CS255893B2 - Process for preparing pyridazo/1,2-a//1,2/diazepin-,diazocin-and-triazepin-1-carboxylic acids - Google Patents

Process for preparing pyridazo/1,2-a//1,2/diazepin-,diazocin-and-triazepin-1-carboxylic acids Download PDF

Info

Publication number: CS255893B2
Authority: CS; Czechoslovakia
Prior art keywords: formula; compound; pyridazo; group; dioxo
Prior art date: 1984-08-24

Application number

CS855928A

Other languages

Czech (cs)

English (en)

Other versions

CS592885A2 (en

Inventor

Cedric H Hassall

Geoffrey Lawton

Sally Redshaw

Original Assignee

Hoffmann La Roche

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.)

1984-08-24

Filing date

1985-08-15

Publication date

1988-03-15

1984-08-24 Priority claimed from GB848421493A external-priority patent/GB8421493D0/en

1985-08-15 Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche

1987-07-16 Publication of CS592885A2 publication Critical patent/CS592885A2/cs

1988-03-15 Publication of CS255893B2 publication Critical patent/CS255893B2/cs

Links

238000004519 manufacturing process Methods 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims description 119
238000000034 method Methods 0.000 claims description 30
239000002253 acid Substances 0.000 claims description 27
239000000203 mixture Substances 0.000 claims description 23
150000003839 salts Chemical class 0.000 claims description 22
125000000217 alkyl group Chemical group 0.000 claims description 21
239000007858 starting material Substances 0.000 claims description 14
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 12
125000004432 carbon atom Chemical group C* 0.000 claims description 10
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
239000001257 hydrogen Substances 0.000 claims description 9
229910052739 hydrogen Inorganic materials 0.000 claims description 9
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
125000003118 aryl group Chemical group 0.000 claims description 5
229910052736 halogen Inorganic materials 0.000 claims description 5
LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 claims description 4
150000007513 acids Chemical class 0.000 claims description 4
125000003435 aroyl group Chemical group 0.000 claims description 4
125000003710 aryl alkyl group Chemical group 0.000 claims description 4
QRKPPWPLSQRGSU-UHFFFAOYSA-N diazepine-1-carboxylic acid Chemical class OC(=O)N1C=CC=CC=N1 QRKPPWPLSQRGSU-UHFFFAOYSA-N 0.000 claims description 4
238000002360 preparation method Methods 0.000 claims description 4
125000001424 substituent group Chemical group 0.000 claims description 4
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
230000003287 optical effect Effects 0.000 claims description 3
125000001589 carboacyl group Chemical group 0.000 claims description 2
125000005843 halogen group Chemical group 0.000 claims description 2
125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
238000006243 chemical reaction Methods 0.000 description 46
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
239000000243 solution Substances 0.000 description 39
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
-1 P-tolyl Chemical group 0.000 description 27
239000002585 base Substances 0.000 description 25
UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 24
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 19
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
239000007787 solid Substances 0.000 description 18
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
239000003960 organic solvent Substances 0.000 description 15
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
229910000085 borane Inorganic materials 0.000 description 13
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
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239000000741 silica gel Substances 0.000 description 12
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ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 11
239000003480 eluent Substances 0.000 description 11
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
125000004043 oxo group Chemical group O=* 0.000 description 10
238000007363 ring formation reaction Methods 0.000 description 10
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ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
150000008282 halocarbons Chemical class 0.000 description 9
125000006239 protecting group Chemical group 0.000 description 9
239000003054 catalyst Substances 0.000 description 8
229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
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229910052783 alkali metal Inorganic materials 0.000 description 7
238000010992 reflux Methods 0.000 description 7
239000002904 solvent Substances 0.000 description 7
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
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LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 6
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
238000001704 evaporation Methods 0.000 description 6
230000008020 evaporation Effects 0.000 description 6
125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
229960000583 acetic acid Drugs 0.000 description 5
150000001408 amides Chemical class 0.000 description 5
239000000908 ammonium hydroxide Substances 0.000 description 5
238000003776 cleavage reaction Methods 0.000 description 5
125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
230000007017 scission Effects 0.000 description 5
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
108010064733 Angiotensins Proteins 0.000 description 4
102000015427 Angiotensins Human genes 0.000 description 4
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
125000001931 aliphatic group Chemical group 0.000 description 4
229910000288 alkali metal carbonate Inorganic materials 0.000 description 4
150000008041 alkali metal carbonates Chemical class 0.000 description 4
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
239000002775 capsule Substances 0.000 description 4
150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
150000002367 halogens Chemical group 0.000 description 4
239000012074 organic phase Substances 0.000 description 4
UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 4
239000000126 substance Substances 0.000 description 4
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 3
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GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
150000008044 alkali metal hydroxides Chemical class 0.000 description 3
150000008064 anhydrides Chemical class 0.000 description 3
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 3
238000009835 boiling Methods 0.000 description 3
238000004587 chromatography analysis Methods 0.000 description 3
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
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239000000454 talc Substances 0.000 description 3
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AAXWBCKQYLBQKY-IRXDYDNUSA-N (2s)-2-[[(2s)-2-[(2-benzamidoacetyl)amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-4-methylpentanoic acid Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)C=1C=CC=CC=1)C1=CN=CN1 AAXWBCKQYLBQKY-IRXDYDNUSA-N 0.000 description 2
CMLRAMXYITUETH-UHFFFAOYSA-N 1-o-benzyl 3-o-tert-butyl piperazine-1,3-dicarboxylate Chemical compound C1CNC(C(=O)OC(C)(C)C)CN1C(=O)OCC1=CC=CC=C1 CMLRAMXYITUETH-UHFFFAOYSA-N 0.000 description 2
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
SYZRZLUNWVNNNV-UHFFFAOYSA-N 2-bromoacetyl chloride Chemical compound ClC(=O)CBr SYZRZLUNWVNNNV-UHFFFAOYSA-N 0.000 description 2
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XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
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AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
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QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
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QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
125000002252 acyl group Chemical group 0.000 description 2
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150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
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UORVGPXVDQYIDP-BJUDXGSMSA-N borane Chemical class [10BH3] UORVGPXVDQYIDP-BJUDXGSMSA-N 0.000 description 2
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
239000007795 chemical reaction product Substances 0.000 description 2
239000003795 chemical substances by application Substances 0.000 description 2
239000000460 chlorine Substances 0.000 description 2
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239000012230 colorless oil Substances 0.000 description 2
239000013078 crystal Substances 0.000 description 2
MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 description 2
150000004292 cyclic ethers Chemical class 0.000 description 2
RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 2
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
150000004820 halides Chemical class 0.000 description 2
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108010016268 hippuryl-histidyl-leucine Proteins 0.000 description 2
239000010410 layer Substances 0.000 description 2
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 2
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239000000047 product Substances 0.000 description 2
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UOUFRTFWWBCVPV-UHFFFAOYSA-N tert-butyl 4-(2,4-dioxo-1H-thieno[3,2-d]pyrimidin-3-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)n1c(=O)[nH]c2ccsc2c1=O UOUFRTFWWBCVPV-UHFFFAOYSA-N 0.000 description 2
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125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
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ZMRRQTHZWIKVLN-UHFFFAOYSA-N 1h-diazocine-2-carboxylic acid Chemical compound OC(=O)N1C=CC=CC=CN1 ZMRRQTHZWIKVLN-UHFFFAOYSA-N 0.000 description 1
JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 description 1
LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 1
YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 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
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
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IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
238000000926 separation method Methods 0.000 description 1
239000011734 sodium Substances 0.000 description 1
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239000000829 suppository Substances 0.000 description 1
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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
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Peptides Or Proteins (AREA)

CS855928A 1984-08-24 1985-08-15 Process for preparing pyridazo/1,2-a//1,2/diazepin-,diazocin-and-triazepin-1-carboxylic acids CS255893B2 (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
GB848421493A GB8421493D0 (en)	1984-08-24	1984-08-24	Bicyclic compounds
GB858513541A GB8513541D0 (en)	1984-08-24	1985-05-29	Bicyclic compounds

Publications (2)

Publication Number	Publication Date
CS592885A2 CS592885A2 (en)	1987-07-16
CS255893B2 true CS255893B2 (en)	1988-03-15

Family

ID=26288155

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CS855928A CS255893B2 (en)	1984-08-24	1985-08-15	Process for preparing pyridazo/1,2-a//1,2/diazepin-,diazocin-and-triazepin-1-carboxylic acids

Country Status (14)

Country	Link
US (4)	US4692438A (da)
EP (1)	EP0172552A3 (da)
AU (1)	AU583843B2 (da)
CS (1)	CS255893B2 (da)
DK (1)	DK384385A (da)
ES (3)	ES8700258A1 (da)
FI (1)	FI853174A7 (da)
HU (1)	HU193446B (da)
IL (1)	IL76133A (da)
MC (1)	MC1694A1 (da)
NO (1)	NO161914C (da)
NZ (1)	NZ213130A (da)
PH (1)	PH21749A (da)
PT (1)	PT81015B (da)

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4692438A (en) *	1984-08-24	1987-09-08	Hoffmann-La Roche Inc.	Pyridazo-diazepines, diazocines, and -triazepines having anti-hypertensive activity
ZW11586A1 (en) *	1985-07-01	1987-12-30	Hoffmann La Roche	Bicyclic compounds
GB8629875D0 (en) *	1986-12-15	1987-01-28	Hoffmann La Roche	Pyridazodiazepine derivatives
US5430145A (en) *	1990-10-18	1995-07-04	Merrell Dow Pharmaceuticals Inc.	Mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace
US5308841A (en) *	1990-12-21	1994-05-03	Merrell Dow Pharmaceuticals Inc.	Amino and nitro containing tricyclic compounds useful as inhibitors of ACE
US5455242A (en) *	1991-09-27	1995-10-03	Merrell Dow Pharmaceuticals Inc.	Carboxyalkyl tricyclic derivatives useful as inhibitors of enkephalinase and ace
ATE155143T1 (de) *	1991-09-27	1997-07-15	Merrell Pharma Inc	2-substituierte indan-2-mercaptoacetylamid- verbindungen mit enkephalinase und ace- hemmwirkung
US5457196A (en) *	1991-09-27	1995-10-10	Merrell Dow Pharmaceuticals Inc.	2-substituted indane-2-carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE
DE69317764T2 (de) *	1992-02-14	1998-07-30	Merrell Pharmaceuticals Inc., Cincinnati, Ohio	Aminoacetylmercaptoacetylamid derivate mit enkephalinase- und ace-hemmwirkung
ATE182892T1 (de) *	1992-05-15	1999-08-15	Merrell Pharma Inc	Mercaptoacetylamide von pyridazo(1,2-a>(1,2>- diazepin -derivaten als eukephalinase und ace- inhibitoren
US5420271A (en) *	1992-08-24	1995-05-30	Merrell Dow Pharmaceuticals, Inc.	2-substituted indane-2-mercaptoacetylamide tricyclic derivatives useful as inhibitors of enkephalinase
PT669936E (pt) *	1992-10-30	2001-04-30	Merrell Pharma Inc	Derivados de lactama biciclica de mercaptoacetilamida uteis como inibidores de encefalinase e de ace
WO1994022440A1 (en) *	1993-03-29	1994-10-13	Smithkline Beecham Corporation	Bicyclic compounds which inhibit platelet aggregation
CA2183313C (en) *	1994-02-14	2001-01-02	Gary A. Flynn	Novel indane-2-mercaptoacetylamide disulfide derivatives useful as inhibitors of enkephalinase
PT750631E (pt) *	1994-02-14	2000-07-31	Merrell Pharma Inc	Novos derivados de dissulfureto de mercapto-aacetilamido-1,3,4,5-tetra-hidro-benzo¬c)azepin-3-ona uteis como inibidores de encefalinase e ace
JP3561753B2 (ja) *	1994-02-14	2004-09-02	メレルファーマスーティカルズインコーポレーテッド	エンケファリナーゼ及びａｃｅの阻害剤として有用な、新規な２−置換インダン−２−メルカプトアセチルアミドジスルフィド誘導体類
JP3596778B2 (ja) *	1994-02-14	2004-12-02	メレルファーマスーティカルズインコーポレーテッド	エンケファリナーゼ及びａｃｅの阻害剤として有用な、新規なメルカプトアセチルアミドジスルフィド誘導体類
US5530013A (en) *	1994-02-14	1996-06-25	American Home Products Corporation	Venlafaxine in the inducement of cognition enhancement
US5484783A (en) *	1994-03-24	1996-01-16	Merrell Dow Pharmaceuticals Inc.	Hypocholesterolemic, antiatherosclerotic and hypotriglyceridemic mercaptoacetylamide and benzazapine derivatives
PT751783E (pt) *	1994-03-24	2000-05-31	Merrell Pharma Inc	Derivados aminoacetilmercapto hipocolesterolemicos antiateroscleroticos e hipotrigliceridemicos
ATE246927T1 (de) *	1994-03-24	2003-08-15	Merrell Pharma Inc	Cholesterin senkende mercaptoacetylamiddisulfidderivate
US6177565B1 (en) *	1998-08-19	2001-01-23	Vertex Pharmaceuticals Inc.	Process for synthesizing piperazic acid
US6559304B1 (en)	1998-08-19	2003-05-06	Vertex Pharmaceuticals Incorporated	Method for synthesizing caspase inhibitors
US6703500B2 (en)	1998-08-19	2004-03-09	Vertex Pharmaceuticals, Incorporated	Method of preparing bicyclic intermediates from piperazic acid or an ester thereof useful in the manufacture of caspase inhibitors
RU2002135314A (ru)	2000-05-04	2004-05-27	Вертекс Фармасьютикалз Инкорпорейтед (Us)	Асимметричный синтез пиперазиновой кислоты и ее производных
GB0119305D0 (en)	2001-04-12	2001-10-03	Aventis Pharma Gmbh	Mercaptoacetylamide derivatives,a process for their preparation and their use
WO2010010427A1 (en) *	2008-07-25	2010-01-28	Chuluun Enkhbold	A method of solid fuel beneficiation and transportation to thermoelectric power stations
ES2546866T3 (es)	2009-12-16	2015-09-29	Hetero Research Foundation	Polimorfos de darunavir
EP2571355B1 (en)	2010-05-20	2016-09-07	Hetero Research Foundation	Crystalline hydrochloride salt of darunavir

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4308094A (en) *	1977-02-02	1981-12-29	Sanyo Electric Co., Ltd.	Diaphragm for speaker and method of producing same
IL60617A0 (en) *	1979-07-23	1980-09-16	Sparamedica Ag	Triazolopyridazine derivative,their preparation and pharmaceutical compositions containing them
EP0025941B1 (de) *	1979-09-19	1983-05-04	F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft	Pyridazopyridazinderivate, Verfahren zu deren Herstellung und Arzneimittel enthaltend solche Pyridazopyridazinderivate
EP0042100A1 (de) *	1980-06-13	1981-12-23	F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft	Pyrazolopyridazin-Derivate, Zwischenprodukte und Verfahren zu deren Herstellung, sowie diese enthaltende Arzneimittel
GB2128984B (en) *	1982-05-12	1985-05-22	Hoffmann La Roche	Diaza-bicyclic compounds
US4692438A (en) *	1984-08-24	1987-09-08	Hoffmann-La Roche Inc.	Pyridazo-diazepines, diazocines, and -triazepines having anti-hypertensive activity

1985
- 1985-08-12 US US06/764,372 patent/US4692438A/en not_active Expired - Fee Related
- 1985-08-15 CS CS855928A patent/CS255893B2/cs unknown
- 1985-08-16 NZ NZ213130A patent/NZ213130A/en unknown
- 1985-08-19 EP EP85110370A patent/EP0172552A3/de not_active Withdrawn
- 1985-08-19 FI FI853174A patent/FI853174A7/fi not_active Application Discontinuation
- 1985-08-19 AU AU46415/85A patent/AU583843B2/en not_active Ceased
- 1985-08-19 IL IL76133A patent/IL76133A/xx unknown
- 1985-08-21 MC MC851791A patent/MC1694A1/fr unknown
- 1985-08-21 PH PH32671A patent/PH21749A/en unknown
- 1985-08-21 HU HU853187A patent/HU193446B/hu not_active IP Right Cessation
- 1985-08-23 DK DK384385A patent/DK384385A/da not_active Application Discontinuation
- 1985-08-23 PT PT81015A patent/PT81015B/pt unknown
- 1985-08-23 ES ES546360A patent/ES8700258A1/es not_active Expired
- 1985-08-23 NO NO853336A patent/NO161914C/no unknown
1986
- 1986-02-17 ES ES552398A patent/ES8705444A1/es not_active Expired
- 1986-02-17 ES ES552397A patent/ES8705443A1/es not_active Expired
1987
- 1987-05-11 US US07/048,172 patent/US4785093A/en not_active Expired - Fee Related
- 1987-06-15 US US07/062,033 patent/US4762924A/en not_active Expired - Fee Related
1988
- 1988-07-12 US US07/217,805 patent/US4826980A/en not_active Expired - Fee Related

Also Published As

Publication number	Publication date
ES8705444A1 (es)	1987-05-01
NZ213130A (en)	1988-05-30
US4826980A (en)	1989-05-02
IL76133A0 (en)	1985-12-31
US4692438A (en)	1987-09-08
ES8700258A1 (es)	1986-10-01
MC1694A1 (fr)	1986-07-18
NO853336L (no)	1986-02-25
AU583843B2 (en)	1989-05-11
FI853174L (fi)	1986-02-25
HUT38644A (en)	1986-06-30
FI853174A7 (fi)	1986-02-25
PH21749A (en)	1988-02-18
EP0172552A3 (de)	1989-01-11
PT81015B (en)	1987-08-24
PT81015A (en)	1985-09-01
US4785093A (en)	1988-11-15
NO161914B (no)	1989-07-03
HU193446B (en)	1987-10-28
ES552397A0 (es)	1987-05-01
DK384385A (da)	1986-02-25
FI853174A0 (fi)	1985-08-19
ES552398A0 (es)	1987-05-01
DK384385D0 (da)	1985-08-23
AU4641585A (en)	1986-02-27
US4762924A (en)	1988-08-09
EP0172552A2 (de)	1986-02-26
ES8705443A1 (es)	1987-05-01
ES546360A0 (es)	1986-10-01
CS592885A2 (en)	1987-07-16
IL76133A (en)	1989-12-15
NO161914C (no)	1989-10-11

Publication	Publication Date	Title
US4762924A (en)	1988-08-09	Bicyclic compounds
KR100265529B1 (ko)	2000-11-01	고지혈증 치료에 유용한 벤조티아제핀 화합물
EP0711280B1 (fr)	1998-09-23	Derives de perhydroisoindole comme antagonistes de la substance p
EP0135349B1 (en)	1988-11-02	Condensed seven-membered ring compounds and their production and use
EP0565396B1 (fr)	1998-01-07	Dérivés de 1-[2-(arylsulfonylamino)-1-oxoéthyl]pipéridine, leur préparation et leur application en thérapeutique
EP0147719A2 (en)	1985-07-10	Novel carbostyril derivative and process for preparing same
EP0054951A1 (en)	1982-06-30	Dibenz(b,f)(1,4)oxazepine derivatives, process for preparing the same, and pharmaceutical compositions comprising the same
HU199842B (en)	1990-03-28	Process for producing pyridazodiazepines and pharmaceutical compositions comprising same
MC1390A1 (fr)	1982-04-27	Derives de pyrazolopyridazine,procede pour leur preparation et compositions pharmaceutiques les contenant
EP0158339B1 (en)	1989-01-18	1,5-benzothiazephine derivatives, processes for preparing the same and pharmaceutical compositions
EP0421861A1 (fr)	1991-04-10	Dérivés d'hydroxy-2 thiophène et furanne condensés avec un cycle azoté, leur procédé de préparation et leur application en thérapeutique
SI9111318A (en)	1997-10-31	Acetamide derivatives
HK32689A (en)	1989-04-28	2-oxo-imidazolidine compounds, a process for preparing the same and a pharmaceutical composition
US4970297A (en)	1990-11-13	Transglutaminase inhibitors
FR2618150A1 (fr)	1989-01-20	Benzazepines 3-substituees a action therapeutique
FR2758329A1 (fr)	1998-07-17	Derives d'imidazole-4-butane boronique, leur preparation et leur utilisation en therapeutique
EP0556119B1 (fr)	1997-05-14	Dérivés de pyrrolidine portant en position 3 un groupe acide gras saturé ou non-saturé, procédé pour leur préparation et compositions pharmaceutiques ayant une activité d'inhibiteurs de thromboxane-A2 les contenant
EP0384843B1 (fr)	1994-08-31	Dérivés de la 1-arylsulfonyl 2-pipéridinone, leur procédé et les intermédiaires de préparation, leur application comme médicaments et les compositions les renfermant
FR2468589A1 (fr)	1981-05-08	Derives aminoacyles de mercaptoacyl amino-acides, a action antihypertensive
EP0719766A1 (en)	1996-07-03	1,4-Benzoxazine derivative, pharmaceutical composition containing the same and use thereof
CA2109774A1 (fr)	1994-05-25	Derives du pyrrole, leur preparation et leur application therapeutique
MC1562A1 (fr)	1984-11-12	Phenothiazines,leur procede de preparation et produits en contenant
KR100306018B1 (ko)	2001-11-30	약리학적 활성을 갖는 에난티오머
EP0335758A2 (fr)	1989-10-04	Dérivés de la 1-arylsulfonyl 2-pyrrolidinone, leur procédé de préparation, leur application comme médicaments et les compositions les renfermant
FR2639946A1 (fr)	1990-06-08	Peptides contenant de l'imidazole, leurs procedes de preparation et compositions pharmaceutiques les contenant