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US 12,605,384 B2Granted
Uses
AssigneeIntra-Cellular Therapies, Inc.
InventorsDavid Kass, Toru Hashimoto, Lawrence P. Wennogle, Joseph Hendrick, Robert Davis
Life of this patent
Estimating the term…
Abstract
The disclosure provides methods, treatments and materials for enhancing the effect of an adenosine A2 receptor agonist in the treatment, mitigation or prophylaxis of a disease or condition characterized by inotropic and/or lusitropic dysfunction, and/or enhancing adenosine A2 receptor function in the treatment, mitigation or prophylaxis of a disease or condition characterized by impaired adenosine A2 receptor function, comprising administration of an effective amount of a PDE1 inhibitor to a patient in need thereof, for example a patient suffering from heart failure.
Claims22
A method of treating NYHA Class II chronic systolic heart failure or NYHA Class III chronic systolic heart failure, comprising administering a pharmaceutically effective amount of a PDE1 inhibitor to a patient in need thereof, wherein administration of the PDE1 inhibitor is sufficient to induce inotropic, lusitropic and/or vasodilatory effect, wherein the PDE1 inhibitor is one of:
- A) a compound according to Formula I′:
- wherein
- (i) R1 is H or C1-4 alkyl;
- (ii) R4 is H or C1-4 alkyl and R2 and R3 are, independently, H or C1-4 alkyl, aryl, heteroaryl, (optionally hetero) arylalkoxy, or (optionally hetero) arylalkyl;
- or
- R2 is H and R3 and R4 together form a di-, tri- or tetramethylene bridge;
- (iii) R5 is a substituted heteroarylalkyl;
- or R5 is attached to one of the nitrogens on the pyrazolo portion of Formula I′ and is a moiety of Formula A′
- wherein X, Y and Z are, independently, N or C, and R8, R9, R11 and R12 are independently H or halogen, and R10 is halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl optionally substituted with halogen, thiadiazolyl, diazolyl, triazolyl, tetrazolyl, arylcarbonyl, alkylsulfonyl, heteroarylcarbonyl, or alkoxycarbonyl;
- provided that when X, Y, or Z is nitrogen, R8, R9, or R10, respectively, is not present;
- and
- (iv) R6 is H, alkyl, aryl, heteroaryl, arylalkyl, arylamino, heteroarylamino, N,N-dialkylamino, N,N-diarylamino, or N-aryl-N-(arylalkyl) amino;
- and
- (v) n=0 or 1;
- (vi) when n=1, A is —C(R13R14)—
- wherein R13 and R14, are, independently, H or C1-4 alkyl, aryl, heteroaryl, (optionally hetero) arylalkoxy or (optionally hetero) arylalkyl;
- in free, salt or prodrug form, including its enantiomers, diastereoisomers and racemates;
- B) a compound according to Formula Ia:
- wherein
- (i) R2 and R5 are independently H or hydroxy and R3 and R4 together form a tri- or tetra-methylene bridge;
- or R2 and R3 are each methyl and R4 and R5 are each H;
- or R2, R4 and R5 are H and R3 is isopropyl;
- (ii) R6 is (optionally halo- or hydroxy-substituted) phenylamino, (optionally halo- or hydroxy-substituted) benzylamino, C1-4alkyl, or C1-4alkyl sulfide;
- (iii) R10 is C1-4alkyl, methylcarbonyl, hydroxyethyl, carboxylic acid, sulfonamide, (optionally halo- or hydroxy-substituted) phenyl, (optionally halo- or hydroxy-substituted) pyridyl, or thiadiazolyl;
- and
- X and Y are independently C or N,
- in free, pharmaceutically acceptable salt or prodrug form, including its enantiomers, diastereoisomers and racemates;
- C) a compound according to Formula II′:
- (i) X is C1-6alkylene;
- (ii) Y is a single bond, alkynylene, arylene or heteroarylene;
- (iii) Z is H, aryl, heteroaryl, halo, haloC1-6alkyl, —C(O)—R1, —N(R2) (R3), or C3-7 cycloalkyl optionally containing at least one atom selected from a group consisting of N or O;
- (iv) R1 is C1-6alkyl, haloC1-6alkyl, —OH or —OC1-6alkyl;
- (v) R2 and R3 are independently H or C1-6alkyl;
- (vi) R4 and R5 are independently H, C1-6alkyl or aryl optionally substituted with one or more halo, hydroxy or C1-6alkoxy;
- (vii) wherein X, Y and Z are independently and optionally substituted with one or more halo, C1-6alkyl, or haloC1-6alkyl,
- in free or salt form;
- D) a compound according to Formula III′:
- wherein
- (i) R1 is H or C1-4 alkyl;
- (ii) R2 and R3 are independently H or C1-6 alkyl;
- (iii) R4 is H or C1-4 alkyl;
- (iv) R5 is aryl optionally substituted with one or more groups independently selected from —C(═O)—C1-6 alkyl and C1-6-hydroxyalkyl;
- (v) R6 and R7 are independently H or aryl optionally substituted with one or more groups independently selected from C1-6 alkyl and halogen;
- and
- (vi) n is 1, 2, 3, or 4,
- in free or salt form;
- E) a compound according to Formula IV′:
- in free or salt form, wherein
- (i) R1 is C1-4alkyl, or —NH(R2), wherein R2 is phenyl optionally substituted with halo;
- (ii) X, Y and Z are, independently, N or C;
- (iii) R3, R4 and R5 are independently H or C1-4alkyl;
- or R3 is H and R4 and R5 together form a tri-methylene bridge,
- (iv) R6, R7 and R8 are independently:
- H,
- C1-4alkyl,
- pyrid-2-yl substituted with hydroxy, or
- —S(O)2—NH2;
- provided that when X, Y and/or Z are N, then R6, R7 and/or R8, respectively, are not present;
- and when X, Y and Z are all C, then at least one of R6, R7 or R8 is —S(O)2—NH2 or pyrid-2-yl substituted with hydroxy;
- F) a compound according to Formula V:
- wherein
- (i) R1is —NH (R4), wherein R4 is phenyl optionally substituted with halo;
- (ii) R2 is H or C1-6alkyl;
- (iii) R3 is —SO2NH2 or —COOH;
- in free or salt form;
- or
- G) a compound according to Formula VI:
- wherein
- (i) R1 is —NH(R4), wherein R4 is phenyl optionally substituted with halo;
- (ii) R2 is H or C1-6alkyl;
- (iii) R3 is H, halogen, C1-6alkyl, aryl optionally substituted with halogen, heteroaryl optionally substituted with halogen, or acyl,
- in free or salt form.
69 more elements
A method of inducing an inotropic, lusitropic and/or vasodilatory effect in a patient suffering from NYHA Class II chronic systolic heart failure or NYHA Class III chronic systolic heart failure, comprising administering a pharmaceutically effective amount of a PDE1 inhibitor to a patient in need thereof, wherein the PDE1 inhibitor is one of:
- A) a compound according to Formula I′:
- wherein
- (i) R1 is H or C1-4 alkyl;
- (ii) R4 is H or C1-4 alkyl and R2 and R3 are, independently, H or C1-4 alkyl, aryl, heteroaryl, (optionally hetero) arylalkoxy, or (optionally hetero) arylalkyl;
- or
- R2 is H and R3 and R4 together form a di-, tri- or tetramethylene bridge;
- (iii) R5 is a substituted heteroarylalkyl;
- or R5 is attached to one of the nitrogens on the pyrazolo portion of Formula I′ and is a moiety of Formula A′
- wherein X, Y and Z are, independently, N or C, and R8, R9, R11 and R12 are independently H or halogen, and R10 is halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl optionally substituted with halogen, thiadiazolyl, diazolyl, triazolyl, tetrazolyl, arylcarbonyl, alkylsulfonyl, heteroarylcarbonyl, or alkoxycarbonyl;
- provided that when X, Y, or Z is nitrogen, R8, R9, or R10, respectively, is not present;
- and
- (iv) R6 is H, alkyl, aryl, heteroaryl, arylalkyl, arylamino, heteroarylamino, N,N-dialkylamino, N,N-diarylamino, or N-aryl-N-(arylalkyl) amino;
- and
- (v) n=0 or 1;
- (vi) when n=1, A is —C(R13R14)—
- wherein R13 and R14, are, independently, H or C1-4 alkyl, aryl, heteroaryl, (optionally hetero) arylalkoxy or (optionally hetero) arylalkyl;
- in free, salt or prodrug form, including its enantiomers, diastereoisomers and racemates;
- B) a compound according to Formula Ia:
- wherein
- (i) R2 and R5 are independently H or hydroxy and R3 and R4 together form a tri- or tetra-methylene bridge;
- or R2 and R3 are each methyl and R4 and R5 are each H;
- or R2, R4 and R5 are H and R3 is isopropyl;
- (ii) R6 is (optionally halo- or hydroxy-substituted) phenylamino, (optionally halo- or hydroxy-substituted) benzylamino, C1-4alkyl, or C1-4alkyl sulfide;
- (iii) R10 is C1-4alkyl, methylcarbonyl, hydroxyethyl, carboxylic acid, sulfonamide, (optionally halo- or hydroxy-substituted) phenyl, (optionally halo- or hydroxy-substituted) pyridyl, or thiadiazolyl;
- and
- X and Y are independently C or N,
- in free, pharmaceutically acceptable salt or prodrug form, including its enantiomers, diastereoisomers and racemates;
- C) a compound according to Formula II′:
- (i) X is C1-6alkylene;
- (ii) Y is a single bond, alkynylene, arylene or heteroarylene;
- (iii) Z is H, aryl, heteroaryl, halo, haloC1-6alkyl, —C(O)—R1, —N(R2) (R3), or C3-7 cycloalkyl optionally containing at least one atom selected from a group consisting of N or O;
- (iv) R1 is C1-6alkyl, haloC1-6alkyl, —OH or —OC1-6alkyl;
- (v) R2 and R3 are independently H or C1-6alkyl;
- (vi) R4 and R5 are independently H, C1-6alkyl or aryl optionally substituted with one or more halo, hydroxy or C1-6alkoxy;
- (vii) wherein X, Y and Z are independently and optionally substituted with one or more halo, C1-6alkyl, or haloC1-6alkyl,
- in free or salt form;
- D) a compound according to Formula III′:
- wherein
- (i) R1 is H or C1-4 alkyl;
- (ii) R2 and R3 are independently H or C1-6 alkyl;
- (iii) R4 is H or C1-4 alkyl;
- (iv) R5 is aryl optionally substituted with one or more groups independently selected from —C(═O)—C1-6 alkyl and C1-6-hydroxyalkyl;
- (v) R6 and R7 are independently H or aryl optionally substituted with one or more groups independently selected from C1-6 alkyl and halogen;
- and
- (vi) n is 1, 2, 3, or 4,
- in free or salt form;
- E) a compound according to Formula IV′:
- in free or salt form, wherein
- (i) R1 is C1-4alkyl, or —NH (R2), wherein R2 is phenyl optionally substituted with halo;
- (ii) X, Y and Z are, independently, N or C;
- (iii) R3, R4 and R5 are independently H or C1-4alkyl;
- or R3 is H and R4 and R5 together form a tri-methylene bridge,
- (iv) R6, R7 and R8 are independently:
- H,
- C1-4alkyl,
- pyrid-2-yl substituted with hydroxy, or
- —S(O)2—NH2;
- provided that when X, Y and/or Z are N, then R6, R7 and/or R8, respectively, are not present;
- and when X, Y and Z are all C, then at least one of R6, R7 or R8 is —S(O)2—NH2 or pyrid-2-yl substituted with hydroxy;
- F) a compound according to Formula V:
- wherein
- (i) R1 is —NH(R4), wherein R4 is phenyl optionally substituted with halo;
- (ii) R2 is H or C1-6alkyl;
- (iii) R3 is —SO2NH2 or —COOH;
- in free or salt form;
- or
- G) a compound according to Formula VI:
- wherein
- (i) R1 is —NH(R4), wherein R4 is phenyl optionally substituted with halo;
- (ii) R2 is H or C1-6alkyl;
- (iii) R3 is H, halogen, C1-6alkyl, aryl optionally substituted with halogen, heteroaryl optionally substituted with halogen, or acyl,
- in free or salt form.
69 more elements
Dependencies are inferred from the claim text.