USPatentGranted
B2Pyrrolobenzodiazepines as unsymmetrical dimeric PBD compounds for inclusion in targeted conjugates
Granted 23 Feb 2016 · 2 office actions
Current assignee: MEDIMMUNE (Astrazeneca) · originally AstraZeneca
Law firm: Law firm · Log in to unlock
Attorney: Attorney · Log in to unlock
Inventors: Philip Wilson Howard · Examiner: Taofiq A Solola · AU 1622 · TC 1600
Application
14/346,006
filed 20 Sep 2012
Publication
US 20150158869
published 11 Jun 2015
Patent· this page
US 9,266,894
granted 23 Feb 2016
76
Claims
3 independent
76
File wrapper
transactions
2032
20-year term
term adjustment not held
none
Litigation
checked
6
Classifications
C07K5/065, C07D487/04
275
Citations
273 cites · 2 cited by
Life of the patent
4 dated events⤢ drag to zoom
Prosecutionhover for detail · click to open
Abstract
A compound with the formula I wherein: R 2 is of formula II where Q is selected from OH, SH and NR N , and R N is selected from H, methyl and ethyl, as well as drug-linkers and drug-conjugates made from this compound. [structure]
Claims
76 · 3 independent · depth 476 granted claims
›1.independentA compound with the formula I:+35
›2.↳ 1A compound according to any claim 1, wherein R7 is selected from H, OH and OR.d2+2
›3.↳ 2A compound according to claim 2, wherein R7 is a C1-4 alkyloxy group.d3+1
›39.↳ 3A compound according to claim 3, wherein Y is O.d4
›4.↳ 1A compound according to claim 1, wherein Y is O.d2
›5.↳ 1A compound according to claim 1, wherein R⬳ is C3-7 alkylene.d2
›6.↳ 1A compound according to claim 1, wherein R9 is H.d2
›7.↳ 1A compound according to claim 1, wherein R6 is selected from H and halo.d2
›8.↳ 1A compound according to claim 1, wherein Q is NHRN.d2+1
›9.↳ 8A compound according to claim 8, wherein RN is H or methyl.d3
›10.↳ 1A compound according to claim 1, wherein Q is OH or SH.d2
›11.↳ 1A compound according to claim 1, wherein there is a single bond between C2⬲ and C3⬲, R12 isd2
›12.↳ 1A compound according to claim 1, wherein there is a single bond between C2⬲ and C3⬲, R12 isd2
›13.↳ 1A compound according to claim 1, wherein there is a single bond between C2⬲ and C3⬲, R12 isd2
›14.↳ 1A compound according to claim 1, wherein there is a double bond between C2⬲ and C3⬲, and R12 is a C5-7 aryl group.d2+1
›15.↳ 14A compound according to claim 14, wherein R12 is phenyl.d3
›16.↳ 1A compound according to claim 1, wherein there is a double bond between C2⬲ and C3⬲, and R12 is a C8-10 aryl group.d2
›17.↳ 1A compound according to claim 1, wherein R12 bears one to three substituent groups.d2
›18.↳ 1A compound according to claim 1, wherein there is a double bond between C2⬲ and C3⬲, and R12 is a C1-5 saturated aliphatic alkyl group.d2+1
›19.↳ 18A compound according to claim 18, wherein R12 is methyl, ethyl or propyl.d3
›20.↳ 1A compound according to claim 1, wherein there is a double bond between C2⬲ and C3⬲, and R12 is a C3-6 saturated cycloalkyl group.d2+1
›21.↳ 20A compound according to claim 20, wherein R12 is cyclopropyl.d3
›22.↳ 1A compound according to claim 1, wherein there is a double bond between C2⬲ and C3⬲, and R12 is a group of formula:d2+4
›23.↳ 22A compound according to claim 22, wherein the total number of carbon atoms in the R12 group is no more than 4.d3+1
›24.↳ 23A compound according to claim 23, wherein the total number of carbon atoms in the R12 group is no more than 3.d4
›25.↳ 22A compound according to claim 22, wherein one of R21, R22 and R23 is H, with the other two groups being selected from H, C1-3 saturated alkyl, C2-3 al…d3
›26.↳ 22A compound according to claim 22, wherein two of R21, R22 and R23 are H, with the other group being selected from H, C1-3 saturated alkyl, C2-3 alkeny…d3
›27.↳ 1A compound according to claim 1, wherein there is a double bond between C2⬲ and C3⬲, and R12 is a group of formula:d2+1
›28.↳ 27A compound according to claim 27, wherein R12 is the group:d3
›29.↳ 1A compound according to claim 1, wherein there is a double bond between C2⬲ and C3⬲, and R12 is a group of formula:d2+2
›30.↳ 29A compound according to claim 29, wherein R24 is selected from H, methyl, ethyl, ethenyl and ethynyl.d3+1
›31.↳ 30A compound according to claim 30, wherein R24 is selected from H and methyl.d4
›32.↳ 1A compound according to claim 1, wherein R10 and R11 and form a nitrogen-carbon double bond.d2
›33.↳ 1A compound according to claim 1 wherein R6⬲, R7⬲, R9⬲, R10⬲, R11⬲ and Y⬲ are the same as R6, R7, R9, R10, R11 and y respectively.d2
›34.↳ 1The use of a compound according to claim 1 in the manufacture of a medicament for treating a proliferative disease.d2
›35.↳ 1A compound according to claim 1 for use in the treatment of a proliferative disease.d2
›36.independentA compound of formula II:+33
›37.↳ 36A compound according to any claim 36, wherein R7 is selected from H, OH and OR.d2+1
›38.↳ 37A compound according to claim 37, wherein R7 is a C1-4 alkyloxy group.d3
›40.↳ 36A compound according to claim 36, wherein R⬳ is C3-7 alkylene.d2
›41.↳ 36A compound according to claim 36, wherein R9 is H.d2
›42.↳ 36A compound according to claim 36, wherein R6 is selected from H and halo.d2
›43.↳ 36A compound according to claim 36, wherein Q is NHRN.d2+1
›44.↳ 43A compound according to claim 43, wherein RN is H or methyl.d3
›45.↳ 36A compound according to claim 36, wherein Q is OH or SH.d2
›46.↳ 36A compound according to claim 36, wherein there is a double bond between C2⬲ and C3⬲, and R12 is a C5-7 aryl group.d2+2
›47.↳ 46A compound according to claim 46, wherein R12 is phenyl.d3
›49.↳ 46A compound according to claim 46, wherein R12 bears one to three substituent groups.d3
›48.↳ 36A compound according to claim 36, wherein there is a double bond between C2⬲ and C3⬲, and R12 is a C8-10 aryl group.d2
›50.↳ 36A compound according to claim 36, wherein there is a single bond between C2⬲ and C3⬲, R12 isd2
›51.↳ 36A compound according to claim 36, wherein there is a single bond between C2⬲ and C3⬲, R12 isd2
›52.↳ 36A compound according to claim 36, wherein there is a single bond between C2⬲ and C3⬲, R12 isd2
›53.↳ 36A compound according to claim 36, wherein there is a double bond between C2⬲ and C3⬲, and R12 is a C1-5 saturated aliphatic alkyl group.d2+1
›54.↳ 53A compound according to claim 53, wherein R12 is methyl, ethyl or propyl.d3
›55.↳ 36A compound according to claim 36, wherein there is a double bond between C2⬲ and C3⬲, and R12 is a C3-6 saturated cycloalkyl group.d2+1
›56.↳ 55A compound according to claim 55, wherein R12 is cyclopropyl.d3
›57.↳ 36A compound according to claim 36, wherein there is a double bond between C2⬲ and C3⬲, and R12 is a group of formula:d2+4
›58.↳ 57A compound according to claim 57, wherein the total number of carbon atoms in the R12 group is no more than 4.d3+1
›59.↳ 58A compound according to claim 58, wherein the total number of carbon atoms in the R12 group is no more than 3.d4
›60.↳ 57A compound according to claim 57, wherein one of R21, R22 and R23 is H, with the other two groups being selected from H, C1-3 saturated alkyl, C2-3 al…d3
›61.↳ 57A compound according to claim 57, wherein two of R21, R22 and R23 are H, with the other group being selected from H, C1-3 saturated alkyl, C2-3 alkeny…d3
›62.↳ 36A compound according to claim 36, wherein there is a double bond between C2⬲ and C3⬲, and R12 is a group of formula:d2+1
›63.↳ 62A compound according to claim 62, wherein R12 is the group:d3
›64.↳ 36A compound according to claim 36, wherein there is a double bond between C2⬲ and C3⬲, and R12 is a group of formula:d2+2
›65.↳ 64A compound according to claim 64 wherein R24 is selected from H, methyl, ethyl, ethenyl and ethynyl.d3+1
›66.↳ 65A compound according to claim 65, wherein R24 is selected from H and methyl.d4
›67.↳ 36A compound according to claim 36, wherein R10 is Troc.d2
›68.↳ 36A compound according to claim 36, wherein R11 is OTBS.d2
›69.↳ 36A compound according to claim 36, wherein R11 is oxo and R10 is SEM.d2
›70.↳ 36A compound according to claim 36, wherein R6⬲, R7⬲, R9⬲, R10⬲, R11⬲ and Y⬲ are the same as R6, R7, R9,R10, R11 and Y respectively.d2
›71.independentA Conjugate having formula III:nL-(LU-D)p ⬒⬒(I)nwherein L is a Ligand unit which is a cell binding agent that specifically binds to a target molecule …+5
›72.↳ 71The Conjugate of claim 71, wherein A1 isd2
›73.↳ 71The Conjugate of claim 71, wherein A1 is:d2+1
›74.↳ 73The Conjugate of claim 73, wherein n is 5.d3
›75.↳ 71The Conjugate of claim 71, wherein L1 is selected from the group consisting of valine-alanine, valine-citrulline and phenyalanine-lysine.d2
›76.↳ 71A method of treating a mammal having a proliferative disease or an autoimmune disease, comprising administering an effective amount of the Conjugate o…d2
Classifications
6 codesIPC · International Patent Classification
Section A — Human necessities
- A61K47/48
Section C — Chemistry; metallurgy
- C07K5/065
- C07D487/04
- C07D519/00
- C07K5/062
- C07K5/078
Claim changes
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Pendency
3.4 y
1,251 days filing → grant
Office actions
1
non-final + final
Responses
2
1 RCE
Examiner
Taofiq A Solola
art unit 1622 · TC 1600
Law firm
Citations: 273 back · 2 forward
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2 priority documentsPriority
20 Sep 2011
earliest claimed
›Priority documents — 2
| Type | Document | Date |
|---|---|---|
| provisional | US 61536669 | 20 Sep 2011 |
| related publication | US 20150158869 A1 | 11 Jun 2015 |
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