Prodrugs of prostate specific membrane antigen (PSMA) inhibitor

Patent metadata

Field	Value
Publication number	US-11325931-B2
Application number	US-202016751556-A
Country	US
Kind code	B2
Filing date	Jan 24, 2020
Priority date	Aug 6, 2014
Publication date	May 10, 2022
Grant date	May 10, 2022

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 composition comprising a dose of a compound of formula (I) or formula (II) dissolved in an aqueous solution, wherein the aqueous solution comprises a pharmaceutically acceptable carrier and a physiologically compatible buffer, and wherein the compound of formula (I) or formula (II) are:

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 ) 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 ;

(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 ) 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 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 composition 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 composition 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 composition 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 composition 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;

Assignees

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

Inventors

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

Classifications

• C07F9/4084

  Esters with hydroxyaryl compounds · CPC title

• C07F9/4006

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

• C07F9/3808

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

• C07F9/4087

  Esters with arylalkanols · CPC title

• C07F9/4075

  Esters with hydroxyalkyl compounds · CPC title