Brain-enhanced delivery of neuroactive peptides by sequential metabolism
First Claim
Patent Images
1. A compound of the formula ##STR95## or a non-toxic pharmaceutically acceptable salt thereof, wherein:
- R1 is C1 -C7 alkyl, C1 -C7 haloalkyl or C7 -C12 aralkyl;
R2 and R3, which are the same or different, are each selected from the group consisting of hydrogen, halo, cyano, C1 -C7 alkyl, C1 -C7 alkoxy, C2 -C8 alkoxycarbonyl, C2 -C8 alkanoyloxy, C1 -C7 haloalkyl, C1 -C7 alkylthio, C1 -C7 alkylsulfinyl, C1 -C7 alkylsulfonyl, --CH═
NOR'"'"'" wherein R'"'"'" is hydrogen or C1 -C7 alkyl, and --CONR'"'"'R" wherein R'"'"' and R", which are the same or different, are each hydrogen or C1 -C7 alkyl;
or one of R2 and R3 together with the adjacent ring carbon atom forms a phenyl ring fused to the six-membered heterocyclic ring, which phenyl ring is unsubstituted or is substituted with one or two substituents, which are the same or different, selected from the group consisting of hydroxy, protected hydroxy, halo, cyano, C1 -C7 alkyl, C1 -C7 alkoxy, C2 -C8 alkoxycarbonyl, C2 -C8 alkanoyloxy, C1 -C7 haloalkyl, C1 -C7 alkylthio, C1 -C7 alkylsulfinyl, C1 -C7 alkylsulfonyl, --CH═
NOR'"'"'" wherein R'"'"'" is hydrogen or C1 -C7 alkyl, and --CONR'"'"'R" wherein R'"'"' and R", which are the same or different, are each hydrogen or C1 -C7 alkyl;
the dotted lines represent a double bond in one of the two indicated positions, the depicted being a 1,4- or 1,6-dihydropyridine, a 1,4- or 1,2-dihydroquinoline, or a 1,2-dihydroisoquinoline;
"spacer" is an L-amino acid unit or a di- or tripeptide consisting of 2 or 3 L-amino acid units, the N-terminal amino acid of said spacer being bonded to the depicted carbonyl carbon via an amide bond;
and "peptide" is a pharmacologically active peptide having 2 to 20 amino acid units, the N-terminal amino acid of said peptide being bonded to the C-terminal amino acid of said spacer via a peptide bond, the C-terminal amino acid of said peptide having an esterified carboxyl function --COOR4 wherein R4 is C6 -C30 polycycloalkyl-Cp H2p -- wherein p is 0, 1, 2 or 3, or C6 -C30 polycycloalkenyl-Cp H2p -- wherein p is defined as above.
3 Assignments
0 Petitions
Accused Products
Abstract
The invention provides novel peptide derivatives which are designed to deliver pharmacologically active peptides into the central nervous system by sequential metabolism. The peptide is placed in a molecular environment which disguises its peptide nature and provides biolabile, lipophilic functions to penetrate the blood-brain barrier by passive transport. The design incorporates a dihydropyridine-type redox targetor moiety, an amino acid or di- or -tripeptide spacer inserted between the targetor and N-terminal amino acid unit of the peptide and a bulky, lipophilic substituent protecting the C-terminal amino acid unit of the peptide. The dihydropyridine-type targetor undergoes an enzymatically mediated oxidation to a hydrophilic, membrane-impermeable pyridinium salt. That polar targetor-peptide conjugate is trapped behind the lipoidal blood-brain barrier. Over time, cleavage of the lipophilic ester from the peptide by esterase and or lipase enzymes and enzymatic cleavage of the targetor-spacer from the peptide results in release of the desired peptide in the brain.
158 Citations
67 Claims
-
1. A compound of the formula ##STR95## or a non-toxic pharmaceutically acceptable salt thereof, wherein:
- R1 is C1 -C7 alkyl, C1 -C7 haloalkyl or C7 -C12 aralkyl;
R2 and R3, which are the same or different, are each selected from the group consisting of hydrogen, halo, cyano, C1 -C7 alkyl, C1 -C7 alkoxy, C2 -C8 alkoxycarbonyl, C2 -C8 alkanoyloxy, C1 -C7 haloalkyl, C1 -C7 alkylthio, C1 -C7 alkylsulfinyl, C1 -C7 alkylsulfonyl, --CH═
NOR'"'"'" wherein R'"'"'" is hydrogen or C1 -C7 alkyl, and --CONR'"'"'R" wherein R'"'"' and R", which are the same or different, are each hydrogen or C1 -C7 alkyl;or one of R2 and R3 together with the adjacent ring carbon atom forms a phenyl ring fused to the six-membered heterocyclic ring, which phenyl ring is unsubstituted or is substituted with one or two substituents, which are the same or different, selected from the group consisting of hydroxy, protected hydroxy, halo, cyano, C1 -C7 alkyl, C1 -C7 alkoxy, C2 -C8 alkoxycarbonyl, C2 -C8 alkanoyloxy, C1 -C7 haloalkyl, C1 -C7 alkylthio, C1 -C7 alkylsulfinyl, C1 -C7 alkylsulfonyl, --CH═
NOR'"'"'" wherein R'"'"'" is hydrogen or C1 -C7 alkyl, and --CONR'"'"'R" wherein R'"'"' and R", which are the same or different, are each hydrogen or C1 -C7 alkyl;the dotted lines represent a double bond in one of the two indicated positions, the depicted being a 1,4- or 1,6-dihydropyridine, a 1,4- or 1,2-dihydroquinoline, or a 1,2-dihydroisoquinoline; "spacer" is an L-amino acid unit or a di- or tripeptide consisting of 2 or 3 L-amino acid units, the N-terminal amino acid of said spacer being bonded to the depicted carbonyl carbon via an amide bond; and "peptide" is a pharmacologically active peptide having 2 to 20 amino acid units, the N-terminal amino acid of said peptide being bonded to the C-terminal amino acid of said spacer via a peptide bond, the C-terminal amino acid of said peptide having an esterified carboxyl function --COOR4 wherein R4 is C6 -C30 polycycloalkyl-Cp H2p -- wherein p is 0, 1, 2 or 3, or C6 -C30 polycycloalkenyl-Cp H2p -- wherein p is defined as above. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)
- R1 is C1 -C7 alkyl, C1 -C7 haloalkyl or C7 -C12 aralkyl;
-
17. A compound of the formula ##STR98## or a non-toxic pharmaceutically acceptable salt thereof, wherein:
- R1 is C1 -C7 alkyl, C1 -C7 haloalkyl or C7 -C12 aralkyl;
R2 and R3, which are the same or different, are each selected from the group consisting of hydrogen, halo, cyano, C1 -C7 alkyl, C1 -C7 alkoxy, C2 -C8 alkoxycarbonyl, C2 -C8 alkanoyloxy, C1 -C7 haloalkyl, C1 -C7 alkylthio, C1 -C7 alkylsulfinyl, C1 -C7 alkylsulfonyl, --CH═
NOR'"'"'" wherein R'"'"'" is hydrogen or C1 -C7 alkyl, and --CONR'"'"'R" wherein R'"'"' and R", which are the same or different, are each hydrogen or C1 -C7 alkyl;or one of R2 and R3 together with the adjacent ring carbon atom forms a phenyl ring fused to the six-membered heterocyclic ring, which phenyl ring is unsubstituted or is substituted with one or two substituents, which are the same or different, selected from the group consisting of hydroxy, protected hydroxy, halo, cyano, C1 -C7 alkyl, C1 -C7 alkoxy, C2 -C8 alkoxycarbonyl, C2 -C8 alkanoyloxy, C1 -C7 haloalkyl, C1 -C7 alkylthio, C1 -C7 alkylsulfinyl, C1 -C7 alkylsulfonyl, --CH═
NOR'"'"'" wherein R'"'"'" is hydrogen or C1 -C7 alkyl, and --CONR'"'"'R" wherein R'"'"' and R", which are the same or different, are each hydrogen or C1 -C7 alkyl;the dotted lines represent a double bond in one of the two indicated positions, the depicted ring system being a 1,4- or 1,6-dihydropyridine, a 1,4- or 1,2-dihydroquinoline, or a 1,2-dihydroisoquinoline; "spacer" is an L-amino acid selected from the group consisting of alanine and proline, or a dipeptide consisting of L-amino acid units selected from said group, the N-terminal amino acid of said spacer being bonded to the depicted carbonyl carbon via an amide bond; and "peptide" is a pharmacologically active peptide having 2 to 20 amino acid units, the N-terminal amino acid of said peptide being bonded to the C-terminal amino acid of said spacer via a peptide bond, the C-terminal amino acid of said peptide having an esterified carboxyl function --COOR4 wherein R4 is C6 -C30 polycycloalkyl-Cp H2p -- wherein p is 0, 1, 2 or 3, or C6 -C30 polycycloalkenyl-Cp H2p -- wherein p is defined as above. - View Dependent Claims (18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29)
- R1 is C1 -C7 alkyl, C1 -C7 haloalkyl or C7 -C12 aralkyl;
-
30. A compound of the formula ##STR100## or a non-toxic pharmaceutically acceptable salt thereof, wherein:
- R1 is C1 -C7 alkyl, C1 -C7 haloalkyl or C7 -C12 aralkyl;
R2 and R3, which are the same or different, are each selected from the group consisting of hydrogen, halo, cyano, C1 -C7 alkyl, C1 -C7 alkoxy, C2 -C8 alkoxycarbonyl, C2 -C8 alkanoyloxy, C1 -C7 haloalkyl, C1 -C7 alkylthio, C1 -C7 alkylsulfinyl, C1 -C7 alkylsulfonyl, --CH═
NOR'"'"'" wherein R'"'"'" is hydrogen or C1 -C7 alkyl, and --CONR'"'"'R" wherein R'"'"' and R", which are the same or different, are each hydrogen or C1 -C7 alkyl;or one of R2 and R3 together with the adjacent ring carbon atom forms a phenyl ring fused to the six-membered heterocyclic ring, which phenyl ring is unsubstituted or is substituted with one or two substituents, which are the same or different, selected from the group consisting of hydroxy, protected hydroxy, halo, cyano, C1 -C7 alkyl, C1 -C7 alkoxy, C2 -C8 alkoxycarbonyl, C2 -C8 alkanoyloxy, C1 -C7 haloalkyl, C1 -C7 alkylthio, C1 -C7 alkylsulfinyl, C1 -C7 alkylsulfonyl, --CH═
NOR'"'"'" wherein R'"'"'" is hydrogen or C1 -C7 alkyl, and --CONR'"'"'R" wherein R'"'"' and R", which are the same or different, are each hydrogen or C1 -C7 alkyl;the dotted lines represent a double bond in one of the two indicated positions, the depicted ring system being a 1,4- or 1,6-dihydropyridine, a 1,4- or 1,2-dihydroquinoline, or a 1,2-dihydroisoquinoline ring system; "spacer" is an L-amino acid selected from the group consisting of alanine and proline, or a dipeptide consisting of L-amino acid units selected from said group, the N-terminal amino acid of said spacer being bonded to the depicted carbonyl carbon via an amide bond; and "peptide" is a pharmacologically active peptide having 2 to 20 amino acid units, the N-terminal amino acid of said peptide being bonded to the C-terminal amino acid of said spacer via a peptide bond, the C-terminal amino acid of said peptide having an esterified carboxyl function --COOR4 wherein --OR4 represents a steroidal alcohol, less a hydrogen atom on the hydroxyl group. - View Dependent Claims (31, 32, 33, 34, 35, 36, 37, 38, 39, 40)
- R1 is C1 -C7 alkyl, C1 -C7 haloalkyl or C7 -C12 aralkyl;
-
41. A quaternary salt of the formula ##STR111## wherein:
- R1 is C1 -C7 alkyl, C1 -C7 haloalkyl or C7 -C12 aralkyl;
R2 and R3, which are the same or different, are each selected from the group consisting of hydrogen, halo, cyano, C1 -C7 alkyl, C1 -C7 alkoxy, C2 -C8 alkoxycarbonyl, C2 -C8 alkanoyloxy, C1 -C7 haloalkyl, C1 -C7 alkylthio, C1 -C7 alkylsulfinyl, C1 -C7 alkylsulfonyl, --CH═
NOR'"'"'" wherein R'"'"'" is hydrogen or C1 -C7 alkyl, and --CONR'"'"'R" wherein R'"'"' and R", which are the same or different, are each hydrogen or C1 -C7 alkyl;or one of R2 and R3 together with the adjacent ring carbon atom forms a phenyl ring fused to the six-membered heterocyclic ring, which phenyl ring is unsubstituted or is substituted with one or two substituents, which are the same or different, selected from the group consisting of hydroxy, protected hydroxy, halo, cyano, C1 -C7 alkyl, C1 -C7 alkoxy, C2 -C8 alkoxycarbonyl, C2 -C8 alkanoyloxy, C1 -C7 haloalkyl, C1 -C7 alkylthio, C1 -C7 alkylsulfinyl, C1 -C7 alkylsulfonyl, --CH═
NOR'"'"'" wherein R'"'"'" is hydrogen or C1 -C7 alkyl, and --CONR'"'"'R" wherein R'"'"' and R", which are the same or different, are each hydrogen or C1 -C7 alkyl;the depicted is a pyridinium, quinolinium or isoquinolinium ion; "spacer" is an L-amino acid unit or a di- or tripeptide consisting of 2 or 3 L-amino acid units, the N-terminal amino acid of said spacer being bonded to the depicted carbonyl carbon via an amide bond; "peptide" is a pharmacologically active peptide having 2 to 20 amino acid units, the N-terminal amino acid of said peptide being bonded to the C-terminal amino acid of said spacer via a peptide bond, the C-terminal amino acid of said peptide having an esterified carboxyl function --COOR4 wherein R4 is C6 -C30 polycycloalkyl-Cp H2p -- wherein p is 0, 1, 2 or 3, or C6 -C30 polycycloalkenyl --Cp H2p -- wherein p is defined as above; and X- is the anion of a non-toxic, pharmaceutically acceptable acid. - View Dependent Claims (44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54)
- R1 is C1 -C7 alkyl, C1 -C7 haloalkyl or C7 -C12 aralkyl;
- 42. The salt according to claim 42, wherein R1 is methyl.
-
55. A quaternary salt of the formula ##STR114## wherein:
- R1 is C1 -C7 alkyl, C1 -C7 haloalkyl or C7 -C12 aralkyl;
R2 and R3, which are the same or different, are each selected from the group consisting of hydrogen, halo, cyano, C1 -C7 alkyl, C1 -C7 alkoxy, C2 -C8 alkoxycarbonyl, C2 -C8 alkanoyloxy, C1 -C7 haloalkyl, C1 -C7 alkylthio, C1 -C7 alkylsulfinyl, C1 -C7 alkylsulfonyl, --CH═
NOR'"'"'" wherein R'"'"'" is hydrogen or C1 -C7 alkyl, and --CONR'"'"'R" wherein R'"'"' and R", which are the same or different, are each hydrogen or C1 -C7 alkyl;or one of R2 and R3 together with the adjacent ring carbon atom forms a phenyl ring fused to the six-membered heterocyclic ring, which phenyl ring is unsubstituted or is substituted with one or two substituents, which are the same or different, selected from the group consisting of hydroxy, protected hydroxy, halo, cyano, C1 -C7 alkyl, C1 -C7 alkoxy, C2 -C8 alkoxycarbonyl, C2 -C8 alkanoyloxy, C1 -C7 haloalkyl, C1 -C7 alkylthio, C1 -C7 alkylsulfinyl, C1 -C7 alkylsulfonyl, --CH═
NOR'"'"'" wherein R'"'"'" is hydrogen or C1 -C7 alkyl, and --CONR'"'"'R" wherein R'"'"' and R", which are the same or different, are each hydrogen or C1 -C7 alkyl;the depicted ring system is a pyridinium, quinolinium or isoquinolinium ion; "spacer" is an L-amino acid selected from the group consisting of alanine and proline, or a dipeptide consisting of L-amino acid units selected from said group, the N-terminal amino acid of said spacer being bonded to the depicted carbonyl carbon via an amide bond; "peptide" is a pharmacologically active peptide having 2 to 20 amino acid units, the N-terminal amino acid of said peptide being bonded to the C-terminal amino acid of said spacer via a peptide bond, the C-terminal amino acid of said peptide having an esterified carboxyl function --COOR4 wherein R4 is C6 -C30 polycycloalkyl-Cp H2p -- wherein p is 0, 1, 2 or 3, or C6 -C30 polycycloalkenyl --Cp H2p -- wherein p is defined as above; and X- is the anion of a non-toxic, pharmaceutically acceptable acid. - View Dependent Claims (56, 57, 58, 59, 60, 61, 62, 63, 64, 65)
- R1 is C1 -C7 alkyl, C1 -C7 haloalkyl or C7 -C12 aralkyl;
-
66. A quaternary salt of the formula ##STR116## wherein:
- R1 is C1 -C7 alkyl, C1 -C7 haloalkyl or C7 -C12 aralkyl;
R2 and R3, which are the same or different, are each selected from the group consisting of hydrogen, halo, cyano, C1 -C7 alkyl, C1 -C7 alkoxy, C2 -C8 alkoxycarbonyl, C2 -C8 alkanoyloxy, C1 -C7 haloalkyl, C1 -C7 alkylthio, C1 -C7 alkylsulfinyl, C1 -C7 alkylsulfonyl, --CH═
NOR'"'"'" wherein R'"'"'" is hydrogen or C1 -C7 alkyl, and --CONR'"'"'R" wherein R'"'"' and R", which are the same or different, are each hydrogen or C1 -C7 alkyl;or one of R2 and R3 together with the adjacent ring carbon atom forms a phenyl ring fused to the six-membered heterocyclic ring, which phenyl ring is unsubstituted or is substituted with one or two substituents, which are the same or different, selected from the group consisting of hydroxy, protected hydroxy, halo, cyano, C1 -C7 alkyl, C1 -C7 alkoxy, C2 -C8 alkoxycarbonyl, C2 -C8 alkanoyloxy, C1 -C7 haloalkyl, C1 -C7 alkylthio, C1 -C7 alkylsulfinyl, C1 -C7 alkylsulfonyl, --CH═
NOR'"'"'" wherein R'"'"'" is hydrogen or C1 -C7 alkyl, and --CONR'"'"'R" wherein R'"'"' and R", which are the same or different, are each hydrogen or C1 -C7 alkyl;the depicted ring system is a pyridinium, quinolinium or isoquinolinium ion; "spacer" is an L-amino acid selected from the group consisting of alanine and proline, or a dipeptide consisting of L-amino acid units selected from said group, the N-terminal amino acid of said spacer being bonded to the depicted carbonyl carbon via an amide bond; "peptide" is a pharmacologically active peptide having 2 to 20 amino acid units, the N-terminal amino acid of said peptide being bonded to the C-terminal amino acid of said spacer via a peptide bond, the C-terminal amino acid of said peptide having an esterified carboxyl function --COOR4 wherein --OR4 represents a steroidal alcohol, less a hydrogen atom on the hydroxyl group; and X- is the anion of a non-toxic, pharmaceutically acceptable acid. - View Dependent Claims (67)
- R1 is C1 -C7 alkyl, C1 -C7 haloalkyl or C7 -C12 aralkyl;
Specification
-
- Resources
Litigation Campaign Assessment
Thank you for your request. You will receive a custom alert email when the Litigation Campaign Assessment is available.
×
-
Current AssigneeRodob Drug Research Inc.
-
Original AssigneeUniversity of Florida (State University System of Florida)
-
InventorsBodor, Nicholas S.
-
Primary Examiner(s)Lukton, David
-
Application NumberUS08/428,488Time in Patent Office733 DaysField of Search514/2, 514/12-17, 530/345, 546/315, 546/316, 546/286, 546/321, 546/134, 546/288, 546/290, 546/314US Class Current514/21.2CPC Class CodesA61K 38/00 Medicinal preparations cont...A61K 47/559 Redox delivery systems, e.g...C07K 14/70 EnkephalinsC07K 5/0806 the side chain containing 0...C07K 5/0823 and Pro-amino acid; Derivat...C07K 5/1008 the side chain containing 0...C07K 5/1024 with the first amino acid b...C07K 7/06 having 5 to 11 amino acids
