CN1553801A - 含三环5,6-二氢-9H-吡唑并(3,4-C)-1,2,4-三唑并(4,3-α)嘧啶的吸入组合物 - Google Patents
含三环5,6-二氢-9H-吡唑并(3,4-C)-1,2,4-三唑并(4,3-α)嘧啶的吸入组合物 Download PDFInfo
- Publication number
- CN1553801A CN1553801A CNA028178874A CN02817887A CN1553801A CN 1553801 A CN1553801 A CN 1553801A CN A028178874 A CNA028178874 A CN A028178874A CN 02817887 A CN02817887 A CN 02817887A CN 1553801 A CN1553801 A CN 1553801A
- Authority
- CN
- China
- Prior art keywords
- pyrazolo
- dihydro
- alkyl
- ethyl
- triazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 13
- 150000003222 pyridines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 239000007787 solid Substances 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 210000004072 lung Anatomy 0.000 claims abstract description 7
- 238000011282 treatment Methods 0.000 claims abstract description 7
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 44
- 238000002360 preparation method Methods 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 239000008187 granular material Substances 0.000 claims description 14
- 239000000843 powder Substances 0.000 claims description 14
- 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 claims description 11
- 229940079593 drug Drugs 0.000 claims description 11
- 239000008101 lactose Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 8
- 208000018569 Respiratory Tract disease Diseases 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 239000004005 microsphere Substances 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 8
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 7
- 208000006673 asthma Diseases 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 229910005965 SO 2 Inorganic materials 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 claims description 4
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 238000009826 distribution Methods 0.000 claims description 3
- 239000004531 microgranule Substances 0.000 claims description 3
- 239000007921 spray Substances 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000006833 (C1-C5) alkylene group Chemical group 0.000 claims description 2
- 125000006823 (C1-C6) acyl group Chemical group 0.000 claims description 2
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 238000000889 atomisation Methods 0.000 claims description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 238000007599 discharging Methods 0.000 claims 1
- 150000002632 lipids Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 206010011224 Cough Diseases 0.000 abstract description 14
- 238000009472 formulation Methods 0.000 abstract description 5
- 239000002245 particle Substances 0.000 abstract description 4
- BAIYDCLETZLHLQ-UHFFFAOYSA-N C1CN2C=NN=C2C2=C1C=NN2 Chemical class C1CN2C=NN=C2C2=C1C=NN2 BAIYDCLETZLHLQ-UHFFFAOYSA-N 0.000 abstract 1
- 208000023504 respiratory system disease Diseases 0.000 abstract 1
- 239000002775 capsule Substances 0.000 description 10
- 229960001375 lactose Drugs 0.000 description 10
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000000443 aerosol Substances 0.000 description 6
- 229960001021 lactose monohydrate Drugs 0.000 description 5
- 238000002156 mixing Methods 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 230000003203 everyday effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000000556 agonist 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
- 229940071648 metered dose inhaler Drugs 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 238000011287 therapeutic dose Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 description 1
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 description 1
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- 229940098778 Dopamine receptor agonist Drugs 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- -1 I-leucine Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 1
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- HVCNNTAUBZIYCG-UHFFFAOYSA-N ethyl 2-[4-[(6-chloro-1,3-benzothiazol-2-yl)oxy]phenoxy]propanoate Chemical compound C1=CC(OC(C)C(=O)OCC)=CC=C1OC1=NC2=CC=C(Cl)C=C2S1 HVCNNTAUBZIYCG-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 description 1
- 229960002848 formoterol Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000005828 hydrofluoroalkanes Chemical class 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- OEXHQOGQTVQTAT-JRNQLAHRSA-N ipratropium Chemical class O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 OEXHQOGQTVQTAT-JRNQLAHRSA-N 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- WTWWXOGTJWMJHI-UHFFFAOYSA-N perflubron Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br WTWWXOGTJWMJHI-UHFFFAOYSA-N 0.000 description 1
- 229960001217 perflubron Drugs 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000009781 safety test method Methods 0.000 description 1
- 229950004959 sorbitan oleate Drugs 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical class O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M13/00—Insufflators for therapeutic or disinfectant purposes, i.e. devices for blowing a gas, powder or vapour into the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Anesthesiology (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Dispersion Chemistry (AREA)
- Biochemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Otolaryngology (AREA)
- Molecular Biology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明涉及一种吸入制剂,它包含选自一种特殊的5,6-二氢-9H-吡唑并(3,4-C)-1,2,4-三唑并(4,3-α)嘧啶类化合物,该制剂能将化合物以固体细粒的形式释放至肺中,并涉及该制剂在治疗诸如呼吸道疾病的某些疾病中的应用。使用这种制剂能消除由于使用这种化合物的溶液计量的剂量吸入器而引起的不必要的咳嗽。
Description
本发明涉及一种吸入制剂,它包含选自一种特殊的5,6-二氢-9H-吡唑并(3,4-C)-1,2,4-三唑并(4,3-α)嘧啶类化合物,该制剂能将化合物以固体细粒的形式释放至肺中,还涉及该制剂在治疗诸如呼吸道疾病的某些疾病中的应用。
用于本发明的化合物为式(I)化合物
和其药学可接受的盐;其中
R1为氢、(C1-C6)烷基、(C1-C6)烷氧基、(C2-C4)链烯基、苯基、二甲基氨基、(C3-C6)环烷基、(C3-C6)环烷基(C1-C3)烷基或(C1-C6)酰基,其中烷基、苯基或链烯基可以用两个羟基、(C1-C3)烷基、或三氟甲基、或三个卤素取代;
R2和R3各自分别选自氢、(C1-C14)烷基、(C1-C7)烷氧基(C1-C7)烷基、(C2-C14)链烯基、(C3-C7)环烷基、(C3-C7)环烷基(C1-C2)烷基、饱和或不饱和的(C4-C7)杂环(CH2)n基团,其中n为0、1或2,包括一个或两个选自氧、硫、磺酰基、氮和NR4的杂原子基团,其中R4为氢或(C1-C4)烷基;或选自式
其中a为1-5的整数;b和c为0或1;R5为氢、羟基、(C1-C5)烷基、(C2-C5)链烯基、(C1-C5)烷氧基、(C3-C6)环烷氧基、卤素、三氟甲基、CO2R6、CONR6R7、NR6R7、NO2或SO2NR6R7,其中R6和R7各自分别为氢或(C1-C4)烷基;其中Z为氧、硫、SO2、CO或NR8,其中R8为氢或(C1-C4)烷基;Y为(C1-C5)亚烃基或(C2-C6)链烯基,它们可任意用两个(C1-C7)烷基或(C3-C7)环烷基取代;其中每一个烷基、链烯基、环烷基、烷氧烷基或杂环基团可用1-14个选自(C1-C2)烷基、三氟甲基或卤素的基团取代;和R9和R10各自分别选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C6-C10)芳基、和(C6-C10)芳氧基。
在国际专利申请WO-A-96/39408中记载了这些化合物,它们是选择性PDE4抑制剂。其中描述了可通过吸入上述三环5,6-二氢-9H-吡唑并[3,4-C]-1,2,4-三唑并[4,3-α]嘧啶而得以治疗的疾病包括呼吸道疾病,例如哮喘和慢性阻塞性气道疾病(COAD,也叫做慢性阻塞性肺疾病(COPD))。
前面所述申请提到其中所描述的化合物的对于一个普通成年患者的最佳治疗剂量通常为0.1-400mg/天。这表示一般将用于吸入器给药的剂量配制为0.1-1%(w/v)溶液。虽然没有明示,但这种溶液的典型给药剂型应该是计量吸入(MDI)。
根据对多剂量患者的研究,即用一种溶液MDI(通过一个‘间隔装置’)一天中多次间隔服用小剂量的所述化合物,已计算出每天吸入3mg活性化合物可有效治疗哮喘和COAD。然而,尝试用MDI溶液以更合理的剂量次数服用,典型的每天不超过四次,大多数患者总是产生中度咳嗽反应。咳嗽程度不一,但在治疗过程中一些哮喘患者症状恶化并伴随更严重的咳嗽。咳嗽反应可阻止足以产生所需治疗效果的药物被吸收到预定部位,并且最重要的是可能对患者的顺应性产生严重的影响。
我们惊奇地发现,当以固体细颗粒的形式服用活性化合物尤其是采用干粉吸入器时,患者很少或不出现咳嗽反应而用同样剂量的溶液MDI则可引起咳嗽。患者可接受全部治疗量的化合物或其主要的合理部分,即患者适应的剂量数(典型的是不超过4次/天)。这完全出乎意料,因为咳嗽反应通常与化合物本身相关,而粉末或悬浮液制剂具有潜在的刺激性。
因此,本发明提供一种含有如上所述的式(I)化合物或其药学上可接受的盐的吸入制剂,其特征在于该制剂能将化合物以固体细粒的形式释放至肺中。
另外,本发明提供该吸入制剂在制备用于治疗可通过抑制PDE4而得以治疗的疾病中的应用,尤其是呼吸道疾病,例如,哮喘或慢性阻塞性肺疾病。
此外,本发明提供一种治疗可通过抑制PDE4而得以治疗的疾病的方法,尤其是呼吸道疾病,例如,哮喘或慢性阻塞性肺疾病,该方法包括给哺乳动物服用这种吸入制剂。
用于本发明的优选化合物在生理pH小于0.15mg/ml时具有水溶性。尤其优选该pH小于0.05mg/ml的水溶性化合物。为了实现本发明的目的,将“生理pH”限定为6.0-8.0。可通过下述方法测定溶解度,用合适的pH缓冲液稀释所称重量的试验化合物、摇动该混合物24小时、过滤此混合物并用LC-MS(液体-色谱-质谱)测定滤液的饱和溶解度。
优选的式(I)化合物包括其中烷基、链烯基、环烷基、烷氧烷基或杂环基团每一个可用1-5个选自(C1-C2)烷基、三氟甲基和氢取代的那些化合物。
优选,R1为甲基、乙基或异丙基。
优选,R3为(C1-C6)烷基、(C2-C6)链烯基、(C3-C7)环烷基、(C3-C7)环烷基、(C1-C2)烷基或苯基,它们可任意用1或2个氢、羟基、(C1-C5)烷基、(C2-C5)链烯基、(C1-C5)烷氧基、卤素、三氟甲基、CO2R6、CONR6R7、NR6R7、NO2、或SO2NR6R7取代,其中R6和R7各自为氢或(C1-C4)烷基。
优选的单个式(I)化合物为:
9-环戊基-5,6-二氢-7-乙基-3-苯基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-]嘧啶;
9-环苯基-5,6-二氢-7-乙基-3-(呋喃-2-yl)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-吡啶基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-(4-吡啶基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-(3-噻吩基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
3-苄基-9-环戊基-5,6-二氢-7-乙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-丙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
3,9-二环戊基-5,6-二氢-7-乙基-9S吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-(1-甲基环己-1-基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
3-(叔-丁基)-9-环戊基-5,6-二氢-7-乙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-甲基苯基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-甲氧基苯基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-(噻吩-2-基)-9H-吡唑并[3,4-c]1,2,4-三唑并[4,3-α]嘧啶;
3-(2-氯苯基)-9-环戊基-5,6-二氢-7-乙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-碘苯基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-三氟甲基苯基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;和
5,6-二氢-7-乙基-9-(4-氟苯基)-3-(1-甲基环己-1-基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
和其药学上可接受的盐。
特别优选的式(I)化合物为3-(叔-丁基)-9-环戊基-5,6-二氢-7-乙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶和9-环戊基-5,6-二氢-7-乙基-3-(噻吩-2-基)-9H-吡唑并[3,4-c]1,2,4-三唑并[4,3-α]嘧啶,和其药学上可接受的盐。
最优选的是9-环戊基-5,6-二氢-7-乙基-3-(噻吩-2-基)-9H-吡唑并[3,4-c]1,2,4-三唑并[4,3-α]嘧啶,和其药学上可接受的盐,尤其是游离碱。
根据本发明的目的,“细”的固体药物颗粒可以是直径小于20微米的那些。优选,所用的粉状药物具有如下粒度大小,其中90%颗粒的直径小于10微米,和50%颗粒的直径小于5微米。更优选,所用的粉状药物具有如下粒度大小,其中90%颗粒的直径小于6微米,和50%颗粒的直径小于3微米。最优选,所用的粉状药物具有如下粒度大小,其中95%颗粒的直径小于5微米,和50%颗粒的直径小于2.5微米。
通过将大体积的药物粉碎(磨碎)或通过微粒工程可得到合适的粒度大小分布。微粒工程的例子有超临界流体结晶和微球体制备(例如通过喷雾干燥)。
能将通过上述工艺生产的固体细粒释放至患者的肺中的装置包括干粉吸入器、悬浮液计量剂量吸入器、悬浮液雾化器和悬浮液喷雾器。优选干粉吸入器。用于本发明的合适的干粉吸入器包括胶囊装置,例如Spinhaler(商标)、Rotahaler(商标)、Handihaler(商标)、Aerohaler(商标)、Eclipse(商标)、Turbospin(商标)和Flowcaps(商标)吸入器。用于本发明的其它干粉吸入器包括多剂量吸入器,例如Turbuhaler(商标),Turbuhaler(商标),Ultrahaler(商标),Diskhaler(商标),Novoliser(商标),Easyhaler(商标),Taifun(商标),Clickhaler(商标),Twisthaler(商标)和Aspirair(商标)。
式(I)化合物可单独给药,但通常与适合的药用赋形剂、稀释剂或载体混合给药,其中的药用赋形剂、稀释剂或载体是根据所选用的吸入方式和标准的药物实践来选择的。
当从加压的容器、泵、喷射器、喷雾器(例如利用水电动力学产生极好的喷雾的喷雾器)或雾化器中产生气溶胶喷雾时,可使用合适的推进剂例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、氢氟烷烃,如1,1,1,2-四氟乙烷(HFA 134A[商标])或1,1,1,2,3,3,3-七氟丙烷(HFA 227EA[商标])、二氧化碳,还包括全氟化的烃例如Perflubron(商标)或其它适合的气体。在加压的气溶胶中,该剂量单位可通过提供一种计量的输送阀来确定。药物将分散在诸如水或含水乙醇的适合试剂中。也可包括润滑剂如失水山梨糖醇油酸酯。
用于吸入器中的胶囊、泡(blisters)和柱体(例如由明胶或HPMC制成)可配制成含式(I)化合物、适合的粉末基质如乳糖或淀粉、和性能调节剂如I-亮氨酸、甘露醇、海藻糖或硬脂酸镁的粉末混合物。根据本发明的目的,优选的干粉制剂由式(I)化合物或其盐、以及乳糖(优选乳糖一水化物)组成的干粉混合物。乳糖应该达到足够细的等级,其90%乳糖颗粒的直径小于1000微米且50%乳糖颗粒的直径小于500微米。优选,90%乳糖颗粒的直径小于300微米且50%乳糖颗粒的直径小于100微米。最优选,90%乳糖颗粒的直径小于100-200微米、50%乳糖颗粒的直径小于40-70微米、10%乳糖颗粒的直径小于10微米。载药量可从干粉混合物的0.1-100%w/w不等,优选5-100%w/w,最优选5-40%w/w。
优选制备的气溶胶或干粉制剂是每一计量或“喷出”的剂量包含1-10000μg式(I)化合物释放至患者。气溶胶每日总剂量范围为1μg-20mg,此剂量可单剂量给药,或者通常为全天分剂量给药。
将细的固体药物颗粒释放至肺中的另一种方法是使用含聚(D,L-乳酸-共-乙二醇酸)的微球体,其中这种微球体是在从溶液计量的剂量吸入器释放后在原位产生的。
根据本发明,所释放的细的固体药物颗粒可任意以脂质体的形式释放以调节它们的释放性能。
本发明的制剂可包括一种或多种药理学活性剂,包括:
(a)A2a激动剂,例如在WO-A-00/23457,WO-A-00/77018,WO-A-01/27131,WO-A-01/27130,WO-A-01/60835,WO-A-02/00676 and WO-A-01/94368中一般和特别公开的化合物之一,优选9-[(2R,3R,4S,5R)-3,4-二羟基-5-(羟基甲基)四氢-2-呋喃基]-6-[(2,2-二苯基乙基)氨基]-N-[2-(1-哌啶基)乙基]-9H-嘌呤-2-羰基酰胺或其药学上可接受的盐或溶剂化物,或6-[(2,2-二苯基乙基)氨基]-9-{(2R,3R,4S,5S)-5-[(乙基氨基)羰基]-3,4-二羟基四氢-2-呋喃基}-N-{2-[({[1-(2-吡啶基)-4-哌啶]氨基}羰基)氨基]乙基}-9H-嘌呤-2-羰基酰胺或其药学上可接受的盐或溶剂化物;
(b)反副交感神经生理作用剂,例如噻托铵盐、异丙托铵盐或氧托铵盐或其溶化物;
(c)β2肾上腺素受体激动剂,例如沙美特罗或福莫特罗或其药学上可接受的盐或溶剂化物;
(d)皮质类固醇;或
(e)多巴胺D2受体激动剂。
应该清楚,本文所指的所有治疗包括治愈性的、缓解性的和预防性的治疗。
实施例
在实施例1-3每一个实施例中,乳糖一水化物粒度分布有90%的直径小于190微米,50%直径小于55微米,以及10%直径小6微米,并且药物粒度分布有90%的直径小于5.8微米,50%直径小于2.9微米,以及10%直径小于1.0微米。
实施例1---干粉吸入胶囊(0.5mg)
将9-环戊基-5,6-二氢-7-乙基-3-(噻吩-2-基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶(0.5mg,通过螺旋空气喷射研磨机粉碎)和乳糖一水化物(9.5mg,Pharmatose 150M(DMV)Ph.Eur)手工混合,并填充到3号不透明胶囊壳(由Capsugel,product code 1505提供)中。
实施例2---干粉吸入胶囊(1mg)
将9-环戊基-5,6-二氢-7-乙基-3-(噻吩-2-基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶(1.0mg,通过螺旋空气喷射研磨机粉碎)和乳糖一水化物(19mg,Pharmatose 150M(DMV)Ph.Eur)手工混合,并填充到3号不透明胶囊壳(由Capsugel,product code 1505提供)中。
实施例3---干粉吸入胶囊(2mg)
将9-环戊基-5,6-二氢-7-乙基-3-(噻吩-2-基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶(2.0mg,通过螺旋空气喷射研磨机粉碎)和乳糖一水化物(38mg,Pharmatose 150M(DMV)Ph.Eur)手工混合,并填充到3号不透明胶囊壳(由Capsugel,product code1505提供)中。
实施例4---干粉吸入器
将根据实施例1-3生产的胶囊装填在单剂量吸入器(supplied by PlastiapeSpA)中,用于病人。
实施例5---临床数据
在临床试验中选用健康志愿者对实施例1-3的制剂进行耐受性和安全性试验。如实施例4所述,用干粉吸入器对志愿者给药,胶囊分别含实施例1、2和3的0.5mg、1mg和2mg剂量,或用仅含乳糖的安慰剂胶囊。采用剂量增加的方式,测定每种咳嗽的数量、严重程度、持续时间和性质。一些结果如表1所示。
剂量 | 在服用下列剂量后的开始5分钟内患者咳嗽的百分数 | |
安慰剂(干粉) | 活性成分(干粉) | |
1×0.5mg | - | 0(0/9) |
2×0.5mg | - | 11(1/9) |
1×1mg | 0(0/6) | 22(2/9) |
2×1mg | 0(0/6) | 22(2/9) |
1×2mg | 0(0/3) | 33(3/9) |
2×2mg | 0(0/3) | 11(1/9) |
3×2mg | 0(0/3) | 29(2/7) |
当相当于1×0.5mg干粉剂量经溶液MDI服用时,大约80-100%患者在给药后的开始5分钟出现咳嗽。与溶液计量吸入器相比,使用干粉吸入器不仅大大减少了咳嗽的百分数,而且这些咳嗽的严重程度也大为降低。并且,使用干粉吸入器的咳嗽发病率在治疗剂量范围内是可接受的。
Claims (27)
1.一种包含式(I)化合物
或其药学上可接受的盐的吸入制剂;其中
R1为氢、(C1-C6)烷基、(C1-C6)烷氧基、(C2-C4)链烯基、苯基、二甲基氨基、(C3-C6)环烷基、(C3-C6)环烷基(C1-C3)烷基或(C1-C6)酰基,其中烷基、苯基或链烯基可以用两个羟基、(C1-C3)烷基、或三氟甲基、或三个卤素取代;
R2和R3各自分别选自氢、(C1-C14)烷基、(C1-C7)烷氧基(C1-C7)烷基、(C2-C14)链烯基、(C3-C7)环烷基、(C3-C7)环烷基(C1-C2)烷基、饱和或不饱和的(C4-C7)杂环(CH2)n基团,其中n为0、1或2,包括一个或两个选自氧、硫、磺酰基、氮和NR4的杂原子基团,其中R4为氢或(C1-C4)烷基;或选自式
其中a为1-5的整数;b和c为0或1;R5为氢、羟基、(C1-C5)烷基、(C2-C5)链烯基、(C1-C5)烷氧基、(C3-C6)环烷氧基、卤素、三氟甲基、CO2R6、CONR6R7、NR6R7、NO2或SO2NR6R7,其中R6和R7各自分别为氢或(C1-C4)烷基;其中Z为氧、硫、SO2、CO或NR8,其中R8为氢或(C1-C4)烷基;Y为(C1-C5)亚烃基或(C2-C6)链烯基,它们可任意用两个(C1-C7)烷基或(C3-C7)环烷基取代;其中每一个烷基、链烯基、环烷基、烷氧烷基或杂环基团可用1-14个选自(C1-C2)烷基、三氟甲基或卤素的基团取代;和R9和R10各自分别选自氢、(C1-C6)烷基、(C1-C6)烷氧基、(C6-C10)芳基、和(C6-C10)芳氧基;
其特征在于该制剂能将化合物以固体细粒的形式释放至肺中。
2.根据权利要求1的吸入制剂,其中每一烷基、链烯基、环烷基、烷氧烷基和杂环基团可用1-5个选自(C1-C2)烷基、三氟甲基和氢的基团取代。
3.根据权利要求1或2的吸入制剂,其中R1为甲基、乙基或异丙基。
4.根据前面任一权利要求的吸入制剂,其中R3为(C1-C6)烷基、(C2-C6)链烯基、(C3-C7)环烷基、(C3-C7)环烷基(C1-C2)烷基或苯基,它们可任意用1或2个氢、羟基、(C1-C5)烷基、(C2-C5)链烯基、(C1-C5)烷氧基、卤素、三氟甲基、CO2R6、CONR6R7、NR6R7、NO2或SO2NR6R1,其中R6和R7各自分别为氢或(C1-C4)烷基。
5.根据权利要求1的吸入制剂,其中式(I)化合物选自:
9-环戊基-5,6-二氢-7-乙基-3-苯基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环苯基-5,6-二氢-7-乙基-3-(呋喃-2-yl)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-吡啶基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-(4-吡啶基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-(3-噻吩基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
3-苄基-9-环戊基-5,6-二氢-7-乙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-丙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
3,9-二环戊基-5,6-二氢-7-乙基-9S吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-(1-甲基环己-1-基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
3-(叔-丁基)-9-环戊基-5,6-二氢-7-乙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-甲基苯基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-甲氧基苯基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-(噻吩-2-基)-9H-吡唑并[3,4-c]1,2,4-三唑并[4,3-α]嘧啶;
3-(2-氯苯基)-9-环戊基-5,6-二氢-7-乙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-碘苯基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
9-环戊基-5,6-二氢-7-乙基-3-(2-三氟甲基苯基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;和
5,6-二氢-7-乙基-9-(4-氟苯基)-3-(1-甲基环己-1-基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶;
及其药学上可接受的盐。
6.根据权利要求1的吸入制剂,其中式(I)化合物为3-(叔-丁基)-9-环戊基-5,6-二氢-7-乙基-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-α]嘧啶。
7.根据权利要求1的吸入制剂,其中式(I)化合物为9-环戊基-5,6-二氢-7-乙基-3-(噻吩-2-基)-9H-吡唑并[3,4-c]1,2,4-三唑并[4,3-α]嘧啶。
8.根据权利要求1的吸入制剂,其中式(I)化合物在小于0.15mg/ml的生理pH时具有水溶性。
9.根据权利要求8的吸入制剂,其中式(I)化合物在小于0.05mg/ml的生理pH时具有水溶性。
10.根据前面任一权利要求的吸入制剂,其中固体药物细颗粒大小分布是90%的直径小于10微米和50%的直径小于5微米。
11.根据权利要求10的吸入制剂,其中固体药物细颗粒大小分布是90%的直径小于6微米和50%的直径小于3微米。
12.根据前面任一权利要求的吸入制剂,其中固体细颗粒通过干粉吸入器释放到肺中。
13.根据权利要求12的吸入制剂,其中干粉混合物包括乳糖,优选其一水合物形式。
14.根据前面权利要求1-11任一的吸入制剂,其中固体细颗粒通过悬浮液计量的剂量吸入器、悬浮液喷雾器和悬浮液雾化器释放。
15.根据前面权利要求1-11任一的吸入制剂,其中固体细颗粒由微球体组成,所述的微球体包含聚(D,L-乳酸-共-乙二醇酸)。
16.用作药剂的前面任一权利要求的吸入制剂。
17.前面权利要求1-15任一的吸入制剂在制备用于治疗通过抑制PDE4可治疗的疾病的药物中的应用。
18.根据权利要求17的应用,其中疾病为呼吸道疾病。
19.根据权利要求18的应用,其中呼吸道疾病为哮喘或慢性阻塞性肺疾病。
20.一种通过抑制PDE4可治疗疾病的治疗方法,包括给哺乳动物服用权利要求1-15任一的吸入制剂。
21.根据权利要求20的治疗方法,其中疾病为呼吸道疾病。
22.根据权利要求21的治疗方法,其中呼吸道疾病为哮喘或慢性阻塞性肺疾病。
23.如权利要求1所述的、在小于0.15mg/ml的生理pH时具有水溶性的式(I)化合物在用于制备吸入给药的药物中的应用,其特征在于所述的药物是以干粉吸入器或其它能释放低溶解性颗粒的器件的形式。
24.根据权利要求23的应用,其中所述的药物是以除干粉吸入器之外的能释放低溶解性颗粒的器件的形式,该器件是悬浮液计量的剂量吸入器、或者是能释放脂质体、微粉化/微粒工程制造的颗粒、或微球体的器件。
25.根据权利要求24的应用,其中所述的器件为能释放微球体的器件,该微球体包含聚(D,L-乳酸-共-乙二醇酸)。
26.一种含权利要求23所述式(I)化合物的干粉吸入器。
27.一种除能释放低溶解性颗粒的干粉吸入器之外的器件,该器件包含权利要求23所述的式(I)化合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0122031.8 | 2001-09-12 | ||
GBGB0122031.8A GB0122031D0 (en) | 2001-09-12 | 2001-09-12 | Use of pde4 inhibitors in a dry powder inhaler |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1553801A true CN1553801A (zh) | 2004-12-08 |
Family
ID=9921954
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA028178874A Pending CN1553801A (zh) | 2001-09-12 | 2002-09-02 | 含三环5,6-二氢-9H-吡唑并(3,4-C)-1,2,4-三唑并(4,3-α)嘧啶的吸入组合物 |
Country Status (34)
Country | Link |
---|---|
US (3) | US20030064031A1 (zh) |
EP (1) | EP1427414A1 (zh) |
JP (1) | JP2005505560A (zh) |
KR (1) | KR20040036940A (zh) |
CN (1) | CN1553801A (zh) |
AP (2) | AP2002002623A0 (zh) |
AR (2) | AR036473A1 (zh) |
BG (1) | BG108569A (zh) |
BR (1) | BR0212449A (zh) |
CA (1) | CA2457717A1 (zh) |
CZ (1) | CZ2004310A3 (zh) |
EA (1) | EA006742B1 (zh) |
EC (1) | ECSP045018A (zh) |
EE (1) | EE200400078A (zh) |
GB (1) | GB0122031D0 (zh) |
HN (2) | HN2002000253A (zh) |
HR (1) | HRP20040162A2 (zh) |
HU (1) | HUP0401890A3 (zh) |
IL (1) | IL160380A0 (zh) |
IS (1) | IS7151A (zh) |
MA (1) | MA27062A1 (zh) |
MX (1) | MXPA04002354A (zh) |
NO (1) | NO20041011L (zh) |
NZ (1) | NZ530929A (zh) |
OA (1) | OA12660A (zh) |
PA (2) | PA8554601A1 (zh) |
PE (2) | PE20030443A1 (zh) |
PL (1) | PL368736A1 (zh) |
SK (1) | SK1272004A3 (zh) |
SV (2) | SV2004001227A (zh) |
TN (1) | TNSN04040A1 (zh) |
TW (1) | TW200602054A (zh) |
WO (2) | WO2003022275A1 (zh) |
ZA (1) | ZA200401002B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106794157A (zh) * | 2014-09-15 | 2017-05-31 | 维罗纳制药公司 | 包含rpl554的液体吸入制剂 |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7931022B2 (en) | 2001-10-19 | 2011-04-26 | Respirks, Inc. | Method and apparatus for dispensing inhalator medicament |
JP2006513235A (ja) * | 2002-12-31 | 2006-04-20 | ネクター セラピューティクス | 真菌感染症療法のためのエアゾール化可能な医薬製剤 |
GB0315889D0 (en) | 2003-07-08 | 2003-08-13 | Aventis Pharma Ltd | Stable pharmaceutical products |
US20060009435A1 (en) * | 2004-06-23 | 2006-01-12 | Joseph Kaspi | Synthesis and powder preparation of fluticasone propionate |
CA2623882A1 (en) * | 2005-09-28 | 2007-04-05 | Merck Frosst Canada Ltd. | Aerosol powder formulation comprising sieved lactose |
GB0801876D0 (en) * | 2008-02-01 | 2008-03-12 | Vectura Group Plc | Suspension formulations |
US8834931B2 (en) | 2009-12-25 | 2014-09-16 | Mahmut Bilgic | Dry powder formulation containing tiotropium for inhalation |
TR200909788A2 (tr) * | 2009-12-25 | 2011-07-21 | Bi̇lgi̇ç Mahmut | Tiotropyum içeren inhalasyona uygun kuru toz formülasyonu |
CN105121439A (zh) | 2013-02-19 | 2015-12-02 | 辉瑞公司 | 作为pde4亚型抑制剂用于治疗cns和其他病症的氮杂苯并咪唑化合物 |
KR20150076005A (ko) | 2013-12-26 | 2015-07-06 | 삼성디스플레이 주식회사 | 액정 표시 장치 |
EP3172210B1 (en) | 2014-07-24 | 2020-01-15 | Pfizer Inc | Pyrazolopyrimidine compounds |
KR102061952B1 (ko) | 2014-08-06 | 2020-01-02 | 화이자 인코포레이티드 | 이미다조피리다진 화합물 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SK282167B6 (sk) * | 1995-06-06 | 2001-11-06 | Pfizer Inc. | Tricyklické 5,6-dihydro-9h-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a] pyridíny a farmaceutický prostriedok na ich báze |
US5985309A (en) * | 1996-05-24 | 1999-11-16 | Massachusetts Institute Of Technology | Preparation of particles for inhalation |
DE19835346A1 (de) * | 1998-08-05 | 2000-02-10 | Boehringer Ingelheim Pharma | Zweiteilige Kapsel zur Aufnahme von pharmazeutischen Zubereitungen für Pulverinhalatoren |
-
2001
- 2001-09-12 GB GBGB0122031.8A patent/GB0122031D0/en not_active Ceased
-
2002
- 2002-09-02 IL IL16038002A patent/IL160380A0/xx unknown
- 2002-09-02 CA CA002457717A patent/CA2457717A1/en not_active Abandoned
- 2002-09-02 EA EA200400301A patent/EA006742B1/ru not_active IP Right Cessation
- 2002-09-02 BR BR0212449-1A patent/BR0212449A/pt not_active IP Right Cessation
- 2002-09-02 OA OA1200400071A patent/OA12660A/en unknown
- 2002-09-02 SK SK127-2004A patent/SK1272004A3/sk not_active Application Discontinuation
- 2002-09-02 KR KR10-2004-7003619A patent/KR20040036940A/ko active IP Right Grant
- 2002-09-02 EE EEP200400078A patent/EE200400078A/xx unknown
- 2002-09-02 NZ NZ530929A patent/NZ530929A/en unknown
- 2002-09-02 CN CNA028178874A patent/CN1553801A/zh active Pending
- 2002-09-02 MX MXPA04002354A patent/MXPA04002354A/es not_active Application Discontinuation
- 2002-09-02 EP EP02767763A patent/EP1427414A1/en not_active Withdrawn
- 2002-09-02 JP JP2003526404A patent/JP2005505560A/ja not_active Withdrawn
- 2002-09-02 CZ CZ2004310A patent/CZ2004310A3/cs unknown
- 2002-09-02 PL PL02368736A patent/PL368736A1/xx not_active Application Discontinuation
- 2002-09-02 HU HU0401890A patent/HUP0401890A3/hu unknown
- 2002-09-02 WO PCT/IB2002/003599 patent/WO2003022275A1/en not_active Application Discontinuation
- 2002-09-02 WO PCT/IB2002/003598 patent/WO2003022279A1/en not_active Application Discontinuation
- 2002-09-05 US US10/236,551 patent/US20030064031A1/en active Pending
- 2002-09-05 US US10/236,228 patent/US20030064034A1/en not_active Abandoned
- 2002-09-10 PE PE2002000894A patent/PE20030443A1/es not_active Application Discontinuation
- 2002-09-10 AR ARP020103426A patent/AR036473A1/es unknown
- 2002-09-10 AR ARP020103427A patent/AR036474A1/es unknown
- 2002-09-10 PE PE2002000893A patent/PE20030509A1/es not_active Application Discontinuation
- 2002-09-11 TW TW094130352A patent/TW200602054A/zh unknown
- 2002-09-11 HN HN2002000253A patent/HN2002000253A/es unknown
- 2002-09-12 SV SV2002001227A patent/SV2004001227A/es not_active Application Discontinuation
- 2002-09-12 AP APAP/P/2002/002623A patent/AP2002002623A0/en unknown
- 2002-09-12 PA PA20028554601A patent/PA8554601A1/es unknown
- 2002-09-12 SV SV2002001226A patent/SV2004001226A/es not_active Application Discontinuation
- 2002-09-12 AP APAP/P/2002/002624A patent/AP2002002624A0/en unknown
- 2002-09-12 PA PA20028554701A patent/PA8554701A1/es unknown
- 2002-10-11 HN HN2002000254A patent/HN2002000254A/es unknown
-
2004
- 2004-02-06 ZA ZA200401002A patent/ZA200401002B/en unknown
- 2004-02-09 BG BG108569A patent/BG108569A/bg unknown
- 2004-02-13 IS IS7151A patent/IS7151A/is unknown
- 2004-02-19 HR HR20040162A patent/HRP20040162A2/xx not_active Application Discontinuation
- 2004-02-26 MA MA27550A patent/MA27062A1/fr unknown
- 2004-03-10 NO NO20041011A patent/NO20041011L/no not_active Application Discontinuation
- 2004-03-10 TN TNP2004000040A patent/TNSN04040A1/fr unknown
- 2004-03-12 EC EC2004005018A patent/ECSP045018A/es unknown
-
2005
- 2005-06-13 US US11/152,741 patent/US20050232871A1/en not_active Abandoned
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106794157A (zh) * | 2014-09-15 | 2017-05-31 | 维罗纳制药公司 | 包含rpl554的液体吸入制剂 |
CN110051627A (zh) * | 2014-09-15 | 2019-07-26 | 维罗纳制药公司 | 包含rpl554的液体吸入制剂 |
CN111249260A (zh) * | 2014-09-15 | 2020-06-09 | 维罗纳制药公司 | 包含rpl554的液体吸入制剂 |
CN106794157B (zh) * | 2014-09-15 | 2021-03-09 | 维罗纳制药公司 | 包含rpl554的液体吸入制剂 |
US10945950B2 (en) | 2014-09-15 | 2021-03-16 | Verona Pharma Plc | Liquid inhalation formulation comprising RPL554 |
CN111249260B (zh) * | 2014-09-15 | 2023-01-10 | 维罗纳制药公司 | 包含rpl554的液体吸入制剂 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20050232871A1 (en) | Use of compounds in a dry powder inhaler | |
CN105102436B (zh) | 微晶二酮哌嗪组合物以及方法 | |
KR20160141776A (ko) | 연령 관련 병태를 치료하기 위한 흡입가능한 라파마이신 제제 | |
CN105101955B (zh) | 至少包含两种通过喷雾干燥以增加制剂稳定性而得到的干粉的组合物 | |
AU2003273273B2 (en) | Trospium containing compositions | |
AU2021200503B2 (en) | Composition comprising at least one dry powder obtained by spray drying to increase the stability of the formulation | |
KR20150018526A (ko) | 아베디테롤의 신규한 투약 형태 및 제형 | |
RU2470639C2 (ru) | Композиции для ингаляции, содержащие кислоту монтелукаст и ингибитор pde-4 или ингаляционный кортикостероид | |
JP2009514779A (ja) | 医薬製剤 | |
Yadav et al. | Dry powder inhalers: a review | |
BRPI0614394A2 (pt) | uso de sais de tiotrópio | |
EA015353B1 (ru) | Применение солей тиотропия для лечения персистирующей астмы средней тяжести | |
AU2002330687A1 (en) | Inhalation compositions comprising tricyclis 5,6-dihydro-9H-pyrazolo (3,4-c)-1,2,4-triazolo (4,3-alpha) pyridines | |
RU2634258C1 (ru) | Наполнитель для капсульного ингалятора | |
WO2009013286A1 (en) | Organic compounds | |
Sharma et al. | Formulation and Characterization of Dry Powder Inhalers for Pulmonary Drug Delivery | |
CN104998250B (zh) | 一种恩替卡韦与甘露聚糖肽药物组合物及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1067552 Country of ref document: HK |
|
AD01 | Patent right deemed abandoned | ||
C20 | Patent right or utility model deemed to be abandoned or is abandoned | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1067552 Country of ref document: HK |