Opioid agonists and uses thereof
AssigneeNektar Therapeutics
InventorsFranco J. Duarte, Neel K. Anand, Pankaj Sharma, Devendrapratap Singh
Life of this patent
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Abstract
Provided are compounds, including those of Formula I; and pharmaceutically acceptable salts and solvates thereof. The compounds described herein relate to and/or have application(s) in (among others) the fields of drug discovery, pharmacotherapy, physiology, organic chemistry and polymer chemistry.
Claims103
A compound selected from the formula:
- wherein:
- R1 is selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, and X-POLY;
- R2 is selected from optionally substituted alkyl and -X-POLY;
- R3 is selected from hydroxyl, optionally substituted alkyl, optionally substituted amino, optionally substituted heterocyclyl, and -X-POLY;
- or
- R1 and R3 are taken together with their intervening atoms to form a fused, optionally substituted heteroaryl or optionally substituted heterocyclyl;
- or
- R3 and R5 are taken together with their intervening atoms to form a fused, optionally substituted heteroaryl;
- is optionally a single bond or a double bond;
- G is —O—R4 or NH—R4 when represents a single bond or G is ═O or ═N—R4 when represents a double bond;
- X is a spacer moiety (e.g. acovalent bond, —C(O)—, —NHC(O)—, —NH—, —CH2CHOHCH2NH—, and —O—);
- POLY is a water soluble, non-peptidic oligomer;
- R4 is -L-POLY or -X-POLY, wherein L is an optional amino acid residue;
- R5 is selected from hydrogen and X-POLY;
- and
- provided one of R1, R2, R3, R4, and R5 comprises a POLY group;
- and pharmaceutically acceptable salts and solvates thereof.
The compound of any one of the preceding claims, wherein R2 is alkyl.
The compound of any one of the preceding claims, wherein R2 is cyclopropylmethyl.
The compound of any one of the preceding claims, wherein G is O and represents a double bond.
The compound of any one of the preceding claims, wherein R1 is hydrogen.
The compound of any one of the preceding claims, wherein R3 is selected from optionally substituted alkyl, optionally substituted amino, and -X-POLY.
The compound of any one of the preceding claims, wherein R3 is optionally substituted amino.
The compound of any one of the preceding claims, wherein R3 is amino substituted with an optionally substituted aryl or optionally substituted alkyl.
The compound of any one of the preceding claims, wherein R3 is amino substituted with an optionally substituted phenyl.
The compound of any one of the preceding claims, wherein the compound of Formula I is selected from a compound of the formula
- wherein:
- q is an integer from 1 to 3;
- each Ra is independently selected from optionally substituted amino, halo, optionally substituted alkyl, and X-POLY;
- X is selected from a covalent bond, —NH— or —O—;
- POLY is a water soluble, non-peptidic oligomer;
- and
- wherein only one Ra is -X-POLY.
The compound of any one of claims 58 to 63, wherein the compound of Formula I is a compound of the formula:
- wherein:
- X is selected from a covalent bond and —C(O)—;
- and
- POLY is a poly(alkylene oxide) oligomer.
The compound of any one of claims 58 to 64, wherein the compound of Formula I is a compound of the formula:
- wherein n is an integer from 1 to 30.
A compound having the following structure:
- n is an integer from 1 to 30, and pharmaceutically acceptable salts thereof.
A compound, selected from
- (2S,6R,11R)-3-(Cyclopropylmethyl)-8-({2-[2-(2-methoxy)ethoxy]ethyl}amino-6.11-dimethyl-3, 4, 5, 6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one;
- (2S,6R11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-8-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one;
- (2S,6R,11R)-3-(Cyclopropylmethyl)-8-(2,5,8,11,14,17,20-heptaoxadocosan-22-ylamino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one;
- (2S,6R,11R)-3-(Cyclopropylmethyl)-8-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one;
- (2S,6R,11R)-3-(Cyclopropylmethyl)-6,11-dimethyl-8-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3,4,5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one;
- (2S,6R,11R)-3-(Cyclopropylmethyl)-8-(2,5,8,11,14,17,20-heptaoxadocosan-22-yloxy)-6,11-dimethyl-3,4, 5,6-tetrahydro-2,6-methano-3-benzazocin-1(2H)-one;
- (2S,6R,11R)-8-((2-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;
- (2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;
- (2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;
- (2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3 (cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;
- (2S,6R,11R)-8-((3-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;
- (2S,6R,11R)-8-((4-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)phenyl)amino)-3-(cyclopropylmethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;
- (6S,10R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-7-(cyclopropylmethyl)-10,12-dimethyl-7,8,9,10-tetrahydro-6,10-methanothiazolo[4′,5′:4,5]benzo[1,2-d]azocin-5(6H)-one;
- (2S,6R,11R)-8-hydroxy-3-(2-(2-methoxyethoxy)ethyl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;
- N-((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)-2-(2-methoxyethoxy)acetamide;
- (2S,6R,11R)-3-(cyclopropylmethyl)-N-(2-methoxyethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocine-8-carboxamide;
- N,N-(((2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-1-oxo-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-yl)methyl)-2-(2-methoxyethoxy)acetamide;
- (2S,6R,11R)-3-(cyclopropylmethyl)-8-(((2-(2-methoxyethoxy) ethyl)amino)methyl)-6,11-dimethyl-3,4,5, 6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;
- (2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;
- (2S,6R,11R)-3-(cyclopropylmethyl)-6,11-dimethyl-8-((4-((1,1,1-trifluoro-2, 5,8,11,14-pentaoxahexadecan-16-yl)amino)phenyl)amino)-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;
- (2S,6R,11R)-3-(cyclopropylmethyl)-8-((16-(hydroxymethyl)-2,5,8,11,14-pentaoxaheptadecan-17-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;
- (7S,11R,12R)-2-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-8-(cyclopropylmethyl)-11,12-dimethyl-8,9,10,11-tetrahydro-7,11-methanothiazolo[5′,4′:3,4]benzo[1,2-d]azocin-6(7H)-one;
- (2S,6R,11R)-3-(Cyclopropylmethyl)-8-((1-hydroxy-2-methylpropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;
- (2S,6R,11R)-3-(cyclopropylmethyl)-8-((1,3-dihydroxypropan-2-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;
- (1R,2S,6R,11R)-1-(2,5,8,11,14-pentaoxahexadecan-16-yloxy)-3-(cyclopropylmethyl)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol;
- (2S,6R,11R)-7-(2,5,8,11,14-pentaoxahexadecan-16-ylamino)-3-(cyclopropylmethyl)-8-hydroxy-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;
- (2S,6R,11R)-3-(cyclopropylmethyl)-8-((1-(2-methoxyethyl)piperidin-4-yl)amino)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one;
- and
- (2S,6R,11R)-3-(cyclopropylmethyl)-8-(4-(2-(2-(2-methoxyethoxy)ethoxy)ethyl) piperazin-1-yl)-6,11-dimethyl-3,4,5,6-tetrahydro-2,6-methanobenzo[d]azocin-1(2H)-one, and pharmaceutically acceptable salts thereof.
A pharmaceutical composition comprising a compound of any one of the preceding claims and at least one pharmaceutically acceptable excipient.
A composition of matter comprising a compound of any one of the preceding claims, wherein the compound is present in a dosage form.
A method comprising administering a compound of any one of the preceding claims to a patient in need thereof.
Dependencies are inferred from the claim text.