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Targeted Prodrug Therapy for Cancer and Neurodegenerative Diseases

Introduction

Cancer and neurodegenerative diseases remain two of the most challenging health conditions to treat due to their complexity and resistance to traditional therapies. Recent advancements in the development of proteasome inhibitors, which regulate protein degradation in cells, have shown great promise in addressing both cancer progression and neurodegenerative disorders. Our patented proteasome-inhibiting β-lactam prodrugs offer a targeted and effective approach to treating these diseases, providing pharmaceutical companies and researchers with a novel solution for creating life-saving therapies.

Addressing the Treatment Gaps in Cancer and Neurodegenerative Diseases

Cancer therapies have evolved over the years, yet many treatments still fall short in targeting tumor cells with precision while minimizing damage to healthy tissues. Additionally, neurodegenerative disorders like Alzheimer’s and Parkinson’s lack effective treatments that can stop or reverse the progression of the disease. Existing medications often focus on managing symptoms rather than addressing the underlying cellular dysfunction that drives these conditions.

The use of proteasome inhibitors has emerged as a promising therapeutic strategy, as proteasomes play a key role in regulating protein degradation in cells. Disrupting this process in cancer cells can lead to cell death, making it an effective anti-tumor strategy. Similarly, targeting proteasome activity in neurodegenerative diseases can help restore proper protein balance, potentially slowing or stopping disease progression. However, developing treatments that can deliver these inhibitors with high specificity and minimal side effects is a critical challenge.

A Targeted Therapeutic Approach with β-Lactam Prodrugs

Our proteasome-inhibiting β-lactam prodrugs introduce a breakthrough approach to targeting and inhibiting proteasome activity in diseased cells. These prodrugs are designed to remain inactive until they reach the target site, where they are converted into active inhibitors within the cancerous or neurodegenerative cells. This ensures high specificity and reduces the risk of systemic side effects, making the treatment both effective and safer for patients.

The prodrugs are especially valuable in treating cancer, as proteasome inhibition disrupts the regulatory systems that cancer cells rely on to survive and proliferate. Similarly, in neurodegenerative diseases, this approach helps manage the accumulation of misfolded proteins that lead to cell damage. By leveraging the selective activation of the prodrugs, this technology offers a precise method for controlling proteasome activity and improving patient outcomes in both oncology and neurology.

Key Benefits

  • Targeted Therapy: Delivers proteasome inhibitors directly to diseased cells, reducing off-target effects and improving treatment efficacy.
  • Versatile Applications: Effective in treating both cancer and neurodegenerative diseases, offering a broad therapeutic scope.
  • Reduced Side Effects: Prodrug design ensures that the active compound is only released in the target cells, minimizing systemic toxicity.
  • Potential to Slow Disease Progression: In neurodegenerative diseases, proteasome inhibition can help restore protein balance and reduce cellular damage.

Transforming Treatment for Complex Diseases

Licensing this proteasome-inhibiting prodrug technology provides pharmaceutical companies with a powerful tool to develop next-generation therapies for cancer and neurodegenerative disorders. By offering a targeted approach to treatment, this technology opens new avenues for addressing some of the most challenging health conditions, bringing hope for improved patient outcomes.

Please see terms and conditions
The present invention relates generally to proteasome inhibiting β-lactam compounds useful for the treatment of cancer and neurodegenerative disorders. The invention also provides pharmaceutical compositions and extended release formulations of said compounds, and medical uses of said compounds and/or pharmaceutical compositions to treat cancer and neurodegenerative disorders.

The invention claimed is:

1. A simonorealide compound of general formula (1a) or (1b):
Figure US11053249-20210706-C00113
wherein
X is H or —CO—O—R7;
Y is NR8, S(O)n, Se(O)n or Te(O)n;
R1 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and substituted derivatives thereof;
R2 is —CH(OH)R9, —SO2—R, —SeO2—R or —TeO2—R with R is an alkyl, and substituted derivatives thereof;
R3 and R4 are independently selected from hydrogen, alkyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, alkyl substituted by group selected from —O—SO2—R′, —O—SeO2—R′ or —O—TeO2—R′ with R′ is an alkyl, or an aryl, and substituted derivatives thereof;
R5 is selected from hydrogen, hydroxyl, sulfhydryl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkynyl, acyl, and substituted derivatives thereof;
R6 is selected from hydrogen, alkyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, alkyl substituted by group selected from —O—SO2—R′, —O—SeO2—R′ or —O—TeO2—R′ with R′ is an alkyl, or an aryl, and substituted derivatives thereof;
R7 is —[C(R10)(R11)—O—CO]m—R12;
R8 is hydrogen, alkyl, and substituted derivatives thereof;
R9 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkynyl, acyl, and substituted derivatives thereof;
R10 and R11 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, alkoxycarbonyl, carbamoyl, and substituted derivatives thereof;
R12 is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkynyl, acyl, and substituted derivatives thereof; or R12 is transport substrate of LAT1 selected from leucine, isoleucine, valine, phenylalanine, tyrosine, tryptophan, histidine, methionine, L-dopa, 3-O-methyldopa, α-methyl-phenylalanine, α-methyl-tyrosine, α-methyldopa, gabapentin, 3-iodo-α-methyl-L-tyrosine, 3-fluoro-α-methyl-L-tyrosine, 3-iodo-O-methyl-L-tyrosine, 3-iodo-O-methyl-α-methyl-L-tyrosine, 4-iodo-L-meta-tyrosine, 6-iodo-L-meta-tyrosine, O-(2-fluoroethyl)-L-tyrosine, 3-O-methyl-6-fluoro-L-dopa, 2-iodo-L-tyrosine, 2-fluoro-L-tyrosine, and substituted derivatives thereof; or R12 is a transport substrate of GLUT1, MCT1, CAT1, CNT2 or SVCT2; or R12 is a peptide substrate; or R12 is a peptide vector;
n is 0, 1 or 2;
m is 0 or 1;
with the proviso that when Y is NH then X is not H.
2. A compound according to claim 1, wherein

X is —CO—O—R12 or CO—O—C(R10)(R11)—O—CO—R12;
R10 and R11 are independently selected from hydrogen and alkyl; and
R12 is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkynyl, acyl, and substituted derivatives thereof, or R12 is transport substrate of LAT1 selected from leucine, isoleucine, valine, phenylalanine, tyrosine, tryptophan, histidine, methionine, L-dopa, 3-O-methyldopa, α-methyl-phenylalanine, α-methyl-tyrosine, α-methyldopa, gabapentin, 3-iodo-α-methyl-L-tyrosine, 3-fluoro-α-methyl-L-tyrosine, 3-iodo-O-methyl-L-tyrosine, 3-iodo-O-methyl-α-methyl-L-tyrosine, 4-iodo-L-meta-tyrosine, 6-iodo-L-meta-tyrosine, O-(2-fluoroethyl)-L-tyrosine, 3-O-methyl-6-fluoro-L-dopa, 2-iodo-L-tyrosine, 2-fluoro-L-tyrosine, and substituted derivatives thereof; or R12 is a transport substrate of GLUT1, MCT1, CAT1, CNT2 or SVCT2; or R12 is a peptide substrate; or R12 is a peptide vector.
3. A compound according to claim 1, wherein said compound corresponds to a general formula (2c), (2d), (3c), (3d), (4c), (4d), (5c) or (5d)
Figure US11053249-20210706-C00114
wherein R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, and n are as defined in claim 1; and
R12 is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkynyl, acyl, and substituted derivatives thereof.
4. A compound according to claim 1, wherein said compound corresponds to a general formula (2c), (2d), (3c), (3d), (4c), (4d), (5c) or (5d)
Figure US11053249-20210706-C00115
wherein R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, and n are as defined herein; and
R12 is a transport substrate of LAT1 selected from leucine, isoleucine, valine, phenylalanine, tyrosine, tryptophan, histidine, methionine, L-dopa, 3-O-methyldopa, α-methyl-phenylalanine, α-methyl-tyrosine, α-methyldopa, gabapentin, 3-iodo-α-methyl-L-tyrosine, 3-fluoro-α-methyl-L-tyrosine, 3-iodo-O-methyl-L-tyrosine, 3-iodo-O-α-methyl-L-tyrosine, 4-iodo-L-meta-tyrosine, 6-iodo-L-meta-tyrosine, O-(2-fluoroethyl)-L-tyrosine, 3-O-methyl-6-fluoro-L-dopa, 2-iodo-L-tyrosine, 2-fluoro-L-tyrosine, and substituted derivatives thereof; or R12 is a transport substrate of GLUT1, MCT1, CAT1, CNT2 or SVCT2; or R12 is a peptide substrate; or R12 is a peptide vector.
5. A compound according to claim 1, wherein said compound corresponds to a general formula (2e), (2f), (3e), (3f), (4e), (4f), (5e) or (5f)
Figure US11053249-20210706-C00116
wherein R1, R2, R3, R4, R5, R6, R8, R9, and n are as defined in claim 1; and
R12 is a transport substrate of LAT1 selected from leucine, isoleucine, valine, phenylalanine, tyrosine, tryptophan, histidine, methionine, L-dopa, 3-O-methyldopa, α-methyl-phenylalanine, α-methyl-tyrosine, α-methyldopa, gabapentin, 3-iodo-α-methyl-L-tyrosine, 3-fluoro-α-methyl-L-tyrosine, 3-iodo-O-methyl-L-tyrosine, 3-iodo-O-methyl-α-methyl-L-tyrosine, 4-iodo-L-meta-tyrosine, 6-iodo-L-meta-tyrosine, O-(2-fluoroethyl)-L-tyrosine, 3-O-methyl-6-fluoro-L-dopa, 2-iodo-L-tyrosine, 2-fluoro-L-tyrosine, and substituted derivatives thereof; or R12 is a transport substrate of GLUT1, MCT1, CAT1, CNT2 or SVCT2; or R12 is a peptide substrate; or R12 is a peptide vector.
6. A compound according to claim 1 wherein R1 is H.
7. A compound according claim 1, wherein

R2 is —CH(OH)R9, —SO2—R, —SeO2—R or —TeO2—R;
R is an alkyl and substituted derivatives thereof;
R9 is selected from alkyl and cycloalkenyl.
8. A compound according to claim 1, wherein

R3 and R4 are independently selected from hydrogen, alkyl and haloalkyl;
R5 is selected from H or alkyl; and
R6 is selected from alkyl or haloalkyl.
9. A compound according to claim 1, wherein R8 is H.
10. A compound according to claim 1, wherein R12 is selected from alkyl, tyrosine, 3-iodo-α-methyl-L-tyrosine, 3-fluoro-α-methyl-L-tyrosine, 3-iodo-O-methyl-L-tyrosine, 3-iodo-O-methyl-α-methyl-L-tyrosine, 4-iodo-L-meta-tyrosine, 6-iodo-L-meta-tyrosine, O-(2-fluoroethyl)-L-tyrosine, 3-O-methyl-6-fluoro-L-dopa or 2-iodo-L-tyrosine, 2-fluoro-L-tyrosine.
11. A compound according to claim 1, wherein

R1 is H;
R3 and R4 are independently selected from hydrogen, alkyl and haloalkyl;
R5 is selected from hydrogen or alkyl;
R6 is selected from alkyl or haloalkyl;
R8 is hydrogen;
R9 is selected from alkyl and cycloalkenyl;
R10 and R11 are independently selected from hydrogen and alkyl.
12. A compound according to claim 11, wherein

R1 is H;
R3 is H;
R4 is methyl or 2-chloroethyl;
R5 is selected from hydrogen or methyl;
R6 is selected from methyl or 2-chloroethyl;
R8 is hydrogen;
R9 is selected from isopropyl and cyclohex-2-enyl;
R10 and R11 are independently selected from hydrogen and methyl.
13. A composition comprising a therapeutically effective amount of a compound as defined in claim 1, and a pharmaceutically acceptable vehicle, carrier or diluent.
14. A process of preparation of compounds of general formula (1b) of claim 1, wherein in general formula (1b) R2 is —SO2—R, —SeO2—R or —TeO2—R with R is an alkyl; R6 is chloroethyl, and X is H; comprising the following steps:

the formation of alkenyl azetidinone by a Staudinger reaction between acyl chloride and imine;
the iodine-promoted cyclization of to form iodopenem adduct;
the Stille cross-coupling between and tributyl(vinyl)tin to form compound;
the reverse Wacker oxidation of the carbon-carbon double bond of compound to form aldehyde;
the reduction of aldehyde to form alcohol;
optionally the oxidation of alcohol to form the corresponding sulfoxyde, sulfone, selenoxide, selenone, telluroxide or tellurone;
the desilylation to form compound;
the chlorination of compound to form chloride; and
the deprotection of the nitrogen of the β-lactam ring of compound to form proteasome inhibitor;
Figure US11053249-20210706-C00117
15. A process of preparation of compounds of general formula (1b) of claim 1, wherein in general formula (1b) R2 is —CH(OH)R9; R6 is chloroethyl; Y is S(O)n, Se(O)n or Te(O)n and n is 0, 1 or 2; and X is H; comprising the following steps:

the formation of alkenyl azetidinone by a Staudinger reaction between acyl chloride and imine;
the iodine-promoted cyclization of to form iodopenem adduct;
the ozonolysis of the carbon-carbon double bond of compound to form aldehyde;
the addition of R9—ZnCl on the aldehyde to form alcohol;
the Stille cross-coupling between and tributyl(vinyl)tin to form compound;
the reverse Wacker oxidation of the carbon-carbon double bond of compound to form aldehyde;
the reduction of aldehyde to form alcohol;
optionally the oxidation of alcohol to form the corresponding sulfoxide, sulfone, selenoxide, selenone, telluroxide or tellurone;
the desilylation to form compound;
the chlorination of compound to form chloride; and
the deprotection of the nitrogen of the β-lactam ring of compound to form proteasome inhibitor;
Figure US11053249-20210706-C00118
16. A process of preparation of compounds of general formula (1b) of claim 1, wherein in general formula (1b) R2 is —SO2—R, —SeO2—R or —TeO2—R with R is an alkyl; R6 is methyl; and X is H; comprising the following steps:

the formation of alkenyl azetidinone by a Staudinger reaction between acyl chloride and imine;
the iodine-promoted cyclization of to form iodopenem adduct;
the cross-coupling between and methylmagnesium bromide to form compound;
optionally the oxidation of alcohol to form the corresponding sulfoxyde, sulfone, selenoxide, selenone, telluroxide or tellurone;
the desilylation to form compound; and
the deprotection of the nitrogen of the β-lactam ring of compound to form proteasome inhibitor;
Figure US11053249-20210706-C00119
17. A process of preparation of compounds of general formula (1b) of claim 1, wherein in general formula (1b) R2 is —CH(OH)R9; R6 is methyl; Y is S(O)n, Se(O)n or Te(O)n and n is 0, 1 or 2; and X is H; comprising the following steps:

the formation of alkenyl azetidinone by a Staudinger reaction between acyl chloride and imine;
the iodine-promoted cyclization of to form iodopenem adduct;
the ozonolysis of the carbon-carbon double bond of compound to form aldehyde;
the addition of R9—ZnCl on the aldehyde to form alcohol;
the cross-coupling between and methylmagnesium bromide to form compound;
optionally the oxidation of alcohol to form the corresponding sulfoxide, sulfone, selenoxide, selenone, telluroxide or tellurone;
the desilylation to form compound; and
the deprotection of the nitrogen of the β-lactam ring of compound to form proteasome inhibitor;
Figure US11053249-20210706-C00120
18. The method of claim 15, wherein n is 0.
19. The method of claim 17, wherein n is 0.
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Title

Proteasome inhibiting β-lactam prodrugs useful for the treatment of cancer and neurodegenerative disorders

Inventor(s)

Philippe Yves-Rémy Simon, Henri Oreal, Gérard Audran, Marvin Schulz, Jean-Patrick Joly, Didier Siri, Anouk Siri

Assignee(s)

Philippe Yves Remy Simon, Aix Marseille Universite, Centre National de la Recherche Scientifique CNRS

Patent #

11053249

Patent Date

July 6, 2021

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