Prodrugs of prostate specific membrane antigen (PSMA) inhibitor

Patent metadata

Field	Value
Publication number	US-11932664-B2
Application number	US-202217739669-A
Country	US
Kind code	B2
Filing date	May 9, 2022
Priority date	Aug 6, 2014
Publication date	Mar 19, 2024
Grant date	Mar 19, 2024

Abstract

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

First claim

That which is claimed:

1. A method for treating a disease or a condition, the method comprising administering to a subject in need of treatment thereof, a compound of formula (I), or a pharmaceutical composition thereof, in an amount effective for treating the disease or condition, wherein the disease or condition results in excess PSMA activity, and wherein the compound of formula (I) is:

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 ),—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 ) 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 ),—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 ),—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 ;

(c) each R 1 is —(CR 5 R 6 ) n —Ar;
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 ),—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 ),—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 ),—C(═O)—NR 8 R 9 ;
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 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 method of claim 1 , further comprising inhibiting the excess PSMA activity when the compound of formula (I), or a pharmaceutical composition thereof, is administered.

3. The method of claim 1 , wherein:
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.

4. The method of claim 1 , wherein:
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.

5. The method of claim 1 , wherein:
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.

6. The method of claim 1 , wherein:
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, an

Assignees

• Univ Johns Hopkins
• Inst Of Organic Chemistry And Biochemistry As Cr V V I
• The Johns Hopkins Universty

Inventors

• Slusher Barbara
• Rais Rana
• Krecmerova Marcela
• Tichy Tomas
• Majer Pavel
• Jancarik Andrej

Classifications

• C07F9/65586 Primary

  at least one of the hetero rings does not contain nitrogen as ring hetero atom · CPC title

• C07F9/3808

  Acyclic saturated acids which can have further substituents on alkyl · CPC title

• C07F9/4006

  Esters of acyclic acids which can have further substituents on alkyl · CPC title

• C07F9/4075

  Esters with hydroxyalkyl compounds · CPC title

• C07F9/4084

  Esters with hydroxyaryl compounds · CPC title