Spirocyclic morphinans and use thereof

Patent metadata

Field	Value
Publication number	US-10030021-B2
Application number	US-201515313323-A
Country	US
Kind code	B2
Filing date	May 26, 2015
Priority date	May 27, 2014
Publication date	Jul 24, 2018
Grant date	Jul 24, 2018

Abstract

In one aspect, the invention provides compounds of Formula I: (I) and pharmaceutically acceptable salts and solvates thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , Y, Z a are defined as set forth in the disclosure. The invention also provides compounds of any one of Formulae II to VII, IA to IC, and IIA to IIC, and pharmaceutically acceptable salts and solvates thereof. Other aspects of the invention include the use of compounds of Formulae I to VII, IA to IC, and IIA to IIC, and pharmaceutically acceptable salts and solvates thereof for the treatment of disorders responsive to modulation of one or more opioid receptors. In certain embodiments, the Compounds of the Invention are useful for treating pain.

First claim

What is claimed is:

1. A compound of Formula IA, or a pharmaceutically acceptable salt or solvate thereof:

Wherein
R 1 is hydroxyl, cyano, aminocarbonyl, —C(═NR 7 )—NR 7a R 7b , or alkoxy;
R 2 is hydrogen or alkyl optionally substituted with dialkylamino or aryl;
R 4 and R 5 are the same, which are hydrogen or alkyl optionally substituted with cycloalkyl;
R 7 is H, hydroxyl, or alkoxy; and
R 7a and R 7b are, each independently, hydrogen or alkyl;
Provided that
1) when R 2 is alkyl substituted with aryl, then R 4 and R 5 are alkyl optionally substituted with cycloalkyl; and
2) when R 2 is alkyl, then R 1 is cyano, aminocarbonyl, or —C(═NR 7 )—NR 7a R 7b .

2. The compound of claim 1 , wherein said compound is a compound of Formula IC:

or a pharmaceutically acceptable salt or solvate thereof.

3. A compound of Formula IIA, or a pharmaceutically acceptable salt or solvate thereof:

Wherein
R 1 is hydroxyl, cyano, aminocarbonyl, —C(═NR 7 )—NR 7a R 7b , or alkoxy;
R 2 is hydrogen or alkyl optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, aryl, and alkoxycarbonyl;
R 4 and R 5 are the same, which are hydrogen or alkyl, wherein said alkyl is optionally substituted with 1 or 2 substituents each independently selected from the group consisting of hydroxyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, carboxamido, cycloalkyl, and heterocyclo; wherein each of said cycloalkyl and said heterocyclo are optionally substituted with 1, 2, or 3 independently selected R 6 groups;
each R 6 is independently selected from the group consisting of hydroxyl, halo, alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, carboxy, alkoxy, carboxamido, and alkoxycarbonyl;
R 7 is H, hydroxyl, alkoxy, alkyl, or cyano; and
R 7a and R 7b are, each independently, hydrogen or alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of hydroxyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, carboxamido, cycloalkyl, and heterocyclo.

4. The compound of claim 3 , wherein said compound is a compound of Formula IIC:

or a pharmaceutically acceptable salt or solvate thereof.

5. The compound of claim 3 , wherein R 2 is (C 1-6 )alkyl; R 1 is hydroxyl or (C 1-6 )alkoxy; and R 4 and R 5 are the same and are hydrogen or (C 1-6 )alkyl.

6. A compound selected from the group consisting of
1)

(4S,4b′S,8a′R,9′R)-3′-methoxy-11′-methyl-8′,8a′,9′,10′-tetrahydro-5′H,7′H-spiro[imidazolidine-4,6′-[9,4b](epiminoethano)phenanthrene]-2,5-dione (Compound 2);
2)

(4S,4b′R,8a′S,9′R)-11′-(2-(dimethylamino)ethyl)-8a′-hydroxy-3′-methoxy-8′,8a′,9′,10′-tetrahydro-5′H,7′H-spiro[imidazolidine-4,6′-[9,4b](epiminoethano)-phenanthrene]-2,5-dione (Compound 3);
3)

(4S,4b′R,8a′S,9′R)-11′-(3-(dimethylamino)propyl)-8a′-hydroxy-3′-methoxy-8′,8a′,9′,10′-tetrahydro-5′H,7′H-spiro[imidazolidine-4,6′-[9,4b](epiminoethano)-phenanthrene]-2,5-dione (Compound 4);
4)

(4S,4b′R,8a′S,9′R)-11′-(2-(dimethylamino)ethyl)-1,3-diethyl-8a′-hydroxy-3′-methoxy-8′,8a′,9′,10′-tetrahydro-5′H,7′H-spiro[imidazolidine-4,6′-[9,4b]-(epiminoethano)phenanthrene]-2,5-dione (Compound 8);
5)

(4S,4b′R,8a′S,9′R)-1,3-bis(cyclopropylmethyl)-11′-(3-(dimethylamino)-propyl)-8a′-hydroxy-3′-methoxy-8′,8a′,9′,10′-tetrahydro-5′H,7′H-spiro[imidazolidine-4,6′-[9,4b]-(epiminoethano)phenanthrene]-2,5-dione (Compound 13);
6)

(4S,4b′R,8a′S,9′R)-11′-(3-(dimethylamino)propyl)-1,3-diethyl-8a′-hydroxy-3′-methoxy-8′,8a′,9′,10′-tetrahydro-5′H,7′H-spiro[imidazolidine-4,6′-[9,4b]-(epiminoethano)phenanthrene]-2,5-dione (Compound 14);
7)

(4S,4b′R,8a′S,9′R)-1,3-bis(cyclopropylmethyl)-11′-(2-(dimethylamino)ethyl)-8a′-hydroxy-3′-methoxy-8′,8a′,9′,10′-tetrahydro-5′H,7′H-spiro[imidazolidine-4,6′-[9,4b]-(epiminoethano)phenanthrene]-2,5-dione (Compound 15);
8)

(4S,4b′R,8a′S,9′R)-1,3-bis(cyclopropylmethyl)-8a′-hydroxy-3′-methoxy-8′,8a′,9′,10′-tetrahydro-5′H,7′H-spiro[imidazolidine-4,6′-[9,4b](epiminoethano)-phenanthrene]-2,5-dione (Compound 17);
9)

(4S,4b′R, 8a′S,9′R)-1,3-diethyl-8a′-hydroxy-3′-methoxy-8′,8a′,9′,10′-tetrahydro-5′H, 7′H-spiro[imidazolidine-4,6′-[9,4b](epiminoethano)phenanthrene]-2,5-dione (Compound 18);
10)

(4S,4b′S, 8a′R,9′R)-3′-hydroxy-11′-methyl-8′,8a′,9′,10′-tetrahydro-5′H,7′H-spiro[imidazolidine-4,6′-[9,4b](epiminoethano)phenanthrene]-2,5-dione (Compound 19);
11)

(4S,4b′R, 8a′S,9′R)-1,3-diethyl-3′,8a′-dihydroxy-8′,8a′,9′,10′-tetrahydro-5′H,7′H-spiro[imidazolidine-4,6′-[9,4b](epiminoethano)phenanthrene]-2,5-dione (Compound 20);
12)

(4S,4b′S, 8a′R,9′R)-1,3-diethyl-3′-hydroxy-11′-methyl-8′,8a′,9′,10′-tetrahydro-5′H,7′H-spiro[imidazolidine-4,6′-[9,4b](epiminoethano)phenanthrene]-2,5-dione (Compound 21);
13)

(4S,4b′R,8a′S,9′R)-3′,8a′-dihydroxy-8′,8a′,9′,10′-tetrahydro-5′H,7′H-spiro[imidazolidine-4,6′-[9,4b](epiminoethano)phenanthrene]-2,5-dione (Compound 22);
14)

(4S,4b′R,8a′S,9′R)-1,3-bis(cyclopropylmethyl)-3′,8a′-dihydroxy-8′,8a′,9′,10′-tetrahydro-5′H,7′H-spiro[imidazolidine-4,6′-[9,4b](epiminoethano)phenanthrene]-2,5-dione (Compound 23);
15)

(4S,4b′R,8a′S,9′R)-1,3-diethyl-3′,8a′-dihydroxy-11′-phenethyl-8′,8a′,9′,10′-tetrahydro-5′H,7′H-spiro[imidazolidine-4,6′-[9,4b](epiminoethano)phenanthrene]-2,5-dione (Compound 24);
16)

(4S,4b′R,8a′S,9′R)-1,3-bis(cyclopropylmethyl)-11′-(2-(dimethylamino)ethyl)-3′,8a′-dihydroxy-8′,8a′,9′,10′-tetrah

Assignees

• Purdue Pharma Lp

Inventors

• Youngman Mark A
• Tafesse Laykea
• Goehring R Richard
• Yu Jianming

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• C07D471/20 Primary

  Spiro-condensed systems · CPC title

• C07D489/09

  containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems · CPC title