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US 2018/0118661 A1Published application
Compounds and methods for the treatment of neurodegenerative diseases
AssigneeResilio Therapeutics, LLC
InventorsFrancis Xavier Tavares, Michael Peter Vitek
Life of this patent
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Abstract
Novel compounds of formula (II) are disclosed. Compounds of formula (II) comprise ornithine derivatives or compounds that may metabolize to ornithine. Also disclosed are methods for the treatment of neurodegenerative diseases such as Alzheimer's Disease using compounds of formula (II).
Claims12
A prodrug of difluoromethylornithine.
A compound of formula (II):
- wherein one or more of Q1, Q2, Q3, Q4 and Q5 is a moiety which is cleavable in vivo to hydrogen and the remainder are hydrogen.
A compound selected from the group consisting of
- a) an N-acyloxyalkoxy carbonyl derivative of,
- b) a (phosphoryloxy)methyl carbamate of,
- c) a redox based system derivative of,
- d) a beta-aminoketone based derivative of,
- e) a Schiff base derivative of,
- f) an N-Mannich base of,
- g) an (oxodioxolenyl)methyl carbamate of,
- h) a trimethyl lock system based derivative of,
- i) an intramolecular bonded derivative of,
- j) a tetrahydrothiadiazine-2-thione derivative of, and
- k) a sulfonamide derivative of difluoromethylornithine or a pharmaceutically acceptable salt thereof.
8 more elements
A compound selected from the group consisting of:
- wherein
- R1 is alkyl of 1-10 carbons, substituted or unsubstituted, aryl of 6 to 10 carbons, substituted or unsubstituted, or heteroaryl of 5 to 9 carbons, substituted or unsubstituted;
- R2 and R2′ are independently hydrogen, alkyl of 1-10 carbons, substituted or unsubstituted, aryl of 6 to 10 carbons, substituted or unsubstituted, or heteroaryl of 5 to 9 carbons, substituted or unsubstituted;
- R3 is hydrogen or
- (a) C1-C5-alkyl,
- (b) C2-C5-alkenyl,
- (c) C2-C5-alkynyl, (d) (CH2)pNR12R13,
- (e) (CH2)5CH(R7) (CH2)5O2CR8,
- (g) —(CH2)pCO2R10,
- or
- (i) C1-C5 alkyl substituted by one or more F;
- R is independently a hydrogen, a cation or alkyl of 1-10 carbons, substituted or unsubstituted, aryl of 6 to 10 carbons, substituted or unsubstituted, or heteroaryl of 5 to 9 carbons, substituted or unsubstituted;
- R4 is hydrogen, alkyl of 1-10 carbons, substituted with one or more F, or unsubstituted, aryl of 6 to 10 carbons, substituted or unsubstituted, or heteroaryl of 5 to 9 carbons, substituted or unsubstituted;
- R5 is alkyl of 1-10 carbons, substituted, substituted with one or more F, or unsubstituted, aryl of 6 to 10 carbons, substituted or unsubstituted, or heteroaryl of about 5 to 9 carbons, substituted or unsubstituted;
- R6 is alkyl of about 1-10 carbons, substituted with one or more F, or unsubstituted, aryl of 6 to 10 carbons, substituted or unsubstituted, or heteroaryl of 5 to 9 carbons, substituted or unsubstituted;
- R7 is H or C1-C4-alkyl, unsubstituted or substituted by one or more F;
- R8 is
- (a) H,
- (b) C1-C5-alkoxy,
- (c) C1-C5-alkyl optionally substituted with a group consisting of:
- i) C1-C5alkoxy,
- ii) aryl, wherein aryl is phenyl or napthyl optionally substituted with one or two substituents selected from the group consisting of halo (F, Cl, Br, I), C1-C4-alkyl, C1-C4-alkoxy, —NO2, —S(O)rC1-C5-alkyl), —OH, —N 12R13, —CO2R15, and —CvCw where v=1 to 3 and w=1 to (2v+1), or
- iii) one or more F;
- R9 is
- (a) C1-C5-alkyl,
- (b) —CvFw, where v=1 to 3 and w=1 to (2v+1), or
- (c) C1-C5-alkyl optionally substituted with a group consisting of:
- i) C1-C5-alkoxy,
- ii) phenyl or phenyl substituted with at least one substituent selected from the group consisting of halo (F, Cl, Br, I), C1-C4-alkyl, C1-C4-alkoxy, —NO2, —S(O)rC1-4-alkyl), —OH, —NR12R13, —CO2R15, and —CvFw where v=1 to 3 and w=1 to (2v+1), or
- iii) benzyl or benzyl substituted with at least one substituent selected from the group consisting of halo (F, Cl, Br, I), C1-C4-alkyl, C1-C4-alkoxy, —NO2, —S(O)r(C1-C4-alkyl), —OH, —NR12R13, —CO2R15, and —CvFw, where v=1 to 3 and w=1 to (2v+1);
- R10 is
- (a) phenyl or phenyl substituted with at least one substituent selected from the group consisting of halo (F, Cl, Br, I), C1-4-alkyl, C1-C4-alkoxy, —NO2, —S(O)r(C1-C4-alkyl), —OH, —NR12R13, —CO2R15, and —CvFw where v=1 to 3 and w=1 to (2v+1), or
- (b) benzyl or benzyl substituted with at least one substituent selected from the group consisting of halo (F, Cl, Br, I), C1-4-alkyl, C1-4-alkoxy, —NO2, —S(O)r(C1-C4-alkyl), —OH, NR12R13, —CO2R15, and —CvFw
- where v=1 to 3 and w=1 to (2v+1);
- R11 is H, C1-C5-alkyl or benzyl;
- R12 and R13 are independently H, C1-C5-alkyl, phenyl or benzyl;
- R15 is H, C1-C5-alkyl, or NR12R13;
- p is 1-5;
- r is 0-2;
- s and s′ are 0-5;
- t is 0 or 1;
- R8 is independently a value of R8 other than (a) H and (b) C1-C5-alkoxy;
- and
- R10 is —SR;
- or a pharmaceutically acceptable salt thereof.
42 more elements
Dependencies are inferred from the claim text.