US 5,624,894 AGranted

Brain-enhanced delivery of neuroactive peptides by sequential metabolism

AssigneeUniversity of Florida

InventorNicholas S. Bodor

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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.

Claims67

Dependent claims

A compound of the formula ##STR95## or a non-toxic pharmaceutically acceptable salt thereof, wherein:

R.sub.1 is C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 haloalkyl or C.sub.7 -C.sub.12 aralkyl;
R.sub.2 and R.sub.3, which are the same or different, are each selected from the group consisting of hydrogen, halo, cyano, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 alkoxy, C.sub.2 -C.sub.8 alkoxycarbonyl, C.sub.2 -C.sub.8 alkanoyloxy, C.sub.1 -C.sub.7 haloalkyl, C.sub.1 -C.sub.7 alkylthio, C.sub.1 -C.sub.7 alkylsulfinyl, C.sub.1 -C.sub.7 alkylsulfonyl, --CH.dbd.NOR'" wherein R'" is hydrogen or C.sub.1 -C.sub.7 alkyl, and --CONR'R" wherein R' and R", which are the same or different, are each hydrogen or C.sub.1 -C.sub.7 alkyl;
or one of R.sub.2 and R.sub.3 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, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 alkoxy, C.sub.2 -C.sub.8 alkoxycarbonyl, C.sub.2 -C.sub.8 alkanoyloxy, C.sub.1 -C.sub.7 haloalkyl, C.sub.1 -C.sub.7 alkylthio, C.sub.1 -C.sub.7 alkylsulfinyl, C.sub.1 -C.sub.7 alkylsulfonyl, --CH.dbd.NOR'" wherein R'" is hydrogen or C.sub.1 -C.sub.7 alkyl, and --CONR'R" wherein R' and R", which are the same or different, are each hydrogen or C.sub.1 -C.sub.7 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 --COOR.sub.4 wherein R.sub.4 is C.sub.6 -C.sub.30 polycycloalkyl-C.sub.p H.sub.2p -- wherein p is 0, 1, 2 or 3, or C.sub.6 -C.sub.30 polycycloalkenyl-C.sub.p H.sub.2p -- wherein p is defined as above.

3 more elements

A compound of the formula ##STR98## or a non-toxic pharmaceutically acceptable salt thereof, wherein:

R.sub.1 is C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 haloalkyl or C.sub.7 -C.sub.12 aralkyl;
R.sub.2 and R.sub.3, which are the same or different, are each selected from the group consisting of hydrogen, halo, cyano, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 alkoxy, C.sub.2 -C.sub.8 alkoxycarbonyl, C.sub.2 -C.sub.8 alkanoyloxy, C.sub.1 -C.sub.7 haloalkyl, C.sub.1 -C.sub.7 alkylthio, C.sub.1 -C.sub.7 alkylsulfinyl, C.sub.1 -C.sub.7 alkylsulfonyl, --CH.dbd.NOR'" wherein R'" is hydrogen or C.sub.1 -C.sub.7 alkyl, and --CONR'R" wherein R' and R", which are the same or different, are each hydrogen or C.sub.1 -C.sub.7 alkyl;
or one of R.sub.2 and R.sub.3 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, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 alkoxy, C.sub.2 -C.sub.8 alkoxycarbonyl, C.sub.2 -C.sub.8 alkanoyloxy, C.sub.1 -C.sub.7 haloalkyl, C.sub.1 -C.sub.7 alkylthio, C.sub.1 -C.sub.7 alkylsulfinyl, C.sub.1 -C.sub.7 alkylsulfonyl, --CH.dbd.NOR'" wherein R'" is hydrogen or C.sub.1 -C.sub.7 alkyl, and --CONR'R" wherein R' and R", which are the same or different, are each hydrogen or C.sub.1 -C.sub.7 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 --COOR.sub.4 wherein R.sub.4 is C.sub.6 -C.sub.30 polycycloalkyl-C.sub.p H.sub.2p -- wherein p is 0, 1, 2 or 3, or C.sub.6 -C.sub.30 polycycloalkenyl-C.sub.p H.sub.2p -- wherein p is defined as above.

3 more elements

A compound of the formula ##STR100## or a non-toxic pharmaceutically acceptable salt thereof, wherein:

R.sub.1 is C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 haloalkyl or C.sub.7 -C.sub.12 aralkyl;
R.sub.2 and R.sub.3, which are the same or different, are each selected from the group consisting of hydrogen, halo, cyano, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 alkoxy, C.sub.2 -C.sub.8 alkoxycarbonyl, C.sub.2 -C.sub.8 alkanoyloxy, C.sub.1 -C.sub.7 haloalkyl, C.sub.1 -C.sub.7 alkylthio, C.sub.1 -C.sub.7 alkylsulfinyl, C.sub.1 -C.sub.7 alkylsulfonyl, --CH.dbd.NOR'" wherein R'" is hydrogen or C.sub.1 -C.sub.7 alkyl, and --CONR'R" wherein R' and R", which are the same or different, are each hydrogen or C.sub.1 -C.sub.7 alkyl;
or one of R.sub.2 and R.sub.3 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, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 alkoxy, C.sub.2 -C.sub.8 alkoxycarbonyl, C.sub.2 -C.sub.8 alkanoyloxy, C.sub.1 -C.sub.7 haloalkyl, C.sub.1 -C.sub.7 alkylthio, C.sub.1 -C.sub.7 alkylsulfinyl, C.sub.1 -C.sub.7 alkylsulfonyl, --CH.dbd.NOR'" wherein R'" is hydrogen or C.sub.1 -C.sub.7 alkyl, and --CONR'R" wherein R' and R", which are the same or different, are each hydrogen or C.sub.1 -C.sub.7 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 --COOR.sub.4 wherein --OR.sub.4 represents a steroidal alcohol, less a hydrogen atom on the hydroxyl group.

3 more elements

A quaternary salt of the formula ##STR111## wherein:

R.sub.1 is C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 haloalkyl or C.sub.7 -C.sub.12 aralkyl;
R.sub.2 and R.sub.3, which are the same or different, are each selected from the group consisting of hydrogen, halo, cyano, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 alkoxy, C.sub.2 -C.sub.8 alkoxycarbonyl, C.sub.2 -C.sub.8 alkanoyloxy, C.sub.1 -C.sub.7 haloalkyl, C.sub.1 -C.sub.7 alkylthio, C.sub.1 -C.sub.7 alkylsulfinyl, C.sub.1 -C.sub.7 alkylsulfonyl, --CH.dbd.NOR'" wherein R'" is hydrogen or C.sub.1 -C.sub.7 alkyl, and --CONR'R" wherein R' and R", which are the same or different, are each hydrogen or C.sub.1 -C.sub.7 alkyl;
or one of R.sub.2 and R.sub.3 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, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 alkoxy, C.sub.2 -C.sub.8 alkoxycarbonyl, C.sub.2 -C.sub.8 alkanoyloxy, C.sub.1 -C.sub.7 haloalkyl, C.sub.1 -C.sub.7 alkylthio, C.sub.1 -C.sub.7 alkylsulfinyl, C.sub.1 -C.sub.7 alkylsulfonyl, --CH.dbd.NOR'" wherein R'" is hydrogen or C.sub.1 -C.sub.7 alkyl, and --CONR'R" wherein R' and R", which are the same or different, are each hydrogen or C.sub.1 -C.sub.7 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 --COOR.sub.4 wherein R.sub.4 is C.sub.6 -C.sub.30 polycycloalkyl-C.sub.p H.sub.2p -- wherein p is 0, 1, 2 or 3, or C.sub.6 -C.sub.30 polycycloalkenyl --C.sub.p H.sub.2p -- wherein p is defined as above;
and X.sup.- is the anion of a non-toxic, pharmaceutically acceptable acid.

4 more elements

A quaternary salt of the formula ##STR114## wherein:

R.sub.1 is C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 haloalkyl or C.sub.7 -C.sub.12 aralkyl;
R.sub.2 and R.sub.3, which are the same or different, are each selected from the group consisting of hydrogen, halo, cyano, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 alkoxy, C.sub.2 -C.sub.8 alkoxycarbonyl, C.sub.2 -C.sub.8 alkanoyloxy, C.sub.1 -C.sub.7 haloalkyl, C.sub.1 -C.sub.7 alkylthio, C.sub.1 -C.sub.7 alkylsulfinyl, C.sub.1 -C.sub.7 alkylsulfonyl, --CH.dbd.NOR'" wherein R'" is hydrogen or C.sub.1 -C.sub.7 alkyl, and --CONR'R" wherein R' and R", which are the same or different, are each hydrogen or C.sub.1 -C.sub.7 alkyl;
or one of R.sub.2 and R.sub.3 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, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 alkoxy, C.sub.2 -C.sub.8 alkoxycarbonyl, C.sub.2 -C.sub.8 alkanoyloxy, C.sub.1 -C.sub.7 haloalkyl, C.sub.1 -C.sub.7 alkylthio, C.sub.1 -C.sub.7 alkylsulfinyl, C.sub.1 -C.sub.7 alkylsulfonyl, --CH.dbd.NOR'" wherein R'" is hydrogen or C.sub.1 -C.sub.7 alkyl, and --CONR'R" wherein R' and R", which are the same or different, are each hydrogen or C.sub.1 -C.sub.7 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 --COOR.sub.4 wherein R.sub.4 is C.sub.6 -C.sub.30 polycycloalkyl-C.sub.p H.sub.2p -- wherein p is 0, 1, 2 or 3, or C.sub.6 -C.sub.30 polycycloalkenyl --C.sub.p H.sub.2p -- wherein p is defined as above;
and X.sup.- is the anion of a non-toxic, pharmaceutically acceptable acid.

4 more elements

A quaternary salt of the formula ##STR116## wherein:

R.sub.1 is C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 haloalkyl or C.sub.7 -C.sub.12 aralkyl;
R.sub.2 and R.sub.3, which are the same or different, are each selected from the group consisting of hydrogen, halo, cyano, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 alkoxy, C.sub.2 -C.sub.8 alkoxycarbonyl, C.sub.2 -C.sub.8 alkanoyloxy, C.sub.1 -C.sub.7 haloalkyl, C.sub.1 -C.sub.7 alkylthio, C.sub.1 -C.sub.7 alkylsulfinyl, C.sub.1 -C.sub.7 alkylsulfonyl, --CH.dbd.NOR'" wherein R'" is hydrogen or C.sub.1 -C.sub.7 alkyl, and --CONR'R" wherein R' and R", which are the same or different, are each hydrogen or C.sub.1 -C.sub.7 alkyl;
or one of R.sub.2 and R.sub.3 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, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 alkoxy, C.sub.2 -C.sub.8 alkoxycarbonyl, C.sub.2 -C.sub.8 alkanoyloxy, C.sub.1 -C.sub.7 haloalkyl, C.sub.1 -C.sub.7 alkylthio, C.sub.1 -C.sub.7 alkylsulfinyl, C.sub.1 -C.sub.7 alkylsulfonyl, --CH.dbd.NOR'" wherein R'" is hydrogen or C.sub.1 -C.sub.7 alkyl, and --CONR'R" wherein R' and R", which are the same or different, are each hydrogen or C.sub.1 -C.sub.7 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 --COOR.sub.4 wherein --OR.sub.4 represents a steroidal alcohol, less a hydrogen atom on the hydroxyl group;
and X.sup.- is the anion of a non-toxic, pharmaceutically acceptable acid.

4 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/428,488Filed 27 Apr 1995 · continuation
Priority: 17 Sep 1992
Granted: 29 Apr 1997
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07K 7/06
Linear peptides containing only normal peptide links: having 5 to 11 amino acids
A61K 47/559
The modifying agent being an organic compound: redox delivery systems, e.g. dihydropyridine pyridinium salt redox systems
C07K 5/0806
And aliphatic: the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
C07K 5/0823
With the first amino acid being heterocyclic, e.g. His, Pro, Trp: and Pro-amino acid; Derivatives thereof