IP Library › Granted Patent US 9,988,407

Granted Patent B2

US 9,988,407 · App. 15/502,105 · Granted Jun 5, 2018

Prodrugs of prostate specific membrane antigen (PSMA) inhibitor

Inventors: Barbara Slusher (Kingsville, MD); Rana Rais (West Firendship, MD); Marcela Krecmerova (Prague, CZ); Tomas Tichy (Prague, CZ); Pavel Majer (Sykesville, MD); Andrej Jancarik (Koprivnice, CZ)

Assignees: THE JOHNS HOPKINS UNIVERSITY; INSTITUTE OF ORGANIC CHEMISTRY AND BIOCHEMISTRY AS CR V.V.I.

C07F9/65586 C07F9/3808 C07F9/4075 C07F9/4084 C07F9/4087 C07F9/4465

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Quick Facts

Patent No.: US 9,988,407
App. No.: 15/502,105
Granted: Jun 5, 2018
Kind: B2

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Abstract

Methods and compounds are disclosed for treating a disease or condition by inhibiting PSMA (Prostate Specific Membrane Antigen) using prodrugs of 2-PMPA.

Claims (60)

1. A compound of formula (I) or formula (II):

wherein:

(a) each R 1 is H;

each R 2 is selected from the group consisting of H, alkyl, Ar, —(CR 5 R 6 ) n -Ar, —(CR 5 R 6 ) n —O—C(═O)—R 7 , —(CR 5 R 6 ) n —C(═O)—O—R 7 , —(CR 5 R 6 ) n O—C(═O)—O—R 7 , —(CR 5 R 6 ) n —O—R 7 , —(CR 5 R 6 ) n O—[(CR 5 R 6 ) n —O] m —R 7 , —(CR 5 R 6 ) n -Ar-O—C(═O)—R 7 , -Ar-C(═O)—O—(CR 5 R 6 ) n —R 7 , —(CR 5 R 6 ) n —NR 8 R 9 , and —(CR 5 R 6 ) n —C(═O)—NR 8 R 9 ;

each R 3 is selected from the group consisting of H, alkyl, Ar, —(CR 5 R 6 ) n -Ar, —(CR 5 R 6 ) n —O—C(═O)—R 7 , —(CR 5 R 6 ) n —C(═O)—O—R 7 , —(CR 5 R 6 ) n O—C(═O)—O—R 7 , —(CR 5 R 6 ) n —O—R 7 , —(CR 5 R 6 ) n —O—[(CR 5 R 6 ) n —O] m —R 7 , —(CR 5 R 6 ) n Ar-O—C(═O)—R 7 , -Ar-C(═O)—O—(CR 5 R 6 ) n —R 7 , —(CR 5 R 6 ) n —NR 8 R 9 , and —(CR 5 R 6 ) n —C(═O)—NR 8 R 9 ; and

each R 4 is selected from the group consisting of —(CR 5 R 6 ) n —O—C(═O)—R 7 , —(CR 5 R 6 ) n —C(═O)—O—R 7 , —(CR 5 R 6 ) n —O—C(═O)—O—R 7 , —(CR 5 R 6 ) n —O—R 7 , —(CR 5 R 6 ) n —O—[(CR 5 R 6 ) n —O] m —R 7 , —(CR 5 R 6 ) n -Ar-O—C(═O)—R 7 , -Ar-C(═O)—O—(CR 5 R 6 ) n —R 7 , —(CR 5 R 6 ) n —NR 8 R 9 , and —(CR 5 R 6 ) n —C(═O)—NR 8 R 9 ;

(b) each R 1 is alkyl;

each R 2 is selected from the group consisting of H, alkyl, Ar, —(CR 5 R 6 ) n -Ar, —(CR 5 R 6 ) n —O—C(═O)—R 7 , —(CR 5 R 6 ) n —C(═O)—O—R 7 , —(CR 5 R 6 ) n —O—C(═O)—O—R 7 , —(CR 5 R 6 ) n —O—R 7 , —(CR 5 R 6 ) n —O—[(CR 5 R 6 ) n —O] m —R 7 , —(CR 5 R 6 ) n -Ar-O—C(═O)—R 7 , -Ar-C(═O)—O—(CR 5 R 6 ) n —R 7 , —(CR 5 R 6 ) n —NR 8 R 9 , and —(CR 5 R 6 ) n —C(═O)—NR 8 R 9 ;

each R 3 is selected from the group consisting of H, alkyl, Ar, —(CR 5 R 6 ) n -Ar, —(CR 5 R 6 ) n —O—C(═O)—R 7 , —(CR 5 R 6 ) n —C(═O)—O—R 7 , —(CR 5 R 6 ) n —O—C(═O)—O—R 7 , —(CR 5 R 6 ) n —O—R 7 , —(CR 5 R 6 ) n —O—[(CR 5 R 6 ) m —O] m —R 7 , —(CR 5 R 6 ) n -Ar-O—C(═O)—R 7 , -Ar-C(═O)—O—(CR 5 R 6 ) n —R 7 , —(CR 5 R 6 ) n —NR 8 R 9 , and —(CR 5 R 6 ) n —C(═O)—NR 8 R 9 ; and

each R 4 is selected from the group consisting of Ar, —(CR 5 R 6 ) n —O—C(═O)—R 7 , —(CR 5 R 6 ) n —C(═O)—O—R 7 , —(CR 5 R 6 ) n O—C(═O)—O—R 7 , —(CR 5 R 6 ) n O—R 7 , —(CR 5 R 6 ) n —O—[(CR 5 R 6 ) n —O] m —R 7 , —(CR 5 R 6 ) n -Ar-O—C(═O)—R 7 , -Ar-C(═O)—O—(CR 5 R 6 ) n —R 7 , —(CR 5 R 6 ) n —NR 8 R 9 , and —(CR 5 R 6 ) n —C(═O)—NR 8 R 9 ;

each R 3 is selected from the group consisting of H, alkyl, Ar, —(CR 5 R 6 ) n -Ar, —(CR 5 R 6 ) n —O—C(═O)—R 7 , —(CR 5 R 6 ) n —C(═O)—O—R 7 , —(CR 5 R 6 ) n —O—C(═O)—O—R 7 , —(CR 5 R 6 ) n —O—R 7 , —(CR 5 R 6 ) n —O—[(CR 5 R 6 ) n —O] m —R 7 , —(CR 5 R 6 ) n -Ar-O—C(═O)—R 7 , -Ar-C(═O)—O—(CR 5 R 6 ) n —R 7 , —(CR 5 R 6 ) n —NR 8 R 9 , and —(CR 5 R 6 ) n —C(═O)—NR 8 R 9 ; and

each R 4 is selected from the group consisting of Ar, —(CR 5 R 6 ) n —O—C(═O)—R 7 , —(CR 5 R 6 ) n —C(═O)—O—R 7 , —(CR 5 R 6 ) n —O—C(═O)—O—R 7 , —(CR 5 R 6 ) n —O—R 7 , —(CR 5 R 6 ) n —O—[(CR 5 R 6 ) n —O] m —R 7 , —(CR 5 R 6 ) n -Ar-O—C(═O)—R 7 , -Ar-C(═O)—O—(CR 5 R 6 ) n R 7 , —(CR 5 R 6 ) n —NR 8 R 9 , and —(CR 5 R 6 ) n —C(═O)—NR 8 R 9 ; or

(d) each R 1 is selected from Ar, —(CR 5 R 6 ) n —O—C(═O)—R 7 , —(CR 5 R 6 ) n —C(═O)—O—R 7 , —(CR 5 R 6 ) n —O—C(═O)—O—R 7 , —(CR 5 R 6 ) n —O—R 7 , —(CR 5 R 6 ) n —O—[(CR 5 R 6 ) n —O] m —R 7 , —(CR 5 R 6 ) n -Ar-O—C(═O)—R 7 , -Ar-C(═O)—O—(CR 5 R 6 ) n —R 7 , —(CR 5 R 6 ) n —NR 8 R 9 , and —(CR 5 R 6 ) n —C(═O)—NR 8 R 9 ;

each R 3 is selected from the group consisting of H, alkyl, Ar, —(CR 5 R 6 ) n -Ar, —(CR 5 R 6 ) n —O—C(═O)—R 7 , —(CR 5 R 6 ) n —C(═O)—O—R 7 , —(CR 5 R 6 ) n —O—C(═O)—O—R 7 , —(CR 5 R 6 ) n —O—R 7 , —(CR 5 R 6 ) n —O—[(CR 5 R 6 ) n —O] m —R 7 , —(CR 5 R 6 ) n -Ar-O—C(═O)—R 7 , -Ar-C(═O)—O—(CR 5 R 6 ) n —R 7 , —(CR 5 R 6 ) n —NR 8 R 9 , and —(CR 5 R 6 ) n —C(═O)—NR 8 R 9 ; and

each R 4 is selected from the group consisting of H, alkyl, Ar, —(CR 5 R 6 ) n Ar, —(CR 5 R 6 ) n —O—C(═O)—R 7 , —(CR 5 R 6 ) n —C(═O)—O—R 7 , —(CR 5 R 6 ) n —O—C(═O)—O—R 7 , —(CR 5 R 6 ) n —O—R 7 , —(CR 5 R 6 ) n —O—[(CR 5 R 6 ) n —O] m —R 7 , —(CR 5 R 6 ) n -Ar-O—C(═O)—R 7 , -Ar-C(═O)—O—(CR 5 R 6 ) n —R 7 , —(CR 5 R 6 ) n —NR 8 R 9 , and —(CR 5 R 6 ) n —C(═O)—NR 8 R 9 ;

wherein:

each n is an integer from 1 to 20;

each m is an integer from 1 to 20;

each R 5 and R 6 is independently selected from the group consisting of H, alkyl, and alkylaryl;

each R 7 is independently straight chain or branched alkyl;

each Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl;

each R 8 and R 9 are independently H or alkyl; and

each R 3 ′ and R 4 ′ are independently H or alkyl; or

pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein the compound is a compound of formula (I) and:

R 1 is H;

R 2 and R 3 are each selected from the group consisting of H, —(CR 5 R 6 ) n —O—R 7 , —(CR 5 R 6 ) n —Ar-O—C(═O)—R 7 , —(CR 5 R 6 ) n —O—C(═O)—R 7 , -Ar-C(═O)—O—(CR 5 R 6 ) n —R 7 , and —(CR 5 R 6 ) n —O—C(═O)—O—R 7 , and

R 4 is selected from the group consisting of —(CR 5 R 6 ) n —O—R 7 , —(CR 5 R 6 ) n -Ar-O—C(═O)—R 7 , —Ar-C(═O)—O—(CR 5 R 6 ) n —R 7 , —(CR 5 R 6 ) n —O—C(═O)—R 7 and —(CR 5 R 6 ) n —O—C(═O)—O—R 7 ; or

pharmaceutically acceptable salts thereof.

3. The compound of claim 1 , wherein the compound is a compound of formula (I) and:

R 1 is alkyl;

R 2 and R 3 are each independently selected from the group consisting of H, alkyl, —(CR 5 R 6 ) n —O—R 7 , —(CR 5 R 6 ) n -Ar-O—C(═O)—R 7 , —(CR 5 R 6 ) n —O—[(CR 5 R 6 ) n —O] m —R 7 , —(CR 5 R 6 ) n —O—C(═O)—R 7 and —(CR 5 R 6 ) n —O—C(═O)—O—R 7 ; and

R 4 is selected from the group consisting of —(CR 5 R 6 ) n —O—R 7 , —(CR 5 R 6 ) n -Ar-O—C(═O)—R 7 , —(CR 5 R 6 ) n —O—[(CR 5 R 6 ) n —O] m —R 7 , —(CR 5 R 6 ) n —O—C(═O)—R 7 and —(CR 5 R 6 ) n —O—C(═O)—O—R 7 ; or

pharmaceutically acceptable salts thereof.

4. The compound of claim 1 , wherein the compound is a compound of formula (I) and:

R 1 is selected from —(CR 5 R 6 ) n —O—C(═O)—R 7 and —(CR 5 R 6 ) n —O—C(═O)—O—R 7 ; and

R 2 R 3 , and R 4 are each independently selected from H, Ar, —(CR 5 R 6 ) n —O—C(═O)—R 7 , and —(CR 5 R 6 ) n —O—C(═O)—O—R 7 ; or

pharmaceutically acceptable salts thereof.

5. The compound of claim 1 , wherein the compound is a compound of formula (I) and:

one of R 1 , R 2 , R 3 , or R 4 is H and the other three are each independently selected from the group consisting of:

—(CR 5 R 6 ) n —O—C(═O)—R 7 and —(CR 5 R 6 ) n —O—C(═O)—O—R 7 ;

wherein R 5 and R 6 are each independently selected from the group consisting of H, C 1-8 straight-chain alkyl, and C 1-8 branched-chain alkyl;

R 7 is C 1-8 straight-chain alkyl, and C 1-8 branched-chain alkyl; or

pharmaceutically acceptable salts thereof.

6. The compound of claim 1 , wherein the compound is a compound of formula (I) and:

R 2 is H; and

R 1 , R 3 , and R 4 are each independently selected from the group consisting of:

—(CR 5 R 6 ) n —O—C(═O)—R 7 and —(CR 5 R 6 ) n —O—C(═O)—O—R 7 ;

wherein R 5 and R 6 are each independently selected from the group consisting of H, C 1-8 straight-chain alkyl, and C 1-8 branched-chain alkyl;

R 7 is C 1-8 straight-chain alkyl or C 1-8 branched-chain alkyl; or

pharmaceutically acceptable salts thereof.

7. The compound of claim 6 , wherein R 5 and R 6 are each H.

8. The compound of claim 1 , wherein the compound of formula (I) is selected from the group consisting of:

or pharmaceutically acceptable salts thereof.

9. A method for treating a disease or a condition, the method comprising administering to a subject in need of treatment thereof a compound of claim 1 , or a pharmaceutical composition thereof, in an amount effective for treating the disease or condition, wherein the disease or condition is selected from the group consisting of multiple sclerosis (MS), colon cancer, prostate cancer, angiogenesis, and inflammatory bowel disease.

10. A method for treating a neurodegenerative disease, the method comprising administering to a subject in need of treatment thereof a compound of claim 1 , or a pharmaceutical composition thereof, in an amount effective for treating the disease or condition, wherein the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease, dementia with Lewy Bodies (DLB), schizophrenia, pain, epilepsy, stroke, and traumatic brain injury (TBI).

11. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 11, 2017

From: SLUSHER, BARBARA; RAIS, RANA

To: THE JOHNS HOPKINS UNIVERSITY

Reel/Frame 042979/0625 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 11, 2017

From: KRECMEROVA, MARCELA; TICHY, TOMAS; MAJER, PAVEL; JANCARIK, ANDREJ

To: INSTITUTE OF ORGANIC CHEMISTRY AND BIOCHEMISTRY AS CR V.V.I.

Reel/Frame 043162/0431 →

Continuity (2)

Provisional Application 62033926 · Aug 6, 2014

Related Publication 20170226141A1 · Aug 10, 2017