US 11,325,931 B2Granted

Prodrugs of prostate specific membrane antigen (PSMA) inhibitor

AssigneesThe Johns Hopkins University, Inst of Organic Chem. and Biochemistry 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.

Claims19

Dependent claims

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 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)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 —(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)n—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)n—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)n—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)n—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)n—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: 16/751,556Filed 24 Jan 2020 · continuation
Priority: 6 Aug 2014
Published: US 2020/0399298 A124 Dec 2020
Granted: 10 May 2022
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 continuation · filed 1 May 2018
US 9,988,407 B2Parent of this division · filed 5 Jun 2018
US 2020/0399298 A1Pre-grant publication · published 24 Dec 2020
US 10,544,176 B2Parent of this continuation
Application15/502,105Parent of this division
Application15/968,074Parent of this division
US 2017/0226141 A1Published application
US 2018/0244705 A1Published application
US 11,325,931 B2This patent

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

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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.

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)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 —(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)n—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)n—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)n—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)n—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)n—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

16/751,556Filed 24 Jan 2020 · continuation

Priority

6 Aug 2014

Published

US 2020/0399298 A124 Dec 2020

Granted

10 May 2022

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 continuation · filed 1 May 2018

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

US 2020/0399298 A1Pre-grant publication · published 24 Dec 2020

US 10,544,176 B2Parent of this continuation

Application15/502,105Parent of this division

Application15/968,074Parent of this division

US 2017/0226141 A1Published application

US 2018/0244705 A1Published application

US 11,325,931 B2This patent

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