IPC분류정보
국가/구분 |
United States(US) Patent
등록
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국제특허분류(IPC7판) |
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출원번호 |
US-0624504
(1996-04-05)
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우선권정보 |
SE-9404467 (1994-12-22); SE-9502453 (1995-07-06) |
국제출원번호 |
PCT/SE95/01540
(1994-12-19)
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국제공개번호 |
WO96/19197
(1996-06-27)
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발명자
/ 주소 |
- Backstrom, Kjell
- Dahlback, Magnus
- Johansson, Ann
- Kallstrand, Goran
- Lindqvist, Elisabet
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출원인 / 주소 |
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대리인 / 주소 |
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인용정보 |
피인용 횟수 :
43 인용 특허 :
78 |
초록
▼
A pharmaceutical aerosol formulation comprising (a) a HFA propellant; (b) a pharmaceutically active polypeptide dispersible in the propellant; and (c) a surfactant which is a C8-C16fatty acid or salt thereof, a bile salt, a phospholipid, or an alkyl saccharide, which surfactant enhances the systemic
A pharmaceutical aerosol formulation comprising (a) a HFA propellant; (b) a pharmaceutically active polypeptide dispersible in the propellant; and (c) a surfactant which is a C8-C16fatty acid or salt thereof, a bile salt, a phospholipid, or an alkyl saccharide, which surfactant enhances the systemic absorption of the polypeptide in the lower respiratory tract. The invention also relates to methods of manufacturing such formulations and the use of such formulations in treating patients.
대표청구항
▼
A pharmaceutical aerosol formulation comprising (a) a HFA propellant; (b) a pharmaceutically active polypeptide dispersible in the propellant; and (c) a surfactant which is a C8-C16fatty acid or salt thereof, a bile salt, a phospholipid, or an alkyl saccharide, which surfactant enhances the systemic
A pharmaceutical aerosol formulation comprising (a) a HFA propellant; (b) a pharmaceutically active polypeptide dispersible in the propellant; and (c) a surfactant which is a C8-C16fatty acid or salt thereof, a bile salt, a phospholipid, or an alkyl saccharide, which surfactant enhances the systemic absorption of the polypeptide in the lower respiratory tract. The invention also relates to methods of manufacturing such formulations and the use of such formulations in treating patients. 3 N, O, or S heteroatoms, wherein said heterocyclic ring is saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7e, hydroxy, C5-C10alkoxy, nitro, N(R10e)R11e, --N(R16e)R17e, C5-C10alkyl substituted with 0-3 R7e, aryl(C0-C6alkyl)carbonyl, aryl(C3-C6alkyl), heteroaryl(C1-C6alkyl), CONR18aeR20e, SO2R18ae,or SO2NR18aeR20eand providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups is unsubstituted or substituted independently with 1-2 R7e; R6eis selected from: H, C1-C10alkyl, hydroxy, C1-C10alkoxy, nitro, C1-C10alkylcarbonyl, --N(R11e)R12e,cyano, halo, CF3,CHO, CO2R18be,C(=O)R18be,CONR17eR18be,OC(=O)R10e,OR10e,OC(=O)NR10eR11e,NR10eC(=O)R10e,NR10eC(=O)OR21e,NR10eC(=O)NR10eR11e,NR10eSO2NR10eR11e,NR10eSO2R21e,S(O)peR11e,SO2NR10eR11e, C6-C10aryl substituted with 0-3 groups selected from halogen, C1-C6alkoxy, C1-C6alkyl, CF3,S(O)meMe, or --NMe2; C7-C11arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C1-C6alkoxy, C1-C6alkyl, CF3,S(O)peMe, or --NMe2,or a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring is saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7e; R7eis selected from: H, C1-C4alkyl, hydroxy, C1-C4alkoxy, C6-C10aryl, C7-C11arylalkyl, (C1-4alkyl)carbonyl, CO2R18ae,SO2R11e,SO2NR10eR11e,OR10e,or N(R11e)R12e; Yeis selected from: --COR20e,--SO3H, --PO3H, --CONHNHSO2CF3,--CONHSO2R18ae,--CONHSO2NHR18be,--NHCOCF3,--NHCONHSO2R18ae,--NHSO2R18ae,--OPO3H2,--OSO3H, --PO3H2,--SO3H, --SO2NHCOR18ae,--SO2NHCO2R18ae,or R10eis selected from: H, C3-C6alkenyl, C3-C11cycloalkyl, C4-C11cycloalkylmethyl, aryl, aryl(C1-C4alkyl), or C1-C10alkyl substituted with 0-2 R4e; R11eis selected from: H, hydroxy, C1-C8alkyl, C3-C6alkenyl, C3-C11cycloalkyl, C4-C11cycloalkylmethyl, C1-C6alkoxy, benzyloxy, C6-C10aryl, heteroaryl, heteroarylalkyl, aryl(C1-4alkyl), adamantylmethyl, or C1-C10alkyl substituted with 0-2 R4e; alternatively, when R10eand R11eare both substituents on the same nitrogen atom they are taken together with the nitrogen atom to which t hey are attached to form a heterocycle selected from: 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl; said heterocycle being optionally substituted with 0-3 groups selected from: C1-C6alkyl, C6-C10aryl, heteroaryl, C7-C11arylalkyl, C1-C6alkylcarbonyl, C3-C7cycloalkylcarbonyl, C1-C6alkoxycarbonyl, C7-C11arylalkoxycarbonyl, C1-C6alkylsulfonyl or C6-C10arylsulfonyl; R4eis selected from: H, C1-C10alkyl, C1-C10alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl; R12eis selected from: H, C1-C6alkyl, triphenylmethyl, methoxymethyl (MOM), methoxyphenyldiphenylmethyl, trimethylsilylethoxymethyl (SEM), (C1-C6alkyl)carbonyl, (C1-C6alkoxy)carbonyl; (C1-C6alkyl)aminocarbonyl, C3-C6alkenyl, C3-C7cycloalkyl, C4-C11cycloalkylalkyl, aryl, heteroaryl(C1-C6alkyl)carbonyl, heteroarylcarbonyl, aryl C1-C6alkyl, (C1-C6alkyl)carbonyl, or arylcarbonyl, C1-C6alkylsulfonyl, arylsulfonyl, aryl(C1-C6alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl(C1-C6alkyl)sulfonyl, aryloxycarbonyl, or aryl(C1-6alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4alkyl, C1-C4alkoxy, halo, CF3,and nitro; R14eis selected from: H, C1-C4alkyl, phenyl(C1-C4alkyl), or a bond to the linking group; R16eis selected from: --C(=O)OR18ae, --C(=O)R18be, --C(=O)N(R18be)2, --C(=O)NHSO2R18ae, --C(=O)NHC(=O)R18be, --C(=O)NHC(=O)OR18ae, --C(=O)NHSO2NHR18be, --SO2R18ae, --SO2N(R18be)2or, --SO2NHC(=O)OR18be; R17eis selected from: H, C1-C6alkyl, C3-C7cycloalkyl, C4-C11cycloalkylalkyl, aryl, aryl(C1-C6alkyl)-, or heteroaryl(C1-6alkyl); R18aeis selected from: C1-C8alkyl optionally substituted with a bond to the linking group, C3-C11cycloalkyl optionally substituted with a bond to the linking group, aryl(C1-C6alkyl)- optionally substituted with a bond to the linking group, heteroaryl(C1-C6alkyl)- optionally substituted with a bond to the linking group, (C1-C6alkyl)heteroaryl optionally substituted with a bond to the linking group, biaryl(C1-C6alkyl) optionally substituted with a bond to the linking group, heteroaryl optionally substituted with a bond to the linking group, phenyl substituted with 3-4 R19eand optionally substituted with a bond to the linking group, naphthyl substituted with 0-4 R19eand optionally substituted with a bond to the linking group, and a bond to the linking group, wherein said aryl or heteroaryl groups are optionally substituted with 0-4 R19e; R18beis selected from: R18aeor H; R19eis selected from: H, halogen, CF3,CO2H, CN, NO2,NR11eR12e,C1-C8alkyl, C2 -C6alkenyl, C2-C6alkynyl, C3-C11cycloalkyl, C4-C11cycloalkylalkyl, aryl(C1-6alkyl)-, C1-C6alkoxy, OCF3,or C1-4alkoxycarbonyl, aryl, --O--aryl, --SO2--aryl, heteroaryl, or --SO2-heteroaryl, wherein said aryl and heteroaryl groups are each substituted with 0-4 groups selected from hydrogen, halogen, CF3,C1-C3alkyl, or C1-C3alkoxy; R20eis selected from: hydroxy, C1-C10alkyloxy, C3-C11cycloalkyloxy, C6-C10aryloxy, C7-C11aralkyloxy, C3-C10alkylcarbonyloxyalkyloxy, C3-C10alkoxycarbonyloxyalkyloxy, C2-C10alkoxycarbonylalkyloxy, C5-C10cycloalkylcarbonyloxyalkyloxy, C5-C10cycloalkoxycarbonyloxyalkyloxy, C5-C10cycloalkoxycarbonylalkyloxy, C7-C11aryloxycarbonylalkyloxy, C8-C12aryloxycarbonyloxyalkyloxy, C8-C12arylcarbonyloxyalkyloxy, C5-C10alkoxyalkylcarbonyloxyalkyloxy, C5-C10(5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C10-C14(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or (R11e)(R12e)N--(C1-C10alkoxy)-; R21eis selected from: C1-C8alkyl, C2-C6alkenyl, C3-C11cycloalkyl, C4-C11cycloalkylmethyl, C6-C10aryl, C7-C11arylalkyl, or C1-C10alkyl substituted with 0-2 R7e; meis 0-2; neis 0-4; peis 0-2; with the following provisos: (1) neand meare selected such that the number of atoms connecting R1eand Yeis in the range of 8-14; (2) in the definition of We,the substituent on the alkylene group is not an unsubstituted pyridyl radical. 2. A compound according to claim 1 wherein the surfactant is a lipid or a compound of the formula: A9is selected from the group: OH and OR27; A10is OR27; R27is C(=O)C1-20alkyl; E1is C1-10alkylene substituted with 1-3 R28; R28is independently selected at each occurrence from the group: R30,--PO3H-R30,=O, --CO2R29,--C(=O)R29,--C(=O)N(R29)2,--CH2OR29,--OR29,--N(R29)2,C1-C5alkyl, and C2-C4alkenyl; R29is independently selected at each occurrence from the group: R30,H, C1-C6alkyl, phenyl, benzyl, and trifluoromethyl; R30is a bond to the linking group. 3. A compound according to claim 1 wherein the linking group is absent. 4. A compound according to claim 1 wherein the linking group is Lnis of the formula: (CR6R7)g--(W)h--(CR6aR7a)g'--(Z)k--(W)h'--(CR8R9)g"--(W)h"--(CR8aR9a)g'" W is independently selected at each occurrence from the group: O, S, NH, NHC(=O), C(=O)NH, C(=O), C(=O)O, OC(=O), NHC(=S)NH, NHC(=O)NH, SO2,(OCH2CH2)20-200,(CH2CH2O)20-200,(OCH2CH2CH2)20-200,(CH2CH2CH2O)20-200,and (aa)t'; aa is independently at each occurrence an amino acid; Z is selected from the group: aryl substituted with 0-3 R10,C3-10cycloalkyl substituted with 0-3 R10,and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R10; R6,R6a,R7,R7a,R8,R8a,R9and R9aare independently selected at each occurrence from the group: H, =O, COOH, SO3H, PO3H, C1-C5alkyl substituted with 0-3 R10,aryl substituted with 0-3 R10,benzyl substituted with 0-3 R10,and C1-C5alkoxy substituted with 0-3 R10,NHC(=O)R11,C(=O)NHR11,NHC(=O)NHR11,NHR11,R11,and a bond to the surfactant; R10is independently selected at each occurrence from the group: a bond to the surfactant, COOR11,OH, NHR11,SO3H, PO3H, aryl substituted with 0-3 R11,C1-5alkyl substituted with 0-1 R12,C1-5alkoxy substituted with 0-1 R12,and a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-3 R11; R11is independently selected at each occurrence from the group: H, aryl substituted with 0-1 R12,a 5-10 membered heterocyclic ring system containing 1-4 heteroatoms independently selected from N, S, and O and substituted with 0-1 R12,C3-10cycloalkyl substituted with 0-1 R12,amino acid substituted with 0-1 R12,and a bond to the surfactant; R12is a bond to the surfactant; k is selected from 0, 1, and 2; h is selected from 0, 1, and 2; h' is selected from 0, 1, 2, 3, 4, and 5; h" is selected from 0, 1, 2, 3, 4, and 5; g is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g' is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g" is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; g'" is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and t' is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. 5. A compound according to claim 1 wherein the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Ax1, αvβ3,αvβ5,α5β1,α4β1,α1β1,and α2β2. 6. A compound according to claim 1, wherein the receptor is selected from the group: EGFR, FGFR, PDGFR, Flk-1/KDR, Flt-1, Tek, Tie, neuropilin-1, endoglin, endosialin, Axl, αvβ3,αvβ5,α5β1,α4β1,α1β1,and α2β2and the linking group is present between the targeting moiety and surfactant. 7. A compound of the formula: (Q)d--Ln--Sf wherein, Q is a compound of Formula (I), which binds to a αvβ3receptor: wherein: R1eis selected from: Deis selected from: --N(R12e)--, or --S--; Jeis selected from: --C(R2e)-- or --N--; Ke,Leand Meare independently selected from:--C(R2e)-- or --C(R3e)--; R2eand R3eare independently selected from: H, C1-C4alkoxy, NR11eR12e,halogen, NO2,CN, CF3,C1-C6alkyl, C3-C6alkenyl, C3-C7cycloalkyl, C4-C11cycloalkylalkyl, C6-C10aryl substituted with 0-4 R7e,C7-C 11arylalkyl, C2-C7alkylcarbonyl, C1-C4alkoxycarbonyl, or C7-C11arylcarbonyl; alternatively, when R2eand R3eare substituents on adjacent atoms, they are taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 groups selected from C1-C4alkyl, C1-C4alkoxy, halo, cyano, amino, CF3or NO2; Ueis selected from: --(CH2)ne--, --(CH2)neO(CH2)me--, --(CH2)neN(R12e)(CH2)me--, --(CH2)neC(=O)(CH2)me--, --(CH2)neS(O)pe(CH2)me--, --(CH2)neNHNH(CH2)me--, --N(R10e)C(=O)--, --C(=O)N(R10e)--, or --N(R10e)S(O)pe--; Weis --C(=O)--N(R10e)--(C1-C3alkylene)-, in which the alkylene group is optionally substituted by: CO2R18ae, C(=O)R18ae, CONR17eR18ae, C1-C10alkyl, substituted with 0-1 R6e, C5-C10alkenyl, substituted with 0-1 R6e, C5-C10alkynyl, substituted with 0-1 R6e, C3-C8cycloalkyl, substituted with 0-1 R6e, C5-C6cycloalkenyl, substituted with 0-1 R6e, C1-C10alkylcarbonyl, C3-C10cycloalkylalkyl, phenyl substituted with 1-3 R6e, naphthyl substituted with 0-3 R6e, a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring is saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7e, hydroxy, C5-C10alkoxy, nitro, N(R10e)R11e, --N(R16e)R17e, C5-C10alkyl substituted with 0-3 R7e, aryl(C0-C6alkyl)carbonyl, aryl(C3-C6alkyl), heteroaryl(C1-C6alkyl), CONR18aeR20e, SO2R18ae,or SO2NR18aeR20eand providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups optionally unsubstituted or substituted independently with 1-2 R7e; R6eis selected from: H, C1-C10alkyl, hydroxy, C1-C10alkoxy, nitro, C1-C10alkylcarbonyl, --N(R11e)R12e,cyano, halo, CF3,CHO, CO2R18be,C(=O)R18be,CONR17eR18be,OC(=O)R10e,OR10e,OC(=O)NR10eR11e,NR10eC(=O)R10e,NR10eC(=O)OR21e,NR10eC(=O)NR10eR11e,NR10eSO2NR11eR11e,NR10eSO2R21e,S(O)peR11e,SO2NR10eR11e,C6-C10aryl optionally substituted with 0-3 groups selected from halogen, C1-C6alkoxy, C1-C6alkyl, CF3,S(O)meMe, or --NMe2; C7-C11arylalkyl, said aryl being optionally subst
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