IP Library › Granted Patent US 8,338,405

Granted Patent B2

US 8,338,405 · App. 12/861,213 · Granted Dec 25, 2012

Therapeutic piperazines

Assignee: Dart Neuroscience LLC

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 8,338,405
App. No.: 12/861,213
Granted: Dec 25, 2012
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The invention includes a compound of formula I: wherein R 1 , X, Z, n, and m have any of the values described herein, as well as salts of such compounds, compositions comprising such compounds, and therapeutic methods that comprise the administration of such compounds. The compounds are inhibitors of PDE4 function and are useful for improving cognitive function in animals.

Claims (118)

1. A method comprising:

treating a disease or condition in an animal wherein the activity of PDE4 receptors is implicated and inhibition of PDE4 receptor activity is desired by administering to the animal an effective PDE inhibiting amount of a compound of formula (I):

wherein:

R 1 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkanoyl, het, het(C 1 -C 6 )alkyl, het(C 1 -C 6 )alkoxy, or het(C 1 -C 6 )alkanoyl;

n is 1;

m is 1;

W is O, S, or two hydrogens;

X is N—Y—R 4 ;

Y is a direct bond, —CH 2 —, —C(═O)—, —C(═S)—, —O—, —C(═O)O—, —OC(═O), —C(═O)NR a , —S—, —S(═O)—, or —S(═O) 2 —, or —S(═O) 2 NR a —;

R 4 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, hydroxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, carboxy, aryl, aryl(C 1 -C 6 )alkyl, het, NR d R e , —C(═O)NR d R e , NR d R e (C 1 -C 6 )alkyl, or het(C 1 -C 6 )alkyl;

R a is H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkyl, or (C 3 -C 8 )cyclo alkyl(C 1 -C 6 )alkyl;

Z is a phenyl ring substituted with one or more substituents independently selected from (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyloxy, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy; or Z is a phenyl ring that is fused to a saturated, partially unsaturated, or aromatic, mono- or bicyclic ring system comprising from about 3 to about 8 atoms selected from carbon, oxygen, and NR b , wherein the mono- or bicyclic ring system of Z is optionally substituted with one or more R c , and wherein the phenyl ring that is fused to the mono- or bicyclic ring system is optionally substituted with one or more substituents independently selected from (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 2 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyloxy, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy;

R b is absent, H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy(C 2 -C 6 )alkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl;

R c is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkanoyl, het, het(C 1 -C 6 )alkyl, het(C 1 -C 6 )alkoxy, or het(C 1 -C 6 )alkanoyl;

each R d and R e is independently H, hydroxy, (C 1 -C 6 )alkyl, amino, amino(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, NR f R g , or aryl(C 1 -C 6 )alkoxy; and each R f and R g is independently H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, or aryl(C 1 -C 6 )alkoxy; or R f and R g together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, or thiomorpholino ring;

wherein any aryl or het of R 1 or R 4 is optionally substituted with one or more substitutents independently selected from (C 1 -C 6 )alkyl, phenyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyloxy, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy, halo(C 2 -C 6 )alkoxy, cyano, nitro, halo, carboxy or NR d R e ;

and wherein the ring containing X is optionally substituted on carbon with one or more halo, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy;

or a pharmaceutically acceptable salt thereof;

wherein said disease or condition is a disorder of the central nervous system selected from one or more of the group consisting of age-associated memory impairment, mild cognitive impairment, Alzheimer's disease, and Parkinson's disease.

2. The method of claim 1 wherein R 1 is (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkanoyl, het, het(C 1 -C 6 )alkyl, het(C 1 -C 6 )alkoxy, or het(C 1 -C 6 )alkanoyl.

3. The method of claim 1 wherein R 1 is H, (C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, or het.

4. The method of claim 1 wherein R 1 is H, benzyl, indolyl, phenyl, 2-methylpropyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, α-phenylbenzyl, phenethyl, 1-naphthylmethyl, 2-naphthylmethyl, 4-phenylbenzyl, 4-ethoxybenzyl, isopropyl, cyclohexylmethyl, 2-methoxyphenyl, 3-methoxyphenyl, or 4-methoxyphenyl.

5. The method of claim 1 wherein Y is a direct bond, —CH 2 —, —C(═O)—, or —S(═O) 2 —.

6. The method of claim 1 wherein R 4 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, carboxy, aryl, aryl(C 1 -C 6 )alkyl, het, NR d R e , —C(═O)NR d R e , NR d R e (C 1 -C 6 )alkyl, or het(C 1 -C 6 )alkyl.

7. The method of claim 1 wherein Y—R 4 is H, tert-butoxycarbonyl, formylmethyl, pyridylmethyl, methyl, ethylaminocarbonyl, ethylsulfonyl, benzylsulfonyl, benzyl, acetyl, methoxycarbonylmethyl, methylsulfonyl, ethyl, carboxymethyl, propyl, 2-hydroxyethyl, methoxyaminocarbonylmethyl, benzyloxyaminocarbonylmethyl, prop-2-eneyloxyaminocarbonylmethyl, hydroxyaminocarbonylmethyl, hydroxyacetyl, 2-methylhydrazocarbonylmethyl, hydrazocarbonylmethyl, 2,2-dimethylhydrazocarbonylmethyl, or ethoxycarbonyl.

8. The method of claim 1 wherein Z is a phenyl ring substituted with one or more substituents independently selected from (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkoxy, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy.

9. The method of claim 1 wherein Z is a phenyl ring that is fused to a saturated, partially unsaturated, or aromatic, mono- or bicyclic ring system comprising from about 3 to about 8 atoms selected from carbon, oxygen, and NR b , wherein the mono- or bicyclic ring system of Z is optionally substituted with one or more R c , and wherein the phenyl ring that is fused is fused to the mono- or bicyclic ring system is optionally substituted with one or more substituents independently selected from (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 2 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyloxy, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy.

10. The method of claim 1 wherein Z has the following formula:

wherein R 2 is (C 1 -C 6 )alkyl, or halo(C 1 -C 6 )alkyl; and R 3 is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl.

11. The compound of claim 10 wherein R 2 is methyl and R 3 is cyclopropyl.

12. The method of claim 1 wherein Z is selected from a structure of formula III, IV, and V:

that is optionally substituted with one or more substituents selected from (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 2 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyloxy, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy; wherein p is 1, 2, 3, 4, 5, or 6.

13. The method of claim 1 wherein Z is selected from a structure of formula VI, VII, and VIII:

wherein: R j , R k , R m , R n , and R p are each independently selected from H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 2 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyloxy, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy; and p is 1, 2, 3, 4, 5, or 6.

14. The method of claim 13 wherein R j and R k are each independently selected from H and methyl; R m is methoxy; R n is cyclopentyl; R p is ethyl; and p is 3.

15. The method of claim 1 , wherein said compound of formula (I) is selected from the group consisting of:

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(2-methyl-benzyl)-piperazine;

(S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine;

(2S,5S)-5-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-2-methyl-piperazine;

(R)-6-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-2-one;

(S)-6-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-2-one;

(R)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine;

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(3-methyl-benzyl)-piperazine;

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(4-methyl-benzyl)-piperazine;

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(2-methoxy-benzyl)-piperazine;

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(3-methoxy-benzyl)-piperazine;

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(4-methoxy-benzyl)-piperazine;

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(4-ethoxy-benzyl)-piperazine;

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-phenethyl-piperazine;

(R)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-phenethyl-piperazine;

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(3-phenyl-propyl)-piperazine;

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-naphthalen-1-ylmethyl-piperazine;

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-naphthalen-2-ylmethyl-piperazine;

(S)-3-Biphenyl-4-ylmethyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine;

(S)-3-Benzhydryl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine;

(R)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-phenyl-piperazine;

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-isopropyl-piperazine;

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-isobutyl-piperazine;

(S)-3-Cyclohexylmethyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine;

3-[(S)-4-(3-Cyclopentyloxy-4-methoxy-phenyl)-piperazin-2-ylmethyl]-1H-indole;

1-(3-Cyclopentyloxy-4-methoxy-phenyl)-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-morpholine;

4-[(S)-3-benzyl-1-piperzinyl]-7-methoxy-spiro[benzofuran-2(3H),1′-cyclopentane];

6-((S)-3-Benzyl-piperazin-1-yl)-1-cyclopentyl-3-methyl-1H-indazole;

1-Cyclopentyl-3-ethyl-6-piperazin-1-yl-1H-indazole;

6-((S)-3-Benzyl-piperazin-1-yl)-1-cyclopentyl-3-ethyl-1H-indazole;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-methyl-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-ethyl-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-benzyl-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-pyridin-2-ylmethyl-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-pyridin-3-ylmethyl-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-pyridin-4-ylmethyl-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-(3H-imidazol-4-ylmethyl)-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-(1H-imidazol-2-ylmethyl)-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-methanesulfonyl-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-ethanesulfonyl-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-benzylsulfonyl-piperazine;

1-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanone;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine-1-carboxylic acid ethylamide;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine-1-carboxylic acid ethyl ester;

1-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-hydroxy-ethanone;

2-Amino-1-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanone, hydrochloride salt;

1-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-methylamino-ethanone, hydrochloride salt;

4-[(1-((S)-3-benzyl-4-piperazin-1-yl)-2-hydroxy-ethanone)]-7-methoxy-spiro[benzofuran-2(3H),1′-cyclopentane];

1-[(S)-2-Benzyl-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-piperazin-1-yl]-2-hydroxy-ethanone;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetamide;

[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid methyl ester;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanol;

[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid;

4-[(1-((S)-3-benzyl-4-piperazin-1-yl)-acetic acid)]-7-methoxy-spiro[benzofuran-2(3H),1′-cyclopentane];

[(S)-2-Benzyl-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-piperazin-1-yl]-acetic acid;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-methyl-acetamide;

[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid hydrazide;

[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid N′-methyl-hydrazide;

[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid N′,N′-dimethyl-hydrazide; 2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-methoxy-acetamide;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-ethoxy-acetamide;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-isobutoxy-acetamide;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-phenoxy-acetamide;

N-Allyloxy-2-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetamide;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-benzyloxy-acetamide;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-hydroxy-acetamide;

(S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine;

1-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-hydroxy-ethanone;

2-Amino-1-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanone, hydrochloride salt;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanol; [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid;