US 11,932,664 B2Granted

Prodrugs of prostate specific membrane antigen (PSMA) inhibitor

AssigneesThe Johns Hopkins Universty, Institute of Organic Chemistry and Biochemistry of the AS CR, V.V.I.

InventorsBarbara Slusher, Rana Rais, Marcela Krecmerova, Tomas Tichy, Pavel Majer, Andrej Jancarik

Life of this patent

Estimating the term…

Abstract

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

Claims9

Dependent claims

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 R1 is H;
each R2 is selected from the group consisting of H, alkyl, Ar, —(CR5R6)n—Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6),—C(═O)—NR8R9;
each R3 is selected from the group consisting of H, alkyl, Ar, —(CR5R6)n—Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n— C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6)n—C(═O)—NR8R9;
and
each R4 is selected from the group consisting of —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n-O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6)n—C(═O)—NR8R9;
(b) each R1 is alkyl;
each R2 is selected from the group consisting of H, alkyl, Ar, —(CR5R6)n—Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6)n—C(═O)—NR8R9;
each R3 is selected from the group consisting of H, alkyl, Ar, —(CR5R6)n—Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6),—C(═O)—NR8R9;
and
each R4 is selected from the group consisting of Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6),—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6)n—C(═O)—NR8R9;
(c) each R1 is —(CR5R6)n—Ar;
each R2 is selected from the group consisting of H, alkyl, Ar, —(CR5R6)n—Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6)n—C(═O)—NR8R9;
each R3 is selected from the group consisting of H, alkyl, Ar, —(CR5R6)n—Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6),—C(═O)—NR8R9;
and
each R4 is selected from the group consisting of Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6),—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6)n—C(═O)—NR8R9;
or
(d) each R1 is selected from Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(=O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6),—C(═O)—NR8R9;
each R2 is selected from the group consisting of H, alkyl, Ar, —(CR5R6)n—Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6)n—C(═O)—NR8R9;
each R3 is selected from the group consisting of H, alkyl, Ar, —(CR5R6)n—Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m-R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6)n—C(═O)—NR8R9;
and
each R4 is selected from the group consisting of H, alkyl, Ar, —(CR5R6)n—Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6)n—C(═O)—NR8R9;
wherein:
each n is an integer from 1 to 20;
each m is an integer from 1 to 20;
each R5 and R6 is independently selected from the group consisting of H, alkyl, and alkylaryl;
each R7 is independently straight chain or branched alkyl;
each Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl;
each R8 and R9 are independently H or alkyl;
and
each R3′ and R4′ are independently H or alkyl;
or
pharmaceutically acceptable salts thereof.

30 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/739,669Filed 9 May 2022 · continuation
Priority: 6 Aug 2014
Published: US 2023/0115651 A113 Apr 2023
Granted: 19 Mar 2024
Term ends: Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07F 9/65586
Containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common…: at…
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…
C07F 9/3808
Not used, see subgroups: acyclic saturated acids which can have further substituents on alkyl

Family

Application62/033,926Us provisional application · filed 6 Aug 2014
PCT/US2015/044053Parent of this division · filed 6 Aug 2015
Application15/968,074Parent of this division · filed 1 May 2018
US 9,988,407 B2Parent of this division · filed 5 Jun 2018
Application16/751,556Parent of this continuation · filed 24 Jan 2020
US 10,544,176 B2Parent of this division · filed 28 Jan 2020
US 2023/0115651 A1Pre-grant publication · published 13 Apr 2023
US 11,325,931 B2Parent of this continuation
Application16/751,556Parent of this division
Application15/502,105Parent of this division
US 2017/0226141 A1Published application
US 2018/0244705 A1Published application
US 2020/0399298 A1Published application
US 11,932,664 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

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

wherein:
(a) each R1 is H;
each R2 is selected from the group consisting of H, alkyl, Ar, —(CR5R6)n—Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6),—C(═O)—NR8R9;
each R3 is selected from the group consisting of H, alkyl, Ar, —(CR5R6)n—Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n— C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6)n—C(═O)—NR8R9;
and
each R4 is selected from the group consisting of —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n-O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6)n—C(═O)—NR8R9;
(b) each R1 is alkyl;
each R2 is selected from the group consisting of H, alkyl, Ar, —(CR5R6)n—Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6)n—C(═O)—NR8R9;
each R3 is selected from the group consisting of H, alkyl, Ar, —(CR5R6)n—Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6),—C(═O)—NR8R9;
and
each R4 is selected from the group consisting of Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6),—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6)n—C(═O)—NR8R9;
(c) each R1 is —(CR5R6)n—Ar;
each R2 is selected from the group consisting of H, alkyl, Ar, —(CR5R6)n—Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6)n—C(═O)—NR8R9;
each R3 is selected from the group consisting of H, alkyl, Ar, —(CR5R6)n—Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6),—C(═O)—NR8R9;
and
each R4 is selected from the group consisting of Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6),—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6)n—C(═O)—NR8R9;
or
(d) each R1 is selected from Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(=O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6),—C(═O)—NR8R9;
each R2 is selected from the group consisting of H, alkyl, Ar, —(CR5R6)n—Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6)n—C(═O)—NR8R9;
each R3 is selected from the group consisting of H, alkyl, Ar, —(CR5R6)n—Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m-R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6)n—C(═O)—NR8R9;
and
each R4 is selected from the group consisting of H, alkyl, Ar, —(CR5R6)n—Ar, —(CR5R6)n—O—C(═O)—R7, —(CR5R6)n—C(═O)—O—R7, —(CR5R6)n—O—C(═O)—O—R7, —(CR5R6)n—O—R7, —(CR5R6)n—O—[(CR5R6)n—O]m—R7, —(CR5R6)n—Ar—O—C(═O)—R7, —Ar—C(═O)—O—(CR5R6)n—R7, —(CR5R6)n—NR8R9, and —(CR5R6)n—C(═O)—NR8R9;
wherein:
each n is an integer from 1 to 20;
each m is an integer from 1 to 20;
each R5 and R6 is independently selected from the group consisting of H, alkyl, and alkylaryl;
each R7 is independently straight chain or branched alkyl;
each Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl;
each R8 and R9 are independently H or alkyl;
and
each R3′ and R4′ are independently H or alkyl;
or
pharmaceutically acceptable salts thereof.

30 more elements

Facts

Application

17/739,669Filed 9 May 2022 · continuation

Priority

6 Aug 2014

Published

US 2023/0115651 A113 Apr 2023

Granted

19 Mar 2024

Term ends

Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07F 9/65586
Containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common…: at…
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…
C07F 9/3808
Not used, see subgroups: acyclic saturated acids which can have further substituents on alkyl

Family

Application62/033,926Us provisional application · filed 6 Aug 2014

PCT/US2015/044053Parent of this division · filed 6 Aug 2015

Application15/968,074Parent of this division · filed 1 May 2018

US 9,988,407 B2Parent of this division · filed 5 Jun 2018

Application16/751,556Parent of this continuation · filed 24 Jan 2020

US 10,544,176 B2Parent of this division · filed 28 Jan 2020

US 2023/0115651 A1Pre-grant publication · published 13 Apr 2023

US 11,325,931 B2Parent of this continuation

Application16/751,556Parent of this division

Application15/502,105Parent of this division

US 2017/0226141 A1Published application

US 2018/0244705 A1Published application

US 2020/0399298 A1Published application

US 11,932,664 B2This patent

From the US filing history. Foreign family members aren’t listed.