US2008234202A1PendingUtilityA1
Non-natural amino acids and neurotensin analogues
Individually held — no corporate assignee on recordPriority: Jun 17, 2004Filed: Apr 17, 2007Published: Sep 25, 2008
Est. expiryJun 17, 2024(expired)· nominal 20-yr term from priority
A61P 7/02A61P 5/00A61P 5/24A61P 5/02A61P 3/10A61P 7/10A61P 43/00C07C 257/14A61P 29/00A61P 25/00C07D 231/06A61P 25/04A61K 38/00C07D 233/48C07K 7/083C07D 239/14A61P 31/12A61P 25/18C07C 279/14C07D 233/46A61P 29/02A61P 3/04C07C 229/08A61P 35/00C07C 229/12
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Claims
Abstract
This invention relates to methods of synthesis of amino acid analogs contained within peptide sequences that is adapted for preparation of peptides containing analogs of basic amino acids lysine and arginine.
Claims
exact text as granted — not AI-modified1 . A method of preparation of a compound of Formula (XI):
or a salt, hydrate, solvate, stereoisomer, or tautomer thereof,
wherein X is OH, O(C 1 -C 6 alkyl), O(C 6 -C 10 aryl), NR 2 , an amino acid residue or a peptide residue, or wherein X is O, NR, an amino acid residue, or a peptide residue, respectively covalently bonded to a polymer;
Z is H, NR 2 , alkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, an amino acid residue, or a peptide residue; or is NR, an amino acid residue, or a peptide residue, respectively covalently bonded to a polymer;
provided that X and Z are not both bonded to polymers; and provided that at least one of X or Z comprises an amino acid residue or a peptide residue, or an amino acid residue or a peptide residue respectively covalently bonded to a polymer;
R is independently at each occurrence H, alkyl, aryl, heterocyclyl, heteroaryl, a nitrogen protecting group, or a nitrogen capping group, or two R groups together with the nitrogen atom to which they are bound form a 5-7 membered heterocyclic ring that can further comprise 1-3 additional heteroatoms N, O or S;
L is a saturated or unsaturated, linear, branched or cyclic hydrocarbyl or a combination thereof, comprising n carbon atoms, wherein any carbon atom can be substituted or unsubstituted, wherein 0-3 heteroatoms O, S, or NR can be substituted for a carbon atom of L;
n is 1 to about 10,
R 1 , R 2 and R 3 are independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, or heteroaryl, wherein one of R 1 , R 2 or R 3 may be absent, wherein any alkyl can contain 0-3 heteroatoms comprising N, O, or S, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl may be unsubstituted or substituted;
the method comprising contacting a compound of Formula (XII):
wherein Y is a leaving group;
with an amine of the formula R 1 R 2 R 3 N, in a solvent for a time period and at a temperature sufficient for the formation of the compound of Formula (XI).
2 . A method for the preparation of a compound of Formula (XIII):
or a salt, hydrate, solvate, stereoisomer, or tautomer thereof,
wherein X is OH, O(C 1 -C 6 alkyl), O(C 6 -C 10 aryl), NR 2 , an amino acid residue or a peptide residue, or wherein X is O, NR, an amino acid residue, or a peptide residue, respectively covalently bonded to a polymer;
Z is H, NR 2 , alkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, an amino acid residue, or a peptide residue, or is NR, an amino acid residue, or a peptide residue, respectively covalently bonded to a polymer;
provided that X and Z are not both bonded to polymers; and provided that at least one of X or Z comprises an amino acid residue or a peptide residue, or an amino acid residue or a peptide residue respectively covalently bonded to a polymer;
R is independently at each occurrence H, alkyl, aryl, heterocyclyl, heteroaryl, a nitrogen protecting group, or a nitrogen capping group, or two R groups together with the nitrogen atom to which they are bound form a 5-7 membered heterocyclic ring that can further comprise 1-3 additional heteroatoms N, O or S;
L is a saturated or unsaturated, linear, branched or cyclic hydrocarbyl or a combination thereof, comprising n carbon atoms, wherein any carbon atom can be substituted or unsubstituted, wherein 0-3 heteroatoms O, S, or NR can be substituted for a carbon atom of L;
n is 1 to about 10;
R 4 and R 5 are independently at each occurrence H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein any alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl residue may be unsubstituted or substituted; provided that R 4 or R 5 is not a Boc group;
the method comprising contacting a compound of Formula (XV):
wherein R 1 is hydrogen, alkyl, aryl, aralkyl, cycloalkyl, heterocycles, or heteroaryl; wherein any alkyl can further contain 0-3 heteroatoms comprising N, O, or S, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl may be unsubstituted or substituted;
with a compound of Formula (XIV):
wherein R 6 is substituted or unsubstituted alkyl or aryl, or a salt thereof;
in a solvent for a time period and at a temperature sufficient for the formation of the compound of Formula (XIII).
3 . A method of preparation of a compound of formula (XIII):
or a salt, hydrate, solvate, stereoisomer, or tautomer thereof,
wherein X is OH, O(C 1 -C 6 alkyl), O(C 6 -C 10 aryl), NR 2 , an amino acid residue or a peptide residue, or wherein X is O, NR, an amino acid residue, or a peptide residue, respectively covalently bonded to a polymer;
Z is H, NR 2 , alkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, an amino acid residue, or a peptide residue, or is NR, an amino acid residue, or a peptide residue, respectively covalently bonded to a polymer;
provided that X and Z are not both bonded to polymers; and provided that at least one of X or Z comprises an amino acid residue or a peptide residue, or an amino acid residue or a peptide residue respectively covalently bonded to a polymer;
R at each occurrence is independently H, alkyl, aryl, heterocyclyl, heteroaryl, a nitrogen protecting group, or a nitrogen capping group, or two R groups together with the nitrogen atom to which they are bound form a 5-7 membered heterocyclic ring that can further comprise 1-3 additional heteroatoms N, O or S;
L is a saturated or unsaturated, linear, branched or cyclic hydrocarbyl or a combination thereof, comprising n carbon atoms, wherein any carbon atom can be substituted or unsubstituted, wherein 0-3 heteroatoms O, S, or NR can be substituted for a carbon atom of L;
n is 1 to about 10;
R 1 is hydrogen, alkyl, aryl, aralkyl, cycloalkyl, heterocycles, or heteroaryl; wherein any alkyl can contain 0-3 heteroatoms comprising N, O, or S, wherein any alkyl, aryl, cycloalkyl, heterocyclyl, or heteroaryl may be unsubstituted or substituted;
R 4 and R 5 are at each occurrence independently H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein any alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl residue may be unsubstituted or substituted; provided that R 4 or R 5 is not a Boc group;
from a compound of formula (XII):
wherein Y is a leaving group;
the method comprising contacting the compound of formula (XII) with an amine of the formula R 1 NH 2 , in a solvent for a time period and at a temperature sufficient for the formation of the compound of Formula (XV):
then, contacting the compound of formula (XV) with a compound of Formula (XIV):
wherein R 6 is substituted or unsubstituted alkyl or aryl, or a salt thereof;
in a solvent for a time period and at a temperature sufficient for the formation of the compound of Formula (XIII).
4 . The method of claim 1 wherein Z is not methyl.
5 . The method of claim 1 wherein Y is halo, alkylsulfonoxy, arylsulfonoxy or alkarylsulfonoxy, wherein the alkyl or aryl is unsubstituted or is substituted with electron-withdrawing groups.
6 . The method of claim 1 wherein Z is H.
7 . The method of claim 1 wherein Z is methyl.
8 . The method of claim 1 wherein the compound of Formula (XI) comprises a lysine residue, a N-methyllysine residue, a N,N-dimethyllysine residue, or an N,N-dimethyllysine N-metho salt residue.
9 . The method of claim 1 wherein the compound of Formula (XI) is a neurotensin analog or an analog of a neurotensin fragment.
10 . The method of claim 1 wherein X comprises a Pro-Tyr-Ile residue.
11 . The method of claim 1 wherein Z comprises a PGlu-Leu-Tyr residue.
12 . The method of claim 2 wherein R 6 is methyl or ethyl.
13 . A compound of Formula (XI) prepared by the method of claim 1 .
14 . A compound of Formula (XIII) prepared by the method of claim 2 .
15 . A compound of Formula (XIV) comprising a salt thereof.
16 . The compound of claim 15 wherein the salt is a hydriodide salt.
17 . The method of claim 1 wherein the solvent is water, methanol, or ethanol, or a mixture thereof.
18 . The method of claim 1 wherein the solvent is DMSO, DMF, DMAc, or NMP, or a mixture thereof.
19 . The method of claim 2 wherein the solvent is water, acetonitrile, methanol, ethanol, tetrahydrofuran, or N,N-dimethylformamide, or a mixture thereof.
20 . The method of claim 1 wherein L is a linear or cycloalkylalkyl, saturated hydrocarbyl of 1 to about 10 carbon atoms.
21 . A method of use of a peptide analog prepared according to claim 1 for treatment of a malcondition in a patient in need thererof, the method comprising administering the analog in a dosage, at a frequency, and over a period of time sufficient to provide a beneficial effect to the patient.
22 . The method of claim 21 wherein the peptide analog is a neurotensin analog.
23 . The method of claim 21 wherein the malcondition comprises pain.
24 . The method of claim 21 wherein the malcondition comprises psychosis.
25 . The method of claim 21 wherein the malcondition comprises obesity.
26 . The method of claim 3 wherein Y is halo, alkylsulfonoxy, arylsulfonoxy or alkarylsulfonoxy, wherein the alkyl or aryl is unsubstituted or is substituted with electron-withdrawing groups.
27 . The method of claim 4 wherein Y is halo, alkylsulfonoxy, arylsulfonoxy or alkarylsulfonoxy, wherein the alkyl or aryl is unsubstituted or is substituted with electron-withdrawing groups.
28 . The method claim 2 wherein Z is H.
29 . The method of claim 3 wherein Z is H.
30 . The method of claim 4 wherein Z is H.
31 . The method of claim 2 wherein Z is methyl.
32 . The method of claim 3 wherein Z is methyl.
33 . The method of claim 3 wherein the compound of Formula (XIII) comprises a lysine residue, a N-methyllysine residue, a N,N-dimethyllysine residue, or an N,N-dimethyllysine N-metho salt residue.
34 . The method of claim 8 wherein Z is not methyl.
35 . The method of claim 33 wherein Z is not methyl.
36 . The method of claim 2 wherein the compound of Formula (XIII) is a neurotensin analog or an analog of a neurotensin fragment.
37 . The method of claim 3 wherein the compound of Formula (XIII) is a neurotensin analog or an analog of a neurotensin fragment.
38 . The method of claim 2 wherein the compound of Formula (XIII) is a neurotensin analog or an analog of a neurotensin fragment.
39 . The method of claim 3 wherein the compound of Formula (XIII) is a neurotensin analog or an analog of a neurotensin fragment.
40 . The method claim 4 wherein the compound of Formula (XI) is a neurotensin analog or an analog of a neurotensin fragment.
41 . The method of claim 2 wherein X comprises a Pro-Tyr-Ile residue.
42 . The method of claim 3 wherein X comprises a Pro-Tyr-Ile residue.
43 . The method of claim 4 wherein X comprises a Pro-Tyr-Ile residue.
44 . The method of claim 2 wherein Z comprises a PGlu-Leu-Tyr residue.
45 . The method of claim 3 wherein Z comprises a PGlu-Leu-Tyr residue.
46 . The method of claim 4 wherein Z comprises a PGlu-Leu-Tyr residue.
47 . The method of claim 3 wherein R 6 is methyl or ethyl.
48 . A compound of Formula (XIII) prepared by the method of claim 3 .
49 . The method of claim 2 wherein the solvent is water, methanol, or ethanol, or a mixture thereof.
50 . The method of claim 3 wherein the solvent is water, methanol, or ethanol, or a mixture thereof.
51 . The method of claim 4 wherein the solvent is water, methanol, or ethanol, or a mixture thereof.
52 . The method of claim 2 wherein the solvent is DMSO, DMF, DMAc, or NMP, or a mixture thereof.
53 . The method of claim 3 wherein the solvent is DMSO, DMF, DMAc, or NMP, or a mixture thereof.
54 . The method of claim 4 wherein the solvent is DMSO, DMF, DMAc, or NMP, or a mixture thereof.
55 . The method of claim 2 wherein L is a linear or cycloalkylalkyl, saturated hydrocarbyl of 1 to about 10 carbon atoms.
56 . The method of claim 3 wherein L is a linear or cycloalkylalkyl, saturated hydrocarbyl of 1 to about 10 carbon atoms.
57 . A method of use of a peptide analog prepared according to claim 2 for treatment of a malcondition in a patient in need thererof, the method comprising administering the analog in a dosage, at a frequency, and over a period of time sufficient to provide a beneficial effect to the patient.
58 . The method of claim 57 wherein the peptide analog is a neurotensin analog.
59 . The method of claim 57 wherein the malcondition comprises pain.
60 . The method of claim 57 wherein the malcondition comprises psychosis.
61 . The method of claim 57 wherein the malcondition comprises obesity.
62 . A method of use of a peptide analog prepared according to claim 3 for treatment of a malcondition in a patient in need thererof, the method comprising administering the analog in a dosage, at a frequency, and over a period of time sufficient to provide a beneficial effect to the patient.
63 . The method of claim 62 wherein the peptide analog is a neurotensin analog.
64 . The method of claim 62 wherein the malcondition comprises pain.
65 . The method of claim 62 wherein the malcondition comprises psychosis.
66 . The method of claim 62 wherein the malcondition comprises obesity.Join the waitlist — get patent alerts
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