
1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No.
295, 30 mg, 0.092 mmol) and bromobimane (28 mg, 1.0 equiv) employing general alkylation procedure. The product was purified by preparative RPLC. RPLC t„ =
1.87 min (>95%), 220 nm (Method B); ESI/MS m/e 517.4 (M'-t-H, C30H37N4O4).
Example 281: Compound No. 196 di-TFA salt (33 mg, 46%) was prepared from
1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 30 mg, 0.092 mmol) andMaybridge CD08063 (29 mg, 1.2 equiv) employing general alkylation procedure. The product was purified by preparative RPLC. RPLC t„ =
2.07 min (>98%). 220 nm (Method B); ESI/MS m/e 557.2 (M*+H, C2,H34C1N404S) .
Example 282: Compound No. 232 tri-TFA salt (6.6 mg. 9.1%) was prepared from 1- [3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295. 30 mg. 0.092 mmol) and Maybridge BTB12299 (18 mg, 1.2 equiv) employing general alkylation procedure. The product was purified bypreparative RPLC. RPLC tR = 1.48 min (>95%), 220 nm (Method B); ESI/MS m/e 451.2 (M*+H, C25H31N404).
Example 283: Compound No. 296 (16 mg, 18%) was prepared from l-[3- hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295,
78 mg, 0.24 mmol) and acetyl chloride (19 mg, 1.0 equiv). Acetyl chloride and
Et3N (121 mg, 1.2 mmol, 5.0 equiv) were added to a solution of l-(3- hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295) in CH3CN (2.0 mL). The reaction mixture was stirred at room temperature for 30 min. saturated aqueous NaHC03 (10 mL) was added to the reaction mixture and the mixture was extracted with AcOEt (3 x 15 mL) . The combined extracts were dried over MgS04. The solvent was removed under reduced presεure to afford an oil which was purified by column chromatography (Si02, 3-10% CH30H/CH2C12) to give 1- acetyl-4-I3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 296): 16 mg, 18% yield, colorless oil; RPLC tR = 4.75 min (89%),
220 nm (Method B); ESI/MS m/e 369.3 (M++H. C22H29N203).
Example 284: Compound No. 263 TFA salt (40 mg, 23%) was prepared from 1-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 80 mg, 0.25 mmol), 2-(4-chlorobutyryl)thiophene (70 mg, 0.3 mmol) and trlethylamine (174 mL, 1.25 mmol) employing general alkylation procedure. TLC Rt = 0.58 (5% Et3N-10% CH30H-CH2C12); RPLC tR = 4.98 min (>85%). 220 nm (Method B); ESI/MS m/e 479.3 (M*+H, C2βH34N203S).
Example 285: Compound No. 188 TFA salt (31 mg, 17%) was prepared from
1-13-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 80 mg, 0.25 mmol), 3-chloropropyl p-tolyl sulfone (70 mg, 0.3 mmol) and trlethylamine (174 mL. 1.25 mmol) employing general alkylation procedure. TLC Rf = 0.62 (5% Et3N-10% CH30H-CH2C12) ; RPLC t„ = 5.25 min (>85%). 220 nm (Method B); ESI/MS m/e 523.3 (Mτ+H, C30H38N2O4S) .
Example 286: Compound No. 192 TFA salt (34 mg, 19%) was prepared from
1- [3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 80 mg, 0.25 mmol), 4-(chloroacetyl)catechol (56 mg, 0.3 mmol) and triethylamine (174 mL. 1.25 mmol) employing general alkylation procedure. TLC Rf = 0.62 (5% Et3N-10% CH30H-CH2C12) , RPLC tR = 4.68 min (>85%), 220 nm (Method B); ESI/MS m/e 477.3 (M*+H, C2βH32N205).
Example 287: Compound No. 230 TFA salt (30 mg, 17%) was prepared from 1- [3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 80 mg, 0.25 mmol), glycidyl methacrylate (43 mg, 0.3 mmol) and triethylamine (174 mL, 1.25 mmol) employing general alkylation procedure. TLC Rf = 0.6 (5% Et3N-10% CH30H-CH2C12). RPLC tR = 4.95 min (90%), 220 nm (Method B); ESI/MS m/e 469.0 (M*+H, C27H3βN205).
Example 288: Compound No. 193 TFA salt (44 mg, 49%) was prepared from l-[3-hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 50 mg, 0.15 mmol), 2-chloro-4 '-fluoro-3 ' -nitroacetanilide (50 mg, 0.12 mmol) and triethylamine (104 mL, 0.75 mmol) employing general alkylation procedure. TLC Rf = 0.6 (5% Et3N-10% CH3OH-CH2Cl2) ; RPLC tR = 5.78 min (>85%). 220 nm (Method B) ; ESI/MS m/e 523.0 (M*+H. C2βH3,N405F) .
Preparation of l-[3-(3-Hydroxyphenyl)-3-phenylpropyl]homopiperazine.
1. Trifluoroacetic acid (4.75 mL) was added to a solution of l-(3- hydroxy-3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine (Compound No. 295, 60 mg, 0.184 mmol) in CH2C12 (0.25 mL). The reaction mixture was stirred at room temperature for 2.5 h. The trifluoroacetic acid was evaporated to afford l-[3-(3-hydroxyphenyl)-3-phenyl-2-propenyl]homopiperazine as a colorlesε oil used without further purification.
2. A solution of l-[3-(3-hydroxyphenyl)-3-phenyl-2- propenyl]homopiperazine in EtOH (6 mL) was hydrogenated at 1 atm for 1.5 h in the presence of 5% palladium on charcoal (60 mg) at room temperature. The catalyst was removed by filtration through Celite and washed with EtOH (30 mL). The combined filtrate was evaporated to give 1-[3-(3-hydroxyphenyl)-3- phenylpropyl]homopiperazine (2TFA salt, 100 mg, quantitative) as a white εolid used without further purification.. RPLC tR = 1.62 min (Method B); ESI/MS m/e 311.2 (MN-H, C20H27N2O).
Example 289: General Alkylation of l-[3-(3-Hydroxyphenyl)-3- phenylpropyl]homopiperazine (Preparation of Compound No. 257).
Maybridge GK02253 (17 mg, 0.074 mmol, 1.2 equiv) and Et3N (37 mg, 0.37 mmol, 6.0 equiv) were added to a solution of 1-[3-(3-hydroxyphenyl)-3- phenylpropyl]homopiperazine 2TFA salt (33 mg, 0.061 mmol) in CH3CN (2.0 mL). The reaction mixture was stirred at 70 •C for 15 h. The solvent was evaporated to afford an oil which was purified by preparative RPLC to give Compound No. 257 di-TFA salt: 8.0 mg, 18% yield, colorless oil. The purity was determined by RPLC/MS. RPLC tR = 1.90 min (>95%). 220 nm (Method B); ESI/MS m/e 507.2 (M*+H, C2βH35N403S) .
Example 290: Compound No. 101 di-TFA salt (6.0 mg, 14%) was prepared from l-[3-(3-hydroxyphenyl)-3-phenylpropyl]homopiperazine di-TFA salt (33 mg,
0.061 mmol) and AT-(phenacyl)chloroacetamide (16 mg, 1.2 equiv) employing general alkylation procedure. The product was purified by preparative RPLC. RPLC tR =
1.92 min (>85%), 220 nm (Method B); ESI/MS m/e 486.2 (M*+H, C30H36N3O3).
Preparation of l-(3,3-Diphenylpropyl)piperazine. l-( tert-butyloxycarbonyl)piperazine (1.00 g.5.4 mmol) was dissolved in CH3CN (27 mL) and was treated with 3,3-diphenylpropyl mesylate (1.6 g, 5.6 mmol, 1.05 equiv) and ^rNEt (1.40 mL, 8.05 mmol, 1.5 equiv). The reaction mixture waε heated to 70 __C for 16 h, cooled and concetrated. The residue was purified by chromatography (Si02, 1% CH30H-CH2C12) to afford the desired Boc-protected material (988 mg, 48%). The product was treated with 3 M HC1-CH30H (26 mL) and stirred at 25 _C for 1 h. The solvent was removed in vacuo and the residue was dissolved in 'BuOH-H20 (26 mL). Dowex 500 anion exchange resin was added until pH = 9. The resin was filtered and solution concetrated to afforded the desired product (702 mg, 98%).
General Alkylation of l-(3,3-Diphenylpropyl)piperazine. l-(3,3-Diphenylpropyl)piperazine (50 mg, 0.178 mmol) was dissolved in
CH3CN (1 mL) and was treated with alkylating agent (0.196 mmol, 1.1 equiv) and
^rNEt 40 μL, 0.232 mmol, 1.3 equiv). The reaction mixture waε heated to 70 _C for 16 h. The solvent was removed and the samples were purified by normal column chromatography or preparative RPLC.
Example 291: Compound No. 236 (di-TFA salt, 72 mg, 53%) was prepared
from l-(3,3-diphenylpropyl )piperazine (50mg.0.178 mmol) andMaybridge GK 02253 (46 mg, 0.196 mmol) employing general alkylation procedure. RPLC t„ = 2.12 min (>90%), 220 nm (Method A ); ESI/MS m/e 477.2 (M*+H. C27H32N402S) .
Example 292: Compound No. 10 (di-TFA salt, 36 mg, 27%) was prepared from 1-(3,3-diphenylpropyl )piperazine (50 mg, 0.178 mmol) and N- (phenacyl)chloroacetamide (42 mg, 0.196 mmol) employing general alkylation procedure. RPLC tR = 2.41 min (>95%), 220 nm (Method A); ESI/MS m/e 456.5 (M*+H, C29H33N302).
Example 293: Compound No. 11 (di-TFA salt, 76 mg, 57%) was prepared from
1-(3,3-diphenylpropyl )piperazine (50 mg. 0.178 mmol) and l-benzoyl-2-
(chloroacetyl)hydrazine (42 mg, 0.196 mmol) employing general alkylation procedure. RPLC tR = 2.26 min (>95%) . 220 nm (Method A); ESI/MS m/e 457.4 (M*+H, C2βH32N402).
Example 294: Compound No. 12 (di-TFA salt, 54 mg, 46%) was prepared from 1-(3,3-diphenylpropy1 )piperazine (50 mg, 0.178 mmol) and 2-hydroxy-5- nitrobenzyl bromide (46 mg, 0.196 mmol) employing general alkylation procedure. RPLC tR = 2.20 min (>95%). 220 nm (Method A); ESI/MS m/e 432.2 (M*+H, C„H29N303).
Example 295: Compound No. 13 (43 mg, 49%) was prepared from l-(3,3- diphenylpropyl )piperazine (50 mg, 0.178 mmol) and W-(4-raethoxy-2- nitrophenyl)-2-bromoacetamide (46 mg, 0.196 mmol) employing general alkylation procedure . RPLC tR = 2.66 min (>95%) . 220 nm (Method A) ; ESI/MS m/e 489.2 (M*+H,
C„H32N404).
Example 296: Compound No. 14 (55 mg, 62%) was prepared from l-(3,3- diphenylpropyl )piperazine (50 mg, 0.178 mmol) and N-(4-acetamido-3- methoxyphenyl)-2-bromoacetamide (46 mg, 0.196 mmol) employing general alkylation procedure. RPLC tR = 2.27 min (>95%), 220 nm (Method A); ESI/MS m/e 501.2 (M*+H, C30H36N403).
Example 297: Measurement of Inhibition of MlP-lα Binding to THP-1 Cells by Test Compounds .
Human monocytic leukemia cell line THP-1 was suspended in assay buffer (RPMI-1640 (Gibco-BRL Co.) containing 0.1% BSA and 25 mM HEPES adjusted to pH
7.4) to give a cell suspension of a concentration of 1 x 107 cells/mL. The test compound waε diluted in the assay buffer and used as the test compound solution. Iodinated human MlP-lα (DuPont NEN Co.) was diluted in assay buffer to 250 nCi/mL and used as the ligand solution. In a 96 well filter plate (Millipore Co. ) , 25 μL of test compound solution, 25 μL of labeled ligand solution and 50 μL of cell suspension were aliquoted into each well in this order, stirred (total reaction volume 100 μL), and incubated for one hour at 18 *C.
After the reaction, the reaction solution was filtered, and the filter was washed twice with 200 μL of cold PBS (200 μL of cold PBS was added and then filtered) . The filter was removed and placed in an RIA tube (Iuchi Seieido Co. ) and the radioactivity retained by the cells on the filter were measured using a gamma counter (Aloka Co. ) .
To calculate the ability of test compoundε to inhibit binding of human
MlP-lα to THP-1 cellε, non-εpecific binding determined by adding 100 ng of unlabeled human MlP-lα (Peprotech Co.) in place of the test compound was εubtracted, while the countε with no test compound added was taken as 100%.
Inhibition (%) = {1 - (A - B)/(C - B)} x 100
(A, counts with test compound added; B, counts with 100 ng of unlabeled human MlP-lα added; C, counts with [ 125I]-labeled human MlP-lα added).
When inhibition by the cyclic diamine derivative of this invention was measured, for example, the following compounds demonstrated >20% inhibitory activity at 100 μM. These compounds are compound Nos. 1. 2, 3, 9, 34, 50, 52. 53, 54, 57, 59, 63, 64, 65, 66. 71. 75. 76. 78. 79. 80. 81. 82. 106. 107. 108. 109, 111, 112, 123. 197. 204. 210. 211 , 212 , 213, 215, 216. 218, 220, 221 , 222. 223, 233, 246, 250, 252, 253. 258. 264. 265, 269, 270, and 297.
Example 298: Measurement of Inhibition of MCP-1 Binding to THP-1 Cells. 1. Construction of recombinant baculovirus carrying the human MCP-1 gene
Based on the previously published human MCP-1 gene sequence (for example T. Yoshimura et al., Febs Letters. 1989, 244. 487-493). two synthetic DNA primers
(5'-CACTCTAGACTCCAGCATGA-3' and 5'-TAGCTGCAGATTCTTGGGTTG-3' ) flanked by restriction enzyme siteε were used to amplify a DNA fragment from cDNA derived fromhuman endothelial cells (purchased from Kurabow Co. ),- the amplified fragment was cut with the restriction enzymes (Pstl and Xbal), ligated into a transfer vector pVL1393 (Invitrogen Co.), and the resulting vector was co-transfected along with infectious baculovirus into Sf-9 inεect cells and the supernatant was plaque asεayed to yield human MCP-1 gene baculovirus recombinant.
2. Synthesis of I 125I]-labeled human MCP-1 expressed in baculovirus
Using the method of K. Iεhii et al. (Biochem Biophys Research Communications 1995, 206, 955-961). 5 x 106 Sf-6 insect cells was infected with 5 x 107 PFU (plaque forming units) of the above human MCP-1 recombinant baculovirus and cultured for 7 days in Ex-Cell 401 medium. The culture supernatant was affinity purified using a heparin Sepharose column (Pharmacia Co.) and then further purified using reverse phase HPLC (Vydac C18 column) to prepare purified human MCP-1. The purified human MCP-1 was protein labeled by Amersham Co. using the Bolton Huntermethod toyield [mI]-labeled baculovirus expressed human MCP-1 (εpecific activity 2000 Ci/mmol).
3. Meaεurement of inhibition of binding of [125I]-labeled baculoviruε expressed human MCP-1 to THP-1 cells
Human monocytic leukemia cell line THP-1 was suspended in assay buffer (RPMI-1640 (Gibco-BRL Co.) containing 0.1% BSA and 25 mM HEPES adjusted to pH 7.4) to give a cell suspension of a concentration of 1 x 107 cells/mL. The test compound was diluted in the assay buffer and used as the test compound solution. [125I]-labeled human MCP-1 described above was diluted in assay buffer to 1 mCi/mL and used as the labeled ligand solution. In a 96 well filter plate (Millipore Co. ) , 25 μL of test compound εolution, 25 μL of labeled ligand solution and 50 μL of cell suspension were aliquoted into ach well in thiε order, εtirred (total reaction volume 100 μL), and incubated or one hour at 18 *C.
After the reaction, the reaction εolution waε filtered, and the filter was washed twice with 200 μL of cold PBS (200 μL of cold PBS was added and then filtered) . The filter was removed andplaced in an RIA tube (Iuchi Seieido Co.. ) , and the radioactivity retained by the cells on the filter were measured using
a gamma counter (Aloka Co.).
To calculate the ability of test compound to inhibit binding of human MCP-1 to THP-1 cells, non-specific binding determined by adding 100 ng of unlabeled human MCP-1 in place of the test compound was subtracted, while the counts with no test compound added was taken as 100%.
Inhibition (%) = {1 - (A - B)/(C - B)} x 100
(A, counts with test compound added; B, counts with 100 ng of unlabeled human MlP-lα added; C, counts with [ 125I]-labeled human MCP-1 added).
When inhibition by the cyclic diamine derivative of this invention was measured, for example, the following compounds demonstrated >20% inhibitory activity at 100 μM. These compounds are compound Nos. 1, 2, 3, 4, 9, 10, 11. 36, 50. 51, 52, 55. 56. 58, 59. 61, 63. 64. 65. 67. 68, 69. 72. 73. 75. 76, 78. 80, 82. 83. 84. 85. 86. 87. 88, 89. 90. 91. 92. 93, 96, 98, 99. 100, 101. 103. 104. 106. 107, 108, 109, 114. 116, 117 , 119. 121, 122, 123. 124. 125. 126. 128. 129, 131, 132. 133, 134, 135. 136. 137. 138. 139. 140, 141, 142, 143. 145. 146. 147. 148. 149. 151. 152. 153. 154. 155, 156. 157, 158, 159. 160. 161, 162, 185. 186. 187. 188. 189, 190. 191. 192, 193, 194, 195, 196. 213. 214. 215. 220. 221. 222. 223. 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 236, 246, 248. 249, 251, 252, 253. 254. 255. 256, 257. 258, 259. 260, 261, 262, 263. 264, 265. 267. 269, 271, 272, 273. 274, 275. 276, 277, 278. 279. 280. 281, 282, 284, 287, 288. 293, 294, 295, 296, 298, and 299.
Example 299: Measurement of Inhibition of Binding of [125I]-Labeled Human
MCP-1 to Cells Expressing the MCP-1 Receptor.
1. Derivation of cells expressing the MCP-1 receptor cDNA fragment containing the MCP-1 receptor reported by S. Yamagami et al.. Biochemical Biophysical Research Communications 1994, 202, 1156-1162) was cloned into the expression plasmid pCEP4 (Invitrogen Co.) at the Notl site, and the plasmid obtained was transfected into the human kidney epithelial cell line
293-EBNA using the Lipofectamine reagent (Gibco-BRL Co.). The cells were
cultured in the presence of the selective agent (Hygromycin), and a stably expressing transfectant line was obtained. The expreεεion of the receptor waε confirmed by binding of [ 125I]-labeled human MCP-1.
2. Meaεurement of inhibition of binding of [125I]-labeled baculovirus expressed human MCP-1 to the MCP-1 receptor expressing cells
The MCP-1 receptor expressing cells on tissue culture dishes were scraped using a cell scraper and suspended in assay buffer (D-MEM(Gibco-BRL Co.) containing 0.1% BSA and 25 mM HEPES adjusted to pH 7.4) to give a cell suspension of a concentration of 6 x 106 cells/mL. The teεt compound was diluted in the assay buffer to concentrations of 0.16, 0.8, 4, 20, and 100 μM. The remainder of the procedure was as described in Example 163.
When inhibition by the cyclic diamine derivative of this invention was measured, compound No.36 for example showed dose dependent inhibition with 50% inhibitory concentration (IC 50) of 17 μM.
Example 300: Measurement of Inhibition of Cell Chemotaxis .
In order to determine the inhibition of cell chemotaxis by the compounds of this invention, we measured cell chemotaxis caused by monocyte chemotactic factorMCP-1 using thehumanmonocytic leukemia cell line THP-1 as the chemotactic cell according tothemethod ofFall et al. (J. Immunol. Methods, 190, 33.239-247). 2 x 10s cells/mL of THP-1 cells (suspended in RPMI-1640 (Flow Laboratories Co.) + 10% FCS) was placed in the upper chamber (200 μL) of a 96 well micro-chemotaxis chamber (Neuroprobe, registered tradename), and human recombinant MCP-1 in a same solution (Peprotech Co.) at a final concentration of 20 ng/mL was placed in the lower chamber, with a polycarbonate filter (PVP-free, Neuroprobe; registered tradename) placed between the two chambers. These were incubated at 37 "C for 2 hr in 5% C02.
The filter was removed, and the cells which had migrated to the underside of the filter was fixed, stained using Diff Quick (Kokusai Shiyaku Co.) and then quantitated using a plate reader (Molecular Device Co.) at a wavelength of 550 nm to determine the index of cell migration as a mean of 3 wells. In addition, test compounds were placed in the upper chamber along with THP-1, and the inhibition of cell migration (inhibition IC50 (uM)) was determined. Inhibition
was defined as {(cells migration induced MCP-1 with no test compound in the upper chamber) - (cells migration with no MCP-1 added in the lower chamber) = 100%}, and the concentration of the test compound which gave 50% inhibition was designated IC50.
When the inhibition of cyclic diamine derivatives of thepresent invention was measured, the 50% inhibition concentration (IC50) for compound No. 36 was 9 μM and for compound No. 240 was 30 μM.
Example 301: Inhibition of Delayed Type Hypersensitivity Reaction in the Mouse DNFB Induced Contact Hypersensitivity Model.
7 week old male Balb/c mice (Charles River Co.) were maintained for 1 week, after which the hair was shaved with an electric razor from the abdomen to the chest. 1 day and 2 days later, the shaved areas were painted twice with 25 μL of 0.5% dinitrofluorobenzene (DNFB) (Wako Pure Chemicals Co.) in acetone:olive oil = 4:1. At day 6. both side of the right ear was painted for an induction with 10 μL of 0.2% dinitrofluorobenzene (DNFB) (Wako Pure Chemicals Co.) in acetone:olive oil = 4:1, while the left ear was painted with 10 μL of acetone:olive oil = 4:1 not containing DNFB. As a test agent, compound No. 36 or compound No. 240 was dissolved in acetone to 20 mg/mL, and applied twice at 30 min before and after the DNFB induction (25 μL/ear/dose) .
In the control group (no drug administration group) , the acetone solution not containing any test compound was applied. There were 8 mice per group in both the control group and the experimental group. In order to prevent licking off of the DNFB and test compound, the necklace for mice were used during the study (Natsume Seisakujo Co.). At 4B hr after DNFB induction, ear lobeε were sampled using a spring loaded micrometer (Ozaki Seisakujo Co.). The change in the ear lobe thickness was calculated according to the following formula.
Increase = 100 x ((right ear lobe thickness after senεitization - right ear lobe thickness prior to sensitization)/right ear lobe thickness prior to sensitization - (left ear lobe thicknesε after εenεitization - left ear lobe thickness prior to senεitization)/left ear lobe thickness prior to sensitization)
After exanguination, the isolated ear was fixed in formalin, and
hematoxylin-eosin stained histopathological sections were prepared for image analysis. Using a digital camera (Fuji Color Service. HC-1000) installed on an upright microscope and a personal computer (Macintosh 8100/100AV, using Photoshop software) , the color images were digitized, and analyzed using a second image analysiε software (NIH Image). The parameters measured were epidermal thickening, edema (area of dermal and subcutaneous tissues), and cellular infiltration of tissue (number of nuclei in the dermis and subcutaneous tissues) .
Both compounds showed significant inhibitory activity.
Claims (20)
1. A cyclic diamine selected from the group consisting of a compound of the formula [I] below:
and a pharmaceutically acceptable acid addition salt thereof wherein R1 and R2 are the same or different from each other and are an unsubstituted or substituted phenyl group or aromatic heterocyclic group having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, nitrogen atoms or combinations thereof, in which the phenyl or aromatic heterocyclic group may be substituted by one or more halogen atoms, hydroxy groups, Cι~CB lower alkyl groups, Cj-C6 lower alkoxy groups, phenyl groups, benzyl groups, phenoxy groups, methylenedioxy groups, Cj-C6 hydroxyalkyl groups, carboxy groups, C2-C7 alkoxycarbonyl groups, C2-C7 alkanoylamino groups, dioxolanyl groups, or by group represented by the formula: -NR5R€, or is condensed with a benzene ring to form a condensed ring, wherein the substituents for the phenyl or aromatic heterocyclic group and the condensed ring condensed with a benzene ring are one or more groups selected from halogen atoms, hydroxy groups, or C!-C6 lower alkoxy groups, and R6 and R6 are the same or different from each other and are hydrogen atoms, lower alkyl groups, or C2-C6 lower alkenyl groups;
R3 represents a hydrogen atom, hydroxy group, cyano group, Cj-C,; lower alkoxy group or C2-C7 lower alkanoyloxy group; j represents an integer of 0-3; k represents 2 or 3;
R4 is a group represented by:
1) -Al-R7 wherein R7 is an unsubstituted or substituted phenyl group which may be substituted with one ore more groups which are the same or different and are halogen atoms, hydroxy groups, amino groups, C^Cg lower alkyl groups, Cj-Cj lower alkoxy groups, cyano groups, nitro groups, trifluoromethyl groups, C2-C7 alkoxycarbonyl groups, C2-C7 alkanoyl groups, Cx-C6 alkylsulfonyl groups, trifluoromethylsulfonyl groups, unsubstituted phenylsulfonyl groups or substituted with a hydroxy group, 1-pyrrolylsulfonyl groups, Cj-Ce hydroxyalkylsulfonyl groups, Cj-Cg alkanoylamino groups, or a group represented by the formula: -CONRβR9 in which Rθ and R9, are the same or different from each other, and are hydrogen atoms or Cx-Cg lower alkyl groups; A1 is a group represented by the formula: -(CH2)m- or a group represented by formula: -(CH2)P-G-(CH2),,- in which G represents G1 or G2, wherein G1 represents -O-, -CO-, -S02-, -C0-0-, -CONH-, -NHCO-, -NHCONH-, or -NH-S02-, and G2 is - (C=NH)NH-S02-, -CO-NH-NH-CO-, -CO-NH-NH-CO-NR10-, -CO-NH-CH2-CO-, -CO-NH-NH-SC^- , or -CO-N(CH2-CO-OCH3)-NH-CO-, R10 is a hydrogen atom or a phenyl group; m is an integer of 0-3; p is an integer of 1-3; and q represents 0 or 1;
2) -A2-R" wherein A2 is -CO- or -S02-; Ru is:
a) and unsubstituted or substituted phenyl group wherein the substituents are one or more groups which are the same or different and are halogen atoms, Cj-Cg lower alkyl groups, Cj-C€ lower alkoxy groups, groups represented by formula -CH2-NR12R13 or groups represented by the formula:
b) an unsubstituted or substituted aromatic monocyclic heterocyclic group having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, nitrogen atoms or combinations thereof, wherein the substituents are one or more groups which are the same or different and are halogen atoms, C^Cg lower alkyl groups, Cι-C6 lower alkoxy groups, or
c) a group of the formula: -CH2-NRlsRl€,
where R12, R13, R14 and R15 are the same or different groups, and are hydrogen atoms or Cj-Cg lower alkyl groups and R16 is an unsubstituted or substituted phenyl group or a phenylalkyl group, wherein the substituents are one or more of the samenor different groups and are halogen atoms, lower alkyl group, or Cx-C6 lower alkoxy group;
3) -<CH2)n-R17 wherein Rπ is a group which may be substituted at any possible sites by one ore more of the same or different groups and are halogen atoms, hydroxy groups, Cj-C6 lower alkyl groups, or C)-C6 lower alkoxy groups, representing a hydrogen atom, cyano group, C2-C7 alkoxycarbonyl group, C^Cg hydroxyalkyl group, Ci-Q; lower alkynyl group, C3-C6 cycloalkyl group, C3-C7 alkenoyl group, a group represented by the formula: -(CHOH)CH2OR18, a group represented by the formula: -CO-NH-NH-CO-OR19, a group represented by the formula:
a group a:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula 3
CH3 a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
in which n is an integer of 1-4 ; Rlβ is a Cj-C6 lower alkyl group, C2-C6 lower alkenyl group, or C2-C6 lower alkynyl group and R19 is a Cj-Ce lower alkyl group;
4) -(CH2)t-A3-R20 wherein r represents an integer of 0-3; A3 represents a single bond, -CO-, - CO-NH-NH-CO-, -CO-NH-NH-CO-NH-, -CO-NH-CH2-CO-, -CO-NH-NH-S02-, - (CHOH) -CH2-, or -(CHOH)-CH2OCH2-; R20 represents an aromatic heterocyclic group containing 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, nitrogen atoms or combinations thereof in which the aromatic heterocyclic group may be substituted by one or more groups which are the same or different and are halogen atoms, lower alkyl groups, Cj-Cβ lower alkoxy groups, or pyrrolyl groups or is condensed with a benzene ring to form a condensed ring; or
5 ) -CH2-CO-NR21R22 wherein R21 is a hydrogen atom or a lower alkyl group; R22 represents a hydrogen atom, C^Cg lower alkyl group, or a group represented by the formula:
—CH- rCHOH (CH2)S-R23 ;θr
a group represented by the formula: o
-CH—C-R26 (CH2)t-R25 .
or R21 and R22' taken together with the nitrogen to which they are attached form a 4 to 7-membered saturated heterocycle, which may contain an oxygen atom, sulfur atom, or another nitrogen atom; where s represents 0 or 1; t represents an integer of 0-2; R23 represents a hydrogen atom, hydroxy group, phenyl group, C^Cg lower alkyl group, or C^Cg lower alkoxy group; R2* represents a hydrogen atom or phenyl group which may be substituted by hydroxy group; R26 represents a hydrogen atom, phenyl group which may be substituted by a hydroxy group, C2-C7 alkoxycarbonyl group, C^Cg lower alkyl group, Cj-C6 alkylthio group, or 3-indolyl group; and R26 represents a hydroxy group, amino group, Cj- C6 lower alkoxy group, or phenylalkyloxy group;
Wuth the proviso that when R3 is a hydrogen atom, then j is not 0, R7 is not hydroxy, Ci-Cg lower alkyl or Cj-Q lower alkoxy; Gl is not -O- or -CO-; its substituents, if Ru is a phenyl group, are not Cx-C6 lower alkyl group; R17 is not a hydrogen atom, C2-C7 alkoxycarbonyl group, or C^Cg hydroxyalkyl group; r is not 0 and A3 is not a single bond or -CO-;
With the further provisto that when R3 is a hydrogen atom and k represents 2, R7 is not unsubstituted; m is not 0 and R11 is not a substituted or unsubstituted phenyl group;
and, when R3 is a cyano group, R7 is not unsubstituted, and the substituent groups for R7 are not a halogen atom, Cj-Cg lower alkyl group or C^Cg lower alkoxy group.
2. A compound as set forth in Claim 1, wherein k is 3 in formula [I] .
3. A compound as forth in Claim 1 wherein j is 2 in formula [I] .
4. A compound as set forth in Claim 1, wherein R3 is a hydrogen atom in formula [I] .
5. A compound as set forth in Claim 1, in which R3 is a hydroxy group in formula [I] .
6. A compound as set forth in Claim 1, wherein R1 and R2 are the same or different from each other and are substituted or unsubstituted phenyl groups in formula [I] .
7. A compound as set forth in Claim 1, wherein R4 in formula [I] is a group represented by the formula: -CH2-R7 wherein R7 is as defined for R7 in formula [I] .
8. A compound as set forth in Claim 1, wherein R* is -CH2-CO-NH-NH-CO-R7, -CH2-CO-NH-NH-CO-CH2-R7, -CH2-CO-NH-NH-CO-NH-R7, -CH2-CO-NH-CH2-CO-R7, -CH2-CO- NH-NH-CO-R20, -CH2-CO-NH-NH-CO-NH-R20, or -CH2-CO-NH-CH2-CO-R20 where R7 and R20 are as defined in formula [I] .
9. A method of inhibiting the binding of chemokines to the receptor of a target cell and/or its action on a target cell using a pharmaceutical preparation containing as an effective ingredient, a cyclic diamine, or its pharmacologically acceptable acid addition salt, represented by the formula [II] below:
wherein R1 and R2 are the same or different from each other and are a phenyl group or an aromatic heterocyclic group having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, nitrogen atoms or combinations thereof, in which the phenyl or aromatic heterocyclic group may be substituted by one or more halogen atoms, hydroxy groups, Cj-Cg lower alkyl groups, Cj-Cj lower alkoxy groups, phenyl groups, benzyl groups, phenoxy groups, methylenedioxy groups, C,-C6 hydroxyalkyl groups, carboxy groups, C2-C7 alkoxycarbonyl groups, C2-C7 alkanoylamino groups, dioxolanyl groups, or by group represented by the formula: -NR5R€, or is condensed with a benzene ring to form a condensed ring, wherein the substituents for the phenyl or aromatic heterocyclic group and the condensed ring condensed with a benzene ring are optionally substituted by one or more substituents independently selected from halogen atoms, hydroxy groups, or C,-C6 lower alkoxy groups, and R5 and R6 are the same or different from each other and are hydrogen atoms, C,-C6 lower alkyl groups, or C2-C6 lower alkenyl groups;
R3 is a hydrogen atom, hydroxy group, cyano group, CJ-CJ lower alkoxy group or C2-C7 lower alkanoyloxy group; j represents an integer of 0-3; k represents 2 or 3;
R4 is a group represented by:
1) -A^R7 wherein R7 is an unsubstituted or substituted phenyl group which may be substituted by one or more groups which are the same or different and are halogen atoms , hydroxy groups , amino groups, Cj-Cg lower alkyl groups , Cj-Cg lower alkoxy groups, cyano groups, nitro groups, trif luoromethyl groups , C2-C7 alkoxycarbonyl groups, C2-C7 alkanoyl groups , Cj-Cg alkylsulfonyl groups , trifluoromethylsulfonyl groups , unsubstituted phenylsulfonyl groups or substituted with a hydroxy group, 1-pyrrolylsulfonyl groups, hydroxyalkylsulfonyl groups , C^Cg alkanoylamino groups , or a group of the formula : -CONRβR9 in which R8 and R? are the same or different from each other, and are hydrogen atoms or Ci-Cg lower alkyl groups ; A1 is a group of the formula : - (CH2) „- or a group represented by formula : - (CH2 ) P-G- (CH2 )q- in which G is G1 or Gz; wherein G1 represents -0- , -CO- , -S02-, -CO-0- , -CONH- , -NHCO- , -NHCONH-, or -NH-S02-; and G2 represents - (C=NH) NH-S02-, -CO-NH-NH-CO- , -CO-NH- NH-CO-NR10-, -CO-NH-CH2-CO-, -CO-NH-NH-S02-, or -CO-N ( CH2-CO-OCH3 ) -NH-CO- ; R10 is a hydrogen atom or a phenyl group; m is an integer of 0-3 ; p is an integer of 1-3 ; q represents 0 or 1 ;
2 ) -A2-Rn wherein A2 is -CO- or -S02-; R11 is;
a) an unsubstituted or substituted phenyl group which is substituted by one or more groups which are the same or different and are halogen atoms, Cι~ C6 lower alkyl groups, Cj-Cg lower alkoxy groups, groups represented by formula -CH2-NR12R13 or groups represented by the formula:
b) an aromatic monocyclic heterocyclic group having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, nitrogen atoms or combinations thereof, which may be substituted with one or more of the same or different groups which are halogen atoms, Cj-Cg lower alkyl groups, or Cj-Cg lower alkoxy groups, or
c) A group represented by the formula: -CH2-NR15R16,
where R12, R13, R14 and R15, are the same or different groups, and are hydrogen atoms or C^Cg lower alkyl groups and R16 is a phenyl group or a phenylalkyl group, which may be substituted by one or more of the same or different groups which are halogen atoms, C,-Cg lower alkyl group, or Cι~C6 lower alkoxy group;
3) -(CH2)n-R17 wherein R17 is a group which may be substituted at any possible sites by one or more of the same or different groups which are halogen atoms, hydroxy groups, C^Cg lower alkyl groups, or Cj-C6 lower alkoxy groups, representing
a hydrogen atom, cyano group, C2-C7 alkoxycarbonyl group, C^Cg hydroxyalkyl group, C^Cg lower alkynyl group, Cj-C6 cycloalkyl group, C3-C, alkenoyl group, a group represented by the formula: -(CHOH)CH2ORlβ, a group represented by the formula: -CO-NH-NH-CO-OR19, a group represented by the formula: a group represented by the formula:
H
.NH
a group represented by the formula:
a group represented by the formula:
a group represented by the formula :
CH: a group represented by the formula: \
°- H
a group repr
a group represented by the formula:
a group represented by the formula:
group represented by the formula:
a group represented by the formula:
in which n is an integer of 1-4; Rlβ is a Q-Cg lower alkyl group, C2-C6 lower alkenyl group, or C2-C6 lower alkynyl group and R19 represents a lower alkyl group; 4) -(CH2)r-A3-R20 wherein r represents an integer of 0-3; A3 represents a single bond, -CO-, - CO-NH-NH-CO-, -CO-NH-NH-CO-NH-, -CO-NH-CH2-CO-, -CO-NH-NH-S02-, - (CHOH)-CH2-, or -(CHOH) -CH2OCH2-; R20 represents an aromatic heterocyclic group containing 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, nitrogen atoms or combinations thereof in which the aromatic heterocyclic group may be substituted by one or more of the same or different groups which are halogen atoms, Cj-Cg lower alkyl groups, Cj-Q lower alkoxy groups, or pyrrolyl groups) or is condensed with a benzene ring to form a condensed ring) ;
5) -CH2-CO-NR21R22 wherein R21 is a hydrogen atom or C^Cg lower alkyl group; R22 represents a hydrogen atom, Ci-C6 lower alkyl group, or a group represented by the formula:
R2Λ -CH—CHOH
(CH2)S-R*3 f Qi a group represented by the formula: o -CΉ — C-R26
(CH2)rR25 .
or R21 and R22, taken together with the nitrogen to which they are attached form a 4 to 7-membered saturated heterocycle, which may contain an oxygen atom, sulfur atom, or another nitrogen atom; where s represents 0 or 1; t represents an integer of 0-2; R23 represents a hydrogen atom, hydroxy group, phenyl group, C^Cg lower alkyl group, or C,-C6 lower alkoxy group; R24 represents a hydrogen atom or phenyl group which may be substituted by a hydroxy group; R25 represents a hydrogen atom, phenyl group which may be substituted a by hydroxy group, C2-C7 alkoxycarbonyl group, C^Cg lower alkyl group, C,-Cg alkylthio group, or 3-indolyl group; and R26 represents a hydroxy group, amino group, Cj-Cg lower alkoxy group, or phenylalkyloxy group;
6) a hydrogen atom, Ci-C6 alkanoyl group, or C2-C7 alkoxycarbonyl group.
10. A method according Claim 9, in which k is 3 in the above formula [II] or its pharmacologically acceptable acid addition salt.
11. A method according to Claim 9, where j is 2 in the above formula [II] or its pharmacologically acceptable acid addition salt.
12. A method according to Claim 9, in which R3 is a hydrogen atom in the above formula [II] or its pharmacologically acceptable acid addition salt.
13. A method according to Claim 9, in which R3 is a hydroxy group in the above formula [II] or its pharmacologically acceptable acid addition salt.
14. A method according to Claim 9, in which Rl and R2 are the same or different from each other and are substituted or unsubstituted phenyl groups in the above formula [II] or its pharmacologically acceptable acid addition salt.
15. A method according to Claim 9, in which R4 is a group represented by the formula: -CH2-R7 where R7 is as defined in R7 in the above formula [II]), or its pharmacologically acceptable acid addition salt.
16. A method according to Claim 9, where R4 is a group represented by the formula: -CH2-R20 wherein R20 is as defined in the above formula [II] or its pharmacologically acceptable acid addition salt.
17. A method according to Claim 9, wherein R4 in the above formula [II] is -CH2CO-NH-NH-CO-R7, -CH2-CO-NH-NH-CO-CH2-R7, -CH2-CO-NH-NH-CO-NH-R7, -CH2-CO-NH- CH2-CO-R7, -CH2-CO-NH-NH-CO-R20, -CH2-CO-NH-NH-CO-NH-R20, or -CH2-CO-NH-CH2-CO- R20, wherein in the formulas, R7 and R20 are the same as defined in the above formula [II] or its pharmacologically acceptable acid addition salt.
18. A method according to Claim 9, wherein the chemokine is MlP-la.
19. A method according to Claim 9, wherein the chemokine is MCP-1.
20. A method according to Claim 9 wherein the chemokine is IL-8.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP8-147846 | 1996-05-20 | ||
JP8147846A JPH09309877A (en) | 1996-05-20 | 1996-05-20 | Cyclic diamine derivative and its production and use |
PCT/US1997/008577 WO1997044329A1 (en) | 1996-05-20 | 1997-05-20 | Diarylalkyl cyclic diamine derivatives as chemokine receptor antagonists |
Publications (2)
Publication Number | Publication Date |
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AU3135497A true AU3135497A (en) | 1997-12-09 |
AU731187B2 AU731187B2 (en) | 2001-03-29 |
Family
ID=15439585
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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AU31354/97A Ceased AU731187B2 (en) | 1996-05-20 | 1997-05-20 | Diarylalkyl cyclic diamine derivatives as chemokine receptor antagonists |
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JP (1) | JPH09309877A (en) |
AU (1) | AU731187B2 (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
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JP4120713B2 (en) * | 1997-09-04 | 2008-07-16 | 大塚製薬株式会社 | Treatment for multiple sclerosis |
US6509329B1 (en) * | 2001-06-29 | 2003-01-21 | Kowa Co., Ltd. | Cyclic diamine compound with 6-membered ring groups |
US6552188B2 (en) * | 2001-06-29 | 2003-04-22 | Kowa Co., Ltd. | Unsymmetrical cyclic diamine compound |
CN117304076B (en) * | 2023-11-28 | 2024-02-20 | 苏州大学 | Preparation method of N-sulfonyl amidine compound |
-
1996
- 1996-05-20 JP JP8147846A patent/JPH09309877A/en active Pending
-
1997
- 1997-05-20 AU AU31354/97A patent/AU731187B2/en not_active Ceased
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JPH09309877A (en) | 1997-12-02 |
AU731187B2 (en) | 2001-03-29 |
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