TWI281468B - Antibacterials - Google Patents
Antibacterials Download PDFInfo
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- TWI281468B TWI281468B TW089114436A TW89114436A TWI281468B TW I281468 B TWI281468 B TW I281468B TW 089114436 A TW089114436 A TW 089114436A TW 89114436 A TW89114436 A TW 89114436A TW I281468 B TWI281468 B TW I281468B
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- aromatic
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- 230000000844 anti-bacterial effect Effects 0.000 title description 3
- 229940088710 antibiotic agent Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 131
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 56
- 239000001257 hydrogen Substances 0.000 claims description 56
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 34
- -1 2-Amino-isobutylcarbonyl Chemical group 0.000 claims description 29
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 26
- 125000000623 heterocyclic group Chemical group 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 21
- 229920000832 Cutin Polymers 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
- 125000003277 amino group Chemical group 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 9
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- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 8
- 241000894006 Bacteria Species 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
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- 239000001301 oxygen Chemical group 0.000 claims description 6
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- 229930182555 Penicillin Natural products 0.000 claims description 5
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 5
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- 239000001307 helium Substances 0.000 claims description 5
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- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 claims description 3
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- 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 8
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- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
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- 206010035664 Pneumonia Diseases 0.000 description 1
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- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 description 1
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- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003103 anti-anaerobic effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 238000009635 antibiotic susceptibility testing Methods 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 150000001621 bismuth Chemical class 0.000 description 1
- FLJPGEWQYJVDPF-UHFFFAOYSA-L caesium sulfate Chemical compound [Cs+].[Cs+].[O-]S([O-])(=O)=O FLJPGEWQYJVDPF-UHFFFAOYSA-L 0.000 description 1
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- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- QBWCMBCROVPCKQ-UHFFFAOYSA-N chlorous acid Chemical compound OCl=O QBWCMBCROVPCKQ-UHFFFAOYSA-N 0.000 description 1
- 229940077239 chlorous acid Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 1
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- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 1
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- 229940032049 enterococcus faecalis Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
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- 239000008273 gelatin Substances 0.000 description 1
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- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
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- 230000002401 inhibitory effect Effects 0.000 description 1
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- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- XVDBWWRIXBMVJV-UHFFFAOYSA-N n-[bis(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)N(C)C XVDBWWRIXBMVJV-UHFFFAOYSA-N 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- HXEACLLIILLPRG-UHFFFAOYSA-N pipecolic acid Chemical compound OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 description 1
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- 238000002953 preparative HPLC Methods 0.000 description 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
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- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000001054 red pigment Substances 0.000 description 1
- 238000007430 reference method Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
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- 229960002771 retapamulin Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
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- 239000002689 soil Substances 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
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- 239000000725 suspension Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 150000004992 toluidines Chemical class 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
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- 229910052727 yttrium Inorganic materials 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/54—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D233/24—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
- C07C2603/80—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Pyrrole Compounds (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Quinoline Compounds (AREA)
- Pyridine Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
R I x = c 經濟部智慧財產局員工消費合作社印製 1281468
五、發明說明(2 R5爲氫或燒基; R3及爲氫或氘;
Re,R7及Rs爲氫或氘;或 R及R2與相接之氮原子—起形 式之基 芳秩^入雜環基,I爲下 其中X及R9如上述定義。 R爲氫或烷基,例如(Cl 4)烷基;較佳爲氫。
Ri爲氳或式-C(一x)r9之基’例如式_c(=x)R9之基。 X爲μ氧NR10 ’其中Ri〇爲氫或烷基,例如(〔μ)垸 基或N (R 10)2 ’其中κ·ι〇爲烷基,例如(D燒基,在一個 適當陰離子存在下;較佳爲氧。 I爲胺基,烷基,烷氧基,例如(Ci 4)烷氧基;芳基, 雜環基,或巯基;例如式_s_Ru之基,其中Ri2爲烷基,例 如(Cl_4)烷基;若X爲氧,則I爲氫,胺基,烷基,烷氧 基,芳基,雜環基,或巯基。 %較佳爲烷基,例如(C1-8)烷基,如(Cm)烷基,例如未 經取代或經取代之纪基,例如經截短側耳素(pleur〇mutiHn) 化學中習知之基,例如一或多個胺基,鹵素,如氟,取 代,例如三氟烷基,如三氟甲基;胍基,羥基,雜環基, 例如包括5或6員環含有1或2個氮原子,例如咪峻基。若 -5- 本紙張尺度迺用中國國家標準(CNS)A4規格(210 X 297公爱) " 一
1281468 A7
經濟部智慧財產局員工消費合作社印製 R9爲經胺基取代之烷基,R9較佳爲一種胺基酸(例如包括 纈胺酸,組胺酸,精胺酸,2-羧六氫p比淀)之殘基,例如 該殘基包括一種胺基酸之羧基裂解所保留之部份。 或R9較佳爲雜環基,例如5或6員雜環基,例如含有一 或二個雜原子,例如選自氮;例如與另一環(系統)縮合, 例如該另一環系統包括苯基;較佳爲六氫吡啶基,峨哈淀 基,吡咯基,吡啶基,苯幷咪唑基,喹琳基,三峻基;例 如未經取代之雜環基或經取代之雜環基,例如經一或多個 烷基(例如甲基),羥基,胺基,硝基,coor13基取代,其 中Ri3爲烷基,例如(Cw)烷基,如第三丁基;例如較佳經 一或個烷基,羥基,胺基,硝基取代。 若R9爲雜環基’例如六氫ρ比淀基,則該雜環基(例如六 氫p比淀基)之氫原子,接於該環系統之氮原子之氫原子可 以氘替代。 R9定義中胺基包括自由胺基,燒基及二燒基胺基,及胺 基經-COORu取代,其中Ru爲烷基,較佳(Cm)烷基。 R2爲次芳基,如次苯基,例如未經取代或經取代之次芳 基,例如經截短側耳素(pleuromutilin)化學中習知之基,例 如一或多個經基,燒基,例如(Ci—4)燒基;鹵素,例如 氟;三氟燒基;硝基取代;或次雜環基。本文中所用之次 雜環基爲二個鍵結合式I化合物中相鄰氮及硫基之雜環。 R2較佳爲次芳基,例如未經取代之次芳基’或經一或多個 截短側耳素化學中習知之基,例如烷基,例如嫁 基,如甲基;卣素,如氟;三氟烷基,如三氟甲基,取 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) --------^---------^ (請先閱讀背面之注t事項再填寫本頁) 1281468 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 A7 五、發明說明(4) 代。R2定義中次芳基及次雜環基結合於式j化合物中—個 硫原子及_Ν(Κ)(Ι^)。這二個鍵可相鄰,或在另一位置,例 如在鄰,對,或間位;在對應環系統中。次雜環基較佳經 由次雜環基之碳原子結合於式j化合物中硫原予及 -NCRXRD。 R4爲氫或烷基;較佳爲氫或(Ci 4)烷基,如甲基。
Rs爲氫或烷基;較佳爲氫或(Ci_4)烷基,如甲基;例如 未經取代或經取代之烷基,例如經羥基取代;Rs更佳爲 氫。 '' R3及R’3爲氫或氘,較佳爲氫。K,R7及Rs爲氫或氘。 若I爲式_C(=X)R9之基,則r及κ與相接之氮原子—起 可形成非芳族次雜環基,例如具有5至6個環成員及—個 雜原子,例如氮;較佳包括六氫吡啶基,吡咯啶基,較佳 爲六氫峨淀基。該次雜環基較佳經由次雜環基之碳原子結 合於式I化合物中硫原子及-Ν(1)基。若未另外定義,雜環 基或次雜環基包括一個5或6員環,具有丨至4個雜原子^ 自S,0及Ν ;例如Ν ;選擇性與另一環(系統)縮合,例如 與一個苯環縮合;或例如與一個雜環(例如包括喹啉,嘌 呤)縮合。(次)雜環基包括未經取代或經取代之(次)雜環 基,例如經截短側耳素化學中習知之基,例如包括燒基,· 羥基,胺基,硝基,COORu基(其中Ru爲烷基)取代。烷 基包括(Cm)垸基,例如(Ci-4)烷基。芳基包括苯芙。 在另一方面,本發明提供式I化合物,其中 R爲氫; 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) --------tl--------- (請先閱讀背面之注t*事項再填寫本頁) 1281468 A7 B7 五、發明說明(6) 「2s
NH I Ris i ' 其中Rls爲氫或下式基
S R
Is
例如下式之基
經濟部智慧財產局員工消費合作社印製 其中R6s爲氳或氘; R2s爲氫,甲基,或第三丁基; R7s爲氫或甲基;及 R3s,R4s &R5s爲氫或氘;及下式之化合物 -9- (請先閱讀背面之注意事項再填寫本頁)
本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 經濟部智慧財產局員工消費合作社印製 1281468 A7
其中R3SS ’ R4SS及R5SS爲氫或沉。 式I化合物包括式Is及Iss化合物。 在另一方面,本發明提供式I化合物,例如 u π包括式Iss及
Iss化合物之鹽,或鹽及溶劑化物,或溶劑化物形式。 在另一方面,本發明提供 14-0- (3-胺基)苯基-硫烷基(sulfanyi)乙醯基_截斷素 (mutilin),例如呈自由形式或鹽形式,例如氫氣酸鹽; 14-0- ( 3-胺基)苯基-硫跪基乙酿基_2,2,4·三氛-截斷素, 例如呈自由形式或鹽形式,例如氫氯酸鹽或氘氯酸鹽; 14-0- ( 3 -(六氫ρ比淀-2-基-羰基胺基)苯基-硫貌基乙醯 基)-截斷素,例如呈自由形式或鹽形式,例如氫氣酸鹽; 14-0-(3-(六氫吡啶-2-基-羰基胺基)苯基-硫烷基乙醯 基)-2,2,4-三氣-截斷素,例如呈自由形式或鹽形式,例如 氫氣酸鹽或氘氯酸鹽; 14-0- ( 3-(六氫吡啶-2-基-羰基胺基)-2,5-二甲基-苯基硫 基·甲基碳基)-截斷素,例如呈自由形式或鹽形式,例如 氫氣酸鹽; -10- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注意事項再填寫本頁)
A7
1281468 五、發明說明(8 ) 14-0· ( 3_ (穴氫吡哫-2-基·羰基胺基)_2,5_二甲基_苯基硫 基-甲基羰基)-2,2,4-三氘_截斷素,例如呈自由形式或鹽形 式,例如氫氯酸鹽或氘氯酸鹽; 14-0_ ( 3-(六氫吡啶-2-基_羰基胺基)_5_第三丁基_苯基· 硫燒基乙醯基)-截斷素,例如呈自由形式或鹽形式,例如 氫氯酸鹽; 14-0- ( 3-(六氫吡啶-2-基-羰基胺基)_5·第三丁基·苯基一 硫烷基乙醯基)-2,2,4-三氘截斷素,例如呈自由形式或鹽 形式’例如氫氣酸鹽或氖氣酸鹽; 14-0-( 1-( 2-胺基·異丁基羰基)-六氫吡啶-3-基·硫烷基 乙醯基)-截斷素,例如呈自由形式或鹽形式,例如氫氯酸 鹽;及 14-0- ( 1_ ( 2-胺基-異丁基羰基)-六氫吡啶-3-基_硫烷基 乙醯基)·2,2,4-三氘-截斷素,例如呈自由形式或鹽形式, 例如氫氣酸鹽或氘氣酸鹽; 式I化合物之鹽包括醫藥可接受鹽,例如包括金屬鹽或 酸加成鹽。金屬鹽包括例如鹼金屬或驗土金屬鹽;酸加成 鹽包括式I化合物與酸,例如氫反丁婦一酸’反丁缔二 酸,蓁-1,5 -續酸,氫氯酸,氛氯故’形成之鹽5較佳爲氫 氯酸或氘氯酸。 式I化合物之自由形式可轉化爲對應化合物之鹽形式; 反之亦然。式I化合物之自由形式或鹽形式及溶劑化物形 式可轉化爲對應化合物之自由形武或鹽形式,非溶劑化物 形式;反之亦然。 ------------411^--------訂---------線 ^__w. (請先閱讀背面之注^事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製
1281468 經濟部智慧財產局員工消費合作社印製 A7 五、發明說明(10 ) 得純異構物或非對映體。本發明包括合物之任何異 構物及非對映體形式及任何異構物及非對映體混合物。式 I化合物之截斷素環之組態較佳相同於天然製造之截斷 素。 在另一方面,本發明提供一種製造如上述定義之式I化 合物之方法,包含下列步驟 al·下式之化合物
其中R3 ’ R’3,R4及R5如式I定義,R6,R7及Rs爲氫, 與式N(R)(Ri)-R2-SH之化合物反應,其中R,心冬R2如式 Ϊ定義’獲得式I化合物,其中R,Rj,R2,R 3,R’3,R4 及R5如式I足義’ R6 ’ r7及r8爲氮;及若需要, M.氘加入步驟ai·中所獲得之式I化合物,獲得式I化合 物,其中 R6,尺7及118爲氘,R,R!,R2,R3,R,3,R4 及 R5如式I定義; 或 a2·步驟al.中所定義之式Η化合物與硫脲反應,然後還原’ (請先閱讀背面之注意事項再填寫本頁)
本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 1281468 A7 五、發明說明(11) 獲得下式之化合物
III 其中 R3,R,3,W5WIt^,R6UR8^, b2.步骤a2.中所定義之式ΠΙ化合物與式R2(NQ2)2之化合物 反應,其中r2如式I中疋義;或與非芳族雜環反應,該 環攜帶式-C(=X)R9之基,其中X及I如申請專利範園第! 項中疋義,呈反應性折生物,例如甲磺酸酯或甲苯磺酸 酯;獲得下式之化合物 ' 々N-Rg-
(請先閱讀背面之注意事項再填寫本頁)
IV 經濟部智慧財產局員工消費合作社印製 其中R2,R3,R,3,R4及R5如式I中定義,R6,汉7及Rs爲 氫, c2·還原步驟b2_中所定義之式IV化合物之硝基,獲得式工化 合物,其中R2,R3,Rr3,114及R5如式I中定義,R,Ri, R6,R7及R8爲氫;及若需要, -14- 本紙張尺度適用中國國家標準(CNS)A4規格(210 χ 297公釐) 1281468 A7 B7 五、發明說明(12 ) d2.步驟c2.中所定笔、』τ 人t 義 < 式I化&物中胺基反應,獲得式I化 合物,其中Ri爲下式之基 R ! x = c 其中 R,R2,R3,R,3,R4,R5,119及 X 如式;[中定義, R0 ’ R7及Rs爲氫;及若需要, e2·氘加入步驟d2·中所定義之式I化合物,獲得式I化合 物,其中R,R!,R2,r3,R,3,R4,,仏及χ如式J中 定義,R6,R7&r8爲氘; 或 a3.下式之化合物 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製
其中R6,117及R8爲氫,R3及r’3爲氫或氘,與下式之化合 物反應 -15- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) --------訂·!------線钃! 1281468
其中R4及如式I中定義,Hal爲鹵素,例如氣,臭 碘;獲得下式之化合物 ' '
VI (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 其中R4,R5,Hd,R6 ’ R7,R8,心及%如步驟a3 義: · b3·步驟a3·中所定義之式VI化合物與式hs_R2(n〇“之化 物反應,其中R,如式I中定義,獲得如步驟b2中所定 攻式IV化合物根據步驟c2·再反應,若需要,根據如 述走我之步驟d2及e 2之任一反應,獲得如式I中所定 之式I化合物。 任何式I化合物’例如包括式Is,iss或化之化合物,可 適當方式,例如根據習知方法,或如本文中所述之方法 備。任何式Is,Iss及Ip之化合物可根據製備式I化合物之 法相似地製備。 式II及式V之化合物爲已知,或可根據習知方法獲得。 -16- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 訂 線 經濟部智慧財產局員工消費合作社印製 1281468 A7 B7 五、發明說明(14 ) 式I化合物(例如鹽形式)中氫原子以氘原子替代可以適 當方式,例如根據習知方法,或例如根據本文中所述之方 法進行,例如式I化合物,例如包括式Is,Iss及Ip之化合 物,以氘氯酸(DC1)於適當溶劑(系統)中處理,及分離式I 化合物’例如鹽形式’其中氫原子例如在尺6 ’ R7及Rs之 定義中,以氘原子替代。 式I中R3及R'3爲氘之化合物之製造可以適當方式,例如 根據習知方法進行,例如經由式V中攜帶R3及Rf3 (均爲氫) 之碳原子一起形成一個雙鍵之化合物(其爲已知之化合物) 以氘處理,獲得式V中R3及Rf3爲氘之化合物;式V中R3及 R,3爲氘之化合物再以適當方式,例如根據習知方法,例 如根據上述步驟a3·至b3.之方法反應,獲得式I化合物。 式I化合物,例如包括式Is,Iss及Ip之化合物,在下文中 稱爲「本發明活性化合物」,具有藥理活性,可用作藥 劑。例如本發明活性化合物顯示抗微生物(例如抗細菌)活 性,對抗革蘭陰性細菌,如大腸样菌(Escherichia coli);及 對抗革蘭陽性細菌,如金黃色葡萄球菌(Staphylococcus aureus),釀膿鏈球菌(Streptococcus pyogenes),肺炎鏈球菌 (Streptococcus pneumoniae),黴漿菌(Mycoplasms),披衣菌 (Chalmydia),及專性厭氣菌例如脆弱样菌(Bacteroides fragilis);在活體夕卜,於瓊月旨稀釋試驗或微稀釋試驗中,根 據 National Commitee for Clinical Laboratory Standards (NCCLS) 1997,Document M7-A4 Vol· 17,No· 2: "Methods for dilution Antimicrobial Susceptibility Tests for Bacteria that Grow -17- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) --------I----------訂---------^ 許 * (請先閱讀背面之注意事項再填寫本頁) 1281468 A7 B7 五、發明說明(15)
Aerobically-Fourth Edition, Approved Standard11 ;及例如在活體 内,於鼠全身性感染中。 本發明活性化合物在活體外於瓊脂稀釋試驗或微稀釋試 驗中顯示抗細菌活性(MIC (微克/毫升))由約幺0.01微克/ 毫升至25微克/毫升,例如對抗上述菌種;及可有效對抗 黴漿菌(Mycoplasms)及披衣菌(Chlamydia)。MIC=最小抑制 濃度。 本發明活性化合物在鼠全身性感染中顯示活性,例如對 抗金黃色葡萄球菌(Staphylococcus aureus)(例如 ATCC 49951 菌種),例如非經腸或經口施用時,例如以約8至150毫克/ 公斤體重之劑量;例如實例23化合物,經皮下施用後, ED5〇値爲7.55毫克/公斤體重;及經口施用後,爲7.72毫克 /公斤體重。ED5〇=有效劑量(毫克/公斤體重),50%經處理 之動物經保護免於死亡;以Probit分析計.算(η == 8動物/ 組)。例如,已測得實例1及5 2之化合物對抗例如金黃色 葡萄球菌如 ATCC 10390,ATCC 29213,ATCC 29506, ATCC 49951 或 ATCC 9144 之 MIC 90% (微克 / 微升)爲約 幺0.0125微克/微升;而例如商業上可得之紅黴素A之MIC 90% (微克/微升)爲約〇·2至0.4。 本發明活性化合物顯示令人驚奇之整體活性範園。例 如,已測得本發明活性化合物在活體外對抗糞腸球菌 (Enterococcus faecium),包括萬古黴素抗性菌種;對抗金黃 色葡萄球菌,包括二甲苯青黴素(methicillin)敏感性(MSSA) 及二甲苯青黴素抗性(MRS A)菌種;及對抗肺炎鏈球菌 -18 - 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注意事項再填寫本頁) --------訂---------線_ 經濟部智慧財產局員工消費合作社印製 A7 1281468 B7 _ 五、發明說明(16 ) (請先閱讀背面之注意事項再填寫本頁) (Streptococcus pneumoniae),包括青黴素抗性菌種;例如在 瓊脂稀釋試驗或於微稀釋試驗中,於Mueller-Hinton瓊脂或 Mueller-Hinton肉湯中,有或無補充物,根據National Committee for Clinical Laboratory Standards (NCCLS), Document M7-A4對於需氣菌核准之標準參考方法,顯示令人驚奇之 活性。例如,已測得實例1及52之化合物(均以鹽酸鹽形式 試驗)對抗例如金黃色葡萄球菌MSSA之MIC (微克/微升) 爲約0.025 ;而商業上可得之阿基索黴素(azithromycin)之 MI C (微克/微升)爲約1 · 6 ;實例1化合物對抗例如金黃 色葡萄球菌MRSA之MIC (微克/微升)爲約幼.0125 ;商業 上可得之阿基索黴素之MIC (微克/微升)爲約>25.6 ;實例 1及52之化合物對抗例如青黴素抗性之肺炎鏈球菌之MIC (微克/微升)爲約<0.0125 ;而商業上可得之阿基索黴素之 MIC (微克/微升)爲約>2.56 ;實例1及52化合物對抗例如 萬古黴素抗性之糞腸球菌之MIC (微克/微升)爲S0.0125至 0.025。 在另一方面,本發明提供式I化合物用作藥劑,較佳用 作抗微生物劑,如抗生素,例如抗厭氣菌。 經濟部智慧財產局員工消費合作社印製 在另一方面,本發明提供式I化合物用於製備一種藥物 以治療微生物疾病,例如細菌,例如選自金黃色葡萄球菌 (Staphylococcus aureus),嚷膿缝球菌(Streptococcus pyogenes) ,肺炎鏈球菌(Streptococcus pneumoniae),黴漿菌(Mycoplasms) ,披衣菌(Chalmydia),及專性厭氣菌;例如包括青黴素或 多藥抗性菌種,例如肺炎鏈球菌;例如包括萬古黴素抗性 -19- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 1281468
五、發明說明(17 經濟部智慧財產局員工消費合作社印製 〈菌種’例如糞腸球菌(Enterococcus faecium);例如包括二 甲表青黴素(methicillin)抗性之菌種,例如金黃色葡萄球 菌,所引起之疾病。 在另一方面’本發明提供一種治療微生物疾病之方法, 其包含對於需要該治療之個體施用有效量之式I化合物; 例如呈醫藥組合物形式。 對於抗微生物治療,適當劑量當然依據例如所用之本發 明活性化合物,宿主,施用方式,及所治療症狀之嚴重性 而定。然而,一般爲於較大哺乳類(例如人類)獲得令人滿 意之結果,適合施用約〇·5至3克範圍内本發明活性化合物 之每日劑量,分劑達每日四次。本發明之活性化合物可以 任何慣用途徑,例如經口,例如以錠或膠囊形式,或非經 腸,例如以注射溶液或懸浮液形式,例如以相似於紅徽 素’例如阿基索黴素(azithromycin)之方式施用。 實例1,12, 21,23,35及52之化合物爲本發明用作抗微 生物劑之較佳化合物。 例如,已測得實例1及52之化合物(均以鹽酸鹽形式試 驗)對抗例如糞腸球菌(Enterococcus faecalis)菌種aTcc 29212之MIC (微克/微升)爲約0.8至6.4 ;而例如商業上 可得之紅黴素A顯示MIC (微克/微升)爲約ι·6。因此, 對於治療微生物疾病,細菌疾病,本發明之較佳化合物可 以紅黴素,例如紅黴素A或阿基索黴 素(azithromycin),慣 用之相似施用方式’以相似劑量施用於較大哺乳類(例如 人類)。 -20- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注意事項再填寫本頁)
1281468
五、發明說明(18) 發明之活性化合物可以醫藥可接受鹽形式,例如酸加 成鹽或金屬鹽;或自由形式;選擇性溶劑化物形式施用。 本發明活性化合物之鹽形式顯示相同於本發明活性化合物 之自由形式之活性。 口 本發明亦提供一種醫藥組合物,包含式J化合物之自由 形式或醫藥可接受鹽形式;例如及/或溶劑化物形式;與 至少一種醫藥載劑或稀釋劑。 該組合物可根據習知方法製造。單位劑型可含有例如約 1〇〇毫克至約1克。 本發明活性化合物另外適合作爲獸醫藥劑,例如獸醫活 性化合物,例如用於預防及治療動物,如家禽,豬,及小 牛之微生物疾病,例如細菌疾病;例如稀釋液體用於人工 授精及浸蛋技術。 在另方面,本發明提供式I化合物用作獸醫藥劑。 在另一方面,本發明提供式I化合物用於製備獸醫組合 物,可用作獸醫藥劑。 本發明另提供一種用於預防及治療微生物疾病(例如細 胞疾病)之獸醫方法,丨包含對於需要該治療之個體施用 有效量之式I化合物,例如呈獸醫組合物形式。 對於本發明活性化合物用於獸醫藥劑,劑量#餘據動 物之大小及年齡及所欲效果而定;例如用於預防治療,可 施用相當低劑量歷較長期間,例如丨至3星期。飲水中較 佳劑量爲由0.0125至0.05重量體積比,特別〇〇125至 0.025 ;在食物中,由20至4〇〇克/公噸,較佳爲2〇至 I _ 21 · 本紙張尺度適用中國國家標準(CNS)A4規格公爱) (請先閱讀背面之注音?事項再填寫本頁) --------訂---------線»11! A7
經濟部智慧財產局員工消費合作社印製 I28l468 五、發明說明 200克/公噸。本發明活性化合物較佳於飲水中施用於母 雞,於食物中施用豬,及經口或非經腸施用於小 母 ,例如 以口服或非經腸製劑形式,作爲獸醫藥劑。 在下列例示本發明之實例中,溫度爲攝氏度。 使用下列簡寫 DCCI 二環己基碳化二亞胺 DIEA 二異丙基乙基胺 BOC 第三丁氧基羰基
PyBOP 六氟磷酸(苯幷三唑-1-基氧基)三吡咯啶鳞 HMPT 六甲基磷三醯胺 DC1 氘氣酸 實例中截斷素(mutilin)環之編號示於下式中:
實例1 14-0- [ ( 3_ (六氫吡啶-2(R)-羰基胺基)苯基硫烷基(sulfanyl)) 乙醯基]-截斷素之鹽酸鹽形式 206毫克DCCI力口入229毫克N-B0C-(R)-2-羧六氫吡啶及 •22- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注意事項再填寫本頁)
1281468 A7 -—------Β7__ —___ 五、發明說明(20 ) 485毫克14-0-[(3-胺基_苯基硫烷基)乙醯基]截斷素於2〇 笔升二氯甲燒中在室溫之溶液内,所獲得之混合物在室溫 攪拌約12小時。脲沉澱物濾出,所獲得之濾液在減壓下 濃縮。所獲得之濃縮物進行層析(矽膠;環己烷/醋酸乙酯 =1/1 )。獲得M-O- [ ( 3_ (N-B0C-(R)-六氫吡啶4⑻羰基胺基) 本基硫燒基)乙醯基]·截斷素,以醚鹽酸在室溫處理約1 小時。所獲得之混合物在減壓下移除溶劑,所獲得之殘餘 物由醋酸乙酯/己烷中結晶。 獲得14-0- [( 3-(六氫吡啶-2(R)-羰基胺基)苯基硫烷基)乙 醯基]-截斷素之鹽酸鹽形式。 實例2 14-0-[(2,6-二甲基-3·(六氫吡啶-2(R)-羰基胺基)苯基硫烷基) 乙醯基]·截斷素之鹽酸鹽形式 200毫克14-0· [ ( 2,6_二甲基-5_胺基·苯基)硫烷基-乙醯基] 截斷素之鹽酸鹽形式,84毫克N-BOC-(R)-2-羧六氫吡啶, 190.1毫克PyBOP,及143毫克DIEA於20毫升二氧陸圜 中之溶液在約40 °C保持約24小時。所獲得之混合物以水 稀釋,以醋酸乙酯萃取。有機相再以〇· 1 N氫氧化鈉,0.1 N鹽酸,及鹽水萃取。所獲得之有機相濃縮,濃縮液進行 層析(矽膠;甲苯/醋酸乙酯=1·5Α )。獲得14-0- [ ( 2,6-二甲 基_3- (N-BOC-(R)-六氫吡啶-2(R)_羰基胺基)苯基硫烷基)乙 醯基]截斷素。BOC在10毫升二氧陸圜及10毫升醚鹽酸 之混合物中裂解移除,獲得14-0 [( 2,6-二甲基-3-(六氫吡 啶-2(R>羰基胺基)苯基硫烷基)乙醯基]截斷素之鹽酸鹽形 -23- 本紙張尺度適用中國國家標準(CNS)A4規格(21G X 297公爱) "" 一 (請先閱讀背面之注意事項再填寫本頁) --------^---------^ . 經濟部智慧財產局員工消費合作社印製 1281468 Δ7 Α7 _____ Β7 五、發明說明(21) 式。 實例3 14-0- [ ( 3-(六氫吡啶-2(R)·羰基胺基)苯基硫烷基)_2(R*)_丙 醯基]截斷素之鹽酸鹽形式 206毫克DCCI加入229毫克N-B0C-(R)-2-羧六氫吡啶及 499毫克14-0- [(3 -胺基-苯基硫燒基)-2-丙醯基]截斷素之 鹽酸鹽形式於20毫升二氣甲烷中在室溫之溶液内,所獲 得之混合物在室溫攪拌約12小時。脲沉澱物濾出,所獲 得之濾液在減壓下濃縮。所獲得之濃縮物進行層析(矽 層;環己烷/醋酸乙酯=1/1)。獲得14-0-[(3-(N-B0C-(R)_六 氫吡啶-2(R)-羰基胺基)苯基硫烷基)-2(R*)-丙醯基]截斷 素,以醚鹽酸在室溫處理約1小時。溶劑由所獲得之混合 物在減壓下移除,所獲得之殘餘物由醋酸乙酯/己烷中結 晶。 獲得14-0_ [(3-(六氫p比淀-2(R)-談基胺基)苯基硫院基)_ 2(R*)-丙醯基]截斷素之鹽酸鹽形式。 根據實例1至3中所述之方法,但使用對應起始物質, 獲得式I化合物,其中 R=R3=R’3=R5=氯; R4在實例37及38中爲甲基,在所有其他實例中爲氫;
Ri在實例1至35,43至49中爲式-C(=X)R9之基,在實例 36至42中爲氫; X在實例1至45中爲〇,在實例46及47中爲s,在實 例48中爲N-CH3,在實例49中爲N+(CH3)2C1·; -24- 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) (請先閱讀背面之注意事項再填寫本頁) in----訂--------線_ 經濟部智慧財產局員工消費合作社印製 1281468 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(22) R6=R7=R8 在實例 1 至 11,13 至 24,26 至 28,30,32 至39,41至49中爲氫,在實例12,25,29,31,40 中爲氘; R2及R9如下表1中定義: 表1
實例 r9 R2 4 ΗΝ·^γ^ xr OH 5 xr 6 rf pr Y T 7 HN u ςτ 8 9T 9 ch3〉_^ dr 10 nh2 Y -25- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注意事項再填寫本頁)
1281468 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明(23) 實例 r9 r2 11 I I no2 ςτ 12 CH, 13 σ ςτ 14 σ 15 ςτ 16 17 ςτ 18 οό 19 ςτ -26- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 χ 297公釐) 1281468 A7 B7五、發明說明(24 ) 經濟部智慧財產局員工消費合作社印製 實例 r9 r2 20 ςτ νο2 pr 21 ( h3〇—I ζ 〕h3 ch3 22 α ch3 23 Η c h3c s 〕H3 ch3 24 Η ch3 25 or 26 ch3 +NH3cr c, ch3 -27- (請先閱讀背面之注意事項再填寫本頁)
本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 1281468 A7 _ B7 五、發明說明(25 ) 經濟部智慧財產局員工消費合作社印製
(請先閱讀背面之注意事項再填寫本頁) 訂---------線» · 本紙張尺度適用中國國家標準(CNS)A4規格(210 χ 297公 1 _) 1281468 A7 B7 五、發明說明(26 經濟部智慧財產局員工消費合作社印製
9Q (請先閱讀背面之注音3事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 χ 297公釐) 1281468 A7 B7 經濟部智慧財產局員工消費合作社印製
(請先閱讀背面之注意事項再填寫本頁) 1281468 A7 B7 五、發明說明(28 ) '實例50 式I化合物中氫原子以氣原子替代 300毫克14-0- [( 3-(六氫吡啶-2(R)-羰基胺基)苯基硫烷基) 乙醯基]截斷素-鹽酸鹽(氫氯酸鹽)於3〇毫升二氧陸圜及 5耄升DC1 (20%於DsO中)之溶液在室溫保持6天,所獲 得之混合物在減壓下濃縮,冰滚乾燥,獲得[ ( 3-(六 氫口比淀-2(R)-羧基胺基)苯基硫燒基)乙醯基]_2,2,4_三說-截 斷素之氘氯酸鹽形式'。 NMR(CDC13):與實例1化合物之NMR數據比較,缺乏三 環基之2- ’ 2’-及4-質子之訊號。 根據實例50中所述之方法,獲得式I化合物,其中 氫;Ri 為式-C(=X)R9 之基,其中 χ=〇 ; RfRfRs為氘;及R2及R9如下表2中定義,呈能氯酸鹽形 式: · 表2 實例1 r9 -------- r2 51 rr 實例52 14-0-[(3-胺基-苯基硫烷基)乙醯基]截斷素 0.92克納及5克3 -胺基-硫自分於1〇〇毫升無水乙醇中之溶 液加入21.3克22-0甲苯磺醯基-截斷侧耳素(pleur〇mutilin) -31 - 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注意事項再填寫本頁) 訂---------線------- 經濟部智慧財產局員工消費合作社印制衣 經濟部智慧財產局員工消費合作社印製 1281468
發明說明( 29 於250毫升乙基甲基酮中在室溫之溶液内,於溫度控制 下。所獲得之反應混合物在室溫保持約〗5小時,過滤,在 減壓下濃縮至乾。殘餘物進行層析(矽膠;環己烷/醋酸乙 酯=1/1 )。獲得14-0_ [ ( 3·胺基_苯基硫烷基)乙醯基]截斷 素。 起始物質之製造 A. 14-0- [(3-胺基-苯基硫烷基)乙醯基]截斷素參見實例52 Β· 14-0- [( 2,6-二甲基-5·胺基苯基)硫烷基·乙醯基]截斷素 之鹽酸鹽形式
Ba· 14-0-(脲基(Carbamimidoyl)硫烷基)乙醯基]截斷素甲苯 磺酸鹽 15.2克硫脈及106.4克截斷侧耳素(pieuromutiiin)_22-0-甲 苯橫酸鹽於250毫升丙酮中之溶液在回流下加熱〗5小時, 务劑在減壓下移除’ 100愛升己燒加入。沉澱物形成,濾、 出,乾燥。獲得14-0-[(脲基硫烷基)乙醯基]截斷素-甲苯 橫酸鹽。
Bb. 14-巯基-乙醯基-截斷素 4.7克焦亞硫酸鈉(Na2S205)於25毫升H20中之溶液加入 12·2克14-0-[(脲基硫烷基)乙醯基]截斷素-甲苯磺酸鹽於 20毫升乙醇及35毫升Η20之混合物中之溶液(加熱至約90 °C)内。100毫升CC14加入所獲得之反應混合物内,混合物 在回流下加熱約2小時。所獲得之二相系統分離,有機相 乾燥,溶劑蒸發移除。獲得14-毓基-乙醯基-截斷素。
Be. 14-0- [( 2,6-二甲基-5_硝基苯基)硫烷基·乙醯基]截斷 -32- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) " " ~ (請先閱讀背面之注意事項再填寫本頁)
經濟部智慧財產局員工消費合作社印製 1281468 A7
素。 0.98克2,4_二硝基二甲苯於3〇毫升ΗΜρτ中之溶液加入 3.94克14-巯基_乙醯基-截斷素及115毫克鈉於15亳升甲醇 中之溶液内。所獲得之反應混合物加熱至約120 X:約工小 時’在A溫保持約12小時,倒於冰上。所獲得之混合物以 甲苯萃取,所獲得之有機相乾燥,溶劑蒸發移除。所獲得 之殘餘物進行層析(矽膠,甲苯/醋酸乙酯=2/1 )。獲得Μ· 0- [ ( 2,6-二甲基硝基苯基)硫烷基_乙醯基]截斷素。 6&14-0-[(2,6-二甲基-5_胺基_苯基)硫烷基_乙醯基]截斷 素之鹽酸鹽形式 2.5克錫粉加入202毫克14_〇_ [ ( 2,6_二甲基-5-硝基苯基) 硫燒基·乙醯基]截斷素於1〇毫升二氧陸圜,L5毫升甲 酸’及0.1毫升HsO中之溶液内,所獲得之反應混合物在回 流下加熱約5小時。所獲得之混合物過濾,所獲得濾液之 落劑蒸發移除。5毫升二氧陸圜及10毫升醚鹽酸之混合物 加入所獲得之殘餘物中,所獲得混合物之溶劑蒸發移除。 殘餘物於己烷/醋酸乙酯中結晶。獲得14_〇_ [ ( 2,卜二甲基_ 5-胺基-苯基)硫烷基-乙醯基]截斷素之鹽酸鹽形式結晶。 C· 14-0- [( 3-胺基·苯基硫烷基)·2_丙醯基]截斷素之鹽酸鹽 形式
Ca· 14·〇_ ( ( 2(R/S)-溴-丙醯基)截斷素 3.2克截斷素,2克N-甲基嗎琳,及4.3克2-溴-丙醯基溴 於50毫升四氫呋喃中之溶液在室溫保持約24小時。所獲得 之混合物在減壓下濃縮,所獲得之殘餘物倒入水及醋酸乙 -33 - 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注意事項再填寫本頁)
1281468 A7 B7 五、發明說明(31) 酯之混合物中。獲得二相系統,各相分離。所獲得之有機 相以1 N HC1及鹽水萃取,進行層析(環己烷/二氧陸圜 =6/1 )。獲得M-O- (( 2(R/S)-溴-丙醯基)截斷素。
Cb. 14-0- [ ( 3·胺基苯基硫烷基)_2(R*)_丙醯基]截斷素之鹽 酸鹽形式;及 14-0- [ ( 3-胺基_苯基硫烷基)_2(S*)_丙醯基]截斷素之鹽 酸鹽形式 45毫克14-0_ ( 2(R/S)-溴-丙醯基)截斷素,ι25毫克3_胺 基硫驗,及24毫克鈉於1〇毫升乙醇及5亳升乙基甲基酮中 之溶液在室溫保持約12小時。所獲得混合物之溶劑蒸發移 除,50毫升醋酸乙酯加入所獲得之殘餘物中。所獲得之有 機相以鹽水萃取,進行層析(矽膠:環己烷/二氧陸圜 土6/1 )。獲得14-0_ [ ( 3_胺基-苯基硫烷基)_2(R/s)·丙醯基]截 斷素之非對映體混合物。非對映體以製備性HPLC層析(環 己坑/ 一氧陸圜=8/1 )分離’以鹽酸處理◦獲得14-0- [( 3 -胺 基-苯基硫燒基)-2(R*)-丙醯基]截斷素之鹽酸鹽形式及14-0- [( 3-胺基-苯基硫燒基)-2(S*)-丙醯基]截斷素之鹽酸鹽 形式。 ^-NMR-光譜(CDC13若未另外說明) 實例. 1 3.1,3.5 (2xm,2H, ε,εΉ-六氫峨淀),ΑΒ-系統 (Va=3.57 ’ Vb=3.62,2Η,Η22,J二 15.2Hz),4.42 (b,1Η,α_ Η-六氫吡啶),7.03 (d5 1Η,芳族 Η6, J=7.7Hz),7.13 (t, 1H,芳族 H5,J=5.9Hz),7.49 (d5 1H,芳族 H4,J=7.7Hz), -34- 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) (請先閱讀背面之注音?事項再填寫本頁) -------訂---------線 _! 經濟部智慧財產局員工消費合作社印製 1281468 A7 一 B7 五、發明說明(32 ) 7.85 (s,1H,芳族H2),10.7 (s,1Η, NH)。 2 2.48,2.52 (2xs,6H,2x 芳族 CH3),AB·系統(Va=3.3, Vb=3.38,2H,H22,J=15.8Hz),4.5 (b,1H,oc_H,7T 鼠 p比淀), 3.1,3.3 (2xb,2H,ε,ε’-Η,六氫吡啶),7.0, 7.4 (2xm,2H, 芳族 H4, H5),8.45, 9.6 (2xb,2H,NH2),9.9 (b,1H,NH). 3 (d6-DMSO):1.48 (d,3H,C22_CH3,J=7.2Hz),2.75, 3.05 (2xb,2H, s,s,-H,六氫吡啶),3.38 (d,1H,Hn,J=6.35Hz), 3.82 (q,1H,H22, J=7.2Hz),7.2 (t,1H,芳族 H5, J=7.8Hz), 7.15 (ddd,1H,芳族 H6, J =7.8Hz,J=1.5Hz,J=2.8Hz),7.55 (ddd,1H,芳族 H4, =7.8Hz,J=1.5Hz,J=2Hz),7.6 (t,1H,芳 族 H2, J=1.8Hz),8.9 (s,1H,NH). 4 3.5 (s,2H,H22),2.7, 3.4, 3.7, 4.6 (4xm,5H,六氫吡啶-H), 8.1,9.7,10.3 (3xb,2xNH,OH),7.45 (d,2H,芳族 H, J=6.2Hz),7.52 (d,2H,芳族 H,J=6.2Hz). 5 1.08 (d,6H,CH(Me)2,J=6.2Hz),AB-系統(Va=3.5, Vb=3.58, 2H,H22, J=15.1Hz),3.92 (d,1H,α-H,J=5.7Hz), 7.7 (d,2H,芳族 H,J=6.2Hz),7.51 (d5 2H,芳族 H, J=6.2Hz). 6 3.5 (s,2H,H22),2.7, 3.4, 3.7, 4.6 (4xm,5H,六氫吡啶-H), 8.1,9.7,10.3 (3xb,2xNH,OH),7.01 (dd,1H,芳族 H6, J=1.5Hz,J=6.2Hz),7.18 (t,1H,芳族 H5, J=6.2Hz),7.4 (dd, 1H,芳族 H4, J=1.5Hz,J=6.2Hz) 7.6 (d,NH,J=6Hz)· 7 3.6 (s,2H,H22),5.01 (m,1H,a_H),7.1 (d,1H,芳族 H4, J=8.2Hz),7.3 (t,1H,芳族 H5, J=8.2Hz),7.49 (d,1H,芳族 -35- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注意事項再填寫本頁) --------訂---------線®® I · 經濟部智慧財產局員工消費合作社印製 A7 1281468 B7 _ 五、發明說明(33 ) H6, J=8.2Hz),7.82 (s,1H,芳族 H2),7.6, 10.8 (2xb,2xNH). 8 1.1 (d,6H,(CH(Me)2),J=6.5Hz),AB-系統(VA=3.6, VB=3.65, 2H,H22, J=15.2Hz),3·92 (d,1H,α-Η, J=6.2Hz), 7·12 (dd,1H,芳族 H6, J=7.9Hz,J=2.1Hz),7.25 (t,1H,芳 族 H5, J=7.9Hz),7.42 (dd,1H,芳族 H4, J=7.9, J=2.1Hz), 7.75 (d,1H,芳族 H2, J=2.1Hz). 9 1.08 (d,6H,(CH(Me)2),J=7Hz),AB·系統(Va=3.42, Vb=3.5, 2H,H22, J=15.2Hz),3.45 (d,1H,α·Η,J=4.1Hz), 7.0, 7.35 (2xm,芳族 H3,H4),7.51 (d,1H,芳族 H2, J=7.5Hz),8·48 (d,1H,芳族 H6, J=7.5Hz),10.55 (s,1H, NH). 10 AB·系統(VA=3.58, VB=3.6, 2H,H22, J=15.8Hz),AB·系 統(VA=3.58, VB=3.59, CH2-OH,J=14.2Hz),3.67 (d,b,α·Η, 4·9Ηζ),7.08 (dd,1H,芳族 H6, J=7.9Hz,J=2.1Hz),7.22 (t, 1H,芳族 H5, J=7.9Hz),7.45 (dd,1H,芳族 H4, J=7.9, J=2.1Hz),7.65 (d,1H,芳族 H2, J=2.1Hz),9.54 (b,1H, NH). 11 3·62 (s,2H,H22), 6.75 (d,1H,吡咯-H,J=4.5Hz),7.12 (d, 1H 吡咯-H,J=4.5Hz),7.18 (dd,1H 芳族 H6, J=6.3Hz, J=1.5Hz),7.28 (t,1H,芳族 H5, J=6.3Hz),7.5 (dd,1H,芳 族 H4, J=6.3Hz,J=1.5Hz),7·62 (d,1H,芳族 H2, J=1.5Hz), 7.95 (s,1H,NH). 12 與實例2之NMR數據比較,缺乏三環部份之2,2’-及 4_ 質子記號。MS m/e626(MH)+. -36- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注咅?事項再填寫本頁) -I I I I I I I ^ ' — — — — — — I— MV I l· . 經濟部智慧財產局員工消費合作社印製 1281468 A7 -----B7 五、發明說明(34 ) 13 3.65 (s,2H,H22),7.3, 7.4, 7.8 (3xm,芳族 H),8.15 (s,1H, 芳族 H2),8.05, 8.8, 9.2, 10.4 (4xb,p比啶-H),1〇·9 (b,1H, NH). 14 3·65 (s,2H,H22),7.18 (dd,1H,芳族 H4, J=lHz,J=7.7Hz), 7.3 (t,1H,芳族 H5, J=7.98Hz),7.73 (dd,1H,芳族 H6, J=1Hz,J=7.7Hz),8.03 (d, 1H,芳族 H2, J=2Hz),7.82, 8·3 (2xm,吡咯-h4, H5),8.6 (d,1H 吡咯-H6, J=7.75Hz),8.73 (d, 1H,吡咯-H3, J=4.5Hz),11.95 (s,1H,NH). 15 3.6 (s,2H,H22),7.10 (dd,1H,芳族 H4, J=7.3Hz,J=1.5Hz), 7.24 (t 1H,芳族 H5,J=8Hz),7.48 (dd,1H,芳族 H6, J=7.3Hz,J=1.5Hz),7.65 (d,1H,芳族 H2, J=1.5Hz),6.3, 6.71,7.0 (3xm,3H,吡咯-H),7.62 (s,1H,NH),9.65 (s, 1H,NH). 16 AB-系統(VA=3.6,VB=3.68,2H,H22,J=15.2Hz),6.52, 6.83, 7.48 (3xm,3H,晚咯-H),7.08 (dd,1H,芳族 H4, J=1.5Hz,J=7.7Hz),7.23 (t,1H,芳族 H5, J=7.9Hz),7.52 (dd,1H,芳族 H6, J=1.5, J=7.7Hz),7.65 (d,1H,芳族 H2, J=1.5Hz),7.42 (s,1H,NH),8.55 (b,1H,NH). 17 3.62 (s,2H,H22),7.15 (dd,1H,芳族 H6, J=2Hz,J=7.8Hz), 7.34 (t,1H,芳族 H5, J=8.2Hz),7.54 (dd,1H,芳族 H4, J=2Hz,J=7.8Hz),7.01,7.18, 7.3, 7.45, 7.7 (5xm,啕哚-H), 7.88 (s,1H,NH),9.43 (s,1H,NH)· 18 AB·系統(VA=3.52, VB=3.58, 2H,H22, J=14.9Hz),6.8, 7.2, 7.4, 7.82, 7.9 (5xm,6H,芳族 H+喹啉·Η),7.83 (t,1H,芳 •37- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注意事項再填寫本頁)
-! I丨丨丨訂-I丨— ! ! 線I 經濟部智慧財產局員工消費合作社印製 A7 1281468 ________B7____ 五、發明說明(35 ) 族 H5, J=7.7Hz),8.5 (d,1H,喹啉-氏),8.75 (d,1H,喹啉 -H7)· 19 3·55 (sb, 2H,H22),7.03, 7.2, 7.55 (3xm,3H,芳族 H4, H5, H6),7.75 (s,1H,芳族 H2),7.7-8.1 (b,NH2, NH),9.6 (b, 1H,NH). 20 3.65 (s,2H,H22),7.15 (dd,1H,芳族 H6,J=1.5Hz, J=7.3Hz),7.32 (t,1H,芳族 H5, J=7.9Hz),7.65 (dd,1H,芳 族 H4, J=1.5Hz, J=7.7Hz),7.8 (d,1H,芳族 H2, J=1.5Hz), 8.22 (dd,1H,吡啶-H5, J=2.2Hz,J=5.3Hz),8.95 (dd,1H, 叶匕淀 H6,J=0.8Hz,J=5.3Hz),8·99 (d5 1H,外t;淀·Η3, J=2.2Hz),9.82 (s,1H,NH). 21 1.45,(s,9H,芳族第三丁基),AB·系統(VA=3.65, VB=3.75, 2H, H22, J=14.8Hz),4·4 (b,1H,α-Η,六氫吡啶), 3.1,3.5 (2xb,2H,ε-H,六氫吡啶),7.18, 7.8 (2xm,2H,芳 族 H4, H3),7.7 (b,1H,芳族 H6),10.4 (b,1H,NH)· 22 2.48,(s,3H,芳族 CH3),AB·系統(VA=3.2, VB=3.36, 2H, H22, J=15.8Hz),4.4 (b,1H,α-H,六氫吡啶),3.1,3.5 (2xb, 2H,ε_Η 六氫吡啶),7.0, 7.4 (2xm,2H,芳族 H4, H3),7·8 (b,1H,芳族 H6),8.45, 9·6 (2xb,2H,NH2),10·4 (b,1H, NH). 23 旋轉異構體·· 1.48,(s,9H,第三丁基),AB_系統 (Va=3.61,Vb=3.68,1.2H,J=15Hz,Va=3.64,Vb=3.66, 〇·8Η,J=14.5Hz),7.1-7.5 (m,2H,芳族 H3, H4),8.35 (d, 1H,芳族 H6, J=2Hz),8.65 (d,0.8H,甲醯基-H,J=llHz, -38- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注意事項再填寫本頁) ! — 訂- - ------線 ^^1 經濟部智慧財產局員工消費合作社印製 A7 B7 I28l468 五 '發明說明(36) 8.67 (sb, 0.2H)· 24 旋轉異構體:2.5, 2.55 (2xs,6H,芳族CH3),AB-系統 (VA=3.30, VB=3.4, 1.2H,J=15Hz,VA=3.34, VB=3.4, 0·8Η, J=14.5Hz),7.05 (d,0.5Η,芳族 Η4, J=8Hz),7·78 (d,0·5Η, 芳族 Η4, J=8Hz),7·1 (d,1Η,芳族 Η5, J=8Hz),8·42 (d, 0.8Η,甲酿基-Η,J=llHz,8·67 (sb,0·2Η),6.9 (b,1Η, NH). 26 (二鹽酸鹽之形式)7.52(s,1H 咪唑-H),9.03(s,1H,咪 唑-H), 8.65(b,2H,NH2),7.16(dd,1H,芳族 H6, J=1.5Hz, 8.3Hz),7.42(dd,1H,芳族 H4, J=1.5Hz,J=8.3Hz), 7.73(d, 1H,芳族 H2, J=1.5Hz),11.4(s,1H,NH),4.45(m,lH,a-H, 胺基酸),3.8(s,3H,N-CH3) AB·系統(VA=4.4, VB=3.48, 2H,CH2CH,J=15.2, 7.8Hz,ΑΒ·系統(Va=3.75, Vb=3.65, 2H,H22, J=15.2Hz,2.25 (s,3H,芳族 CH3)· 27 (二鹽酸鹽之形式)(d6_DMSO, 350K) : 11.8 (s,1H 咪 唑-H),9.03(s,1H,咪唑-H),8.65(b,2H,NH2), 7.16(dd,1H, 芳族 H6,J=1.5Hz,J=8.3Hz),7.38(dd,1H,芳族 H4, J=1.5Hz,J=8.3Hz),7.73(d,1H,芳族 H2, J=1.5Hz),7.54(s, 1H,NH),4.45(m,lH,a_H,胺基酸),3.3(s,3H,N-CH3) AB-系統(Va=3.25, Vb=3.4, 2H,CH2CH,J=15.2, 7.8Hz, AB_ 系統(VA=3.78, VB=3.68, 2H,H22, J=15.2Hz, 2.25 (s, 3H,芳族 CH3). 28 (二鹽酸鹽之形式)9.7 (s,1H,NH),8.82(s,1H,咪唑-H),7.48(s,1H,咪唑·Η),8.45(b,3H,NH3),6.83(d,1H,芳 -39- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閲讀背面之注意事項再填寫本頁) -I I-----訂---------線 --r 經濟部智慧財產局員工消費合作社印製 經濟部智慧財產局員工消費合作社印製 1281468 A7 B7 五、發明說明(37 ) 族 H4,J=8.4Hz),7.25(d,1H,芳族 H5,J=8.4Hz), 4.85(m,lH,α-Η,胺基酸),3.38-3.5(m,2H,CH2CH,胺基 酸),2.3, 2.38(2xCH3,芳族 CH3),AB-系統(VA=3.08, VB=3.18, 2H,H22, J=15.2Hz),MS m/e651(MH)+· 29 與實例28之NMR數據比較,缺乏三環部份之2,2·-及4-質子之訊號。MS m/e684(MH)+· 3〇 (二鹽酸鹽之形式)(d6-DMSO) : 11·8 (s,1H 咪唑 _H), 9.03(s,1H,咪唑-H),8.6(b,2H,NH2),7.09(dd,1H,芳族 H6, J=1.5Hz,J=7.3Hz),7.27(t,1H,芳族 H5, J=7.9Hz),7.43(dd, 1H,芳族 H4, J=1.5Hz,J=7.3Hz),7.64(d,1H,芳族 H2, J=1.5Hz),7·54 (s,1H,NH),4.43(m,lH,α·Η,胺基酸), 3.2-3.4(m,2H, CH2CH 胺基酸)· 31 (二氘氯酸鹽之形式)。與實例3〇之NMR數據比 較,缺乏三環部份之2,2·-及4-質子之訊號。MS m/e625(MH)+. 32 (鹽酸鹽之形式)(d6-DMSO) : 7·52 (s,1H 咪唑·Η), 9.03(s,1Η,咪峻-H),7.8(m,lH,NH2),10.95(s,1Η,ΝΗ), 8.45(s,3H,NH3),7.16(dd,1H,芳族 H6,J=1.5Hz, J=8.3Hz),7.42(dd,1H,芳族 H4,J=1.5Hz,J=8.3Hz), 7.73(d,1H,芳族 H2, J=1.5Hz),4.05(m,lH,α·Η,胺基酸), 3.8(s,3H,N-CH3),AB-系統(VA=4.4,VB=3.48,2H, CH2CH,J=15.2Hz,7.8Hz,AB_ 系統(VA=3.78, VB=3.68, 2H,H22, J=15.2Hz,2.25(s,3H,芳族 CH3). 33 (鹽酸鹽之形式)(d6_DMSO) : 10.2 (b,1H,NH),8.5 -40 - 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注意事項再填寫本頁)
-I I-----訂------I I I 1281468 A7 B7 五、發明說明(38) (b,3H,NH3),7.15 (d,1H 芳族 H4, J=8.2Hz),7.25 (d,1H, 芳族 H5, J=8.2Hz),4.13 (t,lH,α_Η,胺基酸 J=6.6Hz),3·4 (m,2H,δ-Η,胺基酸),AB-系統(VA=3.5, VB=3.36, 2H, Η22, J=15.2Hz),2·41, 2.44(2xs,6H,2xCH3)· 34 NMR (d6麵DMSO,350K): 10·9 (b,1Η,ΝΗ),8.6(b,4H,NH), 7.10(dd,1H,芳族 H6, J=1.5Hz,J=7.3Hz),7.27(t,1H,芳 族 H5, J=7.9Hz),7.50(dd,1H,芳族 H4, J=1.5Hz,J=7.3Hz), 7.74(d,1H,芳族 H2, J=1.5Hz),4.13(t,lH,a_H,胺基酸, J=6.6Hz), 3.4 (m,2 H,δ·Η,胺基酸),AB_ 系統(VA=3.6, Vb=3.68? 2H? H22? J=15.2Hz. 35 (鹽酸鹽之形式)(d6-DMSO,350K) : 8.03 (b,3H,NH3),
4.25 (d, 1H,a-H,胺基酸,J=4.6Hz),AB-系統 (VA=3.45,VB=3.32, 2H,H22,J=15.2Hz. 0.85,0·95 (2xd, CH(CH3)2, J=5.9Hz), 4.0 (m,2H, NCH2CH2). MS m/e577(MH)+. 36 7.26(d,2H,芳族 H,J=8.6Hz),6.58(d,2H,芳族 H, J=8.6Hz),AB_ 系統(Va=3.42,Vb=3.38,2H,H22, J=14.4Hz),Ms m/e:621 (M+ +Na). 37 化合物(22-R*): (d6-DMSO/CDCl3 1:3)): 7.37 (dd,1H,芳 族 H6, J=1.5Hz,J=7.3Hz),7.27(t,1H,芳族 H5, J=7.9Hz), 7.34(dd,1H,芳族 H4, J=1.5Hz,J=7.3Hz ),7.48(d,1H,芳 族 H2, J=1.5Hz),3.82(q,1H,CHCH3, J=7.2Hz),1.49(d, 3H,CHCH3, J=7.2Hz). 38 化合物(22_S*): (d6-DMSO/CDCl3 1:3)): 7.37 (dd,1H,芳 -41- 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) (請先閱讀背面之注意事項再填寫本頁) -----I--訂--I------- 經濟部智慧財產局員工消費合作社印製 A7 1281468 B7_ 五、發明說明(39) (請先閱讀背面之注意事項再填寫本頁) 族 H6, J=1.5Hz,J=7.3Hz),7.27(t,1H,芳族 H5, J二7.9Hz), 7.34(dd,1H,芳族 H4, J=1.5Hz,J=7.3Hz ),7.48(d,1H,芳 族 Hi J二 1.5Hz),3.76(q,1H,CHCH3, J=7.2Hz),1.52(d, 3H,CHCH3, J=7.2Hz). 39 參見下列實例A中數據 40 與化合物39 (鹽酸鹽形式)之NMR數據比較,缺 乏三環部份之 2,2’-及4-質子之訊號。MS m/e 489(M+1)+. 41 7.45(m,1H,芳族 H),AB-系統(VA二3·57, VB=3.63, 2H, H22, J=14.8Hz)· 42 6.88(dd,1H,芳族 H6, J=1.5Hz,J=6.2Hz ),7.32(dd,1H,芳 族 H5, J=1.5Hz,J=6.2Hz ),7.4(m,1H,芳族 H3),3.59(s, 2H,H22). 43 7.38(dd,1H,芳族 H6, J=1.5Hz,J=6.2Hz ),7.2(t,1H,芳族 H5, J=6.2Hz ),7.05(dd,1H,芳族 H4, J=1.5Hz,J=6.2Hz), 7.5(m,1H,芳族 H2 ),3.4(s,2H,H22),2.18(s,3H,COCH3). 經濟部智慧財產局員工消費合作社印製 44 7.9(b,1H,NH),7.22(dd,1H,芳族 H6, J=1.5Hz,J=6.2Hz ), 7.3(t,1H,芳族 H5,J=6.2Hz),7.43(dd,1H,芳族 H4, J=1.5Hz,J二6.2Hz ),7.56(m,1H,芳族 H2 ),3.62(s,2H, H22). 45 7.48(s,1H,CH=0),6.80(dd,1H,芳族 H6,J=1.5Hz, J=6.2Hz ),7.14(t, 1H,芳族 H5, J=6.2Hz ),6.98(dd,1H,芳 族 H4, J=1.5Hz,J=6.2Hz ),6.94(m,1H,芳族 H2 ),3.58(s, 2H,H22). 46 3.62(s,2H,H22),7.23(dd,1H,芳族 H6, J=1.5Hz,J=6.2Hz ), -42 - 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 1281468 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明(4Q) 7.3(t,1H,芳族 H5,J=6.2Hz ),7.48(dd,1H,芳族 H4, J二 1.5Hz,J=6.2Hz ),7.75(m,1H,芳族 H2 ),11.48, 8.05(2xb,NH),4.3(q,2H,OCH2CH3, J二7.2Hz),1.38(t,3H, OCH2CH3, J=7.2Hz). 47 7.72(s,1H,NH), 6.45(q,1H,NH,J=3.2Hz),AB-系統 (VA二3.52, VB二3.6, 2H,H22, J=14.8Hz),6.99(dd,1H,芳族 H6, J=1.5Hz,J=6.2Hz ),7.3(t,1H,芳族 H5, J二6.2Hz ), 7.3(m,2H,芳族 H4, H2 ),3.28 (d,3H,NCH3, J=3.2Hz). 48 7.72(s,1H,NH),6.45(q, 1H,NH,J二3.2Hz),AB-系統 (VA二3.62, VB=3.66, 2H,H22, J=14.9Hz),7.75(m,1H,芳族 H2 ),7.32 (m,3H,芳族 H6,H5,H4),3.18(b,3H, C=NCH3)2.78(s,3H,SCH3)· 49 7.48(s,1H,NHCH=N),6.8(dd,1H,芳族 H6,J=1.5Hz, J二6·2Ηζ),7.15 (t,1H,芳族 H5, J=6.2Hz),6.99(dd,1H,芳 族 H4,J=1.5Hz,J=6.2Hz),6.95 (m,1H,芳族 Η2)·3.4 (s, 2H,H22), 3.01(s,6H,N(CH3)2). A 0.58 (d,3H,H16,J=7.2Hz),0.81 (d,3H,H17, J=7.3Hz), 1.02 (s,3H,H18),1.32 (s,3H,H15),ABX-系統(VA二 1.2, Vb=1.88, H13a,H13b,J=16.1Hz,J=9.1Hz),2.08 (d,1H,H4, 1二2.1沿),八3乂丫-系統(¥八=2.23,¥^2.19,1^,11215, J=16.2Hz,J=9.1Hz,J=1.8Hz),2.3 (m,1H,Η10),3.4 (d,1H, 1111,>5.98取),人6-系統〇/八=3.81,¥3=3.89,21151122, J二 14.1Hz),5.18 (dd,1H,H20a,J=17.5Hz,J=1.6Hz),5·29 (dd,1H,H20b,J=llHz,J=1.6Hz),5.51 (d,1H,H14, -43 - 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注意事項再填寫本頁)
--------訂·--------, A7 1281468 ____B7__ 五、發明說明(41 ) (請先閱讀背面之注音?事項再填寫本頁) J=8.3Hz),6.05 (dd,1H,H19, J=llHz,J=17.5Hz),7.0 (m, 1H,芳族 H),7.18 (m,2H,芳族 H),7.3 (t,1H,芳族 H5, J=8Hz). B.a AB-系統(Va=3.7,Vb=3.82,2H,H22,J—15.8Hz),7.2 (d, 2H,H4,芳族 H,J=8Hz),7·75 (d, 2H,芳族 H,J=8Hz),8·4, 9.8 (2xb,4H,2xNH2). B.b ABX·系統(VA=3.15, VB=3.22, Vx=1.92, 2H,H22, J=15.8Hz, J=8.2Hz). B.c 2.43, 2.48 (2xs,6H,2x 芳族 CH3),AB·系統(Va=3.22, Vb=3.4, 2H,H22, J=13.8Hz),6.7, 6.95 (2xd,2H,芳族 H4, h5). B. d 2.61,2.74 (2xs,6H,2x 芳族 CH3),AB-系統(Va=3.31,
Vb=3.43, 2H,H22, J=15.8Hz), 7.2, 7.7 (2xd, 2H,芳族 H4, h5). C. b(R) (d6-DMSO):1.35 (d,3H,C22_CH3, J=7.2Hz),3.25 (d,1H, 經濟部智慧財產局員工消費合作社印製
Hu,J=6.35Hz),3.75 (q,1H,H22, J=7.2Hz),7.18 (t,1H,芳 族 H5,J=7.8Hz),7.24 (ddd,1H,芳族 H6, J=7.8Hz, J=1.5Hz,J=2.8Hz),7.28 (ddd,1H,芳族 H4? =7.8Hz? J=1.5Hz,J=2Hz),7.43 (t,1H,芳族 H2, J=1.8Hz). C.b (S) (d6-DMSO):1.48 (d,3H,C22-CH3, J=7.2Hz),2.4-3.2 (b,2H, NH2),3.38 (d,1H,Hu, =6.35Hz),3.82 (q,1H,H22, J=7.2Hz),7.28 (t,1H,芳族 H5, J=7.8Hz),7.34 (ddd,1H, 芳族 H6, J=7.8Hz,J=1.5Hz,J=2.8Hz),7.36 (ddd,1H,芳族 H4,=7·8Ηζ,J=1.5Hz,J=2Hz),7·49 (t,1H,芳族 H2, J=1.8Hz). -44· 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐)
Claims (1)
128146¾114436號專利申請案 B8 中文申請專利範圍替換本(95年10月)益 7T、申專利教τ圍
公告本I ____________i 1. 一種下式化合物,
«7 其中 R為氫或(Ci.4)烷基; R:為下式之基 X II —c—R9 其中 X為硫,氧,NR10,其中R1()為氫或(C ! _ 4)烷基,或 N+(R,10)2,其中 R’10為(CbO烷基;
,含一或二個氮 R9為胺基,(C ! _ 8)烷基 原子之5或6員環,或巯基;若X為氧,則R9可另外為 氫; R2為次苯基; R4為氫或(CL4)烷基; R5為氫或(0^-4)烷基; 65361-951027.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1281468 b D8 六、申請專利範圍 R3,R,,R6,117及心獨立為氫或氘;或 R及尺2與相接之氮原子一起形成具有5至6個環原子之非 芳族次雜環基,Ri為下式之基 X II —c—R9 其中X及R9如上述定義。 2.根據申請專利範圍第1項之式I化合物,其中 R為鼠, 心為下式之基 X II —c—R9 其中 X為硫,氧,NR10,其中R10為氫或(C i _ 4)烷基,或 N+(R’10)2,其中ΕΛ。為(Cbd垸基; R9為胺基,(Cn)烷基,含一或二個氮原子之5或6員 環,或巯基;若X為氧,則R9可另外為氫; R2為次苯基; R4為氫或(Ci-4)烷基; R5為風, R3及R〕’為氣, R6 ’ R7及Rs為氯或気;或 65361-951027.DOC -2- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)
本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1281468 g ___D8 六、申請專利範圍
其中R3ss,114^及R5ss為氫或氘。 5·根據申請專利範圍第1項之式I化合物,其為 14-0- (3-(六氫p比淀-2-基-談基胺基)苯基-硫虎基乙酿 基)-截斷素; 14-0- (3 -(六氫晚淀-2-基-羰基胺基)苯基-硫貌基乙驢 基)-2,2,4-三氘-截斷素; 14-0- ( 3_ ( 7T氮p比淀-2-基-談基胺基)-2,5-二甲基_苯基硫 基-甲基碳基)-截斷素; 14·0_ ( 3-(穴氫p比淀-2-基-談基胺基)-2,5-二甲基-苯基硫 基-甲基羰基)-2,2,4-三氘-截斷素; 14-0- ( 3-(穴氮ρ比淀-2-基-談基胺基)-5-第三丁基-苯基_ 硫烷基乙醯基)-截斷素; 14-0- ( 3- ( 鼠ρ比淀-2-基-談基胺基)-5-第三丁基-苯基_ 硫烷基乙醯基)-2,2,4-三氘-截斷素; 14-0- ( 1- ( 2-胺基-異丁基羰基)-六氫吡啶-3-硫烷基乙醯 基)-截斷素;或 -4- 65361-951027.DOC 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐). A8 B8 C8 D8 1281468 六、申請專利範圍 14-0- ( 1 - ( 2-胺基-異丁基援基)-7T氯ρ比咬-3-基-硫基 乙醯基)-2,2,4-三氘-截斷素。 6. 根據申請專利範圍第1項之式I化合物,係呈鹽形 式。 7. —種下式化合物,
其中 Rlp為氫,胺基,(Cn)烷基,胺基(Cn)烷基,或選 擇性經胺基-及/或羥基-及/或硝基取代之具有1至3個 氮原子的5或6員雜芳環或雜脂族環; R2p表選擇性經烷基-,氟-,或三氟甲基取代之 芳族,具有1至3個氮原子之5或6員雜芳族,嘌呤,或 口奎淋; R3P表S或0 ; R4p表氫或甲基; R5p表氫,甲基,或CH2OH ; 65361-951027.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 8 8 8 8 A B c D 1281468 六、申請專利範圍 Xp表NH或0 ;及 R6p,R7p及R8p相同或不同,表氫或氣,呈自由形式或酸 加成鹽或四級鹽形式。 8. —種製造根據申請專利範圍第1項之式I化合物之方 法,包含下列步驟 al.下式之化合物
其中R3,R’3,114及R5如申請專利範圍第1項中定義, R6,尺7及R8為氫,與式NCRXRO-R^SH之化合物反 應,其中R,心及R2如申請專利範圍第1項中定義, 獲得式I化合物,其中R,Ri,R2,R 3,R、,及4及R5 如申請專利範圍第1項中定義,R6,以7及r8為氫; 及若需要, bl.氘加入步驟al.中所獲得之式I化合物,獲得式I化合 物,其中 R6,R7 及 R8 為氘,R,Rq,R2,R3,R、,R4 及R5如申請專利範圍第1項中定義; 或 65361-951027.DOC -6- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) A8 B8 C8 D8 1281468 六、申請專利範圍 a2.步驟al.中所定義之式II化合物與硫脲反應,然後還 原,獲得下式之化合物
其中R3,R’3,R4及R5如申請專利範圍第1項中定 義,R6,R7及Rg為氫, b2.步驟a2.中所定義之式III化合物與式R2(N02)2之化合 物反應,其中R2如式I中定義;或與非芳族雜環反 應,該環攜帶式-C(=X)R9之基,其中X及R9如申請專 利範圍第1項中定義,呈反應性衍生物;獲得下式之 化合物
其中R2,R3,R、,R4及R5如申請專利範圍第1項中定 義,R6,R7及Rs為氫; 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 8 8 8 8 A B c D 1281468 六、申請專利範圍 c2.還原步騾b2.中所定義之式IV化合物之硝基,獲得式 I化合物,其中R2,R3,r’3,R4及R5如申請專利範圍 第1項中定義,R,Ri,R6,R7及R8為氫;及若需 要, d2.步驟c2.中所定義之式I化合物中胺基反應,獲得式I 化合物,其中Ri為下式之基 X II —c—R9 其中R,R2,R3,R’3,R4,R5,R9及X如申請專利範 圍第1項中定義,R6,R7及R8為氫;及若需要, e2.氘加入步驟d2.中所定義之式I化合物,獲得式I化合 物,其中 R,Ri,R2,R3,Rf3,R4,R5,R9及 X 如申 請專利範圍第1項中定義,R6,R7及R8為氘; 或 a3.下式之化合物
65361-951027.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)
A8 B8 .C8 D8 1281468 ---—^ 、申請專利範園 其中R6,RT及R8為氫,Rs及R,s為氫或氘,與下式之 化合物反應 Rc 其中R4及R5如申請專利範圍第1項中定義,Hal為函 素’獲得下式之化合物
其中 R4, R5, Hd,R6’ R7, R8, R3 及 R,3 如步驟 a3 中 定義: b3.步驟a3.中所定義之式VI化合物與式hs_r_士之化 合物反應’ 如申請專利範圍第β中定義,獲 得如步驟b2.中所定義之式IV化合物,式代化合物根 據步驟C2.再反應,及若需要’根據如上述定義之步 驟d2或e2之任一反應,獲得如申請專利範圍第i項中 所定義之式I化合物。 9.根據申請專利範圍第1項之式I化合物,係用作藥 65361-951027.DOC
!281468 、申清專利範園 1〇.=中請專利範圍第9項之式1化合物,係用作抗微生 U.㈣申請專利範圍第1項之式I化合物,係用於製備 種用作抗菌劑之藥物。 12·根據申請專利範圍第i項之式Γ化合物,係用於製備 藥物以治療細菌所引起之微生物疾病,細菌包括 ii:素或夕某仏性菌種,萬古黴素(vancomycin)抗性菌 種’二甲苯青黴素(methicillin)抗性菌種。 13·根據申請專利範圍第i項之式r化合物,其係用作抗 菌劑。 14. 一種用作抗菌劑之醫藥組合物,其包含根據申請專利 範圍第1項之式I化合物呈自由形式或呈醫藥可接受 鹽形式與至少一種醫藥載劑或稀釋劑。 15·根據申請專利範圍第1項之式I化合物,係用作獸醫 藥劑。 16.根據申請專利範圍第1項之式I化合物,係用於製備 一種獸醫組合物,其可用作獸醫藥劑。 •10- 65361-951027.DOC 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐)
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Families Citing this family (144)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PE20020676A1 (es) | 2000-09-13 | 2002-08-27 | Biochemie Gmbh | Compuestos de mutilina como antibacterianos |
GB0207495D0 (en) * | 2002-03-28 | 2002-05-08 | Biochemie Gmbh | Organic compounds |
GB0209262D0 (en) | 2002-04-23 | 2002-06-05 | Biochemie Gmbh | Organic compounds |
WO2004011431A1 (en) * | 2002-07-24 | 2004-02-05 | Sandoz Ag | Pleuromutilin derivatives as antimicrobbials |
ATE450535T1 (de) * | 2003-09-03 | 2009-12-15 | Glaxo Group Ltd | Neues verfahren zur herstellung von pleuromutilinderivaten |
GB0504314D0 (en) * | 2005-03-02 | 2005-04-06 | Glaxo Group Ltd | Novel polymorph |
EP1860943A4 (en) * | 2005-03-10 | 2008-06-18 | Smithkline Beecham Corp | NOVEL PROCEDURE |
GB0513058D0 (en) * | 2005-06-27 | 2005-08-03 | Sandoz Ag | Organic compounds |
GB0515995D0 (en) * | 2005-08-03 | 2005-09-07 | Sandoz Ag | Organic compounds |
WO2007037518A1 (ja) * | 2005-09-29 | 2007-04-05 | Dainippon Sumitomo Pharma Co., Ltd. | ムチリン誘導体及びそれを含有する医薬組成物 |
EP1808431A1 (en) * | 2006-01-16 | 2007-07-18 | Nabriva Therapeutics Forschungs GmbH | Mutilin derivatives and their use as pharmaceutical |
EP2024349B1 (en) * | 2006-05-31 | 2017-08-02 | AbbVie Inc. | Compounds as cannabinoid receptor ligands and uses thereof |
US8841334B2 (en) * | 2006-05-31 | 2014-09-23 | Abbvie Inc. | Compounds as cannabinoid receptor ligands and uses thereof |
WO2007140385A2 (en) * | 2006-05-31 | 2007-12-06 | Abbott Laboratories | Thiazole compounds as cannabinoid receptor ligands and uses thereof |
EP2023721A2 (en) * | 2006-06-05 | 2009-02-18 | Auspex Pharmaceuticals Inc. | Preparation and utility of substituted erythromycin analogs |
EP1908750A1 (en) * | 2006-10-05 | 2008-04-09 | Nabriva Therapeutics Forschungs GmbH | Process for the preparation of pleuromutilins |
EP1972618A1 (en) * | 2007-03-20 | 2008-09-24 | Nabriva Therapeutics AG | Pleuromutilin derivatives for the treatment of diseases mediated by microbes |
MX2009010363A (es) | 2007-03-28 | 2009-12-04 | Abbott Lab | Compuestos de 1,3-tiazol-2(3h)-ilideno como ligandos del receptor canabinoide. |
US8501794B2 (en) * | 2007-04-17 | 2013-08-06 | Abbvie Inc. | Compounds as cannabinoid receptor ligands |
US7872033B2 (en) * | 2007-04-17 | 2011-01-18 | Abbott Laboratories | Compounds as cannabinoid receptor ligands |
JP2010527929A (ja) * | 2007-05-18 | 2010-08-19 | アボット・ラボラトリーズ | カンナビノイド受容体リガンドとしての新規な化合物 |
US8222407B2 (en) * | 2007-05-24 | 2012-07-17 | Kyorin Pharmaceutical Co., Ltd. | Mutilin derivative having heterocyclic aromatic ring carboxylic acid structure in substituent at 14-position |
EP2014640A1 (en) | 2007-07-13 | 2009-01-14 | Nabriva Therapeutics AG | Pleuromutilin derivatives |
US9193713B2 (en) * | 2007-10-12 | 2015-11-24 | Abbvie Inc. | Compounds as cannabinoid receptor ligands |
WO2009114566A1 (en) | 2008-03-11 | 2009-09-17 | Abbott Laboratories | Novel compounds as cannabinoid receptor ligands |
JP5554319B2 (ja) | 2008-04-01 | 2014-07-23 | アボット ゲーエムベーハー ウント カンパニー カーゲー | テトラヒドロイソキノリン類、それを含む医薬組成物および治療におけるそれの使用 |
WO2010017150A1 (en) * | 2008-08-05 | 2010-02-11 | Abbott Laboratories | Compounds useful as inhibitors of protein kinases |
JP2012500198A (ja) * | 2008-08-15 | 2012-01-05 | アボット・ラボラトリーズ | カンナビノイド受容体リガンドとしてのイミン誘導体 |
US8846730B2 (en) | 2008-09-08 | 2014-09-30 | Abbvie Inc. | Compounds as cannabinoid receptor ligands |
WO2010033543A2 (en) * | 2008-09-16 | 2010-03-25 | Abbott Laboratories | Novel compounds as cannabinoid receptor ligands |
CN102186836A (zh) * | 2008-10-17 | 2011-09-14 | 雅培制药有限公司 | Trpv1拮抗剂 |
CN102245587A (zh) * | 2008-10-17 | 2011-11-16 | 雅培制药有限公司 | Trpv1拮抗剂 |
WO2010056855A1 (en) * | 2008-11-13 | 2010-05-20 | Teva Pharmaceutical Industries Ltd. | Preparation of retapamulin via its pleuromutilin-thiol precursor |
UA108193C2 (uk) | 2008-12-04 | 2015-04-10 | Апоптозіндукуючий засіб для лікування раку і імунних і аутоімунних захворювань | |
US8557983B2 (en) | 2008-12-04 | 2013-10-15 | Abbvie Inc. | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
US20100160322A1 (en) | 2008-12-04 | 2010-06-24 | Abbott Laboratories | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
US8586754B2 (en) * | 2008-12-05 | 2013-11-19 | Abbvie Inc. | BCL-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases |
EP2376480B1 (en) | 2008-12-05 | 2016-06-01 | AbbVie Inc. | Sulfonamide derivatives as bcl-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases |
US8563735B2 (en) | 2008-12-05 | 2013-10-22 | Abbvie Inc. | Bcl-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases |
PA8854001A1 (es) * | 2008-12-16 | 2010-07-27 | Abbott Lab | Compuestos novedosos como ligandos de receptores de canabinoides |
CN102282128B (zh) * | 2009-01-19 | 2015-06-17 | Abbvie公司 | 用于治疗癌症和免疫和自身免疫疾病的细胞程序死亡诱导药剂 |
CA2747835A1 (en) * | 2009-01-19 | 2010-07-22 | Abbott Laboratories | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
AR075442A1 (es) | 2009-02-16 | 2011-03-30 | Abbott Gmbh & Co Kg | Derivados de aminotetralina, composiciones farmaceuticas que las contienen y sus usos en terapia |
TW201038569A (en) | 2009-02-16 | 2010-11-01 | Abbott Gmbh & Co Kg | Heterocyclic compounds, pharmaceutical compositions containing them, and their use in therapy |
TWI519530B (zh) * | 2009-02-20 | 2016-02-01 | 艾伯維德國有限及兩合公司 | 羰醯胺化合物及其作為鈣蛋白酶(calpain)抑制劑之用途 |
CA2756178A1 (en) | 2009-03-27 | 2010-09-30 | Abbott Laboratories | Compounds as cannabinoid receptor ligands |
US8236822B2 (en) * | 2009-03-27 | 2012-08-07 | Abbott Laboratories | Compounds as cannabinoid receptor ligands |
WO2010111573A1 (en) * | 2009-03-27 | 2010-09-30 | Abbott Laboratories | Compounds as cannabinoid receptor ligands |
US8507493B2 (en) * | 2009-04-20 | 2013-08-13 | Abbvie Inc. | Amide and amidine derivatives and uses thereof |
US8236798B2 (en) | 2009-05-07 | 2012-08-07 | Abbott Gmbh & Co. Kg | Carboxamide compounds and their use as calpain inhibitors |
US9034875B2 (en) | 2009-05-26 | 2015-05-19 | Abbvie Inc. | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
US20220315555A1 (en) | 2009-05-26 | 2022-10-06 | Abbvie Inc. | Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases |
KR101920202B1 (ko) | 2009-05-26 | 2018-11-21 | 애브비 아일랜드 언리미티드 컴퍼니 | 암,면역 질환 및 자가면역 질환의 치료를 위한 아폽토시스-유도제 |
US8546399B2 (en) | 2009-05-26 | 2013-10-01 | Abbvie Inc. | Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases |
US8962639B2 (en) * | 2009-05-29 | 2015-02-24 | Abbvie Inc. | Potassium channel modulators |
US20110095033A1 (en) | 2009-10-28 | 2011-04-28 | Belkin International, Inc. | Portable Multi-Media Communication Device Protective Carrier and Method of Manufacture Therefor |
US8629143B2 (en) * | 2009-11-25 | 2014-01-14 | Abbvie Inc. | Potassium channel modulators |
TW201130855A (en) | 2009-12-16 | 2011-09-16 | Abbott Lab | Prodrug compounds useful as cannabinoid ligands |
PT2550258E (pt) | 2010-03-25 | 2015-11-30 | Abbvie Inc | Agentes indutores de apoptose para o tratamento de cancro e de doenças imunitárias e autoimunes |
TWI520960B (zh) | 2010-05-26 | 2016-02-11 | 艾伯維有限公司 | 用於治療癌症及免疫及自體免疫疾病之細胞凋亡誘導劑 |
US8586596B2 (en) | 2010-06-15 | 2013-11-19 | Abbvie Inc. | Compounds as cannabinoid receptor ligands |
SG187811A1 (en) | 2010-08-10 | 2013-03-28 | Abbvie Inc | Novel trpv3 modulators |
US9045459B2 (en) | 2010-08-13 | 2015-06-02 | AbbVie Deutschland GmbH & Co. KG | Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy |
US9051280B2 (en) | 2010-08-13 | 2015-06-09 | AbbVie Deutschland GmbH & Co. KG | Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy |
US8846743B2 (en) | 2010-08-13 | 2014-09-30 | Abbott Laboratories | Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy |
US8883839B2 (en) | 2010-08-13 | 2014-11-11 | Abbott Laboratories | Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy |
US8877794B2 (en) | 2010-08-13 | 2014-11-04 | Abbott Laboratories | Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy |
MX336726B (es) | 2010-09-27 | 2016-01-27 | Abbott Gmbh & Co Kg | Compuestos heterociclicos y su uso como inhibidores de la glucogeno sintasa quinasa-3. |
UA113500C2 (xx) | 2010-10-29 | 2017-02-10 | Одержані екструзією розплаву тверді дисперсії, що містять індукуючий апоптоз засіб | |
RU2598345C2 (ru) | 2010-10-29 | 2016-09-20 | Эббви Инк. | Твердые дисперсии, содержащие средства, вызывающие апоптоз |
WO2012059431A1 (en) | 2010-11-01 | 2012-05-10 | Abbott Gmbh & Co. Kg | Benzenesulfonyl or sulfonamide compounds suitable for treating disorders that respond to the modulation of the serotonin 5-ht6 receptor |
WO2012059432A1 (en) | 2010-11-01 | 2012-05-10 | Abbott Gmbh & Co. Kg | N-phenyl-(homo)piperazinyl-benzenesulfonyl or benzenesulfonamide compounds suitable for treating disorders that respond to the modulation of the 5-ht6 receptor |
WO2012067963A1 (en) | 2010-11-15 | 2012-05-24 | Abbott Laboratories | Nampt inhibitors |
TW201238950A (en) | 2010-11-15 | 2012-10-01 | Abbott Lab | NAMPT and rock inhibitors |
US8609674B2 (en) | 2010-11-16 | 2013-12-17 | Abbvie Inc. | Potassium channel modulators |
US8609669B2 (en) | 2010-11-16 | 2013-12-17 | Abbvie Inc. | Potassium channel modulators |
BR112013012740A2 (pt) | 2010-11-23 | 2016-09-13 | Abbvie Inc | sais e formas cristalinas de um agente que induz apoptose |
PT2642999T (pt) | 2010-11-23 | 2017-01-05 | Abbvie Ireland Unlimited Co | Métodos de tratamento que utilizam inibidores seletivos de bcl-2 |
US9090592B2 (en) | 2010-12-30 | 2015-07-28 | AbbVie Deutschland GmbH & Co. KG | Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors |
US8802693B1 (en) | 2011-03-09 | 2014-08-12 | Abbvie Inc. | Azaadamantane derivatives and methods of use |
US9012651B2 (en) | 2011-03-24 | 2015-04-21 | Abbvie Inc. | TRPV3 modulators |
JP5934778B2 (ja) | 2011-03-25 | 2016-06-15 | アッヴィ・インコーポレイテッド | Trpv1拮抗薬 |
US9309200B2 (en) | 2011-05-12 | 2016-04-12 | AbbVie Deutschland GmbH & Co. KG | Benzazepine derivatives, pharmaceutical compositions containing them, and their use in therapy |
US8859549B2 (en) | 2011-05-13 | 2014-10-14 | Abbvie, Inc. | Potassium channel modulators |
US8853196B2 (en) | 2011-08-05 | 2014-10-07 | AbbVie Deutschland GmbH & Co. KG | Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy |
TWI571466B (zh) | 2011-10-14 | 2017-02-21 | 艾伯維有限公司 | 用於治療癌症及免疫與自體免疫疾病之細胞凋亡誘發劑 |
TWI561521B (en) | 2011-10-14 | 2016-12-11 | Abbvie Inc | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
CA2853097A1 (en) | 2011-10-24 | 2013-05-02 | Abbvie Inc. | Novel trpv3 modulators |
US20130116241A1 (en) | 2011-11-09 | 2013-05-09 | Abbvie Inc. | Novel inhibitor compounds of phosphodiesterase type 10a |
US8846741B2 (en) | 2011-11-18 | 2014-09-30 | Abbvie Inc. | N-substituted aminobenzocycloheptene, aminotetraline, aminoindane and phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy |
WO2013096223A1 (en) | 2011-12-19 | 2013-06-27 | Abbvie Inc. | Trpv1 antagonists |
WO2013096226A1 (en) | 2011-12-19 | 2013-06-27 | Abbvie Inc. | Trpv1 antagonists |
CN103204787B (zh) * | 2012-01-17 | 2014-10-01 | 北京艾百诺科技有限公司 | 含有取代方酸的乙酸妙林酯及其应用 |
US9365512B2 (en) | 2012-02-13 | 2016-06-14 | AbbVie Deutschland GmbH & Co. KG | Isoindoline derivatives, pharmaceutical compositions containing them, and their use in therapy |
WO2013149376A1 (en) | 2012-04-02 | 2013-10-10 | Abbott Laboratories | Chemokine receptor antagonists |
MX2014012635A (es) | 2012-04-20 | 2015-05-15 | Abbvie Inc | Derivados de isoindolona. |
WO2013170118A1 (en) | 2012-05-11 | 2013-11-14 | Abbvie Inc. | Thiazolecarboxamide derivatives for use as nampt inhibitors |
US8975398B2 (en) | 2012-05-11 | 2015-03-10 | Abbvie Inc. | NAMPT inhibitors |
BR112014028042A2 (pt) | 2012-05-11 | 2017-06-27 | Abbvie Inc | inibidores de nampt |
CN104684906B (zh) | 2012-05-11 | 2017-06-09 | 艾伯维公司 | Nampt抑制剂 |
US20130317054A1 (en) | 2012-05-24 | 2013-11-28 | Abbvie Inc. | Neuronal nicotinic agonist and methods of use |
US20130317055A1 (en) | 2012-05-24 | 2013-11-28 | Abbvie Inc. | Neuronal nicotinic agonist and methods of use |
EP2858982A4 (en) | 2012-06-12 | 2015-11-11 | Abbvie Inc | PYRIDINONE AND PYRIDAZINONE DERIVATIVES |
US8796328B2 (en) | 2012-06-20 | 2014-08-05 | Abbvie Inc. | TRPV1 antagonists |
CN103626693B (zh) * | 2012-08-28 | 2016-09-14 | 中国科学院上海药物研究所 | 一类截短侧耳素衍生物、其药物组合物及其合成方法与用途 |
UA116216C2 (uk) | 2012-09-14 | 2018-02-26 | Еббві Дойчланд Гмбх Унд Ко. Кг | Трициклічні хінолінові і хіноксалінові похідні |
US20140080813A1 (en) | 2012-09-14 | 2014-03-20 | AbbVie Deutschland GmbH & Co. KG | Tricyclic quinoline and quinoxaline derivatives |
CA2901929A1 (en) | 2013-03-13 | 2014-10-02 | Abbvie Inc. | Cdk9 kinase inhibitors |
JP2016516710A (ja) | 2013-03-13 | 2016-06-09 | アッヴィ・インコーポレイテッド | ピリジン系cdk9キナーゼ阻害薬 |
UY35419A (es) | 2013-03-14 | 2014-10-31 | Abbvie Inc | Inhibidores de cdk9 quinasa de pirrolo (2,3- b) piridina |
CN105189512A (zh) | 2013-03-14 | 2015-12-23 | 艾伯维公司 | 吡咯并嘧啶cdk9激酶抑制剂 |
US20140275082A1 (en) | 2013-03-14 | 2014-09-18 | Abbvie Inc. | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
CN105209462A (zh) | 2013-03-14 | 2015-12-30 | 艾伯维德国有限责任两合公司 | 磷酸二酯酶10a型的新型抑制剂化合物 |
CA2905935A1 (en) | 2013-03-14 | 2014-09-25 | Abbvie Inc. | Pyrrolo[2,3-b]pyridine cdk9 kinase inhibitors |
CN105339366A (zh) | 2013-03-14 | 2016-02-17 | 艾伯维德国有限责任两合公司 | 带有取代的氧杂环丁烷的2-吲哚酮衍生物及其治疗血管加压素相关疾病的用途 |
US9656955B2 (en) | 2013-03-15 | 2017-05-23 | Abbvie Inc. | Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy |
US9650334B2 (en) | 2013-03-15 | 2017-05-16 | Abbvie Inc. | Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy |
KR20160062165A (ko) | 2013-10-17 | 2016-06-01 | 아비에 도이치란트 게엠베하 운트 콤파니 카게 | 아미노테트랄린 및 아미노인단 유도체, 이들을 포함하는 약제학적 조성물, 및 치료에서 이들의 용도 |
WO2015055770A1 (en) | 2013-10-17 | 2015-04-23 | AbbVie Deutschland GmbH & Co. KG | Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy |
US9840495B2 (en) | 2013-12-20 | 2017-12-12 | AbbVie Deutschland GmbH & Co. KG | Oxindole derivatives carrying a piperidyl-substituted azetidinyl substituent and use thereof for treating vasopressine-related diseases |
US9328112B2 (en) | 2014-02-06 | 2016-05-03 | Abbvie Inc. | Tetracyclic CDK9 kinase inhibitors |
WO2015173392A1 (en) | 2014-05-15 | 2015-11-19 | AbbVie Deutschland GmbH & Co. KG | Oxindole compounds carrying a co-bound spiro substituent and use thereof for treating vasopressin-related diseases |
US9617226B2 (en) | 2014-09-05 | 2017-04-11 | AbbVie Deutschland GmbH & Co. KG | Fused heterocyclic or carbocyclic compounds carrying a substituted cycloaliphatic radical and use thereof for treating vasopressin-related diseases |
US9550754B2 (en) | 2014-09-11 | 2017-01-24 | AbbVie Deutschland GmbH & Co. KG | 4,5-dihydropyrazole derivatives, pharmaceutical compositions containing them, and their use in therapy |
US20180243298A1 (en) | 2015-04-02 | 2018-08-30 | Abbvie Inc. | Trpv3 modulators |
WO2017089458A1 (en) | 2015-11-25 | 2017-06-01 | AbbVie Deutschland GmbH & Co. KG | Hexahydropyrazinobenz- or -pyrido-oxazepines carrying an oxygen-containing substituent and use thereof in the treatment of 5-ht2c-dependent disorders |
CN109153686B (zh) | 2016-05-07 | 2021-04-30 | 上海复尚慧创医药研究有限公司 | 一类蛋白激酶抑制剂 |
CN106565564A (zh) * | 2016-09-30 | 2017-04-19 | 华南农业大学 | 一种具有2‑氨基苯巯醇侧链的截短侧耳素衍生物及其制备方法和用途 |
WO2018058534A1 (zh) * | 2016-09-30 | 2018-04-05 | 华南农业大学 | 一种具有2-氨基苯巯醇侧链的截短侧耳素衍生物及其制备方法和用途 |
WO2018095432A1 (en) | 2016-11-28 | 2018-05-31 | Shanghai Fochon Pharmaceutical Co., Ltd. | Sulfoximine, sulfonimidamide, sulfondiimine and diimidosulfonamide compounds as inhibitors of indoleamine 2, 3-dioxygenase |
TWI762573B (zh) | 2017-02-10 | 2022-05-01 | 奧地利商納畢瓦治療有限責任公司 | 截短側耳素之純化 |
WO2018175449A1 (en) | 2017-03-21 | 2018-09-27 | AbbVie Deutschland GmbH & Co. KG | Proline amide compounds and their azetidine analogues carrying a specifically substituted benzyl radical |
CA3057886A1 (en) | 2017-04-18 | 2018-10-25 | Shanghai Fochon Pharmaceutical Co., Ltd. | Bcl-2 inhibitors as apoptosis-inducing agents |
CN107417586A (zh) * | 2017-06-21 | 2017-12-01 | 华南农业大学 | 一种截短侧耳素类抗生素及其制备方法和应用 |
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MX2020009586A (es) | 2018-03-14 | 2020-10-05 | Fochon Biosciences Ltd | Compuestos de (2-azabiciclo[3.1.0]hexan-2-il)pirazolo[1,5-a]pirimi dina e imidazo[1,2-b]piridazina sustituidos como inhibidores de cinasas trk. |
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CN110818648B (zh) * | 2019-12-05 | 2021-03-16 | 华南农业大学 | 一种具有三氮唑侧链的截短侧耳素衍生物及其制备方法和应用 |
CN113666883B (zh) * | 2021-07-23 | 2023-06-16 | 华南理工大学 | 一种合成4-乙烯基异噁唑衍生物的方法 |
CN114940671A (zh) * | 2022-05-10 | 2022-08-26 | 华南农业大学 | 一种具有4-氨基苯硫醇侧链的截短侧耳素衍生物及其制备方法和应用 |
CN115850137B (zh) * | 2022-11-12 | 2024-04-12 | 中国农业科学院兰州畜牧与兽药研究所 | 一种截短侧耳素衍生化合物及其制备方法与应用 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE789629A (fr) * | 1971-10-05 | 1973-04-03 | Sandoz Sa | Nouveaux derives de la pleuromutiline, leur preparation et leurapplication en therapeutique |
US4107164A (en) | 1971-10-05 | 1978-08-15 | Sandoz Ltd. | Certain pleuromulilin ester derivatives |
JPS54160358A (en) * | 1978-06-06 | 1979-12-19 | Sandoz Ag | Improvement for organic compound |
ZA80175B (en) * | 1979-01-12 | 1981-08-26 | Sandoz Ltd | New pleuromutilin derivatives, their production and use |
CY1353A (en) * | 1979-01-12 | 1987-04-24 | Sandoz Ag | New pleuromutilin derivatives, their production and use |
DE3560511D1 (en) | 1984-02-17 | 1987-10-01 | Sandoz Ag | Pleuromutilin derivatives, process for their preparation and their use |
HU208115B (en) * | 1989-10-03 | 1993-08-30 | Biochemie Gmbh | New process for producting pleuromutilin derivatives |
UY25225A1 (es) * | 1997-10-29 | 2000-12-29 | Smithkline Beecham Plc | Derivados de pleuromutilina utiles como agentes antimicrobianos |
WO2000027790A1 (en) * | 1998-11-11 | 2000-05-18 | Smithkline Beecham P.L.C. | Mutilin compounds |
PE20020676A1 (es) * | 2000-09-13 | 2002-08-27 | Biochemie Gmbh | Compuestos de mutilina como antibacterianos |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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