EP0689544A1 - Verfahren zur herstellung imidazol-derivate - Google Patents

Verfahren zur herstellung imidazol-derivate

Info

Publication number: EP0689544A1
Authority: EP; European Patent Office
Prior art keywords: group; lower alkyl; hydrogen atom; alkyl group; formula
Prior art date: 1993-03-19
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 Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Withdrawn

Application number

EP94910736A

Other languages

English (en)

French (fr)

Inventor

Hiroyoshi Yamada

Kiyotaka Munesada

Keiko Koh

Mikio Taniguchi

Yoshiji Fujita

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Pharmacia and Upjohn Co

Original Assignee

Pharmacia and Upjohn Co

Upjohn Co

Priority date (The priority date 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 date listed.)

1993-03-19

Filing date

1994-03-04

Publication date

1996-01-03

1994-03-04 Application filed by Pharmacia and Upjohn Co, Upjohn Co filed Critical Pharmacia and Upjohn Co

1996-01-03 Publication of EP0689544A1 publication Critical patent/EP0689544A1/de

Status Withdrawn legal-status Critical Current

Links

150000002460 imidazoles Chemical class 0.000 title claims abstract description 15
238000000034 method Methods 0.000 title claims description 23
238000004519 manufacturing process Methods 0.000 title description 8
RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 claims abstract description 16
229910000071 diazene Inorganic materials 0.000 claims abstract description 11
-1 -CF group Chemical group 0.000 claims description 48
125000000217 alkyl group Chemical group 0.000 claims description 39
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
150000001875 compounds Chemical class 0.000 claims description 17
125000003545 alkoxy group Chemical group 0.000 claims description 16
125000003118 aryl group Chemical group 0.000 claims description 12
229910052783 alkali metal Inorganic materials 0.000 claims description 11
125000004093 cyano group Chemical group *C#N 0.000 claims description 11
125000005843 halogen group Chemical group 0.000 claims description 10
150000002148 esters Chemical class 0.000 claims description 8
150000003839 salts Chemical class 0.000 claims description 8
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
125000003710 aryl alkyl group Chemical group 0.000 claims description 5
125000000753 cycloalkyl group Chemical group 0.000 claims description 5
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
125000003277 amino group Chemical group 0.000 claims description 4
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
150000001340 alkali metals Chemical group 0.000 claims description 3
125000003342 alkenyl group Chemical group 0.000 claims description 3
125000003282 alkyl amino group Chemical group 0.000 claims description 3
125000004414 alkyl thio group Chemical group 0.000 claims description 3
125000004104 aryloxy group Chemical group 0.000 claims description 3
125000000000 cycloalkoxy group Chemical group 0.000 claims description 3
125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 3
125000002723 alicyclic group Chemical group 0.000 claims description 2
125000001033 ether group Chemical group 0.000 claims description 2
125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 2
125000002541 furyl group Chemical group 0.000 claims description 2
125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
125000001715 oxadiazolyl group Chemical group 0.000 claims description 2
125000002971 oxazolyl group Chemical group 0.000 claims description 2
125000004430 oxygen atom Chemical group O* 0.000 claims description 2
125000003226 pyrazolyl group Chemical group 0.000 claims description 2
125000002098 pyridazinyl group Chemical group 0.000 claims description 2
125000004076 pyridyl group Chemical group 0.000 claims description 2
125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
125000000335 thiazolyl group Chemical group 0.000 claims description 2
125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
238000007327 hydrogenolysis reaction Methods 0.000 claims 1
238000006243 chemical reaction Methods 0.000 abstract description 12
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 abstract description 8
238000004132 cross linking Methods 0.000 abstract description 3
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
239000002904 solvent Substances 0.000 description 7
230000015572 biosynthetic process Effects 0.000 description 5
239000006227 byproduct Substances 0.000 description 5
238000006722 reduction reaction Methods 0.000 description 5
125000004432 carbon atom Chemical group C* 0.000 description 4
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 4
239000000047 product Substances 0.000 description 4
238000000746 purification Methods 0.000 description 4
238000003786 synthesis reaction Methods 0.000 description 4
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
239000003054 catalyst Substances 0.000 description 3
239000013078 crystal Substances 0.000 description 3
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
238000000354 decomposition reaction Methods 0.000 description 3
230000000694 effects Effects 0.000 description 3
125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
239000000203 mixture Substances 0.000 description 3
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 3
125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 3
238000007086 side reaction Methods 0.000 description 3
159000000000 sodium salts Chemical class 0.000 description 3
125000001424 substituent group Chemical group 0.000 description 3
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
206010007559 Cardiac failure congestive Diseases 0.000 description 2
208000010412 Glaucoma Diseases 0.000 description 2
206010019280 Heart failures Diseases 0.000 description 2
206010020772 Hypertension Diseases 0.000 description 2
201000001431 Hyperuricemia Diseases 0.000 description 2
208000001647 Renal Insufficiency Diseases 0.000 description 2
VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
238000004440 column chromatography Methods 0.000 description 2
238000007796 conventional method Methods 0.000 description 2
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
238000006264 debenzylation reaction Methods 0.000 description 2
239000001257 hydrogen Substances 0.000 description 2
229910052739 hydrogen Inorganic materials 0.000 description 2
239000012535 impurity Substances 0.000 description 2
201000006370 kidney failure Diseases 0.000 description 2
239000012046 mixed solvent Substances 0.000 description 2
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
229910052763 palladium Inorganic materials 0.000 description 2
125000006239 protecting group Chemical group 0.000 description 2
238000010992 reflux Methods 0.000 description 2
239000001632 sodium acetate Substances 0.000 description 2
235000017281 sodium acetate Nutrition 0.000 description 2
239000007787 solid Substances 0.000 description 2
239000000243 solution Substances 0.000 description 2
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
USVVENVKYJZFMW-ONEGZZNKSA-N (e)-carboxyiminocarbamic acid Chemical compound OC(=O)\N=N\C(O)=O USVVENVKYJZFMW-ONEGZZNKSA-N 0.000 description 1
125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
125000006039 1-hexenyl group Chemical group 0.000 description 1
125000006023 1-pentenyl group Chemical group 0.000 description 1
125000006017 1-propenyl group Chemical group 0.000 description 1
125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
238000005160 1H NMR spectroscopy Methods 0.000 description 1
125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
125000006024 2-pentenyl group Chemical group 0.000 description 1
125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 description 1
150000007579 7-membered cyclic compounds Chemical class 0.000 description 1
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
229940123413 Angiotensin II antagonist Drugs 0.000 description 1
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
238000005698 Diels-Alder reaction Methods 0.000 description 1
KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
238000005481 NMR spectroscopy Methods 0.000 description 1
229910002651 NO3 Inorganic materials 0.000 description 1
NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
JLCHNBRGUPQWKF-UHFFFAOYSA-J [OH-].[C+4].[OH-].[OH-].[OH-] Chemical compound [OH-].[C+4].[OH-].[OH-].[OH-] JLCHNBRGUPQWKF-UHFFFAOYSA-J 0.000 description 1
HMNQNULAYXDEEQ-UHFFFAOYSA-N acetic acid;hydroxylamine Chemical compound ON.CC(O)=O HMNQNULAYXDEEQ-UHFFFAOYSA-N 0.000 description 1
239000002253 acid Substances 0.000 description 1
230000001476 alcoholic effect Effects 0.000 description 1
229910052784 alkaline earth metal Inorganic materials 0.000 description 1
125000000304 alkynyl group Chemical group 0.000 description 1
229940024606 amino acid Drugs 0.000 description 1
239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
239000007864 aqueous solution Substances 0.000 description 1
229940009098 aspartate Drugs 0.000 description 1
239000002585 base Substances 0.000 description 1
239000012267 brine Substances 0.000 description 1
230000003197 catalytic effect Effects 0.000 description 1
239000003153 chemical reaction reagent Substances 0.000 description 1
239000003795 chemical substances by application Substances 0.000 description 1
229910052801 chlorine Inorganic materials 0.000 description 1
125000001309 chloro group Chemical group Cl* 0.000 description 1
238000010511 deprotection reaction Methods 0.000 description 1
KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical group [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 1
229940079593 drug Drugs 0.000 description 1
239000003814 drug Substances 0.000 description 1
125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
229910052731 fluorine Inorganic materials 0.000 description 1
125000001153 fluoro group Chemical group F* 0.000 description 1
125000003709 fluoroalkyl group Chemical group 0.000 description 1
229910052736 halogen Inorganic materials 0.000 description 1
150000002367 halogens Chemical class 0.000 description 1
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
229910000041 hydrogen chloride Inorganic materials 0.000 description 1
229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
239000012433 hydrogen halide Chemical class 0.000 description 1
229910000039 hydrogen halide Inorganic materials 0.000 description 1
229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
238000010253 intravenous injection Methods 0.000 description 1
229910052740 iodine Inorganic materials 0.000 description 1
239000011981 lindlar catalyst Substances 0.000 description 1
229910052744 lithium Inorganic materials 0.000 description 1
230000005923 long-lasting effect Effects 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
125000001624 naphthyl group Chemical group 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
125000001209 o-nitrophenyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])[N+]([O-])=O 0.000 description 1
238000006053 organic reaction Methods 0.000 description 1
230000003647 oxidation Effects 0.000 description 1
238000007254 oxidation reaction Methods 0.000 description 1
MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
229910003446 platinum oxide Inorganic materials 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
239000011591 potassium Substances 0.000 description 1
BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
239000002994 raw material Substances 0.000 description 1
238000003385 ring cleavage reaction Methods 0.000 description 1
238000010898 silica gel chromatography Methods 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
239000011734 sodium Substances 0.000 description 1
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
231100000419 toxicity Toxicity 0.000 description 1
230000001988 toxicity Effects 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
229920002554 vinyl polymer Polymers 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives

Definitions

the present invention relates to a process for producing an imidazole derivative. More particularly, the present invention relates to a process for producing an imidazole derivative useful for hypertension, congestive heart failure, renal failure, glaucoma, hyperuricemia and the like and an intermediate therefor.
the present inventors have aimed at angiotensin II antagonist as an agent for preventing or treating hypertension, congestive heart failure, renal failure, glaucoma, hyperuricemia and the like, and studied intensively the drugs which have longer shelf life, higher activity, rapid manifestation of action upon intravenous injection, good absorbability into the body upon oral administration, lower toxicity and long-lasting action.
angiotensin II antagonist as an agent for preventing or treating hypertension, congestive heart failure, renal failure, glaucoma, hyperuricemia and the like, and studied intensively the drugs which have longer shelf life, higher activity, rapid manifestation of action upon intravenous injection, good absorbability into the body upon oral administration, lower toxicity and long-lasting action.
novel imidazole derivatives having the hydrazine cross-linking structure represented by the formula:
the object of the present invention is to improve the selectivity on the reduction of C ring double bond of the above imidazole derivative in order to achieve the high yield even in mass production and exclude the necessity of complicated purification steps.
the Means to Solve the Problems In order to solve the above problems, the present inventors have studied intensively and, as a result, found that C ring double bond can be reduced selectively without the C ring cleavage reaction.
the present invention provides a process for producing an imidazole derivative represented by the formula (II):
R, R 1 , R 2 , R 3 , R 4 , R 5 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are as defined below, or a pharmacologically acceptable ester or salt thereof which comprises reacting a compound represented by the formula (I):
R 1 is hydrogen atom, lower alkyl group, lower alkoxy group, lower alkylthio group, lower alkylamino group, lower alkenyl group, -CF 3 group, aryl group or aralkyl group;
R is hydrogen atom, or a group selected from the group consisting of
X is -CH 2 -, -NR'-, oxygen atom or -S(0) n -, wherein R' is hydrogen atom or lower alkyl group, wherein n is 0, 1 or 2; wherein X , X 2 and X are independently hydrogen atom, halogen atom, lower alkyl group, lower alkoxy group, nitro group, cyano group, lH-tetrazol-5-yl group or alkali metal salt thereof, -C0 2 R 7 group, -CONR'R" group, -C0NHS0 2 R 8 group, amino group, -NHS0 2 CF 3 group or -S0 3 H group, or a group selected from the group consisting of
Y is lH-tetrazol-5-yl group or alkali metal salt thereof optionally substituted with cyano group, benzyl group, tosyl group, methoxymethyl group, ethoxymethyl group, n methoxyethoxymethyl group or trimethylsilylethoxymethyl group, -C0 2 R group, -CONR'R" group, -CONHS0 2 R 8 group, amino group, -NHS0 2 CF 3 group or -S0 3 H group;
R 6 is hydrogen atom, halogen atom, lower alkyl group, -CF 3 group or -CF 2 CF 3 group;
R 7 is hydrogen atom, alkali metal atom or lower alkyl group
R' and R" are independently hydrogen atom or lower alkyl group, or R' and R" are taken together to form the alicyclic structure;
R 8 is lower alkyl group, cycloalkyl group or aryl group
R 9 is lower alkyl group, lower alkoxy group, cycloalkyl group, cycloalkoxy group, aryl group or aryloxy group;
R , R 11 and R are independently hydrogen atom, halogen atom, lower alkyl group, lower alkoxy group, nitro group, cyano group, -C0 2 R 7 group or -CONR'R" group;
R there are the alkyls having 1 to 8 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like.
R 1 As the lower alkoxy group represented by R 1 , there are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentoxy, isoamyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy and the like.
R 1 As the lower alkylthio group represented by R 1 , there are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, n- pentylthio, n-hexylthio, n-heptylthio, n-octylthio and the like.
R 1 there are methylamino, dimethylamino, ethylamino, diethylamino, n- propylamino, di(n-propyl)amino, isopropylamino, n-butylamino, n-pentylamino, pyrrolidino, piperidino, piperazino, morpholino and the like.
R As the lower alkenyl group represented by R , there are vinyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 1-heptenyl, 1-octenyl and the like.
R 1 As the lower alkynyl group represented by R 1 , there are acetylene group, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1- pentynyl, 2-pentynyl, 1-hexynyl, 1-heptynyl, 1-octynyl and the like.
aryl group or aralkyl group represented by R 1 there are aryl or aralkyl group having 6 to 10 carbon atoms, for example, phenyl, naphthyl, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl and the like. These aryl and aralkyl groups are optionally substituted with the substituent(s) such as the above described lower alkyl group, or lower alkoxy group, halogen atom, nitro group, cyano group and the like.
R is substituted or unsubstituted phenylmethyl group
halogen atom defined by X 1 , X and X 3
fluorine atom chlorine atom, bromine atom and iodine atom.
lower alkyl group and lower alkoxy group there are above defined lower alkyl group and alkoxy group.
X 1 , X 2 and X 3 are lH-tetrazol-5-yl group, as the alkali metal salt thereof, there are sodium salt, potassium salt and the like.
R 7 when X 1 , X 2 and X 3 are -C0 2 R 7 group, as the examples of R 7 in the group, there are hydrogen atom, alkali metal atom such as lithium, sodium, potassium and the like, alcohol ester of the above defined lower alkyl group.
R 7 alkali metal atom
X 1 , X 2 and X 3 are -CONR'R"
the examples of -NR'R" in the group there are amino, methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, di(n-propyl)amino, diisopropylamino, dibutylamino, pyrrolidyl, piperazino, morpholino and the like.
R 8 in -CONHS0 2 R group there are methyl, trifluoromethyl, ethyl, n-propyl, n- butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl and the like.
X 1 , X 2 and X 3 are the group selected from the following:
R 9 is cycloalkyl group or cycloalkoxy group
the examples are 5 to 7 membered cyclic compounds such as cyclopentyl, cyclohexyl, cyclopentyl and the like.
aryl group or aryloxy group represented by R 9 there are substituted or unsubstituted phenyl compounds such as phenyl, p-hydroxyphenyl, p- carboxyphenyl, o-nitrophenyl and the like.
the example of halogen and lower alkyl group represented by R 6 the examples of alkali metal salts of lH-tetrazol-5-yl represented by Y, and the examples of R 7 , NR'R" and R 8 in -C0 2 R 7 group, -CONR'R" group or -CONHS0 2 R 8 group represented by Y are as defined above.
R 2 , R , R 4 and R 5 are lower alkyl group
the examples of them are the alkyl groups having 1 to 8 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl; isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like.
R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are lower alkyl group
the example of them are the alkyls having 1 to 8 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isoamyl, n-hexyl, n-heptyl, n-octyl and the like.
R , R , R , R , R and R are lower fiuoroalkyl group, the examples of them are trifluoromethyl, 2,2,2,-trifluoroethyl, pentafluoroethyl and the like.
R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are -(CH 2 )j-C0 2 R 7 , -C(R')(R")-OR 19 , or -(CH 2 )j-CONR'R'"
the examples of R 7 , R' and R" are as defined above.
the diimide used in the process of the present invention can be generated by various methods, for example, by oxidation of hydrazine, decomposition of the dipotassium salt of azodicarboxylic acid by an acid, the decomposition of arylsulfohydrazide by a base, the hydroxylamine-acetic acid ester method, and the like (Organic Reactions, 40, 91-155 (1991)).
the use of decomposition of p-toluenesulfohydrazide by sodium acetate is suitable in view of simplicity of the operations and high safety.
the reaction between the diimide and the compound of the general formula (I) proceeds effectively at room temperature to 120 °C.
the reaction is carried out in a solvent.
a solvent there are the alcoholic solvents such as methanol, ethanol, propanol and the like, and the etheric solvent such as tetrahydrofuran, dimethoxyethane and the like.
the alcoholic solvents such as methanol, ethanol, propanol and the like
the etheric solvent such as tetrahydrofuran, dimethoxyethane and the like.
R is a protecting group such as benzyl group and the like
the reduced product is reacted in methanol in the presence of the catalytic amount of 20 % palladium hydroxide-carbon under 1 to 3 atmospheric pressure hydrogen by a conventional method to easily effect the deprotection such as debenzylation and the like. Therefore, a process of the present invention is also useful for preparing an intermediate (4) for synthesis (see the above Reaction Scheme).
the end imidazole derivative (5) can be obtained as crystals almost without side products by attaching the biphenyltetrazole part to the intermediate according to the method described in JP- A 3-277537, JP-A 3-323474, JP-A 4-095191 and JP-A 4-216809 and WO 93/08193 (see the above Reaction Scheme).
the purification by column chromatography which was indispensable to the previous process becomes unnecessary, and it was found that the present process can be applied to the mass production in the good reproductivity.
the compounds produced by the present process can be converted into the ester or salt thereof by a conventional method.
the esters or salts are pharmacologically acceptable and non-toxic ones.
Suitable esters include esters of lower alcohol having a straight or branched chain such as methanol, ethanol and the like.
Suitable salts include alkali metal salts such as sodium salt, potassium salt and the like, and alkaline earth metal salts, hydrogen halide salts such as hydrogen fluoride, hydrogen chloride and the like, inorganic acid salts such as nitrate, sulfate and the like, lower alkylsulfonate salts such as methanesulfonate and the like, organic acid salts such as maleate, fumarate and the like, and amino acid salts such as aspartate and the like.
the mixture was cooled to room temperature, further cooled to 0 °C, and the precipitated crystals were filtered.
the crystals were dissolved in methylene chloride, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.

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EP94910736A 1993-03-19 1994-03-04 Verfahren zur herstellung imidazol-derivate Withdrawn EP0689544A1 (de)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
JP5060067A JPH06271576A (ja)	1993-03-19	1993-03-19	イミダゾール誘導体の製法
JP60067/93		1993-03-19
PCT/US1994/001949 WO1994021641A1 (en)	1993-03-19	1994-03-04	Process for production of an imidazole derivative

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EP (1)	EP0689544A1 (de)
JP (2)	JPH06271576A (de)
CN (1)	CN1120337A (de)
AU (1)	AU6351994A (de)
CA (1)	CA2155573A1 (de)
NZ (1)	NZ263008A (de)
WO (1)	WO1994021641A1 (de)

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ATE146474T1 (de) *	1991-09-10	1997-01-15	Tanabe Seiyaku Co	Imidazoindolizinderivate mit angiotensin-ii hemmwirkung
JPH06107661A (ja) *	1991-10-24	1994-04-19	Upjohn Co:The	イミダゾール誘導体およびこれを有効成分とする医薬組成物

1993
- 1993-03-19 JP JP5060067A patent/JPH06271576A/ja active Pending
1994
- 1994-03-04 AU AU63519/94A patent/AU6351994A/en not_active Abandoned
- 1994-03-04 CN CN94191674A patent/CN1120337A/zh active Pending
- 1994-03-04 WO PCT/US1994/001949 patent/WO1994021641A1/en not_active Ceased
- 1994-03-04 JP JP6521039A patent/JPH08508468A/ja active Pending
- 1994-03-04 NZ NZ263008A patent/NZ263008A/en unknown
- 1994-03-04 EP EP94910736A patent/EP0689544A1/de not_active Withdrawn
- 1994-03-04 CA CA002155573A patent/CA2155573A1/en not_active Abandoned

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Title
See references of WO9421641A1 *

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AU6351994A (en)	1994-10-11
JPH06271576A (ja)	1994-09-27
CA2155573A1 (en)	1994-09-29

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