US 11,072,584 B2Granted

Carbon monoxide releasing norbornenone compounds

AssigneeOtago Innovation Limited

InventorsIvan Andrew Sammut, Joanne Clare Harrison, Russell James Hewitt, Morgayn Iona Read, Nathan John Stanley, Laura Molly Woods, Jui Thiang Brian Kueh, Morgan Jay-Smith, Robin Andrew James Smith, Gregory Giles, Lesley Larsen, David Rennison, Margaret Anne Brimble, David Samuel Larsen

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Abstract

The present invention provides organic compounds which are capable of releasing carbon monoxide under physiological conditions or pH trigger, and to the use of such compounds for conditioning a cell, tissue or organ, for example, to protect against ischaemic injury during a transplant event.

Claims18

Dependent claims

A norbornenone compound of Formula 1, or a biologically or pharmaceutically acceptable salt thereof:

wherein
R1, R2, R3 and R4, are each independently selected from hydrogen, halo, CN, NO2, OC(O)R5, C(O)R5, C(O)OR5, OR5, OS(O)2R5, NR5R6, SR5, C1-20alkyl, C2-20alkenyl, C2-20alkynyl, monocyclic or polycyclic carbocyclyl or heterocyclyl, polyethylene glycol, amino acid, and saccharide;
wherein the C1-20alkyl, C2-20alkenyl, C2-20alkynyl, are each optionally interrupted with one or more heteroatoms selected from O, N and S;
and wherein the C1-20alkyl, C2-20alkenyl, C2-20alkynyl, carbocycle, and heterocycle, are each optionally substituted with 1-3 substituents independently selected from halo, CN, NO2, OC(O)R5, C(O)R5, C(O)OR5, OR5, OS(O)2R5, NR5R6, SR5, polyethylene glycol, amino acid, and saccharide;
and R5 and R6 are each independently selected from hydrogen, C1-10alkyl, and C1-10haloalkyl;
and wherein two or more of R1, R2, R3 and R4, may together form an optionally substituted monocyclic or polycyclic carbocyclyl or heterocyclyl;
X is selected from halo, ONO2, OP(O)(OR7), OS(O)2R7, OS(O)2OR7, SR7, S(O)R7, S(O)2R7, OR7, and NR7R8;
and R7 and R8 are each independently selected from hydrogen, C1-10alkyl, C1-10haloalkyl, aryl, arylalkyl and arylhaloalkyl;
A1 and A2 are each independently selected from hydrogen, halo, CN, NO2, S(O)R9, S(O)2R9, S(O)2OR9, SR9, NR9R10, C(═O)R9, C(═S)R9, C(═CR10R11)R9, or A1 and A2 together form an optionally substituted monocyclic or polycyclic carbocyclyl or heterocyclyl;
R9 is selected from hydrogen, hydroxyl, C1-20alkyl, C1-20haloalkyl, aryl, arylalkyl and arylhaloalkyl;
and R10 and R11 are each independently selected from hydrogen, C1-10alkyl, and C1-10haloalkyl;
with the proviso that a compound of Formula 1 does not include any of the following compounds:
3,3a,5,6-tetrachloro-3a,4,7,7a-tetrahydro-4,7-methano-1H-indene-1,8-dione;
(1α,4α,4aβ,4bα,5β,8β,8aαβ,12bβ) 8a,12b-dibromo-1,2,3,4,5,6,7,8-octachloro-1,4,4a,4b,5,8,8a,12b-octahydro-1,4:5,8-dimethanotriphenylene-13,14-dione;
4,7,7a-tribromo-3a,4,7,7a-tetrahydro-2,3,5,6-tetraphenyl-4,7-methano-1H-indene-1,8-dione;
7,7a-dibromo-2,3,4,5-tetrachloro-3a,4,7,7a-tetrahydro-4,7-methano-1H-indene-1,8-dione;
4,7a-dibromo-2,3,6,7-tetrachloro-3a,4,7,7a-tetrahydro-4,7-methano-1H-indene-1,8-dione;
methyl (2-exo,3-endo)-3-nitro-7-oxo-1,4,5,6-tetraphenyl-bicyclo[2.2.1]hept-5-ene-2-carboxylate;
1,2,3,4-tetraphenyl-5-(phenylthio)-bicyclo[2.2.1]hept-2-en-7-one;
2-[(4-bromophenyl)thio]-1,2,3,4-tetrahydro-1,4-diphenyl-1,4-methanotriphenylen-13-one;
(1α,4α,5β)-1,4-dimethyl-2,3-diphenyl-5-(phenylsulfinyl)-bicyclo[2.2.1]hept-2-en-7-one.

18 more elements

A norbornenone compound or salt selected form any one of the following compounds, or a pharmaceutically acceptable salt thereof:

Compound Structure
Compound Name
3a-Bromo-3a,4,7,7a-tetrahydro-4,7-dimethyl- 2,5,6-triphenyl-4,7-methano-1H-isoindole- 1,3,8(2H)-trione;
3a-Chloro-3a,4,7,7a-tetrahydro-4,7-dimethyl- 2,5,6-triphenyl-4,7-methano-1H-isoindole- 1,3,8(2H)-trione
3a-Iodo-3a,4,7,7a-tetrahydro-4,7-dimethyl-2,5,6- triphenyl-4,7-methano-1H-isoindole-1,3,8(2H)- trione
3a-Phenylthio-3a,4,7,7a-tetrahydro-4,7-dimethyl- 2,5,6-triphenyl-4,7-methano-1H-isoindole- 1,3,8(2H)-trione
3a-Phenylsulfinyl-3a,4,7,7a-tetrahydro-4,7- dimethyl-2,5,6-triphenyl-4,7-methano-1H- isoindole-1,3,8(2H)-trione
3a-Phenylsulfonyl-3a,4,7,7a-tetrahydro-4,7- dimethyl-2,5,6-triphenyl-4,7-methano-1H- isoindole-1,3,8(2H)-trione
3a-Bromo-4,7-dimethyl-5,6-diphenyl-3a,4,7,7a- tetrahydro-1H-4,7-methanoisoindole-1,3,8(2H)- trione
3a-Bromo-3a,4,7,7a-tetrahydro-4,7-dimethyl-2-(4- hydroxyphenyl)-5,6-diphenyl-4,7-methano-1H- isoindole-1,3,8(2H)-trione
3a-Bromo-3a,4,7,7a-tetrahydro-4,7-dimethyl-5,6- diphenyl-2-tri-(3,4-methylenedioxyphenyl)-4,7- methano-1H-isoindole-1,3,8(2H)-trione
3a-Bromo-3a,4,7,7a-tetrahydro-4,7-dimethyl-2- (3,4-dihydroxyphenyl)-5,6-diphenyl-4,7-methano- 1H-isoindole-1,3,8(2H)-trione
3a-Bromo-3a,4,7,7a-tetrahydro-4,7-dimethyl-2-(4- hydroxy-3-nitrophenyl)-5,6-diphenyl-4,7- methano-1H-isoindole-1,3,8(2H)-trione
3a-Bromo-3a,4,7,7a-tetrahydro-4,7-dimethyl-2-(4- (2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)- 5,6-diphenyl-4,7-methano-1H-isoindole-1,3,8(2H)- trione
3a-Bromo-3a,4,7,7a-tetrahydro-4,7-dimethyl-2-(4- (2-methoxy(2-polyethoxy)phenyl)-5,6-diphenyl- 4,7-methano-1H-isoindole-1,3,8(2H)-trione
3a-Bromo-3a,4,7,7a-tetrahydro-4,7-dimethyl-2-(4- (2,3,4,6-tetra-O-acetyl-β-D- glucopyranosyloxy)phenyl)-5,6-diphenyl-4,7- methano-1H-isoindole-1,3,8(2H)-trione
3a-Bromo-3a,4,7,7a-tetrahydro-4,7-dimethyl- 2,5,6-tri-(4-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)-4,7- methano-1H-isoindole-1,3,8(2H)-trione
3a-Bromo-3a,4,7,7a-tetrahydro-4,7-dimethyl-2-(2- acetoxyethyl)-5,6-diphenyl-4,7-methano-1H- isoindole-1,3,8(2H)-trione
2,5-Dioxopyrrolidin-1-yl 3-(3a-bromo-4,7- dimethyl-1,3,8-trioxo-5,6-diphenyl-1,3,3a,4,7,7a- hexahydro-2H-4,7-methanoisoindol-2- yl)propanoate
tert-Butyl (2-(3-((4S,7R)-3a-bromo-4,7-dimethyl- 1,3,8-trioxo-5,6-diphenyl-3a,4,7,7a-tetrahydro- 1H-4,7-methanoisoindol-2(2H)- yl)propanamido)ethyl)carbamate
2-(3-(3a-Bromo-4,7-dimethyl-1,3,8-trioxo-5,6- diphenyl-1,3,3a,4,7,7a-hexahydro-2H-4,7- methanoisoindol-2-yl)propanamido)ethan-1- aminium trifluoroacetate and chloride
tert-Butyl (2-(3a-bromo-4,7-dimethyl-1,3,8-trioxo- 5,6-diphenyl-3a,4,7,7a-tetrahydro-2H-4,7- methanoisoindol-2-yl)ethyl)carbamate
2-(3a-Bromo-4,7-dimethyl-1,3,8-trioxo-5,6- diphenyl-2H-4,7-methanoisoindolin-2-yl)ethan-1- aminium 2,2,2-trifluoroacetate, chloride, and bromide
tert-Butyl (2-(3a-bromo-4,7-dimethyl-1,3,8-trioxo- 5,6-diphenyl-3a,4,7,7a-tetrahydro-1H-4,7- methanoisoindol-2(2H)-yl)ethyl)(2-((tert- butoxycarbonyl)amino)ethyl)carbamate
2-(2-(2-Aminoethyl)aminoethyl)-3a-bromo- 3a,4,7,7a-tetrahydro-4,7-dimethyl--5,6-diphenyl- 4,7-methano-1H-isoindole-1,3,8(2H)-trione bis- trifluoroacetate salt
N-(2-Hydroxy-1,1-bis(hydroxymethyl)ethyl)-3-(3a- bromo-4,7-dimethyl-1,3,8-trioxo-5,6-diphenyl- 3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindol- 2(2H)-yl)propanamide
tert-Butyl (5-(3a-bromo-4,7-dimethyl-1,3,8-trioxo- 5,6-diphenyl-3a,4,7,7a-tetrahydro-2H-4,7- methanoisoindol-2-yl)pentyl)carbamate
5-(3a-Bromo-4,7-dimethyl-1,3,8-trioxo-5,6- diphenyl-2H-4,7-methanoisoindolin-2-yl)pentan-1- aminium 2,2,2-trifluoroacetate
(2S)-2-tert-butoxycarbonylamino-6-(3a-bromo- 4,7-dimethyl-1,3,8-trioxo-5,6-diphenyl- 1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindol- 2-yl)hexanoic acid
(2S)-2-Amino-6-(3a-bromo-4,7-dimethyl-1,3,8- trioxo-5,6-diphenyl-1,3,3a,4,7,7a-hexahydro-2H- 4,7-methanoisoindol-2-yl)hexanoic acid trifluoroacetic acid salt
Methyl (2S)-2-tert-butoxycarbonylamino-6-(3a- bromo-4,7-dimethyl-1,3,8-trioxo-5,6-diphenyl- 1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindol- 2-yl)hexanoate
Methyl (2S)-2-amino-6-(3a-bromo-4,7-dimethyl- 1,3,8-trioxo-5,6-diphenyl-1,3,3a,4,7,7a- hexahydro-2H-4,7-methanoisoindol-2- yl)hexanoate trifluoroacetic acid salt
Ethyl (2S)-2-tert-butoxycarbonylamino-6-(3a- bromo-4,7-dimethyl-1,3,8-trioxo-5,6-diphenyl- 1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindol- 2-yl)hexanoate
Ethyl (2S)-2-amino-6-(3a-bromo-4,7-dimethyl- 1,3,8-trioxo-5,6-diphenyl-1,3,3a,4,7,7a- hexahydro-2H-4,7-methanoisoindol-2- yl)hexanoate trifluoroacetic acid salt
nPropyl (2S)-2-tert-butoxycarbonylamino-6-(3a- bromo-4,7-dimethyl-1,3,8-trioxo-5,6-diphenyl- 1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindol- 2-yl)hexanoate
nPropyl (2S)-2-amino-6-(3a-bromo-4,7-dimethyl- 1,3,8-trioxo-5,6-diphenyl-1,3,3a,4,7,7a- hexahydro-2H-4,7-methanoisoindol-2- yl)hexanoate trifluoroacetic acid salt
N,N-Dimethyl (2S)-2-tert-butoxycarbonylamino-6- (3a-bromo-4,7-dimethyl-1,3,8-trioxo-5,6-diphenyl- 1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindol- 2-yl)hexanamide
N,N-Dimethyl (2S)-2-amino-6-(3a-bromo-4,7- dimethyl-1,3,8-trioxo-5,6-diphenyl-1,3,3a,4,7,7a- hexahydro-2H-4,7-methanoisoindol-2- yl)hexanamide trifluoroacetic acid salt
tert-Butyl 6-(3a-bromo-4,7-dimethyl-1,3,8-trioxo- 5,6-diphenyl-1,3,3a,4,7,7a-hexahydro-2H-4,7- methanoisoindol-2-yl)hexanoate
6-(3a-bromo-4,7-dimethyl-1,3,8-trioxo-5,6- diphenyl-1,3,3a,4,7,7a-hexahydro-2H-4,7- methanoisoindol-2-yl)hexanoic acid
Methyl (2S)-2-tert-butoxycarbonylamino-5-(3a- bromo-4,7-dimethyl-1,3,8-trioxo-5,6-diphenyl- 1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindol- 2-yl)pentanoate
Methyl (2S)-2-amino-5-(3a-bromo-4,7-dimethyl- 1,3,8-trioxo-5,6-diphenyl-1,3,3a,4,7,7a- hexahydro-2H-4,7-methanoisoindol-2- yl)pentanoate trifluoroacetic acid salt
Methyl (2S)-2-acetamido-6-(3a-bromo-4,7- dimethyl-1,3,8-trioxo-5,6-diphenyl-1,3,3a,4,7,7a- hexahydro-2H-4,7-methanoisoindol-2- yl)hexanoate
(1S)-1-tert-butoxycarbonylamino-5-(3a-bromo- 4,7-dimethyl-1,3,8-trioxo-5,6-diphenyl- 1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindol- 2-yl)-1-(3-methyl-1,2,4-oxadiazol-5′-yl)pentane
(1S)-1-amino-5-(3a-bromo-4,7-dimethyl-1,3,8- trioxo-5,6-diphenyl-1,3,3a,4,7,7a-hexahydro-2H- 4,7-methanoisoindol-2-yl)-1-(3-methyl-1,2,4- oxadiazol-5-yl)pentane trifluoroacetic acid salt
(1S)-1-tert-butoxycarbonylamino-5-(3a-bromo- 4,7-dimethyl-1,3,8-trioxo-5,6-diphenyl- 1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindol- 2-yl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)pentane
(1S)-1-Amino-5-(3a-bromo-4,7-dimethyl-1,3,8- trioxo-5,6-diphenyl-1,3,3a,4,7,7a-hexahydro-2H- 4,7-methanoisoindol-2-yl)-1-(5-methyl-1,3,4- oxadiazol-2-yl)pentane trifluoroacetic acid salt
3a,4,7,7a-Tetrahydro-7a-bromo-4,7-dimethyl-5,6- diphenyl-1H-4,7-methanoisobenzofuran- 1,3,8(2H)-trione
3a-Bromo-3a,4,7,7a-tetrahydro-4,7-dimethyl-2-(2- propyn-1-yl)-5,6-diphenyl-4,7-methano-1H- isoindole-1,3,8(2H)-trione
3a-Bromo-3a,4,7,7a-tetrahydro-4,7-dimethyl-2- [[1-(2-(2:3,4:6-bis-O-(1-methylethylidene)-α-D- mannopyranosyloxy)ethyl]-1H-1,2,3-triazol- 4yl]methyl-5,6-diphenyl-4,7-methano-1H- isoindole-1,3,8(2H)-trione
3a-Bromo-3a,4,7,7a-tetrahydro-4,7-dimethyl-2- [[1-(2-α-D-mannopyranosyloxy)ethyl]-1H-1,2,3- triazol-4yl]methyl-5,6-diphenyl-4,7-methano-1H- isoindole-1,3,8(2H)-trione
2-Bromo-1,4-dimethyl-7-oxo-5,6-diphenyl- bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid
4a,7-Dibromo-1,4-dimethyl-2,3-diphenyl- 1,4,4a,8a-tetrahydro-1,4-methanonaphthalene- 5,8,9-trione

50 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/702,205Filed 3 Dec 2019 · continuation
Priority: 30 Nov 2015
Published: US 2020/0109115 A19 Apr 2020
Granted: 27 Jul 2021
Term ends: Not estimatedThe source records don’t support an estimate.

Classification26 codes

C07D 209/76
4,7-Endo-alkylene-iso-indoles: with oxygen atoms in positions 1 and 3
A61P 7/00
Drugs for disorders of the blood or the extracellular fluid
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
A61P 9/00
Drugs for disorders of the cardiovascular system

Family

Application62/261,072Us provisional application · filed 30 Nov 2015
PCT/NZ2016/050188Parent of this continuation · filed 30 Nov 2016
US 10,494,344 B2Parent of this continuation · filed 3 Dec 2019
US 2020/0109115 A1Pre-grant publication · published 9 Apr 2020
Application15/779,929Parent of this continuation
US 2018/0346420 A1Published application
US 11,072,584 B2This patent

From the US filing history. Foreign family members aren’t listed.