Ergoline derivatives as dopamine receptor modulators

Patent metadata

Field	Value
Publication number	US-9670199-B2
Application number	US-201314443576-A
Country	US
Kind code	B2
Filing date	Nov 19, 2013
Priority date	Nov 19, 2012
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

The invention provides compounds of formula I:

wherein R 1 -R 4 have any of the values defined in the specification, and salts thereof. The compounds are useful as dopamine receptor modulators for the treatment of diseases where modulation of dopamine receptors is implicated (e.g. sexual dysfunction, prolactinoma, Parkinson's disease, and Cushings disease).

First claim

What is claimed is:

1. A compound of formula I:

wherein:
R 1 is —C(═O)NR a R b ;
R 2 is (C 1 -C 6 )alkyl;
R 3 is methyl;
R 4 is H, halo, —C(═O)NR h R k , —C(═O)OK, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, or (C 1 -C 6 )alkanoyloxy, wherein any (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, or (C 1 -C 6 )alkanoyloxy can optionally be substituted with one or more halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, or NR m R n ;
R a is —C(═O)NR f R g ;
R b is (C 1 -C 6 )alkyl that is substituted with one or more NR f R g ;
R c is H, (C 1 -C 6 )alkyl, or aryl;
R f and R g are each independently H or (C 1 -C 6 )alkyl; or R f and R g together with the nitrogen to which they are attached form a heterocyclic ring;
R h and R k are each independently H, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkanoyl, wherein any (C 1 -C 6 )alkyl or (C 1 -C 6 )alkanoyl can optionally be substituted with one or more NR f R g ; or R h and R k together with the nitrogen to which they are attached form a heterocyclic ring; and
R m and R n are each independently H or (C 1 -C 6 )alkyl; or R m and R n together with the nitrogen to which they are attached form a heterocyclic ring;
or a salt thereof.

2. The compound of claim 1 which is a compound of formula Ia:

or a salt thereof.

3. A compound of formula I:

wherein R 1 is:

R 2 is (C 1 -C 6 )alkyl;
R 3 is methyl;
R 4 is H, —C(═O)NR h R k , —C(═O)OR c , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanol, (C 1 -C 6 )alkoxycarbonyl, or (C 1 -C 6 )alkanoyloxy, wherein any (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, or (C 1 -C 6 )alkanoyloxy can optionally be substituted with one or more halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, or NR m R n ;
R c is H, (C 1 -C 6 )alkyl, or aryl;
R h and R k are each independently H, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkanoyl, wherein any (C 1 -C 6 )alkyl or (C 1 -C 6 )alkanoyl can optionally be substituted with one or more NR f R g ; or R h and R k together with the nitrogen to which they are attached form a heterocyclic ring; and
R m and R n are each independently H or (C 1 -C 6 )alkyl; or R m and R n together with the nitrogen to which they are attached form a heterocyclic ring;
or a salt thereof.

4. A compound of formula I:

wherein R 1 is:

R 2 is H or (C 1 -C 6 )alkyl;
R 3 is methyl;
R 4 is H, halo, —C(═O)NR h R k , —C(═O)OR c , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, or (C 1 -C 6 )alkanoyloxy, wherein any (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, or (C 1 -C 6 )alkanoyloxy can optionally be substituted with one or more halo, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, or NR m R n ;
R c is H, (C 1 -C 6 )alkyl, or aryl;
R h and R k are each independently H, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkanoyl, wherein any (C 1 -C 6 )alkyl or (C 1 -C 6 )alkanoyl can optionally be substituted with one or more NR f R g ; or R h and R k together with the nitrogen to which they are attached form a heterocyclic ring; and
R m and R n are each independently H or (C 1 -C 6 )alkyl; or R m and R n together with the nitrogen to which they are attached form a heterocyclic ring;
or a salt thereof.

5. The compound of claim 1 wherein R 2 is (C 1 -C 6 )alkyl.

6. The compound of claim 1 wherein R 2 is methyl.

7. A pharmaceutical composition comprising a compound as described in claim 1 and a pharmaceutically acceptable diluent or carrier.

8. A compound which is:

or a salt thereof.

9. A method for treating depression in an animal comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof as described in claim 1 to the animal.

10. The method of claim 9 wherein the animal is human.

Assignees

• Univ Minnesota

Inventors

• Dosa peter
• Kim Suck Won
• Walters Michael

Classifications

• C07D457/06 Primary

  Lysergic acid amides · CPC title

• C07D457/04

  with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8 · CPC title

• C07D457/02

  with hydrocarbon or substituted hydrocarbon radicals, attached in position 8 · CPC title