Prodrugs of prostate specific membrane antigen (PSMA) inhibitor

Patent metadata

Field	Value
Publication number	US-9988407-B2
Application number	US-201515502105-A
Country	US
Kind code	B2
Filing date	Aug 6, 2015
Priority date	Aug 6, 2014
Publication date	Jun 5, 2018
Grant date	Jun 5, 2018

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 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 ;

(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 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 a

Assignees

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

Inventors

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

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07F9/4006

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

• C07F9/65586 Primary

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

• C07F9/4465

  of aliphatic amines · CPC title