U.S. patent application number 14/776675 was filed with the patent office on 2016-06-02 for substituted 3-phenylpropylamine derivatives for the treatment of ophthalmic diseases and disorders.
The applicant listed for this patent is ACUCELA INC.. Invention is credited to Feng Hong, Ryo Kubota, Vladimir A. Kuksa, Mark W. Orme.
Application Number | 20160151369 14/776675 |
Document ID | / |
Family ID | 51529939 |
Filed Date | 2016-06-02 |
United States Patent
Application |
20160151369 |
Kind Code |
A1 |
Kuksa; Vladimir A. ; et
al. |
June 2, 2016 |
SUBSTITUTED 3-PHENYLPROPYLAMINE DERIVATIVES FOR THE TREATMENT OF
OPHTHALMIC DISEASES AND DISORDERS
Abstract
The present invention relates generally to compositions and
methods for treating neurodegenerative diseases and disorders,
particularly ophthalmic diseases and disorders. Provided herein are
substituted 3-phenylpropylamine derivative compounds and
pharmaceutical compositions comprising said compounds. The subject
compositions are useful for treating and preventing ophthalmic
diseases and disorders, including age-related macular degeneration
(AMD) and Stargardt's Disease.
Inventors: |
Kuksa; Vladimir A.;
(Bothell, WA) ; Orme; Mark W.; (Seattle, WA)
; Hong; Feng; (Bellevue, WA) ; Kubota; Ryo;
(Seattle, WA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ACUCELA INC. |
Seattle |
WA |
US |
|
|
Family ID: |
51529939 |
Appl. No.: |
14/776675 |
Filed: |
March 11, 2014 |
PCT Filed: |
March 11, 2014 |
PCT NO: |
PCT/US14/23751 |
371 Date: |
September 14, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61777903 |
Mar 12, 2013 |
|
|
|
Current U.S.
Class: |
514/256 ;
514/330; 514/357; 514/432; 514/459; 514/461; 514/469 |
Current CPC
Class: |
C07D 209/14 20130101;
C07D 211/96 20130101; A61K 31/341 20130101; C07D 211/60 20130101;
C07D 307/12 20130101; A61K 31/4406 20130101; C07D 211/22 20130101;
A61K 31/505 20130101; C07D 333/16 20130101; C07D 335/02 20130101;
A61K 31/343 20130101; A61P 27/02 20180101; C07D 233/64 20130101;
A61K 31/351 20130101; C07D 207/09 20130101; A61K 31/44 20130101;
C07D 307/14 20130101; C07D 333/20 20130101; C07D 213/30 20130101;
C07D 279/02 20130101; C07D 207/08 20130101; C07D 307/80 20130101;
C07D 333/12 20130101; C07D 309/06 20130101; C07D 207/26 20130101;
A61K 31/445 20130101; A61K 31/382 20130101; C07D 211/26 20130101;
C07D 309/04 20130101; A61K 31/4465 20130101; A61K 31/4409 20130101;
C07D 307/81 20130101; C07D 209/08 20130101; C07D 211/76 20130101;
A61P 25/28 20180101; C07D 233/96 20130101; C07D 239/26 20130101;
C07D 311/04 20130101; C07D 311/58 20130101; C07D 213/38
20130101 |
International
Class: |
A61K 31/505 20060101
A61K031/505; A61K 31/4409 20060101 A61K031/4409; A61K 31/4406
20060101 A61K031/4406; A61K 31/4465 20060101 A61K031/4465; A61K
31/445 20060101 A61K031/445; A61K 31/44 20060101 A61K031/44; A61K
31/343 20060101 A61K031/343; A61K 31/341 20060101 A61K031/341; A61K
31/351 20060101 A61K031/351; A61K 31/382 20060101 A61K031/382 |
Claims
1.-20. (canceled)
21. A method for treating an ophthalmic disease or disorder in a
subject in need thereof, comprising administering to the subject a
compound of Formula (C), or a pharmaceutically acceptable salt
thereof, wherein the compound of Formula (C) has the following
structure: ##STR00201## wherein, A is selected from --O-- or
--CH.sub.2--; Y is ##STR00202## R.sup.A is OH, R.sup.B is H; or
optionally, R.sup.A and R.sup.B together form an oxo; R.sup.1 and
R.sup.2 are each independently selected from hydrogen,
C.sub.1-C.sub.4 alkyl, --C(.dbd.O)R.sup.3; and R.sup.3 is selected
from alkyl, alkoxy, or --OCH.sub.2OC(O)R.sup.4, wherein R.sup.4 is
an alkyl or alkoxy.
22. The method of claim 21, wherein A is --O--.
23. The method of claim 21, wherein A is --CH.sub.2--.
24. The method of claim 21, wherein R.sup.A is OH and R.sup.B is
H.
25. The method of claim 21, wherein R.sup.1 and R.sup.2 are both
hydrogen.
26. The method of claim 21, wherein R.sup.1 is hydrogen and R.sup.2
is C.sub.1-C.sub.4 alkyl.
27. The method of claim 21, wherein R.sup.1 is hydrogen and R.sup.2
is --C(.dbd.O)R.sup.3.
28. The method of claim 21, wherein Y is ##STR00203##
29. The method of claim 21, wherein Y is ##STR00204##
30. A method for treating an ophthalmic disease or disorder in a
subject in need thereof, comprising administering to the subject a
compound, or a pharmaceutically acceptable salt thereof, selected
from the group consisting of:
(R)-3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol;
3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol;
(1R)-3-Amino-1-(3-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)propan-1-ol;
(R)-3-Amino-1-(3-(pyridin-4-ylmethoxy)phenyl)propan-1-ol;
(R)-3-Amino-1-(3-(pyridin-3-ylmethoxy)phenyl)propan-1-ol;
(R)-3-Amino-1-(3-(pyridin-2-ylmethoxy)phenyl)propan-1-ol;
(1R)-3-amino-1-(3-((tetrahydro-2H-thiopyran-3-yl)methoxy)phenyl)propan-1--
ol;
(R)-3-Amino-1-(3-((tetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)propan--
1-ol;
(R)-4-((3-(3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thio-
pyran 1,1-dioxide;
3-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thiopyran
1,1-dioxide;
(R)-1-(4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidin-1-yl)ethan-
one;
(R)-3-Amino-1-(3-((6-methylpyridin-2-yl)methoxy)phenyl)propan-1-ol;
(1R)-3-Amino-1-(3-((2,3-dihydrobenzofuran-2-yl)methoxy)phenyl)propan-1-ol-
;
(1R)-3-Amino-1-(3-((tetrahydrofuran-2-yl)methoxy)phenyl)propan-1-ol;
(R)-3-Amino-1-(3-(piperidin-4-ylmethoxy)phenyl)propan-1-ol;
(R)-3-Amino-1-(3-((1-methylpiperidin-4-yl)methoxy)phenyl)propan-1-ol;
(R)-Methyl
4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidine-1-carboxylate;
(R)-3-Amino-1-(3-(pyrimidin-5-ylmethoxy)phenyl)propan-1-ol;
(1R)-3-Amino-1-(3-(chroman-3-ylmethoxy)phenyl)propan-1-ol;
(R)-4-((3-(3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thiopyran
1-oxide;
(R)-3-Amino-1-(3-(((S)-1-methylpyrrolidin-2-yl)methoxy)phenyl)pr-
opan-1-ol;
(R)-3-Amino-1-(3-((S)-pyrrolidin-2-ylmethoxy)phenyl)propan-1-ol- ;
(R)-3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)propan--
1-ol;
3-Amino-1-(3-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)sulfo-
nyl)-phenyl)propan-1-one;
3-Amino-1-(3-(((tetrahydro-2H-pyran-3-yl)methyl)sulfonyl)phenyl)propan-1--
one;
3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)propa-
n-1-one;
3-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)piperidin-2-one-
; (R)-3-Amino-1-(3-(thiophen-2-ylmethoxy)phenyl)propan-1-ol;
(R)-3-Amino-1-(3-(thiophen-3-ylmethoxy)phenyl)propan-1-ol;
(R)-tert-Butyl
4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidine-1-carboxylate;
(E)-3-(3-((Tetrahydro-2H-pyran-4-yl)methoxy)phenyl)prop-2-en-1-amine;
3-(3-((Tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-amine;
(R)-3-(Methylamino)-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-
-1-ol;
1-((S)-2-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)pyrrolidin-
-1-yl)ethanone;
5-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)piperidin-2-one;
4-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)piperidin-2-one;
6-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)-1-methylpiperidin-2-on-
e;
5-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)pyrrolidin-2-one;
5-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)-1-methylpyrrolidin-2-o-
ne;
N-(3-(3-Amino-1-hydroxypropyl)phenyl)-6-oxopiperidine-3-carboxamide;
3-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)-1,2-thiazinane
1,1-dioxide;
(R)-1-(3-((1H-Pyrrol-2-yl)methoxy)phenyl)-3-aminopropan-1-ol;
(R)-3-Amino-1-(3-(furan-2-ylmethoxy)phenyl)propan-1-ol;
(R)-3-Amino-1-(3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)propan-
-1-ol;
(R)-1-(3-(((1H-Indol-6-yl)methyl)amino)phenyl)-3-aminopropan-1-ol;
(R)-1-(3-((1H-Indol-6-yl)methoxy)phenyl)-3-aminopropan-1-ol;
(R)-3-Amino-1-(3-(benzofuran-2-ylmethoxy)phenyl)propan-1-ol;
3-(3-((Tetrahydro-2H-pyran-4-yl)methoxy)phenyl)prop-2-yn-1-amine;
3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)thio)phenyl)propan-1-ol;
3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)propan-1--
ol;
3-Amino-1-(3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)phenyl)propan-1-ol;
3-Amino-1-(3-(2-(pyridin-3-yl)ethyl)phenyl)propan-1-ol;
3-Amino-1-(3-(2-(thiophen-3-yl)ethyl)phenyl)propan-1-ol;
(E)-1-(3-(3-Amino-1-hydroxypropyl)styryl)pyrrolidin-2-one;
1-(3-(3-Amino-1-hydroxypropyl)phenethyl)pyrrolidin-2-one;
3-Amino-1-(3-(2-(pyrrolidin-1-yl)ethyl)phenyl)propan-1-ol;
(E)-1-(3-(2-(1H-Imidazol-1-yl)vinyl)phenyl)-3-aminopropan-1-ol;
1-(3-(2-(1H-Imidazol-1-yl)ethyl)phenyl)-3-aminopropan-1-ol;
(E)-3-Amino-1-(3-(2-(pyridin-2-yl)vinyl)phenyl)propan-1-ol;
3-Amino-1-(3-(2-(pyridin-2-yl)ethyl)phenyl)propan-1-ol;
(E)-3-Amino-1-(3-(2-(tetrahydro-2H-pyran-4-yl)vinyl)phenyl)propan-1-ol;
and
3-Amino-1-(3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)phenyl)propan-1-ol.
31. The method of claim 21, wherein the ophthalmic disease or
disorder is dry age-related macular degeneration or Stargardt's
macular dystrophy.
32. The method of claim 30, wherein the ophthalmic disease or
disorder is dry age-related macular degeneration or Stargardt's
macular dystrophy.
33. The method of claim 21, wherein the ophthalmic disease or
disorder is geographic atrophy associated with dry age-related
macular degeneration.
34. The method of claim 30, wherein the ophthalmic disease or
disorder is geographic atrophy associated with dry age-related
macular degeneration.
Description
CROSS REFERENCE
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/777,903, filed Mar. 12, 2013, the content of
which is hereby incorporated by reference in its entirety.
BACKGROUND
[0002] Neurodegenerative diseases, such as glaucoma, macular
degeneration, and Alzheimer's disease, affect millions of patients
throughout the world. Because the loss of quality of life
associated with these diseases is considerable, drug research and
development in this area is of great importance.
BRIEF SUMMARY OF THE INVENTION
[0003] We have identified a need for effective therapies for
treating ophthalmic diseases or disorders resulting in ophthalmic
dysfunction including those described above. In particular, we have
identified a pressing need for compositions and methods for
treating Stargardt's disease and age-related macular degeneration
(AMD) without causing further unwanted side effects such as
progressive retinal degeneration, LCA-like conditions, night
blindness, or systemic vitamin A deficiency. We have also
identified a need for effective treatments for other ophthalmic
diseases and disorders that adversely affect the retina.
[0004] One embodiment provides a compound of Formula (C), or a
pharmaceutically acceptable salt thereof:
##STR00001##
wherein, A is selected from --O-- or --CH.sub.2--;
Y is
##STR00002##
[0005] R.sup.A is OH, R.sup.B is H; or optionally, R.sup.A and
R.sup.B together form an oxo; R.sup.1 and R.sup.2 are each
independently selected from hydrogen, C.sub.1-C.sub.4 alkyl,
--C(.dbd.O)R.sup.3; and R.sup.3 is selected from alkyl, alkoxy, or
--OCH.sub.2OC(O)R.sup.4, wherein R.sup.4 is an alkyl or alkoxy.
[0006] In a further embodiment is a compound, or a pharmaceutically
acceptable salt thereof, selected from the group consisting of:
[0007]
(R)-3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol;
[0008]
3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol-
; [0009]
(1R)-3-Amino-1-(3-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)propa-
n-1-ol; [0010]
(R)-3-Amino-1-(3-(pyridin-4-ylmethoxy)phenyl)propan-1-ol; [0011]
(R)-3-Amino-1-(3-(pyridin-3-ylmethoxy)phenyl)propan-1-ol; [0012]
(R)-3-Amino-1-(3-(pyridin-2-ylmethoxy)phenyl)propan-1-ol; [0013]
(1R)-3-amino-1-(3-((tetrahydro-2H-thiopyran-3-yl)methoxy)phenyl)propan-1--
ol; [0014]
(R)-3-Amino-1-(3-((tetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)-
propan-1-ol; [0015]
(R)-4-((3-(3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thiopyran
1,1-dioxide; [0016]
3-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thiopyran
1,1-dioxide; [0017]
(R)-1-(4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidin-1-yl)ethan-
one; [0018]
(R)-3-Amino-1-(3-((6-methylpyridin-2-yl)methoxy)phenyl)propan-1-ol;
[0019] (1R)-3-Amino-1-(3-((2,3-dihydrobenzo
furan-2-yl)methoxy)phenyl)propan-1-ol; [0020]
(1R)-3-Amino-1-(3-((tetrahydrofuran-2-yl)methoxy)phenyl)propan-1-ol;
[0021] (R)-3-Amino-1-(3-(piperidin-4-ylmethoxy)phenyl)propan-1-ol;
[0022]
(R)-3-Amino-1-(3-((1-methylpiperidin-4-yl)methoxy)phenyl)propan-1-ol;
[0023] (R)-Methyl
4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidine-1-carboxylate;
[0024] (R)-3-Amino-1-(3-(pyrimidin-5-ylmethoxy)phenyl)propan-1-ol;
[0025] (1R)-3-Amino-1-(3-(chroman-3-ylmethoxy)phenyl)propan-1-ol;
[0026]
(R)-4-((3-(3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thiopyran
1-oxide; [0027]
(R)-3-Amino-1-(3-(((S)-1-methylpyrrolidin-2-yl)methoxy)phenyl)propan-1-ol-
; [0028]
(R)-3-Amino-1-(3-((S)-pyrrolidin-2-ylmethoxy)phenyl)propan-1-ol;
[0029]
(R)-3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)p-
ropan-1-ol; [0030]
3-Amino-1-(3-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)sulfonyl)--
phenyl)propan-1-one; [0031]
3-Amino-1-(3-(((tetrahydro-2H-pyran-3-yl)methyl)sulfonyl)phenyl)propan-1--
one; [0032]
3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)propan-1--
one; [0033]
3-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)piperidin-2-one;
[0034] (R)-3-Amino-1-(3-(thiophen-2-ylmethoxy)phenyl)propan-1-ol;
[0035] (R)-3-Amino-1-(3-(thiophen-3-ylmethoxy)phenyl)propan-1-ol;
[0036] (R)-tert-Butyl
4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidine-1-carboxylate;
[0037]
(E)-3-(3-((Tetrahydro-2H-pyran-4-yl)methoxy)phenyl)prop-2-en-1-ami-
ne; [0038]
3-(3-((Tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-amine;
[0039]
(R)-3-(Methylamino)-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl-
)propan-1-ol; [0040]
1-((S)-2-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)pyrrolidin-1-yl)-
ethanone; [0041]
5-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)piperidin-2-one;
[0042]
4-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)piperidin-2-one;
[0043]
6-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)-1-methylpiperidin-2-on-
e; [0044]
5-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)pyrrolidin-2-o-
ne; [0045]
5-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)-1-methylpyrr-
olidin-2-one; [0046]
N-(3-(3-Amino-1-hydroxypropyl)phenyl)-6-oxopiperidine-3-carboxamide;
[0047]
3-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)-1,2-thiazinane
1,1-dioxide; [0048]
(R)-1-(3-((1H-Pyrrol-2-yl)methoxy)phenyl)-3-aminopropan-1-ol;
[0049] (R)-3-Amino-1-(3-(furan-2-ylmethoxy)phenyl)propan-1-ol;
[0050]
(R)-3-Amino-1-(3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)propan-
-1-ol; [0051]
(R)-1-(3-(((1H-Indol-6-yl)methyl)amino)phenyl)-3-aminopropan-1-ol;
[0052] (R)-1-(3-((1H-Indol-6-yl)methoxy)phenyl)-3-aminopropan-1-ol;
[0053] (R)-3-Amino-1-(3-(benzofuran-2-ylmethoxy)phenyl)propan-1-ol;
[0054]
3-(3-((Tetrahydro-2H-pyran-4-yl)methoxy)phenyl)prop-2-yn-1-amine;
[0055]
3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)thio)phenyl)propan-1-ol;
[0056]
3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)pr-
opan-1-ol; [0057]
3-Amino-1-(3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)phenyl)propan-1-ol;
[0058] 3-Amino-1-(3-(2-(pyridin-3-yl)ethyl)phenyl)propan-1-ol;
[0059] 3-Amino-1-(3-(2-(thiophen-3-yl)ethyl)phenyl)propan-1-ol;
[0060] (E)-1-(3-(3-Amino-1-hydroxypropyl)styryl)pyrrolidin-2-one;
[0061] 1-(3-(3-Amino-1-hydroxypropyl)phenethyl)pyrrolidin-2-one;
[0062] 3-Amino-1-(3-(2-(pyrrolidin-1-yl)ethyl)phenyl)propan-1-ol;
[0063]
(E)-1-(3-(2-(1H-Imidazol-1-yl)vinyl)phenyl)-3-aminopropan-1-ol;
[0064] 1-(3-(2-(1H-Imidazol-1-yl)ethyl)phenyl)-3-aminopropan-1-ol;
[0065] (E)-3-Amino-1-(3-(2-(pyridin-2-yl)vinyl)phenyl)propan-1-ol;
[0066] 3-Amino-1-(3-(2-(pyridin-2-yl)ethyl)phenyl)propan-1-ol;
[0067]
(E)-3-Amino-1-(3-(2-(tetrahydro-2H-pyran-4-yl)vinyl)phenyl)propan-1-ol;
and [0068]
3-Amino-1-(3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)phenyl)propan-1-ol.
[0069] One embodiment provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound of
Formula (C), or a pharmaceutically acceptable salt thereof.
[0070] One embodiment provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound
described in Table 1, or a pharmaceutically acceptable salt
thereof.
[0071] One embodiment provides a method for treating an ophthalmic
disease or disorder in a subject, comprising administering to the
subject a pharmaceutical composition comprising a compound of
Formula (C), or a pharmaceutically acceptable salt thereof.
[0072] Another embodiment provides the method for treating an
ophthalmic disease or disorder in a subject, wherein the ophthalmic
disease or disorder is age-related macular degeneration or
Stargardt's macular dystrophy. Another embodiment provides the
method for treating an ophthalmic disease or disorder in a subject,
wherein the ophthalmic disease or disorder is geographic atrophy
(GA) associated with dry age-related macular degeneration.
[0073] One embodiment provides a method for treating an ophthalmic
disease or disorder in a subject, comprising administering to the
subject a pharmaceutical composition comprising a compound
disclosed in Table 1, or a pharmaceutically acceptable salt
thereof. Another embodiment provides the method for treating an
ophthalmic disease or disorder in a subject, wherein the ophthalmic
disease or disorder is age-related macular degeneration or
Stargardt's macular dystrophy. Another embodiment provides the
method for treating an ophthalmic disease or disorder in a subject,
wherein the ophthalmic disease or disorder is geographic atrophy
(GA) associated with dry age-related macular degeneration.
[0074] All publications, patents, and patent applications mentioned
in this specification are herein incorporated by reference to the
same extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated by reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0075] The novel features of the invention are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present invention will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the invention
are utilized, and the accompanying drawings of which:
[0076] FIG. 1 provides a summary of an illustrative time course
experiment for in vivo isomerase inhibition as described in
biological evaluation example 2;
[0077] FIGS. 2 (a) and (b) provides a summary of an illustrative
dose response experiment comparing between
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A) and
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(compound D);
[0078] FIGS. 3 (a) and (b) provides a summary of an illustrative
dose response experiment comparing between
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A) and
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(compound D); and
[0079] FIGS. 4 (a) and (b) provides a summary of an illustrative
time course experiment comparing between
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A) and
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(compound D).
DETAILED DESCRIPTION OF THE INVENTION
[0080] As used herein and in the appended claims, the singular
forms "a," "and," and "the" include plural referents unless the
context clearly dictates otherwise. Thus, for example, reference to
"an agent" includes a plurality of such agents, and reference to
"the cell" includes reference to one or more cells (or to a
plurality of cells) and equivalents thereof known to those skilled
in the art, and so forth. When ranges are used herein for physical
properties, such as molecular weight, or chemical properties, such
as chemical formulae, all combinations and subcombinations of
ranges and specific embodiments therein are intended to be
included. The term "about" when referring to a number or a
numerical range means that the number or numerical range referred
to is an approximation within experimental variability (or within
statistical experimental error), and thus the number or numerical
range may vary between 1% and 15% of the stated number or numerical
range. The term "comprising" (and related terms such as "comprise"
or "comprises" or "having" or "including") is not intended to
exclude that in other certain embodiments, for example, an
embodiment of any composition of matter, composition, method, or
process, or the like, described herein, may "consist of" or
"consist essentially of" the described features.
DEFINITIONS
[0081] As used in the specification and appended claims, unless
specified to the contrary, the following terms have the meaning
indicated below.
[0082] As used herein and in the appended claims, the singular
forms "a," "and," and "the" include plural referents unless the
context clearly dictates otherwise. Thus, for example, reference to
"a compound" includes a plurality of such compounds, and reference
to "the cell" includes reference to one or more cells (or to a
plurality of cells) and equivalents thereof known to those skilled
in the art, and so forth. When ranges are used herein for physical
properties, such as molecular weight, or chemical properties, such
as chemical formulae, all combinations and subcombinations of
ranges and specific embodiments therein are intended to be
included. The term "about" when referring to a number or a
numerical range means that the number or numerical range referred
to is an approximation within experimental variability (or within
statistical experimental error), and thus the number or numerical
range may vary between 1% and 15% of the stated number or numerical
range. The term "comprising" (and related terms such as "comprise"
or "comprises" or "having" or "including") is not intended to
exclude that in other certain embodiments, for example, an
embodiment of any composition of matter, composition, method, or
process, or the like, described herein, may "consist of" or
"consist essentially of" the described features.
[0083] "Amino" refers to the --NH.sub.2 radical.
[0084] "Cyano" refers to the --CN radical.
[0085] "Nitro" refers to the --NO.sub.2 radical.
[0086] "Oxa" refers to the --O-- radical.
[0087] "Oxo" refers to the .dbd.O radical.
[0088] "Thioxo" refers to the .dbd.S radical.
[0089] "Imino" refers to the .dbd.N--H radical.
[0090] "Hydrazino" refers to the .dbd.N--NH.sub.2 radical.
[0091] "Alkyl" refers to a straight or branched hydrocarbon chain
radical consisting solely of carbon and hydrogen atoms, containing
no unsaturation, having from one to fifteen carbon atoms (e.g.,
C.sub.1-C.sub.15 alkyl). In certain embodiments, an alkyl comprises
one to thirteen carbon atoms (e.g., C.sub.1-C.sub.3 alkyl). In
certain embodiments, an alkyl comprises one to eight carbon atoms
(e.g., C.sub.1-C.sub.8 alkyl). In other embodiments, an alkyl
comprises five to fifteen carbon atoms (e.g., C.sub.5-C.sub.15
alkyl). In other embodiments, an alkyl comprises five to eight
carbon atoms (e.g., C.sub.5-C.sub.8 alkyl). The alkyl is attached
to the rest of the molecule by a single bond, for example, methyl
(Me), ethyl (Et), n-propyl, 1-methylethyl (iso-propyl), n-butyl,
n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl,
2-methylhexyl, and the like. Unless stated otherwise specifically
in the specification, an alkyl group is optionally substituted by
one or more of the following substituents: halo, cyano, nitro, oxo,
thioxo, trimethylsilanyl, --OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a,
--N(R.sup.a).sub.2, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--N(R.sup.a)C(O)R.sup.a, --N(R.sup.a)S(O).sub.tR.sup.a (where t is
1 or 2), --S(O).sub.tOR.sup.a (where t is 1 or 2) and
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2) where each R.sup.a
is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,
carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl or heteroarylalkyl.
[0092] "Alkenyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one double bond, and having from two to twelve
carbon atoms. In certain embodiments, an alkenyl comprises two to
eight carbon atoms. In other embodiments, an alkenyl comprises two
to four carbon atoms. The alkenyl is attached to the rest of the
molecule by a single bond, for example, ethenyl (i.e., vinyl),
prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl,
penta-1,4-dienyl, and the like. Unless stated otherwise
specifically in the specification, an alkenyl group is optionally
substituted by one or more of the following substituents: halo,
cyano, nitro, oxo, thioxo, trimethylsilanyl, --OR.sup.a,
--SR.sup.a, --OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--N(R.sup.a)C(O)R.sup.a, --N(R.sup.a)S(O).sub.tR.sup.a (where t is
1 or 2), --S(O).sub.tOR.sup.a (where t is 1 or 2) and
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2) where each R.sup.a
is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,
carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl or heteroarylalkyl.
[0093] "Alkynyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one triple bond, having from two to twelve
carbon atoms. In certain embodiments, an alkynyl comprises two to
eight carbon atoms. In other embodiments, an alkynyl has two to
four carbon atoms. The alkynyl is attached to the rest of the
molecule by a single bond, for example, ethynyl, propynyl, butynyl,
pentynyl, hexynyl, and the like. Unless stated otherwise
specifically in the specification, an alkynyl group is optionally
substituted by one or more of the following substituents: halo,
cyano, nitro, oxo, thioxo, trimethylsilanyl, --OR.sup.a,
--SR.sup.a, --OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--N(R.sup.a)C(O)R.sup.a, --N(R.sup.a)S(O).sub.tR.sup.a (where t is
1 or 2), --S(O).sub.tOR.sup.a (where t is 1 or 2) and
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2) where each R.sup.a
is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,
carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl or heteroarylalkyl.
[0094] "Alkylene" or "alkylene chain" refers to a straight or
branched divalent hydrocarbon chain linking the rest of the
molecule to a radical group, consisting solely of carbon and
hydrogen, containing no unsaturation and having from one to twelve
carbon atoms, for example, methylene, ethylene, propylene,
n-butylene, and the like. The alkylene chain is attached to the
rest of the molecule through a single bond and to the radical group
through a single bond. The points of attachment of the alkylene
chain to the rest of the molecule and to the radical group can be
through one carbon in the alkylene chain or through any two carbons
within the chain. Unless stated otherwise specifically in the
specification, an alkylene chain is optionally substituted by one
or more of the following substituents: halo, cyano, nitro, aryl,
cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo,
trimethylsilanyl, --OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a,
--N(R.sup.a).sub.2, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--N(R.sup.a)C(O)R.sup.a, --N(R.sup.a)S(O).sub.tR.sup.a (where t is
1 or 2), --S(O).sub.tOR.sup.a (where t is 1 or 2) and
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2) where each R.sup.a
is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl,
carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl or heteroarylalkyl.
[0095] "Alkenylene" or "alkenylene chain" refers to a straight or
branched divalent hydrocarbon chain linking the rest of the
molecule to a radical group, consisting solely of carbon and
hydrogen, containing at least one double bond and having from two
to twelve carbon atoms, for example, ethenylene, propenylene,
n-butenylene, and the like.
[0096] The alkenylene chain is attached to the rest of the molecule
through a double bond or a single bond and to the radical group
through a double bond or a single bond. The points of attachment of
the alkenylene chain to the rest of the molecule and to the radical
group can be through one carbon or any two carbons within the
chain. Unless stated otherwise specifically in the specification,
an alkenylene chain is optionally substituted by one or more of the
following substituents: halo, cyano, nitro, aryl, cycloalkyl,
heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl,
--OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a, --N(R.sup.a).sub.2,
--C(O)R.sup.a, --C(O)OR.sup.a, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.a, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2) and
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2) where each R.sup.a
is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl,
cycloalkylalkyl, aryl (optionally substituted with one or more halo
groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or
heteroarylalkyl, and where each of the above substituents is
unsubstituted unless otherwise indicated.
[0097] "Aryl" refers to a radical derived from an aromatic
monocyclic or multicyclic hydrocarbon ring system by removing a
hydrogen atom from a ring carbon atom. The aromatic monocyclic or
multicyclic hydrocarbon ring system contains only hydrogen and
carbon from six to eighteen carbon atoms, where at least one of the
rings in the ring system is fully unsaturated, i.e., it contains a
cyclic, delocalized (4n+2) .pi.-electron system in accordance with
the Huckel theory. Aryl groups include, but are not limited to,
groups such as phenyl, fluorenyl, and naphthyl. Unless stated
otherwise specifically in the specification, the term "aryl" or the
prefix "ar-" (such as in "aralkyl") is meant to include aryl
radicals optionally substituted by one or more substituents
independently selected from alkyl, alkenyl, alkynyl, halo,
fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted carbocyclyl,
optionally substituted carbocyclylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.b--OR.sup.a, --R.sup.b--OC(O)--R.sup.a,
--R.sup.b--N(R.sup.a).sub.2, --R.sup.b--C(O)R.sup.a,
--R.sup.b--C(O)OR.sup.a, --R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R.sup.c--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,
--R.sup.b--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl, fluoroalkyl,
cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one
or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl or heteroarylalkyl, each R.sup.b is independently a
direct bond or a straight or branched alkylene or alkenylene chain,
and R.sup.e is a straight or branched alkylene or alkenylene chain,
and where each of the above substituents is unsubstituted unless
otherwise indicated.
[0098] "Aralkyl" refers to a radical of the formula --Re-aryl where
R.sup.e is an alkylene chain as defined above, for example, benzyl,
diphenylmethyl and the like. The alkylene chain part of the aralkyl
radical is optionally substituted as described above for an
alkylene chain. The aryl part of the aralkyl radical is optionally
substituted as described above for an aryl group.
[0099] "Aralkenyl" refers to a radical of the formula
--R.sup.d-aryl where R.sup.d is an alkenylene chain as defined
above. The aryl part of the aralkenyl radical is optionally
substituted as described above for an aryl group. The alkenylene
chain part of the aralkenyl radical is optionally substituted as
defined above for an alkenylene group.
[0100] "Aralkynyl" refers to a radical of the formula
--R.sup.e-aryl, where R.sup.e is an alkynylene chain as defined
above. The aryl part of the aralkynyl radical is optionally
substituted as described above for an aryl group. The alkynylene
chain part of the aralkynyl radical is optionally substituted as
defined above for an alkynylene chain.
[0101] "Carbocyclyl" refers to a stable non-aromatic monocyclic or
polycyclic hydrocarbon radical consisting solely of carbon and
hydrogen atoms, which may include fused or bridged ring systems,
having from three to fifteen carbon atoms. In certain embodiments,
a carbocyclyl comprises three to ten carbon atoms. In other
embodiments, a carbocyclyl comprises five to seven carbon atoms.
The carbocyclyl is attached to the rest of the molecule by a single
bond. Carbocyclyl may be saturated, (i.e., containing single C--C
bonds only) or unsaturated (i.e., containing one or more double
bonds or triple bonds.) A fully saturated carbocyclyl radical is
also referred to as "cycloalkyl." Examples of monocyclic
cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl
is also referred to as "cycloalkenyl." Examples of monocyclic
cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl,
cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals
include, for example, adamantyl, norbornyl (i.e.,
bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,
7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise
stated specifically in the specification, the term "carbocyclyl" is
meant to include carbocyclyl radicals that are optionally
substituted by one or more substituents independently selected from
alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano,
nitro, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted carbocyclyl, optionally substituted
carbocyclylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.b--OR.sup.a,
--R.sup.b--SR.sup.a, --R.sup.b--OC(O)--R.sup.a,
--R.sup.b--N(R.sup.a).sub.2, --R.sup.b--C(O)R.sup.a,
--R.sup.b--C(O)OR.sup.a, --R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R.sup.c--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,
--R.sup.b--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl, fluoroalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R.sup.b is
independently a direct bond or a straight or branched alkylene or
alkenylene chain, and Re is a straight or branched alkylene or
alkenylene chain, and where each of the above substituents is
unsubstituted unless otherwise indicated.
[0102] "Carbocyclylalkyl" refers to a radical of the formula
--R.sup.c-carbocyclyl where Re is an alkylene chain as defined
above. The alkylene chain and the carbocyclyl radical is optionally
substituted as defined above.
[0103] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo
substituents.
[0104] "Fluoroalkyl" refers to an alkyl radical, as defined above,
that is substituted by one or more fluoro radicals, as defined
above, for example, trifluoromethyl, difluoromethyl,
2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
The alkyl part of the fluoroalkyl radical is optionally substituted
as defined above for an alkyl group.
[0105] "Heterocyclyl" refers to a stable 3- to 18-membered
non-aromatic ring radical that comprises two to twelve carbon atoms
and from one to six heteroatoms selected from nitrogen, oxygen and
sulfur. Unless stated otherwise specifically in the specification,
the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or
tetracyclic ring system, which may include fused or bridged ring
systems. The heteroatoms in the heterocyclyl radical may be
optionally oxidized. One or more nitrogen atoms, if present, are
optionally quaternized. The heterocyclyl radical is partially or
fully saturated. The heterocyclyl may be attached to the rest of
the molecule through any atom of the ring(s). Examples of such
heterocyclyl radicals include, but are not limited to, dioxolanyl,
thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,
imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,
octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,
piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,
quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,
tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,
1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated
otherwise specifically in the specification, the term
"heterocyclyl" is meant to include heterocyclyl radicals as defined
above that are optionally substituted by one or more substituents
selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted carbocyclyl,
optionally substituted carbocyclylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.b--OR.sup.a, --R.sup.b--SR.sup.a,
--R.sup.b--OC(O)--R.sup.a, --R.sup.b--N(R.sup.a).sub.2,
--R.sup.b--C(O)R.sup.a, --R.sup.b--C(O)OR.sup.a,
--R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R.sup.c--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,
--R.sup.b--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl, fluoroalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R.sup.b is
independently a direct bond or a straight or branched alkylene or
alkenylene chain, and R.sup.c is a straight or branched alkylene or
alkenylene chain, and where each of the above substituents is
unsubstituted unless otherwise indicated.
[0106] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a
heterocyclyl radical as defined above containing at least one
nitrogen and where the point of attachment of the heterocyclyl
radical to the rest of the molecule is through a nitrogen atom in
the heterocyclyl radical. An N-heterocyclyl radical is optionally
substituted as described above for heterocyclyl radicals. Examples
of such N-heterocyclyl radicals include, but are not limited to,
1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl,
pyrazolidinyl, imidazolinyl, and imidazolidinyl.
[0107] "C-heterocyclyl" or "C-attached heterocyclyl" refers to a
heterocyclyl radical as defined above containing at least one
heteroatom and where the point of attachment of the heterocyclyl
radical to the rest of the molecule is through a carbon atom in the
heterocyclyl radical. A C-heterocyclyl radical is optionally
substituted as described above for heterocyclyl radicals. Examples
of such C-heterocyclyl radicals include, but are not limited to,
2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or
3-pyrrolidinyl, and the like.
[0108] "Heterocyclylalkyl" refers to a radical of the formula
--R.sup.c-heterocyclyl where R.sup.c is an alkylene chain as
defined above. If the heterocyclyl is a nitrogen-containing
heterocyclyl, the heterocyclyl is optionally attached to the alkyl
radical at the nitrogen atom. The alkylene chain of the
heterocyclylalkyl radical is optionally substituted as defined
above for an alkylene chain. The heterocyclyl part of the
heterocyclylalkyl radical is optionally substituted as defined
above for a heterocyclyl group.
[0109] "Heteroaryl" refers to a radical derived from a 3- to
18-membered aromatic ring radical that comprises two to seventeen
carbon atoms and from one to six heteroatoms selected from
nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical
may be a monocyclic, bicyclic, tricyclic or tetracyclic ring
system, wherein at least one of the rings in the ring system is
fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)
.pi.-electron system in accordance with the Huckel theory.
Heteroaryl includes fused or bridged ring systems. The
heteroatom(s) in the heteroaryl radical is optionally oxidized. One
or more nitrogen atoms, if present, are optionally quaternized. The
heteroaryl is attached to the rest of the molecule through any atom
of the ring(s). Examples of heteroaryls include, but are not
limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl,
1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl,
benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl,
1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl,
benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl,
benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl),
benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,
benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,
cyclopenta[d]pyrimidinyl,
6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,
5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl,
dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl,
furo[3,2-c]pyridinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl,
imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl,
isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl,
5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,
1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,
oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl,
1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,
phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,
pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl,
pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl,
pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,
tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,
5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,
5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl,
thiadiazolyl, triazolyl, tetrazolyl, triazinyl,
thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl,
thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated
otherwise specifically in the specification, the term "heteroaryl"
is meant to include heteroaryl radicals as defined above which are
optionally substituted by one or more substituents selected from
alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,
haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
aralkenyl, optionally substituted aralkynyl, optionally substituted
carbocyclyl, optionally substituted carbocyclylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.b--OR.sup.a, --R.sup.b--SR.sup.a,
--R.sup.b--OC(O)--R.sup.a, --R.sup.b--N(R.sup.a).sub.2,
--R.sup.b--C(O)R.sup.a, --R.sup.b--C(O)OR.sup.a,
--R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R.sup.c--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,
--R.sup.b--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl, fluoroalkyl,
cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R.sup.b is
independently a direct bond or a straight or branched alkylene or
alkenylene chain, and R.sup.c is a straight or branched alkylene or
alkenylene chain, and where each of the above substituents is
unsubstituted unless otherwise indicated.
[0110] "N-heteroaryl" refers to a heteroaryl radical as defined
above containing at least one nitrogen and where the point of
attachment of the heteroaryl radical to the rest of the molecule is
through a nitrogen atom in the heteroaryl radical. An N-heteroaryl
radical is optionally substituted as described above for heteroaryl
radicals.
[0111] "C-heteroaryl" refers to a heteroaryl radical as defined
above and where the point of attachment of the heteroaryl radical
to the rest of the molecule is through a carbon atom in the
heteroaryl radical. A C-heteroaryl radical is optionally
substituted as described above for heteroaryl radicals.
[0112] "Heteroarylalkyl" refers to a radical of the formula
--R.sup.c-heteroaryl, where R.sup.c is an alkylene chain as defined
above. If the heteroaryl is a nitrogen-containing heteroaryl, the
heteroaryl is optionally attached to the alkyl radical at the
nitrogen atom. The alkylene chain of the heteroarylalkyl radical is
optionally substituted as defined above for an alkylene chain. The
heteroaryl part of the heteroarylalkyl radical is optionally
substituted as defined above for a heteroaryl group.
[0113] The compounds disclosed herein may contain one or more
asymmetric centers and may thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms that may be defined,
in terms of absolute stereochemistry, as (R)- or (S)-. Unless
stated otherwise, it is intended that all stereoisomeric forms of
the compounds disclosed herein are contemplated by this disclosure.
When the compounds described herein contain alkene double bonds,
and unless specified otherwise, it is intended that this disclosure
includes both E and Z geometric isomers (e.g., cis or trans.)
Likewise, all possible isomers, as well as their racemic and
optically pure forms, and all tautomeric forms are also intended to
be included. The term "geometric isomer" refers to E or Z geometric
isomers (e.g., cis or trans) of an alkene double bond. The term
"positional isomer" refers to structural isomers around a central
ring, such as ortho-, meta-, and para-isomers around a benzene
ring.
[0114] The compounds presented herein may exist as tautomers. A
"tautomer" refers to a proton shift from one atom of a molecule to
another atom of the same molecule, accompanied by an isomerization
of an adjacent double bond. In bonding arrangements where
tautomerization is possible, a chemical equilibrium of the
tautomers will exist.
[0115] All tautomeric forms of the compounds disclosed herein are
contemplated. The exact ratio of the tautomers depends on several
factors, including temperature, solvent, and pH. Some examples of
tautomeric interconversions include:
##STR00003##
[0116] "Optional" or "optionally" means that a subsequently
described event or circumstance may or may not occur and that the
description includes instances when the event or circumstance
occurs and instances in which it does not. For example, "optionally
substituted aryl" means that the aryl radical may or may not be
substituted and that the description includes both substituted aryl
radicals and aryl radicals having no substitution.
[0117] "Pharmaceutically acceptable salt" includes both acid and
base addition salts. A pharmaceutically acceptable salt of any one
of the 3-phenylpropylamine derivative compound as described herein
is intended to encompass any and all pharmaceutically suitable salt
forms. Preferred pharmaceutically acceptable salts of the compounds
described herein are pharmaceutically acceptable acid addition
salts and pharmaceutically acceptable base addition salts.
[0118] "Pharmaceutically acceptable acid addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free bases, which are not biologically or
otherwise undesirable, and which are formed with inorganic acids
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, hydroiodic acid, hydrofluoric acid,
phosphorous acid, and the like. Also included are salts that are
formed with organic acids such as aliphatic mono- and dicarboxylic
acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,
alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic
acids, etc. and include, for example, acetic acid, trifluoroacetic
acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,
maleic acid, malonic acid, succinic acid, fumaric acid, tartaric
acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
salicylic acid, and the like. Exemplary salts thus include
sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates,
phosphates, monohydrogenphosphates, dihydrogenphosphates,
metaphosphates, pyrophosphates, chlorides, bromides, iodides,
acetates, trifluoroacetates, propionates, caprylates, isobutyrates,
oxalates, malonates, succinate suberates, sebacates, fumarates,
maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates,
dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,
phenylacetates, citrates, lactates, malates, tartrates,
methanesulfonates, and the like. Also contemplated are salts of
amino acids, such as arginates, gluconates, and galacturonates
(see, for example, Berge S. M. et al., "Pharmaceutical Salts,"
Journal of Pharmaceutical Science, 66:1-19 (1997), which is hereby
incorporated by reference in its entirety). Acid addition salts of
basic compounds may be prepared by contacting the free base forms
with a sufficient amount of the desired acid to produce the salt
according to methods and techniques with which a skilled artisan is
familiar.
[0119] "Pharmaceutically acceptable base addition salt" refers to
those salts that retain the biological effectiveness and properties
of the free acids, which are not biologically or otherwise
undesirable. These salts are prepared from addition of an inorganic
base or an organic base to the free acid. Pharmaceutically
acceptable base addition salts may be formed with metals or amines,
such as alkali and alkaline earth metals or organic amines. Salts
derived from inorganic bases include, but are not limited to,
sodium, potassium, lithium, ammonium, calcium, magnesium, iron,
zinc, copper, manganese, aluminum salts and the like. Salts derived
from organic bases include, but are not limited to, salts of
primary, secondary, and tertiary amines, substituted amines
including naturally occurring substituted amines, cyclic amines and
basic ion exchange resins, for example, isopropylamine,
trimethylamine, diethylamine, triethylamine, tripropylamine,
ethanolamine, diethanolamine, 2-dimethylaminoethanol,
2-diethylaminoethanol, dicyclohexylamine, lysine, arginine,
histidine, caffeine, procaine, N,N-dibenzylethylenediamine,
chloroprocaine, hydrabamine, choline, betaine, ethylenediamine,
ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine,
theobromine, purines, piperazine, piperidine, N-ethylpiperidine,
polyamine resins and the like. See Berge et al., supra.
[0120] "Non-retinoid compound" refers to any compound that is not a
retinoid. A retinoid is a compound that has a diterpene skeleton
possessing a trimethylcyclohexenyl ring and a polyene chain that
terminates in a polar end group. Examples of retinoids include
retinaldehyde and derived imine/hydrazide/oxime, retinol and any
derived ester, retinyl amine and any derived amide, retinoic acid
and any derived ester or amide. A non-retinoid compound can
comprise though not require an internal cyclic group (e.g.,
aromatic group). A non-retinoid compound can contain though not
require an alkoxyphenyl-linked amine group.
[0121] As used herein, "treatment" or "treating," or "palliating"
or "ameliorating" are used interchangeably herein. These terms
refers to an approach for obtaining beneficial or desired results
including but not limited to therapeutic benefit and/or a
prophylactic benefit. By "therapeutic benefit" is meant eradication
or amelioration of the underlying disorder being treated. Also, a
therapeutic benefit is achieved with the eradication or
amelioration of one or more of the physiological symptoms
associated with the underlying disorder such that an improvement is
observed in the patient, notwithstanding that the patient may still
be afflicted with the underlying disorder. For prophylactic
benefit, the compositions are optionally administered to a patient
at risk of developing a particular disease, or to a patient
reporting one or more of the physiological symptoms of a disease,
even though a diagnosis of this disease may not have been made.
[0122] "Prodrug" is meant to indicate a compound that may be
converted under physiological conditions or by solvolysis to a
biologically active compound described herein. Thus, the term
"prodrug" refers to a precursor of a biologically active compound
that is pharmaceutically acceptable. A prodrug is inactive when
administered to a subject, but is converted in vivo to an active
compound, for example, by hydrolysis. The prodrug compound often
offers advantages of solubility, tissue compatibility or delayed
release in a mammalian organism (see, e.g., Bundgard, H., Design of
Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
[0123] A discussion of prodrugs is provided in Higuchi, T., et al.,
"Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series,
Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward
B. Roche, American Pharmaceutical Association and Pergamon Press,
1987, both of which are incorporated in full by reference
herein.
[0124] The term "prodrug" is also meant to include any covalently
bonded carriers, which release the active compound in vivo when
such prodrug is administered to a mammalian subject. Prodrugs of an
active compound, as described herein, are optionally prepared by
modifying functional groups present in the active compound in such
a way that the modifications are cleaved, either in routine
manipulation or in vivo, to the parent active compound. Prodrugs
include compounds wherein a hydroxy, amino or mercapto group is
bonded to any group that, when the prodrug of the active compound
is administered to a mammalian subject, cleaves to form a free
hydroxy, free amino or free mercapto group, respectively. Examples
of prodrugs include, but are not limited to, acetate, formate and
benzoate derivatives of alcohol or amine functional groups in the
active compounds and the like.
[0125] Substituted 3-phenylpropylamine derivative compounds are
described herein that inhibit an isomerization step of the retinoid
cycle. These compounds and compositions comprising these compounds
are useful for inhibiting degeneration of retinal cells or for
enhancing retinal cell survival. The compounds described herein
are, therefore, be useful for treating ophthalmic diseases and
disorders, including retinal diseases or disorders, such as age
related macular degeneration and Stargardt's disease.
Substituted 3-Phenylpropylamine Derivative Compounds
[0126] In one embodiment is a compound of Formula (A), or a
pharmaceutically acceptable salt thereof:
##STR00004## [0127] wherein, [0128] X is selected from
*--O--C(R.sup.9).sub.2--, *--O--C(.dbd.O)--,
*--S--C(R.sup.9).sub.2--, *--S(O)--C(R.sup.9).sub.2--,
*--S(O).sub.2--C(R.sup.9).sub.2--, *--SO.sub.2(NR.sup.9)--,
*--NR.sup.9--C(R.sup.9).sub.2--, *--NR.sup.9--C(.dbd.O)--,
*--NR.sup.9--S(O).sub.2--, --C(R.sup.9).sub.2--C(R.sup.9).sub.2--,
*--C(.dbd.O)--C(R.sup.9).sub.2--, *--C(R.sup.9).sub.2--C(.dbd.O)--,
--C(R.sup.9).dbd.C(R.sup.9)--, *--C(.dbd.O)--N(R.sup.9)--,
*--C(.dbd.O)--O--, *--C(R.sup.9).sub.2--O--, and
*--C(R.sup.9).sub.2--NR.sup.9--; wherein the * indicates point of
attachment to the phenylene ring; [0129] Y is selected from
heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;
[0130] Z is --C(R)(R.sup.2)--; [0131] R.sup.1 and R.sup.2 are each
independently selected from hydrogen, halogen, alkyl, fluoroalkyl,
--OR.sup.9, --NR.sup.10R.sup.11 or carbocyclyl; or R.sup.1 and
R.sup.2 form an oxo; or optionally, R.sup.1 and R.sup.3 together
form a direct bond to provide a double bond; or optionally, R.sup.1
and R.sup.3 together form a direct bond, and R.sup.2 and R.sup.4
together form a direct bond to provide a triple bond; [0132]
R.sup.3 and R.sup.4 are each independently selected from hydrogen,
halogen, C.sub.1-C.sub.5 alkyl, fluoroalkyl, --OR.sup.9 or
--NR.sup.10R.sup.11; or R.sup.3 and R.sup.4 together form an oxo;
[0133] R.sup.5 and R.sup.6 are each independently selected from
hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl,
carbocyclyl or C-attached heterocyclyl; or R.sup.5 and R.sup.6
together with the carbon atom to which they are attached, form a
carbocyclyl or heterocyclyl; or R.sup.5 and R.sup.6 together form
an imino; [0134] R.sup.7 and R.sup.8 are each independently
selected from hydrogen, alkyl, carbocyclyl, --C(.dbd.O)R.sup.13,
SO.sub.2R.sup.13, CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or
R.sup.7 and R.sup.8, together with the nitrogen atom to which they
are attached, form an N-heterocyclyl; [0135] each R.sup.9
independently hydrogen or alkyl; [0136] each R.sup.10 and R.sup.11
is independently selected from hydrogen, alkyl, carbocyclyl,
heterocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or R.sup.10 and
R.sup.11 together with the nitrogen atom to which they are
attached, form an N-heterocyclyl; [0137] each R.sup.13 is
independently selected from alkyl, heteroalkyl, alkenyl, aryl,
aralkyl, carbocyclyl, heteroaryl or heterocyclyl; and [0138] each
R.sup.33 is independently selected from halogen, OR.sup.9, alkyl,
or fluoroalkyl, and n is 0, 1, 2, 3, or 4, [0139] with the
provision that the compound is not
##STR00005##
[0140] In one embodiment, R.sup.3 and R.sup.4 are both hydrogen. In
another embodiment, R.sup.5 and R.sup.6 are both hydrogen. In
another embodiment, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are
hydrogen. In another embodiment, R.sup.1 and R.sup.2 are both
hydrogen. In another embodiment, R.sup.1 is hydrogen and R.sup.2 is
--OH. In another embodiment, R.sup.1 and R.sup.2 together form an
oxo. In another embodiment, R.sup.7 and R.sup.8 are both hydrogen.
In another embodiment, R.sup.7 is hydrogen and R.sup.8 is
--C(.dbd.O)R.sup.13 or CO.sub.2R.sup.13. In a further embodiment,
R.sup.13 is an alkyl. In another further embodiment, wherein
R.sup.8 is CO.sub.2R.sup.13 and R.sup.13 is
##STR00006##
[0141] In another embodiment, R.sup.1, R.sup.3, and R.sup.4 are all
hydrogen, and R.sup.2 is --OH. In another embodiment, R.sup.3,
R.sup.4, R.sup.7 and R.sup.8 are all hydrogen. In another
embodiment, R.sup.1, R.sup.7, and R.sup.8 are all hydrogen, and
R.sup.2 is --OH. In another embodiment, R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are all hydrogen, and
R.sup.2 is --OH.
[0142] In another embodiment, Y is selected from:
##STR00007## ##STR00008## [0143] wherein R.sup.34 is selected from
hydrogen, alkyl, carbocyclyl, --C(.dbd.O)R.sup.13,
SO.sub.2R.sup.13, CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11;
[0144] each R.sup.35 is independently selected from hydrogen,
halogen, OR.sup.9, alkyl, or fluoroalkyl; [0145] each R.sup.10 and
R.sup.11 is independently selected from hydrogen, alkyl,
carbocyclyl, heterocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or R.sup.10 and
R.sup.11 together with the nitrogen atom to which they are
attached, form an N-heterocyclyl; [0146] each R.sup.13 is
independently selected from alkyl, heteroalkyl, alkenyl, aryl,
aralkyl, carbocyclyl, heteroaryl or heterocyclyl.
[0147] In another embodiment, Y is selected from:
##STR00009##
[0148] In another embodiment, Y is selected from:
##STR00010## [0149] wherein R.sup.34 is selected from hydrogen,
alkyl, carbocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11, [0150] each R.sup.10
and R.sup.11 is independently selected from hydrogen, alkyl,
carbocyclyl, heterocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or R.sup.10 and
R.sup.11 together with the nitrogen atom to which they are
attached, form an N-heterocyclyl; [0151] each R.sup.13 is
independently selected from alkyl, heteroalkyl, alkenyl, aryl,
aralkyl, carbocyclyl, heteroaryl or heterocyclyl.
[0152] In another embodiment, Y is selected from:
##STR00011## [0153] wherein R.sup.34 is selected from hydrogen,
alkyl, carbocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11, [0154] each R.sup.10
and R.sup.11 is independently selected from hydrogen, alkyl,
carbocyclyl, heterocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or R.sup.10 and
R.sup.11 together with the nitrogen atom to which they are
attached, form an N-heterocyclyl; [0155] each R.sup.13 is
independently selected from alkyl, heteroalkyl, alkenyl, aryl,
aralkyl, carbocyclyl, heteroaryl or heterocyclyl.
[0156] In another embodiment, X is selected from
*--O--C(R.sup.9).sub.2--, *--S(O).sub.2--C(R.sup.9).sub.2--,
*--SO.sub.2(NR.sup.9)--, *--NR.sup.9--C(R.sup.9).sub.2--,
*--NR.sup.9--C(.dbd.O)--, and *--NR.sup.9--S(O).sub.2--.
[0157] In another embodiment, X is selected from
--C(R.sup.9).sub.2--C(R.sup.9).sub.2--,
--C(R.sup.9).dbd.C(R.sup.9)--, *--C(.dbd.O)--N(R.sup.9)--,
*--C(R.sup.9).sub.2--O--, and *--C(R.sup.9).sub.2--NR.sup.9--.
[0158] In another embodiment, X is selected from
*--O--C(R.sup.9).sub.2--, or
--C(R.sup.9).sub.2--C(R.sup.9).sub.2--.
[0159] In a further embodiment is a compound of Formula (A1), or a
pharmaceutically acceptable salt thereof:
##STR00012## [0160] wherein, [0161] X is selected from
*--O--C(R.sup.9).sub.2--, *--O--C(.dbd.O)--,
*--S--C(R.sup.9).sub.2--, *--S(O)--C(R.sup.9).sub.2--,
*--S(O).sub.2--C(R.sup.9).sub.2--, *--SO.sub.2(NR.sup.9)--,
*--NR.sup.9--C(R.sup.9).sub.2--, *--NR.sup.9--C(.dbd.O)--,
*--NR.sup.9--S(O).sub.2--, --C(R.sup.9).sub.2--C(R.sup.9).sub.2--,
*--C(.dbd.O)--C(R.sup.9).sub.2--, *--C(R.sup.9).sub.2--C(.dbd.O)--,
--C(R.sup.9).dbd.C(R.sup.9)--, *--C(.dbd.O)--N(R.sup.9)--,
*--C(.dbd.O)--O--, *--C(R.sup.9).sub.2--O--, and
*--C(R.sup.9).sub.2--NR.sup.9--; wherein the * indicates point of
attachment to the phenylene ring; [0162] Y is selected from
heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl with
the provision that Y is not
[0162] ##STR00013## [0163] Z is --C(R.sup.1)(R.sup.2)--; [0164]
R.sup.1 and R.sup.2 are each independently selected from hydrogen,
halogen, alkyl, fluoroalkyl, --OR.sup.9, --NR.sup.10R.sup.11 or
carbocyclyl; or R.sup.1 and R.sup.2 form an oxo; or optionally,
R.sup.1 and R.sup.3 together form a direct bond to provide a double
bond; or optionally, R.sup.1 and R.sup.3 together form a direct
bond, and R.sup.2 and R.sup.4 together form a direct bond to
provide a triple bond; [0165] R.sup.3 and R.sup.4 are each
independently selected from hydrogen, halogen, C.sub.1-C.sub.5
alkyl, fluoroalkyl, --OR.sup.9 or --NR.sup.10R.sup.11; or R.sup.3
and R.sup.4 together form an oxo; [0166] R.sup.5 and R.sup.6 are
each independently selected from hydrogen, alkyl, alkenyl,
fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached
heterocyclyl; or R.sup.5 and R.sup.6 together with the carbon atom
to which they are attached, form a carbocyclyl or heterocyclyl; or
R.sup.5 and R.sup.6 together form an imino; [0167] R.sup.7 and
R.sup.8 are each independently selected from hydrogen, alkyl,
carbocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or R.sup.7 and
R.sup.8, together with the nitrogen atom to which they are
attached, form an N-heterocyclyl; [0168] each R.sup.9 independently
hydrogen or alkyl; [0169] each R.sup.10 and R.sup.11 is
independently selected from hydrogen, alkyl, carbocyclyl,
heterocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or R.sup.10 and
R.sup.11 together with the nitrogen atom to which they are
attached, form an N-heterocyclyl; [0170] each R.sup.13 is
independently selected from alkyl, heteroalkyl, alkenyl, aryl,
aralkyl, carbocyclyl, heteroaryl or heterocyclyl; and [0171] each
R.sup.33 is independently selected from halogen, OR.sup.9, alkyl,
or fluoroalkyl, and n is 0, 1, 2, 3, or 4.
[0172] In one embodiment, R.sup.3 and R.sup.4 are both hydrogen. In
another embodiment, R.sup.5 and R.sup.6 are both hydrogen. In
another embodiment, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are
hydrogen. In another embodiment, R.sup.1 and R.sup.2 are both
hydrogen. In another embodiment, R.sup.1 is hydrogen and R.sup.2 is
--OH. In another embodiment, R.sup.1 and R.sup.2 together form an
oxo. In another embodiment, R.sup.7 and R.sup.8 are both hydrogen.
In another embodiment, R.sup.7 is hydrogen and R.sup.8 is
--C(.dbd.O)R.sup.13 or CO.sub.2R.sup.13. In a further embodiment,
R.sup.13 is an alkyl. In another further embodiment, wherein
R.sup.8 is CO.sub.2R.sup.13 and R.sup.13 is
##STR00014##
[0173] In another embodiment, R.sup.1, R.sup.3, and R.sup.4 are all
hydrogen, and R.sup.2 is --OH. In another embodiment, R.sup.3,
R.sup.4, R.sup.7 and R.sup.8 are all hydrogen. In another
embodiment, R.sup.1, R.sup.7, and R.sup.8 are all hydrogen, and
R.sup.2 is --OH. In another embodiment, R.sup.1, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are all hydrogen, and
R.sup.2 is --OH.
[0174] In another embodiment, Y is selected from:
##STR00015## ##STR00016## ##STR00017## [0175] wherein R.sup.34 is
selected from hydrogen, alkyl, carbocyclyl, --C(.dbd.O)R.sup.13,
SO.sub.2R.sup.13CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11;
[0176] each R.sup.35 is independently selected from hydrogen,
halogen, OR.sup.9, alkyl, or fluoroalkyl; [0177] each R.sup.10 and
R.sup.11 is independently selected from hydrogen, alkyl,
carbocyclyl, heterocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or R.sup.10 and
R.sup.11 together with the nitrogen atom to which they are
attached, form an N-heterocyclyl; [0178] each R.sup.13 is
independently selected from alkyl, heteroalkyl, alkenyl, aryl,
aralkyl, carbocyclyl, heteroaryl or heterocyclyl.
[0179] In another embodiment, Y is selected from:
##STR00018##
[0180] In another embodiment, Y is selected from:
##STR00019## [0181] wherein R.sup.34 is selected from hydrogen,
alkyl, carbocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11, [0182] each R.sup.10
and R.sup.11 is independently selected from hydrogen, alkyl,
carbocyclyl, heterocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or R.sup.10 and
R.sup.11 together with the nitrogen atom to which they are
attached, form an N-heterocyclyl; [0183] each R.sup.13 is
independently selected from alkyl, heteroalkyl, alkenyl, aryl,
aralkyl, carbocyclyl, heteroaryl or heterocyclyl.
[0184] In another embodiment, Y is selected from:
##STR00020## [0185] wherein R.sup.34 is selected from hydrogen,
alkyl, carbocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11, [0186] each R.sup.10
and R.sup.11 is independently selected from hydrogen, alkyl,
carbocyclyl, heterocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or R.sup.10 and
R.sup.11 together with the nitrogen atom to which they are
attached, form an N-heterocyclyl; [0187] each R.sup.13 is
independently selected from alkyl, heteroalkyl, alkenyl, aryl,
aralkyl, carbocyclyl, heteroaryl or heterocyclyl.
[0188] In another embodiment, X is selected from
*--O--C(R.sup.9).sub.2--, *--S(O).sub.2--C(R.sup.9).sub.2--,
*--SO.sub.2(NR.sup.9)--, *--NR.sup.9--C(R.sup.9).sub.2--,
*--NR.sup.9--C(.dbd.O)--, and *--NR.sup.9--S(O).sub.2--.
[0189] In another embodiment, X is selected from
*--C(R.sup.9).sub.2--C(R.sup.9).sub.2--,
--C(R.sup.9).dbd.C(R.sup.9)--, *--C(.dbd.O)--N(R.sup.9)--,
*--C(R.sup.9).sub.2--O--, and *--C(R.sup.9).sub.2--NR.sup.9--.
[0190] In another embodiment, X is selected from
*--O--C(R.sup.9).sub.2--, or
--C(R.sup.9).sub.2--C(R.sup.9).sub.2--.
[0191] In a further embodiment is a compound of Formula (A2), or a
pharmaceutically acceptable salt thereof:
##STR00021## [0192] wherein, [0193] X is selected from
*--O--C(R.sup.9).sub.2--, *--O--C(.dbd.O)--,
*--S--C(R.sup.9).sub.2--, *--S(O)--C(R.sup.9).sub.2--,
*--S(O).sub.2--C(R.sup.9).sub.2--, *--SO.sub.2(NR.sup.9)--,
*--NR.sup.9--C(R.sup.9).sub.2--, *--NR.sup.9--C(.dbd.O)--,
*--NR.sup.9--S(O).sub.2--, --C(R.sup.9).sub.2--C(R.sup.9).sub.2--,
*--C(.dbd.O)--C(R.sup.9).sub.2--, *--C(R.sup.9).sub.2--C(.dbd.O)--,
--C(R.sup.9).dbd.C(R.sup.9)--, *--C(.dbd.O)--N(R.sup.9)--,
*--C(.dbd.O)--O--, *--C(R.sup.9).sub.2--O--, and
*--C(R.sup.9).sub.2--NR.sup.9--; wherein the * indicates point of
attachment to the phenylene ring; [0194] Y is selected from
heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;
[0195] Z is --O--; [0196] R.sup.3 and R.sup.4 are each
independently selected from hydrogen, halogen, C.sub.1-C.sub.5
alkyl, fluoroalkyl, --OR.sup.9 or --NR.sup.10R.sup.11; or R.sup.3
and R.sup.4 together form an oxo; [0197] R.sup.5 and R.sup.6 are
each independently selected from hydrogen, alkyl, alkenyl,
fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached
heterocyclyl; or R.sup.5 and R.sup.6 together with the carbon atom
to which they are attached, form a carbocyclyl or heterocyclyl; or
R.sup.5 and R.sup.6 together form an imino; [0198] R.sup.7 and
R.sup.8 are each independently selected from hydrogen, alkyl,
carbocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or R.sup.7 and
R.sup.8, together with the nitrogen atom to which they are
attached, form an N-heterocyclyl; [0199] each R.sup.9 independently
hydrogen or alkyl; [0200] each R.sup.10 and R.sup.11 is
independently selected from hydrogen, alkyl, carbocyclyl,
heterocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or R.sup.10 and
R.sup.11 together with the nitrogen atom to which they are
attached, form an N-heterocyclyl; [0201] each R.sup.13 is
independently selected from alkyl, heteroalkyl, alkenyl, aryl,
aralkyl, carbocyclyl, heteroaryl or heterocyclyl; and [0202] each
R.sup.33 is independently selected from halogen, OR.sup.9, alkyl,
or fluoroalkyl, and n is 0, 1, 2, 3, or 4, with the provision that
the compound is not
##STR00022##
[0203] In one embodiment, R.sup.3 and R.sup.4 are both hydrogen. In
another embodiment, R.sup.5 and R.sup.6 are both hydrogen. In
another embodiment, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are
hydrogen. In another embodiment, R.sup.7 and R.sup.8 are both
hydrogen. In another embodiment R.sup.7 is hydrogen and R.sup.8 is
--C(.dbd.O)R.sup.13 or CO.sub.2R.sup.13. In a further embodiment,
R.sup.13 is an alkyl. In a further embodiment, R.sup.8 is
CO.sub.2R.sup.13 and R.sup.13 is
##STR00023##
[0204] In another embodiment, R.sup.3, R.sup.4, R.sup.7 and R.sup.8
are all hydrogen. In another embodiment, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, and R.sup.8 are all hydrogen.
[0205] In another embodiment, Y is selected from:
##STR00024## ##STR00025## [0206] wherein R.sup.34 is selected from
hydrogen, alkyl, carbocyclyl, --C(.dbd.O)R.sup.13,
SO.sub.2R.sup.13, CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11;
[0207] each R.sup.35 is independently selected from hydrogen,
halogen, OR.sup.9, alkyl, or fluoroalkyl; [0208] each R.sup.10 and
R.sup.11 is independently selected from hydrogen, alkyl,
carbocyclyl, heterocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or R.sup.10 and
R.sup.11 together with the nitrogen atom to which they are
attached, form an N-heterocyclyl; [0209] each R.sup.13 is
independently selected from alkyl, heteroalkyl, alkenyl, aryl,
aralkyl, carbocyclyl, heteroaryl or heterocyclyl.
[0210] In another embodiment, Y is selected from:
##STR00026##
[0211] In another embodiment, Y is selected from:
##STR00027## [0212] wherein R.sup.34 is selected from hydrogen,
alkyl, carbocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11, [0213] each R.sup.10
and R.sup.11 is independently selected from hydrogen, alkyl,
carbocyclyl, heterocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or R.sup.10 and
R.sup.11 together with the nitrogen atom to which they are
attached, form an N-heterocyclyl; [0214] each R.sup.13 is
independently selected from alkyl, heteroalkyl, alkenyl, aryl,
aralkyl, carbocyclyl, heteroaryl or heterocyclyl.
[0215] In another embodiment, Y is selected from:
##STR00028## [0216] wherein R.sup.34 is selected from hydrogen,
alkyl, carbocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11, [0217] each R.sup.10
and R.sup.11 is independently selected from hydrogen, alkyl,
carbocyclyl, heterocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or R.sup.10 and
R.sup.11 together with the nitrogen atom to which they are
attached, form an N-heterocyclyl; [0218] each R.sup.13 is
independently selected from alkyl, heteroalkyl, alkenyl, aryl,
aralkyl, carbocyclyl, heteroaryl or heterocyclyl.
[0219] In another embodiment, X is selected from
*--O--C(R.sup.9).sub.2--, *--S(O).sub.2--C(R.sup.9).sub.2--,
*--SO.sub.2(NR.sup.9)--, *--NR.sup.9--C(R.sup.9).sub.2--,
*--NR.sup.9--C(.dbd.O)--, and *--NR.sup.9--S(O).sub.2--.
[0220] In another embodiment, X is selected from
--C(R.sup.9).sub.2--C(R.sup.9).sub.2--,
--C(R.sup.9).dbd.C(R.sup.9)--, *--C(.dbd.O)--N(R.sup.9)--,
*--C(R.sup.9).sub.2--O--, and *--C(R.sup.9).sub.2--NR.sup.9--.
[0221] In another embodiment, X is selected from
*--O--C(R.sup.9).sub.2--, or
--C(R.sup.9).sub.2--C(R.sup.9).sub.2--.
[0222] In a further embodiment is a compound Formula (A3), or a
pharmaceutically acceptable salt thereof:
##STR00029## [0223] wherein, [0224] X is selected from
*--O--C(R.sup.9).sub.2--, *--O--C(.dbd.O)--,
*--S--C(R.sup.9).sub.2--, *--S(O)--C(R.sup.9).sub.2--,
*--S(O).sub.2--C(R.sup.9).sub.2--, *--SO.sub.2(NR.sup.9)--,
*--NR.sup.9--C(R.sup.9).sub.2--, *--NR.sup.9--C(.dbd.O)--,
*--NR.sup.9--S(O).sub.2--, --C(R.sup.9).sub.2--C(R.sup.9).sub.2--,
*--C(.dbd.O)--C(R.sup.9).sub.2--, *--C(R.sup.9).sub.2--C(.dbd.O)--,
--C(R.sup.9).dbd.C(R.sup.9)--, *--C(.dbd.O)--N(R.sup.9)--,
*--C(.dbd.O)--O--, *--C(R.sup.9).sub.2--O--, and
*--C(R.sup.9).sub.2--NR.sup.9--; wherein the * indicates point of
attachment to the phenylene ring; [0225] Y is
[0225] ##STR00030## [0226] Z is --C(R.sup.1)(R.sup.2)-- or --O--;
[0227] R.sup.1 and R.sup.2 are each independently selected from
hydrogen, halogen, alkyl, fluoroalkyl, --OR.sup.9,
--NR.sup.10R.sup.11 or carbocyclyl; or R.sup.1 and R.sup.2 form an
oxo; or optionally, R.sup.1 and R.sup.3 together form a direct bond
to provide a double bond; or optionally, R.sup.1 and R.sup.3
together form a direct bond, and R.sup.2 and R.sup.4 together form
a direct bond to provide a triple bond; [0228] R.sup.3 and R.sup.4
are each independently selected from hydrogen, halogen,
C.sub.1-C.sub.5 alkyl, fluoroalkyl, --OR.sup.9 or
--NR.sup.10R.sup.11; or R.sup.3 and R.sup.4 together form an oxo;
[0229] R.sup.5 and R.sup.6 are each independently selected from
hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl,
carbocyclyl or C-attached heterocyclyl; or R.sup.5 and R.sup.6
together with the carbon atom to which they are attached, form a
carbocyclyl or heterocyclyl; or R.sup.5 and R.sup.6 together form
an imino; [0230] R.sup.7 and R.sup.8 are each independently
selected from hydrogen, alkyl, carbocyclyl, --C(.dbd.O)R.sup.13,
SO.sub.2R.sup.13, CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or
R.sup.7 and R.sup.8, together with the nitrogen atom to which they
are attached, form an N-heterocyclyl; [0231] each R.sup.9
independently hydrogen or alkyl; [0232] each R.sup.10 and R.sup.11
is independently selected from hydrogen, alkyl, carbocyclyl,
heterocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or R.sup.10 and
R.sup.11 together with the nitrogen atom to which they are
attached, form an N-heterocyclyl; [0233] each R.sup.13 is
independently selected from alkyl, heteroalkyl, alkenyl, aryl,
aralkyl, carbocyclyl, heteroaryl or heterocyclyl; and [0234] each
R.sup.33 is independently selected from halogen, OR.sup.9, alkyl,
or fluoroalkyl, and n is 0, 1, 2, 3, or 4.
[0235] In one embodiment, R.sup.3 and R.sup.4 are both hydrogen. In
another embodiment, R.sup.5 and R.sup.6 are both hydrogen. In
another embodiment, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are
hydrogen. In another embodiment, R.sup.7 and R.sup.8 are both
hydrogen. In another embodiment, R.sup.7 is hydrogen and R.sup.8 is
--C(.dbd.O)R.sup.13 or CO.sub.2R.sup.13. In a further embodiment,
R.sup.13 is an alkyl. In a further embodiment, R.sup.8 is
CO.sub.2R.sup.13 and R.sup.13 is
##STR00031##
[0236] In another embodiment, R.sup.3, R.sup.4, R.sup.7 and R.sup.8
are all hydrogen.
[0237] In another embodiment, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, and R.sup.8 are all hydrogen.
[0238] In another embodiment, X is selected from
*--O--C(R.sup.9).sub.2--, *--S(O).sub.2--C(R.sup.9).sub.2--,
*--SO.sub.2(NR.sup.9)--, *--NR.sup.9--C(R.sup.9).sub.2--,
*--NR.sup.9--C(.dbd.O)--, and *--NR.sup.9--S(O).sub.2--.
[0239] In another embodiment, X is selected from
--C(R.sup.9).sub.2--C(R.sup.9).sub.2--,
--C(R.sup.9).dbd.C(R.sup.9)--, *--C(.dbd.O)--N(R.sup.9)--,
*--C(R.sup.9).sub.2--O--, and *--C(R.sup.9).sub.2--NR.sup.9--.
[0240] In another embodiment, X is selected from
*--O--C(R.sup.9).sub.2--, or
--C(R.sup.9).sub.2--C(R.sup.9).sub.2--.
[0241] In a further embodiment is a compound of Formula (A4), or a
pharmaceutically acceptable salt thereof:
##STR00032## [0242] wherein, [0243] X is selected from
*--O--C(R.sup.9).sub.2--, *--O--C(.dbd.O)--,
*--S--C(R.sup.9).sub.2--, *--S(O)--C(R.sup.9).sub.2--,
*--S(O).sub.2--C(R.sup.9).sub.2--, *--SO.sub.2(NR.sup.9)--,
*--NR.sup.9--C(R.sup.9).sub.2--, *--NR.sup.9--C(.dbd.O)--,
*--NR.sup.9--S(O).sub.2--, --C(R.sup.9).sub.2--C(R.sup.9).sub.2--,
*--C(.dbd.O)--C(R.sup.9).sub.2--, *--C(R.sup.9).sub.2--C(.dbd.O)--,
--C(R.sup.9).dbd.C(R.sup.9)--, *--C(.dbd.O)--N(R.sup.9)--,
*--C(.dbd.O)--O--, *--C(R.sup.9).sub.2--O--, and
*--C(R.sup.9).sub.2--NR.sup.9--; wherein the * indicates point of
attachment to the phenylene ring; [0244] Y is
[0244] ##STR00033## [0245] Z is --C(R.sup.1)(R.sup.2)-- or --O--;
[0246] R.sup.1 and R.sup.2 are each independently selected from
hydrogen, halogen, alkyl, fluoroalkyl, --OR.sup.9,
--NR.sup.10R.sup.11 or carbocyclyl; or R.sup.1 and R.sup.2 form an
oxo; or optionally, R.sup.1 and R.sup.3 together form a direct bond
to provide a double bond; or optionally, R.sup.1 and R.sup.3
together form a direct bond, and R.sup.2 and R.sup.4 together form
a direct bond to provide a triple bond; [0247] R.sup.3 and R.sup.4
are each independently selected from hydrogen, halogen,
C.sub.1-C.sub.5 alkyl, fluoroalkyl, --OR.sup.9 or
--NR.sup.10R.sup.11; or R.sup.3 and R.sup.4 together form an oxo;
[0248] R.sup.5 and R.sup.6 are each independently selected from
hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl,
carbocyclyl or C-attached heterocyclyl; or R.sup.5 and R.sup.6
together with the carbon atom to which they are attached, form a
carbocyclyl or heterocyclyl; or R.sup.5 and R.sup.6 together form
an imino; [0249] R.sup.7 and R.sup.8 are each independently
selected from hydrogen, alkyl, carbocyclyl, --C(.dbd.O)R.sup.13,
SO.sub.2R.sup.13, CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or
R.sup.7 and R.sup.8, together with the nitrogen atom to which they
are attached, form an N-heterocyclyl; [0250] each R.sup.9
independently hydrogen or alkyl; [0251] each R.sup.10 and R.sup.11
is independently selected from hydrogen, alkyl, carbocyclyl,
heterocyclyl, --C(.dbd.O)R.sup.13, SO.sub.2R.sup.13,
CO.sub.2R.sup.13 or SO.sub.2NR.sup.10R.sup.11; or R.sup.10 and
R.sup.11 together with the nitrogen atom to which they are
attached, form an N-heterocyclyl; [0252] each R.sup.13 is
independently selected from alkyl, heteroalkyl, alkenyl, aryl,
aralkyl, carbocyclyl, heteroaryl or heterocyclyl; and [0253] each
R.sup.33 is independently selected from halogen, OR.sup.9, alkyl,
or fluoroalkyl, and n is 0, 1, 2, 3, or 4.
[0254] In one embodiment, R.sup.3 and R.sup.4 are both hydrogen. In
another embodiment, R.sup.5 and R.sup.6 are both hydrogen. In
another embodiment, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are
hydrogen. In another embodiment, R.sup.7 and R.sup.8 are both
hydrogen. In another embodiment, R.sup.7 is hydrogen and R.sup.8 is
--C(.dbd.O)R.sup.13 or CO.sub.2R.sup.13. In a further embodiment,
R.sup.13 is an alkyl. In a further embodiment, R.sup.8 is
CO.sub.2R.sup.13 and R.sup.13 is
##STR00034##
[0255] In another embodiment, R.sup.3, R.sup.4, R.sup.7 and R.sup.8
are all hydrogen.
[0256] In another embodiment, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, and R.sup.8 are all hydrogen.
[0257] In another embodiment, X is selected from
*--O--C(R.sup.9).sub.2--, *--S(O).sub.2--C(R.sup.9).sub.2--,
*--SO.sub.2(NR.sup.9)--, *--NR.sup.9--C(R.sup.9).sub.2--,
*--NR.sup.9--C(.dbd.O)--, and *--NR.sup.9--S(O).sub.2--.
[0258] In another embodiment, X is selected from
--C(R.sup.9).sub.2--C(R.sup.9).sub.2--,
--C(R.sup.9).dbd.C(R.sup.9)--, *--C(.dbd.O)--N(R.sup.9)--,
*--C(R.sup.9).sub.2--O--, and *--C(R.sup.9).sub.2--NR.sup.9--.
[0259] In another embodiment, X is selected from
*--O--C(R.sup.9).sub.2--, or
--C(R.sup.9).sub.2--C(R.sup.9).sub.2--.
[0260] One embodiment provides a compound of Formula (B), or a
pharmaceutically acceptable salt thereof:
##STR00035##
wherein, [0261] X is selected from *--O--CH.sub.2--,
*--S--CH.sub.2--, *--S(O)--CH.sub.2--, *--S(O).sub.2--CH.sub.2--,
*--NH--CH.sub.2--, *--NH--C(.dbd.O)--, --CH.sub.2--CH.sub.2--, or
--CH.dbd.CH--; wherein the * indicates point of attachment to the
phenylene ring; [0262] Y is selected from heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl; [0263] Z is
--C(H)(H)--C(H)(H)--, *--C(H)(OH)--C(H)(H)--,
*--C(.dbd.O)--C(H)(H)--, --CH.dbd.CH--, --C.ident.C--; wherein the
* indicates point of attachment to the phenylene ring; [0264]
R.sup.1 and R.sup.2 are each independently selected from hydrogen,
C.sub.1-C.sub.4 alkyl, --C(.dbd.O)R.sup.3; [0265] R.sup.3 is
selected from alkyl, alkoxy, or --OCH.sub.2OC(O)R.sup.4, wherein
R.sup.4 is an alkyl or alkoxy; [0266] with the provision that the
compound is not
##STR00036##
[0267] Another embodiment provides the compound of Formula (B),
wherein Z is --C(H)(OH)--C(H)(H)--. Another embodiment provides the
compound of Formula (B), wherein R.sup.1 and R.sup.2 are both
hydrogen. Another embodiment provides the compound of Formula (B),
wherein R.sup.1 is hydrogen and R.sup.2 is C.sub.1-C.sub.4 alkyl.
Another embodiment provides the compound of Formula (B), wherein
R.sup.1 is hydrogen and R.sup.2 is --C(.dbd.O)R.sup.3. Another
embodiment provides the compound of Formula (B), wherein X is
selected from *--O--CH.sub.2--, --CH.sub.2--CH.sub.2--, or
--CH.dbd.CH--. Another embodiment provides the compound of Formula
(B), wherein X is selected from *--O--CH.sub.2--, or
--CH.sub.2--CH.sub.2--. Another embodiment provides the compound of
Formula (B), wherein X is *--O--CH.sub.2--.
[0268] Another embodiment provides the compound of Formula (B),
wherein Y is selected from:
##STR00037##
[0269] Another embodiment provides the compound of Formula (B),
wherein Y is selected from:
##STR00038##
[0270] Another embodiment provides the compound of Formula (B),
wherein Y is selected from:
##STR00039##
[0271] Another embodiment provides the compound of Formula (B),
wherein Y is selected from:
##STR00040## ##STR00041##
[0272] Another embodiment provides the compound of Formula (B),
wherein Y is selected from:
##STR00042## ##STR00043##
[0273] One embodiment provides a compound of Formula (B1), or a
pharmaceutically acceptable salt thereof:
##STR00044##
wherein, [0274] X is selected from *--O--CH.sub.2--,
*--S--CH.sub.2--, *--S(O)--CH.sub.2--, *--S(O).sub.2--CH.sub.2--,
*--NH--CH.sub.2--, *--NH--C(.dbd.O)--, --CH.sub.2--CH.sub.2--, or
--CH.dbd.CH--; wherein the * indicates point of attachment to the
phenylene ring; [0275] Y is selected from heterocyclyl,
heterocyclylalkyl, heteroaryl or heteroarylalkyl; [0276] Z is
--C(H)(H)--C(H)(H)--, *--C(H)(OH)--C(H)(H)--,
*--C(.dbd.O)--C(H)(H)--, --CH.dbd.CH--, --C.ident.C--; wherein the
* indicates point of attachment to the phenylene ring; [0277]
R.sup.1 and R.sup.2 are each independently selected from hydrogen,
C.sub.1-C.sub.4 alkyl, --C(.dbd.O)R.sup.3; [0278] R.sup.3 is
selected from alkyl, alkoxy, or --OCH.sub.2OC(O)R.sup.4, wherein
R.sup.4 is an alkyl or alkoxy; [0279] with the provision that Y is
not
##STR00045##
[0280] Another embodiment provides the compound of Formula (B1),
wherein Z is --C(H)(OH)--C(H)(H)--. Another embodiment provides the
compound of Formula (B1), wherein R.sup.1 and R.sup.2 are both
hydrogen. Another embodiment provides the compound of Formula (B1),
wherein R.sup.1 is hydrogen and R.sup.2 is C.sub.1-C.sub.4 alkyl.
Another embodiment provides the compound of Formula (B1), wherein
R.sup.1 is hydrogen and R.sup.2 is --C(.dbd.O)R.sup.3. Another
embodiment provides the compound of Formula (B1), wherein X is
selected from *--O--CH.sub.2--, --CH.sub.2--CH.sub.2--, or
--CH.dbd.CH--. Another embodiment provides the compound of Formula
(B1), wherein X is selected from *--O--CH.sub.2--, or
--CH.sub.2--CH.sub.2--. Another embodiment provides the compound of
Formula (B1), wherein X is *--O--CH.sub.2--.
[0281] Another embodiment provides the compound of Formula (B1),
wherein Y is selected from:
##STR00046##
[0282] Another embodiment provides the compound of Formula (B1),
wherein Y is selected from:
##STR00047##
[0283] Another embodiment provides the compound of Formula (B1),
wherein Y is selected from:
##STR00048##
[0284] Another embodiment provides the compound of Formula (B1),
wherein Y is selected from:
##STR00049## ##STR00050##
[0285] Another embodiment provides the compound of Formula (B1),
wherein Y is selected from:
##STR00051## ##STR00052##
[0286] One embodiment provides a compound of Formula (B2), or a
pharmaceutically acceptable salt thereof:
##STR00053##
wherein, [0287] X is selected from *--O--CH.sub.2--,
*--S--CH.sub.2--, *--S(O)--CH.sub.2--, *--S(O).sub.2--CH.sub.2--,
*--NH--CH.sub.2--, *--NH--C(.dbd.O)--, --CH.sub.2--CH.sub.2--, or
--CH.dbd.CH--; wherein the * indicates point of attachment to the
phenylene ring; [0288] Y is
[0288] ##STR00054## [0289] Z is --C(H)(H)--C(H)(H)--,
*--C(H)(OH)--C(H)(H)--, *--C(.dbd.O)--C(H)(H)--, --CH.dbd.CH--,
--C.ident.C--; wherein the * indicates point of attachment to the
phenylene ring; [0290] R.sup.1 and R.sup.2 are each independently
selected from hydrogen, C.sub.1-C.sub.4 alkyl, --C(.dbd.O)R.sup.3;
and [0291] R.sup.3 is selected from alkyl, alkoxy, or
--OCH.sub.2OC(O)R.sup.4, wherein R.sup.4 is an alkyl or alkoxy.
[0292] Another embodiment provides the compound of Formula (B2),
wherein Z is --C(H)(OH)--C(H)(H)--. Another embodiment provides the
compound of Formula (B2), wherein R.sup.1 and R.sup.2 are both
hydrogen. Another embodiment provides the compound of Formula (B2),
wherein R.sup.1 is hydrogen and R.sup.2 is C.sub.1-C.sub.4 alkyl.
Another embodiment provides the compound of Formula (B2), wherein
R.sup.1 is hydrogen and R.sup.2 is --C(.dbd.O)R.sup.3. Another
embodiment provides the compound of Formula (B2), wherein X is
selected from *--O--CH.sub.2--, --CH.sub.2--CH.sub.2--, or
--CH.dbd.CH--. Another embodiment provides the compound of Formula
(B2), wherein X is selected from *--O--CH.sub.2--, or
--CH.sub.2--CH.sub.2--. Another embodiment provides the compound of
Formula (B2), wherein X is *--O--CH.sub.2--. Another embodiment
provides the compound of Formula (B2), wherein Y is
##STR00055##
Another embodiment provides the compound of Formula (B2), wherein Y
is
##STR00056##
[0293] One embodiment provides a compound of Formula (B3), or a
pharmaceutically acceptable salt thereof:
##STR00057##
wherein, [0294] X is selected from *--O--CH.sub.2--,
*--S--CH.sub.2--, *--S(O)--CH.sub.2--, *--S(O).sub.2--CH.sub.2--,
*--NH--CH.sub.2--, *--NH--C(.dbd.O)--, --CH.sub.2--CH.sub.2--, or
--CH.dbd.CH--; wherein the * indicates point of attachment to the
phenylene ring; [0295] Y is
[0295] ##STR00058## [0296] Z is --C(H)(H)--C(H)(H)--,
*--C(H)(OH)--C(H)(H)--, *--C(.dbd.O)--C(H)(H)--, --CH.dbd.CH--,
--C.ident.C--; wherein the * indicates point of attachment to the
phenylene ring; [0297] R.sup.1 and R.sup.2 are each independently
selected from hydrogen, C.sub.1-C.sub.4 alkyl, --C(.dbd.O)R.sup.3;
and [0298] R.sup.3 is selected from alkyl, alkoxy, or
--OCH.sub.2OC(O)R.sup.4, wherein R.sup.4 is an alkyl or alkoxy.
[0299] Another embodiment provides the compound of Formula (B3),
wherein Z is *--C(H)(OH)--C(H)(H)--. Another embodiment provides
the compound of Formula (B3), wherein R.sup.1 and R.sup.2 are both
hydrogen. Another embodiment provides the compound of Formula (B3),
wherein R.sup.1 is hydrogen and R.sup.2 is C.sub.1-C.sub.4 alkyl.
Another embodiment provides the compound of Formula (B3), wherein
R.sup.1 is hydrogen and R.sup.2 is --C(.dbd.O)R.sup.3. Another
embodiment provides the compound of Formula (B3), wherein X is
selected from *--O--CH.sub.2--, --CH.sub.2--CH.sub.2--, or
--CH.dbd.CH--. Another embodiment provides the compound of Formula
(B3), wherein X is selected from *--O--CH.sub.2--, or
--CH.sub.2--CH.sub.2--. Another embodiment provides the compound of
Formula (B3), wherein X is *--O--CH.sub.2--.
[0300] One embodiment provides a compound of Formula (C), or a
pharmaceutically acceptable salt thereof:
##STR00059##
wherein, A is selected from --O-- or --CH.sub.2--;
Y is
##STR00060##
[0301] R.sup.A is OH, R.sup.B is H; or optionally, R.sup.A and
R.sup.B together form an oxo; R.sup.1 and R.sup.2 are each
independently selected from hydrogen, C.sub.1-C.sub.4 alkyl,
--C(.dbd.O)R.sup.3; and R.sup.3 is selected from alkyl, alkoxy, or
--OCH.sub.2OC(O)R.sup.4, wherein R.sup.4 is an alkyl or alkoxy.
[0302] Another embodiment provides the compound of Formula (C),
wherein A is --O--. Another embodiment provides the compound of
Formula (C), wherein A is --CH.sub.2--. Another embodiment provides
the compound of Formula (C), wherein R.sup.A is OH and R.sup.B is
H. Another embodiment provides the compound of Formula (C), wherein
R.sup.1 and R.sup.2 are both hydrogen. Another embodiment provides
the compound of Formula (C), wherein R.sup.1 is hydrogen and
R.sup.2 is C.sub.1-C.sub.4 alkyl. Another embodiment provides the
compound of Formula (C), wherein R.sup.1 is hydrogen and R.sup.2 is
--C(.dbd.O)R.sup.3. Another embodiment provides the compound of
Formula (C), wherein Y is
##STR00061##
Another embodiment provides the compound of Formula (C), wherein Y
is
##STR00062##
Another embodiment provides the compound of Formula (C), wherein Y
is
##STR00063##
and R.sup.1 and R.sup.2 are both hydrogen. Another embodiment
provides the compound of Formula (C), wherein Y is
##STR00064##
A is --O--, and R.sup.1 and R.sup.2 are both hydrogen. Another
embodiment provides the compound of Formula (C), wherein Y is
##STR00065##
A is --O--, R.sup.A is OH, R.sup.B is H, and R.sup.1 and R.sup.2
are both hydrogen.
[0303] Certain compounds disclosed herein have the structures shown
in Table 1. The example number refers to a specific chemical
synthesis Example herein that describes the preparation of the
compound having the structure and name shown.
TABLE-US-00001 TABLE 1 Example Structure Name 1 ##STR00066##
(R)-3-Amino-1-(3-((tetrahydro-2H- pyran-4-
yl)methoxy)phenyl)propan-1-ol 2 ##STR00067##
3-Amino-1-(3-((tetrahydro-2H- pyran-4-
yl)methoxy)phenyl)propan-1-ol 3 ##STR00068##
(1R)-3-Amino-1-(3-((tetrahydro- 2H-pyran-3-
yl)methoxy)phenyl)propan-1-ol 4 ##STR00069##
(R)-3-Amino-1-(3-(pyridin-4- ylmethoxy)phenyl)propan-1-ol 5
##STR00070## (R)-3-Amino-1-(3-(pyridin-3-
ylmethoxy)phenyl)propan-1-ol 6 ##STR00071##
(R)-3-Amino-1-(3-(pyridin-2- ylmethoxy)phenyl)propan-1-ol 7
##STR00072## (1R)-3-Amino-1-(3-((tetrahydro- 2H-thiopyran-3-
yl)methoxy)phenyl)propan-1-ol 8 ##STR00073##
(R)-3-Amino-1-(3-((tetrahydro-2H- thiopyran-4-
yl)methoxy)phenyl)propan-1-ol 9 ##STR00074## (R)-4-((3-(3-Amino-1-
hydroxypropyl)- phenoxy)methyl)tetrahydro-2H- thiopyran 1,1-dioxide
10 ##STR00075## 3-((3-((R)-3-Amino-1- hydroxypropyl)phenoxy)methyl)
tetrahydro-2H-thiopyran 1,1-dioxide 11 ##STR00076##
(R)-1-(4-((3-(3-amino-1- hydroxypropyl)phenoxy)methyl)
piperidin-1-yl)ethanaone 12 ##STR00077## (R)-3-Amino-1-(3-((6-
methylpyridin-2- yl)methoxy)phenyl)propan-1-ol 13 ##STR00078##
(1R)-3-Amino-1-(3-((2,3-dihydro- benzofuran-2-
yl)methoxy)phenyl)propan-1-ol 14 ##STR00079## (1R)-3-Amino-1-(3-
((tetrahydrofuran-2- yl)methoxy)phenyl)propan-1-ol 15 ##STR00080##
(R)-3-Amino-1-(3-(piperidin-4- ylmethoxy)phenyl)propan-1-ol 16
##STR00081## (R)-3-Amino-1-(3-((1- methylpiperidin-4-
yl)methoxy)phenyl)propan-1-ol 17 ##STR00082## (R)-Methyl
4-((3-(3-amino-1- hydroxypropyl)phenoxy)methyl)
piperidine-1-carboxylate 18 ##STR00083##
(R)-3-Amino-1-(3-(pyrimidin-5- ylmethoxy)phenyl)propan-1-ol 19
##STR00084## (1R)-3-Amino-1-(3-(chroman-3-
ylmethoxy)phenyl)propan-1-ol 20 ##STR00085## (R)-4-((3-(3-Amino-1-
hydroxypropyl)phenoxy)methyl) tetrahydro-2H-thiopyran 1-oxide 21
##STR00086## (R)-3-Amino-1-(3-(((S)-1- methylpyrrolidin-2-
yl)methoxy)phenyl)propan-1-ol 22 ##STR00087##
(R)-3-Amino-1-(3-((S)-pyrrolidin- 2-ylmethoxy)phenyl)propan-1-ol 23
##STR00088## (R)-3-Amino-1-(3-(((tetrahydro- 2H-pyran-4-
yl)methyl)amino)phenyl)propan-1- ol 24 ##STR00089##
3-Amino-1-(3-(((1,1- dioxidotetrahydro-2H-thiopyran-4-
yl)methyl)sulfonyl)phenyl)propan- 1-one 25 ##STR00090##
3-Amino-1-(3-(((tetrahydro-2H- pyran-3-
yl)methyl)sulfonyl)phenyl)propan- 1-one 26 ##STR00091##
3-Amino-1-(3-(((tetrahydro-2H- pyran-4-yl)
methyl)sulfonyl)phenyl)propan-1- one 27 ##STR00092##
3-((3-((R)-3-Amino-1- hydroxypropyl)phenoxy)methyl) piperidin-2-one
28 ##STR00093## (R)-3-Amino-1-(3-(thiophen-2-
ylmethoxy)phenyl)propan-1-ol 29 ##STR00094##
(R)-3-Amino-1-(3-(thiophen-3- ylmethoxy)phenyl)propan-1-ol 30
##STR00095## (R)-tert-Butyl 4-((3-(3-amino-1-
hydroxypropyl)phenoxy)methyl) piperidine-1-carboxylate 31
##STR00096## (E)-3-(3-((Tetrahydro-2H-pyran-4-
yl)methoxy)phenyl)prop-2-en-1- amine 32 ##STR00097##
3-(3-((Tetrahydro-2H-pyran-4- yl)methoxy)phenyl)propan-1- amine 33
##STR00098## (R)-3-(Methylamino)-1-(3- ((tetrahydro-2H-pyran-4-
yl)methoxy)phenyl)propan-1-ol 34 ##STR00099##
1-((S)-2-((3-((R)-3-Amino-1- hydroxypropyl)phenoxy)methyl)
pyrrolidin-1-yl)ethanone 35 ##STR00100## 5-((3-((R)-3-Amino-1-
hydroxypropyl)phenoxy)methyl) piperidin-2-one 36 ##STR00101##
4-((3-((R)-3-Amino-1- hydroxypropyl)phenoxy)methyl) piperidin-2-one
37 ##STR00102## 6-((3-((R)-3-Amino-1-
hydroxypropyl)phenoxy)methyl)- 1-methylpiperidin-2-one 38
##STR00103## 5-((3-((R)-3-Amino-1- hydroxypropyl)phenoxy)methyl)
pyrrolidin-2-one 39 ##STR00104## 5-((3-((R)-3-Amino-1-
hydroxypropyl)phenoxy)methyl)- 1-methylpyrrolidin-2-one 40
##STR00105## N-(3-(3-Amino-1- hydroxypropyl)phenyl)-6-
oxopiperidine-3-carboxamide 41 ##STR00106## 3-((3-((R)-3-Amino-1-
hydroxypropyl)phenoxy)methyl)- 1,2-thiazinane 1,1-dioxide 42
##STR00107## (R)-1-(3-((1H-Pyrrol-2- yl)methoxy)phenyl)-3-
aminopropan-1-ol 43 ##STR00108## (R)-3-Amino-1-(3-(furan-2-
ylmethoxy)phenyl)propan-1-ol 44 ##STR00109## (R)-3-Amino-1-(3-((1-
(methylsulfonyl)piperidin-4- yl)methoxy)phenyl)propan-1-ol 45
##STR00110## (R)-1-(3-(((1H-Indol-6- yl)methyl)amino)phenyl)-3-
aminopropan-1-ol 46 ##STR00111## (R)-1-(3-((1H-Indol-6-
yl)methoxy)phenyl)-3- aminopropan-1-ol 47 ##STR00112##
(R)-3-Amino-1-(3-(benzofuran-2- ylmethoxy)phenyl)propan-1-ol 48
##STR00113## 3-(3-((Tetrahydro-2H-pyran-4-
yl)methoxy)phenyl)prop-2-yn-1- amine 49 ##STR00114##
3-Amino-1-(3-(((tetrahydro-2H- pyran-4-
yl)methyl)thio)phenyl)propan-1-ol 50 ##STR00115##
3-Amino-1-(3-(((tetrahydro-2H- pyran-4-
yl)methyl)sulfonyl)phenyl)propan- 1-ol 51 ##STR00116##
3-Amino-1-(3-(2-(tetrahydro-2H- pyran-4-yl)ethyl)phenyl)propan-1-
ol 52 ##STR00117## 3-Amino-1-(3-(2-(pyridin-3-
yl)ethyl)phenyl)propan-1-ol 53 ##STR00118##
3-Amino-1-(3-(2-(thiophen-3- yl)ethyl)phenyl)propan-1-ol 54
##STR00119## (E)-1-(3-(3-Amino-1-
hydroxypropyl)styryl)pyrrolidin-2- one 55 ##STR00120##
1-(3-(3-Amino-1- hydroxypropyl)phenethyl)pyrrolidin- 2-one 56
##STR00121## 3-Amino-1-(3-(2-(pyrrolidin-1-
yl)ethyl)phenyl)propan-1-ol 57 ##STR00122##
(E)-1-(3-(2-(1H-Imidazol-1- yl)vinyl)phenyl)-3-aminopropan-1- ol 58
##STR00123## 1-(3-(2-(1H-Imidazol-1-
yl)ethyl)phenyl)-3-aminopropan-1- ol 59 ##STR00124##
(E)-3-Amino-1-(3-(2-(pyridin-2- yl)vinyl)phenyl)propan-1-ol 60
##STR00125## 3-Amino-1-(3-(2-(pyridin-2-
yl)ethyl)phenyl)propan-1-ol 61 ##STR00126##
(E)-3-Amino-1-(3-(2-(tetrahydro- 2H-pyran-4-
yl)vinyl)phenyl)propan-1-ol 62 ##STR00127##
3-Amino-1-(3-(2-(tetrahydro-2H- pyran-4-yl)ethyl)phenyl)propan-1-
ol
Preparation of the Substituted 3-Phenylpropylamine Derivative
Compounds
[0304] The compounds used in the reactions described herein are
made according to organic synthesis techniques known to those
skilled in this art, starting from commercially available chemicals
and/or from compounds described in the chemical literature.
"Commercially available chemicals" are obtained from standard
commercial sources including Acros Organics (Pittsburgh Pa.),
Aldrich Chemical (Milwaukee Wis., including Sigma Chemical and
Fluka), Apin Chemicals Ltd. (Milton Park UK), Avocado Research
(Lancashire U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall,
U.K.), Chemservice Inc. (West Chester Pa.), Crescent Chemical Co.
(Hauppauge N.Y.), Eastman Organic Chemicals, Eastman Kodak Company
(Rochester N.Y.), Fisher Scientific Co. (Pittsburgh Pa.), Fisons
Chemicals (Leicestershire UK), Frontier Scientific (Logan Utah),
ICN Biomedicals, Inc. (Costa Mesa Calif.), Key Organics (Cornwall
U.K.), Lancaster Synthesis (Windham N.H.), Maybridge Chemical Co.
Ltd. (Cornwall U.K.), Parish Chemical Co. (Orem Utah), Pfaltz &
Bauer, Inc. (Waterbury Conn.), Polyorganix (Houston Tex.), Pierce
Chemical Co. (Rockford Ill.), Riedel de Haen AG (Hanover, Germany),
Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCI America
(Portland Oreg.), Trans World Chemicals, Inc. (Rockville Md.), and
Wako Chemicals USA, Inc. (Richmond Va.).
[0305] Methods known to one of ordinary skill in the art are
identified through various reference books and databases. Suitable
reference books and treatise that detail the synthesis of reactants
useful in the preparation of compounds described herein, or provide
references to articles that describe the preparation, include for
example, "Synthetic Organic Chemistry", John Wiley & Sons,
Inc., New York; S. R. Sandler et al., "Organic Functional Group
Preparations," 2nd Ed., Academic Press, New York, 1983; H. O.
House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc.
Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry",
2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced
Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed.,
Wiley-Interscience, New York, 1992. Additional suitable reference
books and treatise that detail the synthesis of reactants useful in
the preparation of compounds described herein, or provide
references to articles that describe the preparation, include for
example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts,
Methods, Starting Materials", Second, Revised and Enlarged Edition
(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V.
"Organic Chemistry, An Intermediate Text" (1996) Oxford University
Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic
Transformations: A Guide to Functional Group Preparations" 2nd
Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced
Organic Chemistry: Reactions, Mechanisms, and Structure" 4th
Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera,
J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN:
3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of
Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Quin,
L. D. et al. "A Guide to Organophosphorus Chemistry" (2000)
Wiley-Interscience, ISBN: 0-471-31824-8; Solomons, T. W. G.
"Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN:
0-471-19095-0; Stowell, J. C., "Intermediate Organic Chemistry" 2nd
Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial
Organic Chemicals: Starting Materials and Intermediates: An
Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN:
3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John
Wiley & Sons, in over 55 volumes; and "Chemistry of Functional
Groups" John Wiley & Sons, in 73 volumes.
[0306] Specific and analogous reactants may also be identified
through the indices of known chemicals prepared by the Chemical
Abstract Service of the American Chemical Society, which are
available in most public and university libraries, as well as
through on-line databases (the American Chemical Society,
Washington, D.C., may be contacted for more details). Chemicals
that are known but not commercially available in catalogs may be
prepared by custom chemical synthesis houses, where many of the
standard chemical supply houses (e.g., those listed above) provide
custom synthesis services. A reference for the preparation and
selection of pharmaceutical salts of the 3-phenylpropylamine
derivative compound as described herein is P. H. Stahl & C. G.
Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica
Chimica Acta, Zurich, 2002.
Pharmaceutical Compositions
[0307] In certain embodiments, a 3-phenylpropylamine derivative
compound as described herein are administered as a pure chemical.
In other embodiments, the 3 -phenylpropylamine derivative compound
is combined with a pharmaceutically suitable or acceptable carrier
(also referred to herein as a pharmaceutically suitable (or
acceptable) excipient, physiologically suitable (or acceptable)
excipient, or physiologically suitable (or acceptable) carrier)
selected on the basis of a chosen route of administration and
standard pharmaceutical practice as described, for example, in
Remington: The Science and Practice of Pharmacy (Gennaro, 21.sup.st
Ed. Mack Pub. Co., Easton, Pa. (2005)), the disclosure of which is
hereby incorporated herein by reference, in its entirety.
[0308] One embodiment provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound of
Formula (A), or a pharmaceutically acceptable salt thereof.
[0309] One embodiment provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound of
Formula (A1), or a pharmaceutically acceptable salt thereof.
[0310] One embodiment provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound of
Formula (A2), or a pharmaceutically acceptable salt thereof.
[0311] One embodiment provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound of
Formula (A3), or a pharmaceutically acceptable salt thereof.
[0312] One embodiment provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound of
Formula (A4), or a pharmaceutically acceptable salt thereof.
[0313] One embodiment provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound of
Formula (B), or a pharmaceutically acceptable salt thereof.
[0314] One embodiment provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound of
Formula (B1), or a pharmaceutically acceptable salt thereof.
[0315] One embodiment provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound of
Formula (B2), or a pharmaceutically acceptable salt thereof.
[0316] One embodiment provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound of
Formula (B3), or a pharmaceutically acceptable salt thereof.
[0317] One embodiment provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound of
Formula (C), or a pharmaceutically acceptable salt thereof.
[0318] One embodiment provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound
described in Table 1, or a pharmaceutically acceptable salt
thereof.
[0319] Accordingly, provided herein is a pharmaceutical composition
comprising one or more 3-phenylpropylamine derivative compounds as
described herein, or a stereoisomer, prodrug, pharmaceutically
acceptable salt, hydrate, solvate, acid salt hydrate, or N-oxide
thereof, together with one or more pharmaceutically acceptable
carriers and, optionally, other therapeutic and/or prophylactic
ingredients. The carrier(s) (or excipient(s)) is acceptable or
suitable if the carrier is compatible with the other ingredients of
the composition and not deleterious to the recipient (i.e., the
subject) of the composition. A pharmaceutically acceptable or
suitable composition includes an ophthalmologically suitable or
acceptable composition.
[0320] In an additional embodiment is a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and any of the
compounds disclosed herein, or tautomer, stereoisomer, geometric
isomer, or pharmaceutically acceptable solvate, hydrate, salt, or
N-oxide thereof.
[0321] A pharmaceutical composition (e.g., for oral administration
or delivery by injection, or combined devices, or for application
as an eye drop) may be in the form of a liquid or solid. A liquid
pharmaceutical composition optionally include, for example, one or
more of the following: sterile diluents such as water for
injection, saline solution, preferably physiological saline,
Ringer's solution, isotonic sodium chloride, fixed oils that may
serve as the solvent or suspending medium, polyethylene glycols,
glycerin, propylene glycol or other solvents; antibacterial agents;
antioxidants; chelating agents; buffers and agents for the
adjustment of tonicity such as sodium chloride or dextrose. A
parenteral preparation is optionally enclosed in ampoules,
disposable syringes or multiple dose vials made of glass or
plastic. Physiological saline is commonly used as an excipient, and
an injectable pharmaceutical composition or a composition that is
delivered ocularly is preferably sterile.
[0322] The 3-phenylpropylamine derivative compounds are
administered to human or other nonhuman vertebrates. In certain
embodiments, the compound is substantially pure, in that it
contains less than about 5% or less than about 1%, or less than
about 0.1%, of other organic small molecules, such as contaminating
intermediates or by-products that are created, for example, in one
or more of the steps of a synthesis method. In other embodiments, a
combination of one or more 3-phenylpropylamine derivative compounds
is administered.
[0323] The 3-phenylpropylamine derivative compound is optionally
delivered to a subject by any suitable means, including, for
example, orally, parenterally, intraocularly, intravenously,
intraperitoneally, intranasally (or other delivery methods to the
mucous membranes, for example, of the nose, throat, and bronchial
tubes), or by local administration to the eye, or by an intraocular
or periocular device. Modes of local administration include, for
example, eye drops, intraocular injection or periocular injection.
Periocular injection typically involves injection of the synthetic
isomerization inhibitor, i.e., 3-phenylpropylamine derivative
compound as described herein under the conjunctiva or into the
Tennon's space (beneath the fibrous tissue overlying the eye).
Intraocular injection typically involves injection of the
3-phenylpropylamine derivative compound as described herein into
the vitreous. In certain embodiments, the administration is
non-invasive, such as by eye drops or oral dosage form, or as a
combined device.
[0324] The 3-phenylpropylamine derivative compound described herein
is optionally formulated for administration using pharmaceutically
acceptable (suitable) carriers or vehicles as well as techniques
routinely used in the art. A pharmaceutically acceptable or
suitable carrier includes an ophthalmologically suitable or
acceptable carrier. A carrier is selected according to the
solubility of the 3-phenylpropylamine derivative compound as
described herein. Suitable ophthalmological compositions include
those that are administrable locally to the eye, such as by eye
drops, injection or the like. In the case of eye drops, the
formulation also optionally includes, for example,
ophthalmologically compatible agents such as isotonizing agents
such as sodium chloride, concentrated glycerin, and the like;
buffering agents such as sodium phosphate, sodium acetate, and the
like; surfactants such as polyoxyethylene sorbitan mono-oleate
(also referred to as Polysorbate 80), polyoxyl stearate 40,
polyoxyethylene hydrogenated castor oil, and the like;
stabilization agents such as sodium citrate, sodium edentate, and
the like; preservatives such as benzalkonium chloride, parabens,
and the like; and other ingredients. Preservatives are optionally
employed, for example, at a level of from about 0.001 to about 1.0%
weight/volume. The pH of the formulation is usually within the
range acceptable to ophthalmologic formulations, such as within the
range of about pH 4 to 8.
[0325] For injection, the 3-phenylpropylamine derivative compound
as described herein is optionally provided in an injection grade
saline solution, in the form of an injectable liposome solution,
slow-release polymer system or the like. Intraocular and periocular
injections are known to those skilled in the art and are described
in numerous publications including, for example, Spaeth, Ed.,
Ophthalmic Surgery: Principles of Practice, W. B. Sanders Co.,
Philadelphia, Pa., 85-87, 1990.
[0326] For delivery of a composition comprising at least one of the
3-phenylpropylamine derivative compound described herein via a
mucosal route, which includes delivery to the nasal passages,
throat, and airways, the composition is optionally delivered in the
form of an aerosol. The compound is optionally in a liquid or
powder form for intramucosal delivery. For example, the composition
may be delivered via a pressurized aerosol container with a
suitable propellant, such as a hydrocarbon propellant (e.g.,
propane, butane, isobutene). The composition is optionally
delivered via a non-pressurized delivery system such as a nebulizer
or atomizer.
[0327] Suitable oral dosage forms include, for example, tablets,
pills, sachets, or capsules of hard or soft gelatin,
methylcellulose or of another suitable material easily dissolved in
the digestive tract. Suitable nontoxic solid carriers include, for
example, pharmaceutical grades of mannitol, lactose, starch,
magnesium stearate, sodium saccharin, talcum, cellulose, glucose,
sucrose, magnesium carbonate, and the like. (See, e.g., Remington:
The Science and Practice of Pharmacy (Gennaro, 21.sup.st Ed. Mack
Pub. Co., Easton, Pa. (2005)).
[0328] The 3-phenylpropylamine derivative compound described herein
are optionally formulated for sustained or slow-release. Such
compositions may generally be prepared using well known technology
and administered by, for example, oral, periocular, intraocular,
rectal or subcutaneous implantation, or by implantation at the
desired target site. Sustained-release formulations may contain an
agent dispersed in a carrier matrix and/or contained within a
reservoir surrounded by a rate controlling membrane. Excipients for
use within such formulations are biocompatible, and may also be
biodegradable; preferably the formulation provides a relatively
constant level of active component release. The amount of active
compound contained within a sustained-release formulation depends
upon the site of implantation, the rate and expected duration of
release, and the nature of the condition to be treated or
prevented.
[0329] Systemic drug absorption of a drug or composition
administered via an ocular route is known to those skilled in the
art (see, e.g., Lee et al., Int. J. Pharm. 233:1-18 (2002)). In one
embodiment, a 3-phenylpropylamine derivative compound is delivered
by a topical ocular delivery method (see, e.g., Curr. Drug Metab.
4:213-22 (2003)). The composition is optionally in the form of an
eye drop, salve, or ointment or the like, such as, aqueous eye
drops, aqueous ophthalmic suspensions, non-aqueous eye drops, and
non-aqueous ophthalmic suspensions, gels, ophthalmic ointments,
etc. For preparing a gel, for example, carboxyvinyl polymer, methyl
cellulose, sodium alginate, hydroxypropyl cellulose, ethylene
maleic anhydride polymer and the like can be used.
[0330] The dose of the composition comprising at least one of the
3-phenylpropylamine derivative compounds described herein may
differ, depending upon the patient's (e.g., human) condition, that
is, stage of the disease, general health status, age, and other
factors that a person skilled in the medical art will use to
determine dose. When the composition is used as eye drops, for
example, one to several drops per unit dose, preferably 1 or 2
drops (about 50 .mu.l per 1 drop), are applied about 1 to about 6
times daily.
[0331] Pharmaceutical compositions are administered in a manner
appropriate to the disease to be treated (or prevented). An
appropriate dose and a suitable duration and frequency of
administration will be determined by such factors as the condition
of the patient, the type and severity of the patient's disease, the
particular form of the active ingredient, and the method of
administration. In general, an appropriate dose and treatment
regimen provides the composition(s) in an amount sufficient to
provide therapeutic and/or prophylactic benefit (e.g., an improved
clinical outcome, such as more frequent complete or partial
remissions, or longer disease-free and/or overall survival, or a
lessening of symptom severity). For prophylactic use, a dose should
be sufficient to prevent, delay the onset of, or diminish the
severity of a disease associated with neurodegeneration of retinal
neuronal cells and/or degeneration of other mature retinal cells
such as RPE cells. Optimal doses are generally determined using
experimental models and/or clinical trials. The optimal dose
depends upon the body mass, weight, or blood volume of the
patient.
[0332] The doses of the 3-phenylpropylamine derivative compound
described herein are suitably selected depending on the clinical
status, condition and age of the subject, dosage form and the like.
In the case of eye drops, a 3-phenylpropylamine derivative compound
as described herein is administered, for example, from about 0.01
mg, about 0.1 mg, or about 1 mg, to about 25 mg, to about 50 mg, to
about 90 mg per single dose. Eye drops are administered one or more
times per day, as needed. In the case of injections, suitable doses
are, for example, about 0.0001 mg, about 0.001 mg, about 0.01 mg,
or about 0.1 mg to about 10 mg, to about 25 mg, to about 50 mg, or
to about 90 mg of the 3-phenylpropylamine derivative compound as
described herein, one to seven times per week. In other
embodiments, about 1.0 to about 30 mg of the 3-phenylpropylamine
derivative compound described herein is administered one to seven
times per week.
[0333] Oral doses typically range from 1.0 to 1000 mg, one to four
times, or more, per day. An exemplary dosing range for oral
administration is from 10 to 250 mg one to three times per day. If
the composition is a liquid formulation, the composition comprises
at least 0.1% active compound at particular mass or weight (e.g.,
from 1.0 to 1000 mg) per unit volume of carrier, for example, from
about 2% to about 60%.
[0334] In certain embodiments, at least one 3-phenylpropylamine
derivative compound described herein is administered under
conditions and at a time that inhibits or prevents dark adaptation
of rod photoreceptor cells. In certain embodiments, the compound is
administered to a subject at least 30 minutes (half hour), 60
minutes (one hour), 90 minutes (1.5 hour), or 120 minutes (2 hours)
prior to sleeping. In certain embodiments, the compound is
administered at night before the subject sleeps. In other
embodiments, a light stimulus is blocked or removed during the day
or under normal light conditions by placing the subject in an
environment in which light is removed, such as placing the subject
in a darkened room or by applying an eye mask over the eyes of the
subject. When the light stimulus is removed in such a manner or by
other means contemplated in the art, the agent may be administered
prior to sleeping.
[0335] The doses of the 3-phenylpropylamine derivative compound
described herein that are administered to prevent or inhibit dark
adaptation of a rod photoreceptor cell are suitably selected
depending on the clinical status, condition and age of the subject,
dosage form and the like. In the case of eye drops, the compound
(or the composition comprising the compound) is administered, for
example, from about 0.01 mg, about 0.1 mg, or about 1 mg, to about
25 mg, to about 50 mg, to about 90 mg per single dose. In the case
of injections, suitable doses are, for example, about 0.0001 mg,
about 0.001 mg, about 0.01 mg, or about 0.1 mg to about 10 mg, to
about 25 mg, to about 50 mg, or to about 90 mg of the compound,
administered any number of days between one to seven days per week
prior to sleeping or prior to removing the subject from all light
sources. In certain other embodiments, for administration of the
compound by eye drops or injection, the dose is between 1-10 mg
(compound)/kg (body weight of subject) (i.e., for example, 80-800
mg total per dose for a subject weighing 80 kg). In other
embodiments, about 1.0 to about 30 mg of compound is administered
one to seven times per week. Oral doses typically range from about
1.0 to about 1000 mg, administered any number of days between one
to seven days per week. An exemplary dosing range for oral
administration is from about 10 to about 800 mg once per day prior
to sleeping. In other embodiments, the composition is delivered by
intravitreal administration.
[0336] Also provided are methods of manufacturing the compounds and
pharmaceutical compositions described herein. A composition
comprising a pharmaceutically acceptable excipient or carrier and
at least one of the 3-phenylpropylamine derivative compound
described herein are optionally prepared by synthesizing the
compound according to any one of the methods described herein or
practiced in the art and then formulating the compound with a
pharmaceutically acceptable carrier. Formulation of the composition
will be appropriate and dependent on several factors, including but
not limited to, the delivery route, dose, and stability of the
compound.
Treatment of Ophthalmic Diseases and Disorders
[0337] Age-related macular degeneration (AMD) affects between ten
and fifteen million patients in the United States, and it is the
leading cause of blindness in aging populations worldwide. AMD
affects central vision and causes the loss of photoreceptor cells
in the central part of retina called the macula. Macular
degeneration is classified into two types: dry-form and wet-form.
The dry-form is more common than the wet; about 90% of age-related
macular degeneration patients are diagnosed with the dry-form. The
wet-form of the disease and geographic atrophy, which is the
end-stage phenotype of dry-form AMD, causes the most serious vision
loss. All patients who develop wet-form AMD are believed to
previously have developed dry-form AMD for a prolonged period of
time. The exact causes of AMD are still unknown. The dry-form of
AMD may result from the senescence and thinning of macular tissues
associated with the deposition of pigment in the macular retinal
pigment epithelium. In wet-form AMD, new blood vessels grow beneath
the retina, form scar tissue, bleed, and leak fluid. The overlying
retina can be severely damaged, creating "blind" areas in the
central vision.
[0338] For the vast majority of patients who have the dry-form of
AMD, no effective treatment is yet available. Because the dry-form
of AMD precedes development of the wet-form of AMD, therapeutic
intervention to prevent or delay disease progression in the
dry-form AMD would benefit patients with dry-form of AMD and might
reduce the incidence of the wet-form of AMD.
[0339] Decline of vision noticed by the patient or characteristic
features detected by an ophthalmologist during a routine eye exam
may be the first indicator of AMD. The formation of "drusen," or
membranous debris beneath the retinal pigment epithelium of the
macula is often the first physical sign that AMD is developing.
Late symptoms include the perceived distortion of straight lines
and, in advanced cases, a dark, blurry area or area with absent
vision appears in the center of vision; and/or there may be color
perception changes.
[0340] Different forms of genetically-linked macular degenerations
may also occur in younger patients. In other maculopathies, factors
in the disease are heredity, nutritional, traumatic, infection, or
other ecologic factors.
[0341] Neuronal cell death underlies the pathology of retinal
diseases. Unfortunately, very few compositions and methods that
enhance retinal neuronal cell survival, particularly photoreceptor
cell survival, have been discovered. A need therefore exists to
identify and develop compositions that can be used for treatment
and prophylaxis of a number of retinal diseases and disorders that
have neuronal cell death as a primary, or associated, element in
their pathogenesis.
[0342] In vertebrate photoreceptor cells, the irradiance of a
photon causes isomerization of 11-cis-retinylidene chromophore to
all-trans-retinylidene and uncoupling from the visual opsin
receptors. This photoisomerization triggers conformational changes
of opsins, which, in turn, initiate the biochemical chain of
reactions termed phototransduction (Filipek et al., Annu. Rev.
Physiol. 65:851-79 (2003)). Regeneration of the visual pigments
requires that the chromophore be converted back to the
11-cis-configuration in the processes collectively called the
retinoid (visual) cycle (see, e.g., McBee et al., Prog. Retin. Eye
Res. 20:469-52 (2001)). First, the chromophore is released from the
opsin and reduced in the photoreceptor by retinol dehydrogenases.
The product, all-trans-retinol, is trapped in the adjacent retinal
pigment epithelium (RPE) in the form of insoluble fatty acid esters
in subcellular structures known as retinosomes (Imanishi et al., J.
Cell Biol. 164:373-87 (2004)).
[0343] In Stargardt's disease (Allikmets et al., Nat. Genet.
15:236-46 (1997)), a disease associated with mutations in the ABCR
transporter that acts as a flippase, the accumulation of
all-trans-retinal may be responsible for the formation of a
lipofuscin pigment, A2E, which is toxic towards retinal pigment
epithelial cells and causes progressive retinal degeneration and,
consequently, loss of vision (Mata et al., Proc. Natl. Acad. Sci.
USA 97:7154-59 (2000); Weng et al., Cell 98:13-23 (1999)). Treating
patients with an inhibitor of retinol dehydrogenases, 13-cis-RA
(Isotretinoin, Accutane.RTM., Roche), has been considered as a
therapy that might prevent or slow the formation of A2E and might
have protective properties to maintain normal vision (Radu et al.,
Proc. Natl. Acad. Sci. USA 100:4742-47 (2003)). 13-cis-RA has been
used to slow the synthesis of 11-cis-retinal by inhibiting
11-cis-RDH (Law et al., Biochem. Biophys. Res. Commun. 161:825-9
(1989)), but its use can also be associated with significant night
blindness. Others have proposed that 13-cis-RA works to prevent
chromophore regeneration by binding RPE65, a protein essential for
the isomerization process in the eye (Gollapalli et al., Proc.
Natl. Acad. Sci. USA 101:10030-35 (2004)). Gollapalli et al.
reported that 13-cis-RA blocked the formation of A2E and suggested
that this treatment may inhibit lipofuscin accumulation and, thus,
delay either the onset of visual loss in Stargardt's disease or
age-related macular degeneration, which are both associated with
retinal pigment-associated lipofuscin accumulation. However,
blocking the retinoid cycle and forming unliganded opsin may result
in more severe consequences and worsening of the patient's
prognosis (see, e.g., Van Hooser et al., J. Biol. Chem.
277:19173-82 (2002); Woodruff et al., Nat. Genet. 35:158-164
(2003)). Failure of the chromophore to form may lead to progressive
retinal degeneration and may produce a phenotype similar to Leber
Congenital Amaurosis (LCA), which is a very rare genetic condition
affecting children shortly after birth.
[0344] In an additional embodiment is a method for treating an
ophthalmic disease or disorder in a subject, comprising
administering to the subject any of the compounds disclosed herein,
or tautomer, stereoisomer, geometric isomer or a pharmaceutically
acceptable solvate, hydrate, salt, or N-oxide thereof.
[0345] In a further embodiment is the method of treating an
ophthalmic disease or disorder in a subject as described herein
resulting in a reduction of lipofuscin pigment accumulated in an
eye of the subject. In a further embodiment is the method of
treating an ophthalmic disease or disorder in a subject as
described herein resulting in a reduction of lipofuscin pigment
accumulated in an eye of the subject, wherein the lipofuscin
pigment is N-retinylidene-N-retinyl-ethanolamine (A2E). In an
additional embodiment is a method of reducing lipofuscin pigment
accumulated in a subject's retina wherein the lipofuscin is
N-retinylidene-N-retinyl-ethanolamine (A2E). In an additional
embodiment is a method of inhibiting or reducing lipofuscin pigment
accumulated in a subject's retina comprising administering to the
subject a pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound as described herein. In another
embodiment is a method of reducing lipofuscin pigment accumulated
in a subject's retina comprising administering to the subject a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and any of the compounds disclosed herein, or tautomer,
stereoisomer, geometric isomer or a pharmaceutically acceptable
solvate, hydrate, salt, or N-oxide thereof.
[0346] In a further embodiment is the method of treating an
ophthalmic disease or disorder in a subject as described herein,
wherein the ophthalmic disease or disorder is age-related macular
degeneration or Stargardt's macular dystrophy. Another embodiment
provides the method for treating an ophthalmic disease or disorder
in a subject, wherein the ophthalmic disease or disorder is
geographic atrophy (GA) associated with dry age-related macular
degeneration.
[0347] One embodiment provides a method for treating an ophthalmic
disease or disorder in a subject, comprising administering to the
subject a compound of Formula (A), or a pharmaceutically acceptable
salt thereof. A further embodiment is the method, wherein the
ophthalmic disease or disorder is age-related macular degeneration
or Stargardt's macular dystrophy. Another embodiment provides the
method for treating an ophthalmic disease or disorder in a subject,
wherein the ophthalmic disease or disorder is geographic atrophy
(GA) associated with dry age-related macular degeneration.
[0348] One embodiment provides a method for treating an ophthalmic
disease or disorder in a subject, comprising administering to the
subject a compound of Formula (A1), or a pharmaceutically
acceptable salt thereof. A further embodiment is the method,
wherein the ophthalmic disease or disorder is age-related macular
degeneration or Stargardt's macular dystrophy. Another embodiment
provides the method for treating an ophthalmic disease or disorder
in a subject, wherein the ophthalmic disease or disorder is
geographic atrophy (GA) associated with dry age-related macular
degeneration.
[0349] One embodiment provides a method for treating an ophthalmic
disease or disorder in a subject, comprising administering to the
subject a compound of Formula (A2), or a pharmaceutically
acceptable salt thereof. A further embodiment is the method,
wherein the ophthalmic disease or disorder is age-related macular
degeneration or Stargardt's macular dystrophy. Another embodiment
provides the method for treating an ophthalmic disease or disorder
in a subject, wherein the ophthalmic disease or disorder is
geographic atrophy (GA) associated with dry age-related macular
degeneration.
[0350] One embodiment provides a method for treating an ophthalmic
disease or disorder in a subject, comprising administering to the
subject a compound of Formula (A3), or a pharmaceutically
acceptable salt thereof. A further embodiment is the method,
wherein the ophthalmic disease or disorder is age-related macular
degeneration or Stargardt's macular dystrophy. Another embodiment
provides the method for treating an ophthalmic disease or disorder
in a subject, wherein the ophthalmic disease or disorder is
geographic atrophy (GA) associated with dry age-related macular
degeneration.
[0351] One embodiment provides a method for treating an ophthalmic
disease or disorder in a subject, comprising administering to the
subject a compound of Formula (A4), or a pharmaceutically
acceptable salt thereof. A further embodiment is the method,
wherein the ophthalmic disease or disorder is age-related macular
degeneration or Stargardt's macular dystrophy. Another embodiment
provides the method for treating an ophthalmic disease or disorder
in a subject, wherein the ophthalmic disease or disorder is
geographic atrophy (GA) associated with dry age-related macular
degeneration.
[0352] One embodiment provides a method for treating an ophthalmic
disease or disorder in a subject, comprising administering to the
subject a compound of Formula (B), or a pharmaceutically acceptable
salt thereof. A further embodiment is the method, wherein the
ophthalmic disease or disorder is age-related macular degeneration
or Stargardt's macular dystrophy. Another embodiment provides the
method for treating an ophthalmic disease or disorder in a subject,
wherein the ophthalmic disease or disorder is geographic atrophy
(GA) associated with dry age-related macular degeneration.
[0353] One embodiment provides a method for treating an ophthalmic
disease or disorder in a subject, comprising administering to the
subject a compound of Formula (B1), or a pharmaceutically
acceptable salt thereof. A further embodiment is the method,
wherein the ophthalmic disease or disorder is age-related macular
degeneration or Stargardt's macular dystrophy. Another embodiment
provides the method for treating an ophthalmic disease or disorder
in a subject, wherein the ophthalmic disease or disorder is
geographic atrophy (GA) associated with dry age-related macular
degeneration.
[0354] One embodiment provides a method for treating an ophthalmic
disease or disorder in a subject, comprising administering to the
subject a compound of Formula (B2), or a pharmaceutically
acceptable salt thereof. A further embodiment is the method,
wherein the ophthalmic disease or disorder is age-related macular
degeneration or Stargardt's macular dystrophy. Another embodiment
provides the method for treating an ophthalmic disease or disorder
in a subject, wherein the ophthalmic disease or disorder is
geographic atrophy (GA) associated with dry age-related macular
degeneration.
[0355] One embodiment provides a method for treating an ophthalmic
disease or disorder in a subject, comprising administering to the
subject a compound of Formula (B3), or a pharmaceutically
acceptable salt thereof. A further embodiment is the method,
wherein the ophthalmic disease or disorder is age-related macular
degeneration or Stargardt's macular dystrophy. Another embodiment
provides the method for treating an ophthalmic disease or disorder
in a subject, wherein the ophthalmic disease or disorder is
geographic atrophy (GA) associated with dry age-related macular
degeneration.
[0356] One embodiment provides a method for treating an ophthalmic
disease or disorder in a subject, comprising administering to the
subject a compound of Formula (C), or a pharmaceutically acceptable
salt thereof. A further embodiment is the method, wherein the
ophthalmic disease or disorder is age-related macular degeneration
or Stargardt's macular dystrophy. Another embodiment provides the
method for treating an ophthalmic disease or disorder in a subject,
wherein the ophthalmic disease or disorder is geographic atrophy
(GA) associated with dry age-related macular degeneration.
[0357] One embodiment provides a method for treating an ophthalmic
disease or disorder in a subject, comprising administering to the
subject a compound described in Table 1, or a pharmaceutically
acceptable salt thereof. A further embodiment is the method,
wherein the ophthalmic disease or disorder is age-related macular
degeneration or Stargardt's macular dystrophy. Another embodiment
provides the method for treating an ophthalmic disease or disorder
in a subject, wherein the ophthalmic disease or disorder is
geographic atrophy (GA) associated with dry age-related macular
degeneration.
[0358] One embodiment provides a method for treating an ophthalmic
disease or disorder resulting at least in part from lipofuscin
accumulation in a subject, comprising administering to the subject
a compound of Formula (A), or a pharmaceutically acceptable salt
thereof. A further embodiment is the method, wherein the ophthalmic
disease or disorder is age-related macular degeneration or
Stargardt's macular dystrophy. Another embodiment provides the
method for treating an ophthalmic disease or disorder in a subject,
wherein the ophthalmic disease or disorder is geographic atrophy
(GA) associated with dry age-related macular degeneration.
[0359] One embodiment provides a method for treating an ophthalmic
disease or disorder resulting at least in part from lipofuscin
accumulation in a subject, comprising administering to the subject
a compound of Formula (A1), or a pharmaceutically acceptable salt
thereof. A further embodiment is the method, wherein the ophthalmic
disease or disorder is age-related macular degeneration or
Stargardt's macular dystrophy. Another embodiment provides the
method for treating an ophthalmic disease or disorder in a subject,
wherein the ophthalmic disease or disorder is geographic atrophy
(GA) associated with dry age-related macular degeneration.
[0360] One embodiment provides a method for treating an ophthalmic
disease or disorder resulting at least in part from lipofuscin
accumulation in a subject, comprising administering to the subject
a compound of Formula (A2), or a pharmaceutically acceptable salt
thereof. A further embodiment is the method, wherein the ophthalmic
disease or disorder is age-related macular degeneration or
Stargardt's macular dystrophy. Another embodiment provides the
method for treating an ophthalmic disease or disorder in a subject,
wherein the ophthalmic disease or disorder is geographic atrophy
(GA) associated with dry age-related macular degeneration.
[0361] One embodiment provides a method for treating an ophthalmic
disease or disorder resulting at least in part from lipofuscin
accumulation in a subject, comprising administering to the subject
a compound of Formula (A3), or a pharmaceutically acceptable salt
thereof. A further embodiment is the method, wherein the ophthalmic
disease or disorder is age-related macular degeneration or
Stargardt's macular dystrophy. Another embodiment provides the
method for treating an ophthalmic disease or disorder in a subject,
wherein the ophthalmic disease or disorder is geographic atrophy
(GA) associated with dry age-related macular degeneration.
[0362] One embodiment provides a method for treating an ophthalmic
disease or disorder resulting at least in part from lipofuscin
accumulation in a subject, comprising administering to the subject
a compound of Formula (A4), or a pharmaceutically acceptable salt
thereof. A further embodiment is the method, wherein the ophthalmic
disease or disorder is age-related macular degeneration or
Stargardt's macular dystrophy. Another embodiment provides the
method for treating an ophthalmic disease or disorder in a subject,
wherein the ophthalmic disease or disorder is geographic atrophy
(GA) associated with dry age-related macular degeneration.
[0363] One embodiment provides a method for treating an ophthalmic
disease or disorder resulting at least in part from lipofuscin
accumulation in a subject, comprising administering to the subject
a compound of Formula (B), or a pharmaceutically acceptable salt
thereof. A further embodiment is the method, wherein the ophthalmic
disease or disorder is age-related macular degeneration or
Stargardt's macular dystrophy. Another embodiment provides the
method for treating an ophthalmic disease or disorder in a subject,
wherein the ophthalmic disease or disorder is geographic atrophy
(GA) associated with dry age-related macular degeneration.
[0364] One embodiment provides a method for treating an ophthalmic
disease or disorder resulting at least in part from lipofuscin
accumulation in a subject, comprising administering to the subject
a compound of Formula (B1), or a pharmaceutically acceptable salt
thereof. A further embodiment is the method, wherein the ophthalmic
disease or disorder is age-related macular degeneration or
Stargardt's macular dystrophy. Another embodiment provides the
method for treating an ophthalmic disease or disorder in a subject,
wherein the ophthalmic disease or disorder is geographic atrophy
(GA) associated with dry age-related macular degeneration.
[0365] One embodiment provides a method for treating an ophthalmic
disease or disorder resulting at least in part from lipofuscin
accumulation in a subject, comprising administering to the subject
a compound of Formula (B2), or a pharmaceutically acceptable salt
thereof. A further embodiment is the method, wherein the ophthalmic
disease or disorder is age-related macular degeneration or
Stargardt's macular dystrophy. Another embodiment provides the
method for treating an ophthalmic disease or disorder in a subject,
wherein the ophthalmic disease or disorder is geographic atrophy
(GA) associated with dry age-related macular degeneration.
[0366] One embodiment provides a method for treating an ophthalmic
disease or disorder resulting at least in part from lipofuscin
accumulation in a subject, comprising administering to the subject
a compound of Formula (B3), or a pharmaceutically acceptable salt
thereof. A further embodiment is the method, wherein the ophthalmic
disease or disorder is age-related macular degeneration or
Stargardt's macular dystrophy. Another embodiment provides the
method for treating an ophthalmic disease or disorder in a subject,
wherein the ophthalmic disease or disorder is geographic atrophy
(GA) associated with dry age-related macular degeneration.
[0367] One embodiment provides a method for treating an ophthalmic
disease or disorder resulting at least in part from lipofuscin
accumulation in a subject, comprising administering to the subject
a compound of Formula (C), or a pharmaceutically acceptable salt
thereof. A further embodiment is the method, wherein the ophthalmic
disease or disorder is age-related macular degeneration or
Stargardt's macular dystrophy. Another embodiment provides the
method for treating an ophthalmic disease or disorder in a subject,
wherein the ophthalmic disease or disorder is geographic atrophy
(GA) associated with dry age-related macular degeneration.
[0368] One embodiment provides a method for treating an ophthalmic
disease or disorder resulting at least in part from lipofuscin
accumulation in a subject, comprising administering to the subject
a compound described in Table 1, or a pharmaceutically acceptable
salt thereof. A further embodiment is the method, wherein the
ophthalmic disease or disorder is age-related macular degeneration
or Stargardt's macular dystrophy. Another embodiment provides the
method for treating an ophthalmic disease or disorder in a subject,
wherein the ophthalmic disease or disorder is geographic atrophy
(GA) associated with dry age-related macular degeneration.
[0369] 3-Phenylpropylamine derivative compounds as described in
detail herein are useful for treating ophthalmic diseases or
disorders. The compounds described herein, may inhibit, block, or
in some manner interfere with the isomerization step in the visual
cycle, in particular the activity of trans-cis isomerase (also
including a visual cycle trans-cis isomerohydrolase). In a
particular embodiment, the compound inhibits isomerization of an
all-trans-retinyl ester; in certain embodiments, the
all-trans-retinyl ester is a fatty acid ester of all-trans-retinol,
and the compound inhibits isomerization of all-trans-retinol to
11-cis-retinol. The compound may bind to, or in some manner
interact with, and inhibit the isomerase activity of at least one
visual cycle isomerase, which may also be referred to herein and in
the art as a retinal isomerase or an isomerohydrolase. The compound
may block or inhibit binding of an all-trans-retinyl ester
substrate to an isomerase. Alternatively, or in addition, the
compound may bind to the catalytic site or region of the isomerase,
thereby inhibiting the capability of the enzyme to catalyze
isomerization of an all-trans-retinyl ester substrate. On the basis
of scientific data to date, at least one isomerase that catalyzes
the isomerization of all-trans-retinyl esters is believed to be
located in the cytoplasm of RPE cells. As discussed herein, each
step, enzyme, substrate, intermediate, and product of the visual
cycle is not yet elucidated (see, e.g., Moiseyev et al., Proc.
Natl. Acad. Sci. USA 102:12413-18 (2004); Chen et al., Invest.
Ophthalmol. Vis. Sci. 47:1177-84 (2006); Lamb et al. supra).
[0370] A method for determining the effect of a compound on
isomerase activity is performed in vitro as described herein and in
the art (Stecher et al., J Biol Chem 274:8577-85 (1999); see also
Golczak et al., Proc. Natl. Acad. Sci. USA 102:8162-67 (2005)).
Retinal pigment epithelium (RPE) microsome membranes isolated from
an animal (such as bovine, porcine, human, for example) may serve
as the source of the isomerase. The capability of the
3-phenylpropylamine derivative compounds to inhibit isomerase may
also be determined by an in vivo murine isomerase assay. Brief
exposure of the eye to intense light ("photobleaching" of the
visual pigment or simply "bleaching") is known to photo-isomerize
almost all 11-cis-retinal in the retina. The recovery of
11-cis-retinal after bleaching can be used to estimate the activity
of isomerase in vivo (see, e.g., Maeda et al., J. Neurochem
85:944-956 (2003); Van Hooser et al., J Biol Chem 277:19173-82,
2002). Electroretinographic (ERG) recording may be performed as
previously described (Haeseleer et al., Nat. Neurosci. 7:1079-87
(2004); Sugitomo et al., J. Toxicol. Sci. 22 Suppl 2:315-25 (1997);
Keating et al., Documenta Ophthalmologica 100:77-92 (2000)). See
also Deigner et al., Science, 244: 968-971 (1989); Gollapalli et
al., Biochim Biophys Acta. 1651: 93-101 (2003); Parish, et al.,
Proc. Natl. Acad. Sci. USA 95:14609-13 (1998); Radu, et al., Proc
Natl Acad Sci USA 101: 5928-33 (2004)). In certain embodiments,
compounds that are useful for treating a subject who has or who is
at risk of developing any one of the ophthalmic and retinal
diseases or disorders described herein have IC.sub.50 levels
(compound concentration at which 50% of isomerase activity is
inhibited) as measured in the isomerase assays described herein or
known in the art that is less than about 1 .mu.M; in other
embodiments, the determined IC.sub.50 level is less than about 10
nM; in other embodiments, the determined IC.sub.50 level is less
than about 50 nM; in certain other embodiments, the determined
IC.sub.50 level is less than about 100 nM; in other certain
embodiments, the determined IC.sub.50 level is less than about 10
.mu.M; in other embodiments, the determined IC.sub.50 level is less
than about 50 .mu.M; in other certain embodiments, the determined
IC.sub.50 level is less than about 100 .mu.M or about 500 .mu.M; in
other embodiments, the determined IC.sub.50 level is between about
1 .mu.M and 10 .mu.M; in other embodiments, the determined
IC.sub.50 level is between about 1 nM and 10 nM. When adminstered
into a subject, one or more compounds of the present invention
exhibits an ED.sub.50 value of about 5 mg/kg or less as ascertained
by inhibition of an isomerase reaction that results in production
of 11-cis retinol. In some embodiments, the compounds of the
present invention have ED.sub.50 values of about 1 mg/kg when
administered into a subject. In other embodiments, the compounds of
the present invention have ED.sub.50 values of about 0.1 mg/kg when
administered into a subject. The ED.sub.50 values can be measured
after about 2 hours, 4 hours, 6 hours, 8 hours or longer upon
administering to a subject a 3-phenylpropylamine derivative
compound or a pharmaceutical composition thereof.
[0371] The 3-phenylpropylamine derivative compounds described
herein are useful for treating a subject who has an ophthalmic
disease or disorder, particularly a retinal disease or disorder
such as age-related macular degeneration or Stargardt's macular
dystrophy. In one embodiment, the compounds described herein may
inhibit (i.e., prevent, reduce, slow, abrogate, or minimize)
accumulation of lipofuscin pigments and lipofuscin-related and/or
associated molecules in the eye. In another embodiment, the
compounds may inhibit (i.e., prevent, reduce, slow, abrogate, or
minimize)N-retinylidene-N-retinylethanolamine (A2E) accumulation in
the eye. The ophthalmic disease may result, at least in part, from
lipofuscin pigments accumulation and/or from accumulation of A2E in
the eye. Accordingly, in certain embodiments, methods are provided
for inhibiting or preventing accumulation of lipofuscin pigments
and/or A2E in the eye of a subject. These methods comprise
administering to the subject a composition comprising a
pharmaceutically acceptable or suitable excipient (i.e.,
pharmaceutically acceptable or suitable carrier) and a
3-phenylpropylamine derivative compound as described in detail
herein, or a pharmaceutically acceptable salt thereof.
[0372] Accumulation of lipofuscin pigments in retinal pigment
epithelium (RPE) cells has been linked to progression of retinal
diseases that result in blindness, including age-related macular
degeneration (De Laey et al., Retina 15:399-406 (1995)). Lipofuscin
granules are autofluorescent lysosomal residual bodies (also called
age pigments). The major fluorescent species of lipofuscin is A2E
(an orange-emitting fluorophore), which is a positively charged
Schiff-base condensation-product formed by all-trans retinaldehyde
with phosphatidylethanolamine (2:1 ratio) (see, e.g., Eldred et
al., Nature 361:724-6 (1993); see also, Sparrow, Proc. Natl. Acad.
Sci. USA 100:4353-54 (2003)). Much of the indigestible lipofuscin
pigment is believed to originate in photoreceptor cells; deposition
in the RPE occurs because the RPE internalize membranous debris
that is discarded daily by the photoreceptor cells. Formation of
this compound is not believed to occur by catalysis by any enzyme,
but rather A2E forms by a spontaneous cyclization reaction. In
addition, A2E has a pyridinium bisretinoid structure that once
formed may not be enzymatically degraded. Lipofuscin, and thus A2E,
accumulate with aging of the human eye and also accumulate in a
juvenile form of macular degeneration called Stargardt's disease,
and in several other congenital retinal dystrophies.
[0373] A2E may induce damage to the retina via several different
mechanisms. At low concentrations, A2E inhibits normal proteolysis
in lysosomes (Holz et al., Invest. Ophthalmol. Vis. Sci. 40:737-43
(1999)). At higher, sufficient concentrations, A2E may act as a
positively charged lysosomotropic detergent, dissolving cellular
membranes, and may alter lysosomal function, release proapoptotic
proteins from mitochondria, and ultimately kill the RPE cell (see,
e.g., Eldred et al., supra; Sparrow et al., Invest. Ophthalmol.
Vis. Sci. 40:2988-95 (1999); Holz et al., supra; Finneman et al.,
Proc. Natl. Acad. Sci. USA 99:3842-347 (2002); Suter et al., J.
Biol. Chem. 275:39625-30 (2000)). A2E is phototoxic and initiates
blue light-induced apoptosis in RPE cells (see, e.g., Sparrow et
al., Invest. Ophthalmol. Vis. Sci. 43:1222-27 (2002)). Upon
exposure to blue light, photooxidative products of A2E are formed
(e.g., epoxides) that damage cellular macromolecules, including DNA
(Sparrow et al., J. Biol. Chem. 278(20):18207-13 (2003)). A2E
self-generates singlet oxygen that reacts with A2E to generate
epoxides at carbon-carbon double bonds (Sparrow et al., supra).
Generation of oxygen reactive species upon photoexcitation of A2E
causes oxidative damage to the cell, often resulting in cell death.
An indirect method of blocking formation of A2E by inhibiting
biosynthesis of the direct precursor of A2E, all-trans-retinal, has
been described (see U.S. Patent Application Publication No.
2003/0032078). However, the usefulness of the method described
therein is limited because generation of all-trans retinal is an
important component of the visual cycle. Other therapies described
include neutralizing damage caused by oxidative radical species by
using superoxide-dismutase mimetics (see, e.g., U.S. Patent
Application Publication No. 2004/0116403) and inhibiting
A2E-induced cytochrome C oxidase in retinal cells with negatively
charged phospholipids (see, e.g., U.S. Patent Application
Publication No. 2003/0050283).
[0374] The 3-phenylpropylamine derivative compounds described
herein are useful for preventing, reducing, inhibiting, or
decreasing accumulation (i.e., deposition) of A2E and A2E-related
and/or derived molecules in the RPE. Because the RPE is critical
for the maintenance of the integrity of photoreceptor cells,
preventing, reducing, or inhibiting damage to the RPE may inhibit
degeneration (i.e., enhance the survival or increase or prolong
cell viability) of retinal neuronal cells, particularly,
photoreceptor cells. Compounds that bind specifically to, or
interact with, A2E, A2E-related and/or derived molecules, or that
affect A2E formation or accumulation may also reduce, inhibit,
prevent, or decrease one or more toxic effects of A2E or of
A2E-related and/or derived molecules that result in retinal
neuronal cell (including a photoreceptor cell) damage, loss, or
neurodegeneration, or in some manner decrease retinal neuronal cell
viability. Such toxic effects include induction of apoptosis,
self-generation of singlet oxygen and generation of oxygen reactive
species; self-generation of singlet oxygen to form A2E-epoxides
that induce DNA lesions, thus damaging cellular DNA and inducing
cellular damage; dissolving cellular membranes; altering lysosomal
function; and effecting release of proapoptotic proteins from
mitochondria.
[0375] Retinyl esters may be analyzed by gradient HPLC according to
methods practiced in the art (see, for example, Mata et al., Neuron
36:69-80 (2002); Trevino et al. J. Exp. Biol. 208:4151-57 (2005)).
To measure 11-cis and all-trans retinals, retinoids may be
extracted by a formaldehyde method (see, e.g., Suzuki et al., Vis.
Res. 28:1061-70 (1988); Okajima and Pepperberg, Exp. Eye Res.
65:331-40 (1997)) or by a hydroxylamine method (see, e.g.,
Groenendijk et al., Biochim. Biophys. Acta. 617:430-38 (1980))
before being analyzed on isocratic HPLC (see, e.g., Trevino et al.,
supra). The retinoids may be monitored spectrophotometrically (see,
e.g., Maeda et al., J. Neurochem. 85:944-956 (2003); Van Hooser et
al., J. Biol. Chem. 277:19173-82 (2002)).
[0376] The ophthalmic disease may result, at least in part, from
lipofuscin pigment(s) accumulation and/or from accumulation of
N-retinylidene-N-retinylethanolamine (A2E) in the eye. Accordingly,
in certain embodiments, methods are provided for inhibiting or
preventing accumulation of lipofuscin pigment(s) and/or A2E in the
eye of a subject. These methods comprise administering to the
subject a composition comprising a pharmaceutically acceptable
carrier and a 3-phenylpropylamine derivative compound as described
in detail herein, or a pharmaceutically acceptable salt
thereof.
[0377] The 3-phenylpropylamine derivative compound described herein
can be administered to a subject who has an excess of a retinoid in
an eye (e.g., an excess of 11-cis-retinol or 11-cis-retinal), an
excess of retinoid waste products or intermediates in the recycling
of all-trans-retinal, or the like. Methods described herein and
practiced in the art may be used to determine whether the level of
one or more endogenous retinoids in a subject are altered
(increased or decreased in a statistically significant or
biologically significant manner) during or after administration of
any one of the compounds described herein. Rhodopsin, which is
composed of the protein opsin and retinal (a vitamin A form), is
located in the membrane of the photoreceptor cell in the retina of
the eye and catalyzes the only light-sensitive step in vision. The
11-cis-retinal chromophore lies in a pocket of the protein and is
isomerized to all-trans retinal when light is absorbed. The
isomerization of retinal leads to a change of the shape of
rhodopsin, which triggers a cascade of reactions that lead to a
nerve impulse that is transmitted to the brain by the optic
nerve.
[0378] Methods of determining endogenous retinoid levels in a
vertebrate eye, and an excess or deficiency of such retinoids, are
disclosed in, for example, U.S. Patent Application Publication No:
2005/0159662 (the disclosure of which is incorporated by reference
herein in its entirety). Other methods of determining endogenous
retinoid levels in a subject, which is useful for determining
whether levels of such retinoids are above the normal range, and
include for example, analysis by high pressure liquid
chromatography (HPLC) of retinoids in a biological sample from a
subject. For example, retinoid levels can be determined in a
biological sample that is a blood sample (which includes serum or
plasma) from a subject. A biological sample may also include
vitreous fluid, aqueous humor, intraocular fluid, subretinal fluid,
or tears.
[0379] For example, a blood sample can be obtained from a subject,
and different retinoid compounds and levels of one or more of the
retinoid compounds in the sample can be separated and analyzed by
normal phase high pressure liquid chromatography (HPLC) (e.g., with
a HP1100 HPLC and a Beckman, Ultrasphere-Si, 4.6 mm.times.250 mm
column using 10% ethyl acetate/90% hexane at a flow rate of 1.4
ml/minute). The retinoids can be detected by, for example,
detection at 325 nm using a diode-array detector and HP Chemstation
A.03.03 software. An excess in retinoids can be determined, for
example, by comparison of the profile of retinoids (i.e.,
qualitative, e.g., identity of specific compounds, and
quantitative, e.g., the level of each specific compound) in the
sample with a sample from a normal subject. Persons skilled in the
art who are familiar with such assays and techniques and will
readily understand that appropriate controls are included.
[0380] As used herein, increased or excessive levels of endogenous
retinoid, such as 11-cis-retinol or 11-cis-retinal, refer to levels
of endogenous retinoid higher than those found in a healthy eye of
a young vertebrate of the same species. Administration of a
3-phenylpropylamine derivative compound can reduce or eliminate the
requirement for endogenous retinoid. In certain embodiments, the
level of endogenous retinoid may be compared before and after one
or more doses of a 3-phenylpropylamine derivative compound as
described herein is administered to a subject to determine the
effect of the compound on the level of endogenous retinoids in the
subject.
[0381] A biological sample may be a blood sample (from which serum
or plasma may be prepared), biopsy specimen, body fluids (e.g.,
vitreous fluid, aqueous humor, intraocular fluid, subretinal fluid,
or tears), tissue explant, organ culture, or any other tissue or
cell preparation from a subject or a biological source. A sample
may further refer to a tissue or cell preparation in which the
morphological integrity or physical state has been disrupted, for
example, by dissection, dissociation, solubilization,
fractionation, homogenization, biochemical or chemical extraction,
pulverization, lyophilization, sonication, or any other means for
processing a sample derived from a subject or biological source.
The subject or biological source may be a human or non-human
animal, a primary cell culture (e.g., a retinal cell culture), or
culture adapted cell line, including but not limited to,
genetically engineered cell lines that may contain chromosomally
integrated or episomal recombinant nucleic acid sequences,
immortalized or immortalizable cell lines, somatic cell hybrid cell
lines, differentiated or differentiatable cell lines, transformed
cell lines, and the like. Mature retinal cells, including retinal
neuronal cells, RPE cells, and Muller glial cells, may be present
in or isolated from a biological sample as described herein. For
example, the mature retinal cell may be obtained from a primary or
long-term cell culture or may be present in or isolated from a
biological sample obtained from a subject (human or non-human
animal).
In Vivo and In Vitro Methods for Determining Therapeutic
Effectiveness of Compounds
[0382] In one embodiment, methods are provided for using the
compounds described herein for enhancing or prolonging retinal cell
survival, including retinal neuronal cell survival and RPE cell
survival. Also provided herein are methods for inhibiting or
preventing degeneration of a retinal cell, including a retinal
neuronal cell (e.g., a photoreceptor cell, an amacrine cell, a
horizontal cell, a bipolar cell, and a ganglion cell) and other
mature retinal cells such as retinal pigment epithelial cells and
Muller glial cells using the compounds described herein. Such
methods comprise, in certain embodiments, administration of a
3-phenylpropylamine derivative compound as described herein. Such a
compound is useful for enhancing retinal cell survival, including
photoreceptor cell survival and retinal pigment epithelia survival,
inhibiting or slowing degeneration of a retinal cell, and thus
increasing retinal cell viability, which results in slowing or
halting the progression of an ophthalmic disease or disorder or
retinal injury, which are described herein.
[0383] The effect of a 3-phenylpropylamine derivative compound on
retinal cell survival (and/or retinal cell degeneration) may be
determined by using cell culture models, animal models, and other
methods that are described herein and practiced by persons skilled
in the art. By way of example, and not limitation, such methods and
assays include those described in Oglivie et al., Exp. Neurol.
161:675-856 (2000); U.S. Pat. No. 6,406,840; WO 01/81551; WO
98/12303; U.S. Patent Application No. 2002/0009713; WO 00/40699;
U.S. Pat. No. 6,117,675; U.S. Pat. No. 5,736,516; WO 99/29279; WO
01/83714; WO 01/42784; U.S. Pat. No. 6,183,735; U.S. Pat. No.
6,090,624; WO 01/09327; U.S. Pat. No. 5,641,750; U.S. Patent
Application Publication No. 2004/0147019; and U.S. Patent
Application Publication No. 2005/0059148.
[0384] The compounds described herein that are useful for treating
an ophthalmic disease or disorder (including a retinal disease or
disorder) may inhibit, block, impair, or in some manner interfere
with one or more steps in the visual cycle (also called the
retinoid cycle herein and in the art). The 3-phenylpropylamine
derivative compound as described herein inhibits or blocks an
isomerization step in the visual cycle, for example, by inhibiting
or blocking a functional activity of a visual cycle trans-cis
isomerase. The compounds described herein inhibit, directly or
indirectly, isomerization of all-trans-retinol to 11-cis-retinol.
The compounds bind to, or in some manner interact with, and inhibit
the isomerase activity of at least one isomerase in a retinal cell.
Any one of the compounds described herein directly or indirectly
inhibit or reduce the activity of an isomerase that is involved in
the visual cycle. The compound blocks or inhibits the capability of
the isomerase to bind to one or more substrates, including but not
limited to, an all-trans-retinyl ester substrate or
all-trans-retinol. Alternatively, or in addition, the compound
binds to the catalytic site or region of the isomerase, thereby
inhibiting the capability of the enzyme to catalyze isomerization
of at least one substrate. On the basis of scientific data to date,
an at least one isomerase that catalyzes the isomerization of a
substrate during the visual cycle is believed to be located in the
cytoplasm of RPE cells. As discussed herein, each step, enzyme,
substrate, intermediate, and product of the visual cycle is not yet
elucidated. While a polypeptide called RPE65, which has been found
in the cytoplasm and membrane bound in RPE cells, is hypothesized
to have isomerase activity (and has also been referred to in the
art as having isomerohydrolase activity) (see, e.g., Moiseyev et
al., Proc. Natl. Acad. Sci. USA 102:12413-18 (2004); Chen et al.,
Invest. Ophthalmol. Vis. Sci. 47:1177-84 (2006)), other persons
skilled in the art believe that the RPE65 acts primarily as a
chaperone for all-trans-retinyl esters (see, e.g., Lamb et al.
supra).
[0385] Exemplary methods are described herein and practiced by
persons skilled in the art for determining the level of enzymatic
activity of a visual cycle isomerase in the presence of any one of
the 3-phenylpropylamine derivative compounds described herein. A
compound that decreases isomerase activity may be useful for
treating an ophthalmic disease or disorder. Thus, methods are
provided herein for detecting inhibition of isomerase activity
comprising contacting (i.e., mixing, combining, or in some manner
permitting the compound and isomerase to interact) a biological
sample comprising the isomerase and a 3-phenylpropylamine
derivative compound as described herein and then determining the
level of enzymatic activity of the isomerase. A person having skill
in the art will appreciate that as a control, the level of activity
of the isomerase in the absence of a compound or in the presence of
a compound known not to alter the enzymatic activity of the
isomerase can be determined and compared to the level of activity
in the presence of the compound. A decrease in the level of
isomerase activity in the presence of the compound compared to the
level of isomerase activity in the absence of the compound
indicates that the compound may be useful for treating an
ophthalmic disease or disorder, such as age-related macular
degeneration or Stargardt's disease.
[0386] Animal models may be used to characterize and identify
compounds that may be used to treat retinal diseases and disorders.
A recently developed animal model may be useful for evaluating
treatments for macular degeneration has been described by Ambati et
al. (Nat. Med. 9:1390-97 (2003); Epub 2003 Oct. 19). This animal
model is one of only a few exemplary animal models presently
available for evaluating a compound or any molecule for use in
treating (including preventing) progression or development of a
retinal disease or disorder. Animal models in which the ABCR gene,
which encodes an ATP-binding cassette transporter located in the
rims of photoreceptor outer segment discs, may be used to evaluate
the effect of a compound. Mutations in the ABCR gene are associated
with Stargardt's disease, and heterozygous mutations in ABCR have
been associated with AMD. Accordingly, animals have been generated
with partial or total loss of ABCR function and may used to
characterize the 3-phenylpropylamine derivative compounds described
herein. (See, e.g., Mata et al., Invest. Ophthalmol. Sci.
42:1685-90 (2001); Weng et al., Cell 98:13-23 (1999); Mata et al.,
Proc. Natl. Acad. Sci. USA 97:7154-49 (2000); US 2003/0032078; U.S.
Pat. No. 6,713,300). Other animal models include the use of mutant
ELOVL4 transgenic mice to determine lipofuscin accumulation,
electrophysiology, and photoreceptor degeneration, or prevention or
inhibition thereof (see, e.g., Karan et al., Proc. Natl. Acad. Sci.
USA 102:4164-69 (2005)).
[0387] A method for determining the effect of a compound on
isomerase activity may be performed in vitro as described herein
and in the art (Stecher et al., J. Biol. Chem. 274:8577-85 (1999);
see also Golczak et al., Proc. Natl. Acad. Sci. USA 102:8162-67
(2005)). Retinal pigment epithelium (RPE) microsome membranes
isolated from an animal (such as bovine, porcine, human, for
example) may serve as the source of the isomerase. The capability
of the 3-phenylpropylamine derivative compounds to inhibit
isomerase may also be determined by an in vivo murine isomerase
assay. Brief exposure of the eye to intense light ("photobleaching"
of the visual pigment or simply "bleaching") is known to
photo-isomerize almost all 11-cis-retinal in the retina. The
recovery of 11-cis-retinal after bleaching can be used to estimate
the activity of isomerase in vivo (see, e.g., Maeda et al., J.
Neurochem. 85:944-956 (2003); Van Hooser et al., J. Biol. Chem.
277:19173-82, 2002). Electroretinographic (ERG) recording may be
performed as previously described (Haeseleer et al., Nat. Neurosci.
7:1079-87 (2004); Sugitomo et al., J. Toxicol. Sci. 22 Suppl
2:315-25 (1997); Keating et al., Documenta Ophthalmologica
100:77-92 (2000)). See also Deigner et al., Science, 244: 968-971
(1989); Gollapalli et al., Biochim. Biophys. Acta 1651: 93-101
(2003); Parish, et al., Proc. Natl. Acad. Sci. USA 95:14609-13
(1998); Radu et al., Proc Natl Acad Sci USA 101: 5928-33
(2004).
[0388] In the vertebrate eye, for example, a mammalian eye, the
formation of A2E is a light-dependent process and its accumulation
leads to a number of negative effects in the eye. These include
destabilization of retinal pigment epithelium (RPE) membranes,
sensitization of cells to blue-light damage, and impaired
degradation of phospholipids. Products of the oxidation of A2E (and
A2E related molecules) by molecular oxygen (oxiranes) were shown to
induce DNA damage in cultured RPE cells. All these factors lead to
a gradual decrease in visual acuity and eventually to vision loss.
If reducing the formation of retinals during vision processes were
possible, this reduction would lead to decreased amounts of A2E in
the eye. Decreased accumulation of A2E may reduce or delay
degenerative processes in the RPE and retina and thus may slow down
or prevent vision loss in dry AMD and Stargardt's Disease.
[0389] In another embodiment, the subject is being treated for
Stargardt's disease or Stargardt's macular degeneration. In
Stargardt's disease, which is associated with mutations in the
ABCA4 (also called ABCR) transporter, the accumulation of
all-trans-retinal has been proposed to be responsible for the
formation of a lipofuscin pigment, A2E, which is toxic towards
retinal cells and causes retinal degeneration and consequently loss
of vision.
[0390] In yet another embodiment, the subject is being treated for
age-related macular degeneration (AMD). In some embodiments, AMD is
dry-form. In other embodiments, the AMD condition is dry-form AMD
associated with geographic atrophy. In AMD, vision loss primarily
occurs when complications late in the disease either cause new
blood vessels to grow under the macula or the macula atrophies. The
accumulation of all-trans-retinal has been proposed to be
responsible for the formation of a lipofuscin pigment,
N-retinylidene-N-retinylethanolamine (A2E) and A2E related
molecules, which are toxic towards RPE and retinal cells and cause
retinal degeneration and consequently loss of vision.
[0391] A neurodegenerative retinal disease or disorder for which
the compounds and methods described herein may be used for
treating, curing, preventing, ameliorating the symptoms of, or
slowing, inhibiting, or stopping the progression of, is a disease
or disorder that leads to or is characterized by retinal neuronal
cell loss, which is the cause of visual impairment. Such a disease
or disorder includes but is not limited to age-related macular
degeneration (including dry-form of macular degeneration) and
Stargardt's macular dystrophy.
[0392] Age-related macular degeneration as described herein is a
disorder that affects the macula (central region of the retina) and
results in the decline and loss of central vision. Age-related
macular degeneration occurs typically in individuals over the age
of 55 years. The etiology of age-related macular degeneration may
include both environmental influences and genetic components (see,
e.g., Lyengar et al., Am. J. Hum. Genet. 74:20-39 (2004) (Epub 2003
Dec. 19); Kenealy et al., Mol. Vis. 10:57-61 (2004); Gorin et al.,
Mol. Vis. 5:29 (1999)). More rarely, macular degeneration occurs in
younger individuals, including children and infants, and generally,
these disorders results from a genetic mutation. Types of juvenile
macular degeneration include Stargardt's disease (see, e.g., Glazer
et al., Ophthalmol. Clin. North Am. 15:93-100, viii (2002); Weng et
al., Cell 98:13-23 (1999)); Doyne's honeycomb retinal dystrophy
(see, e.g., Kermani et al., Hum. Genet. 104:77-82 (1999)); Sorsby's
fundus dystrophy, Malattia Levintinese, fundus flavimaculatus, and
autosomal dominant hemorrhagic macular dystrophy (see also Seddon
et al., Ophthalmology 108:2060-67 (2001); Yates et al., J. Med.
Genet. 37:83-7 (2000); Jaakson et al., Hum. Mutat. 22:395-403
(2003)). Geographic atrophy of the RPE is an advanced form of
non-neovascular dry-type age-related macular degeneration, and is
associated with atrophy of the choriocapillaris, RPE, and
retina.
[0393] Stargardt's macular degeneration, a recessive inherited
disease, is an inherited blinding disease of children. The primary
pathologic defect in Stargardt's disease is also an accumulation of
toxic lipofuscin pigments such as A2E in cells of the retinal
pigment epithelium (RPE). This accumulation appears to be
responsible for the photoreceptor death and severe visual loss
found in Stargardt's patients. The compounds described herein may
slow the synthesis of 1-cis-retinaldehyde (11cRAL or retinal) and
regeneration of rhodopsin by inhibiting isomerase in the visual
cycle. Light activation of rhodopsin results in its release of
all-trans-retinal, which constitutes the first reactant in A2E
biosynthesis. Treatment with 3-phenylpropylamine derivative
compounds may inhibit lipofuscin accumulation and thus delay the
onset of visual loss in Stargardt's and AMD patients without toxic
effects that would preclude treatment with a 3-phenylpropylamine
derivative compound. The compounds described herein may be used for
effective treatment of other forms of retinal or macular
degeneration associated with lipofuscin accumulation.
[0394] Administration of a 3-phenylpropylamine derivative compound
as described herein to a subject prevents formation of the
lipofuscin pigment, A2E (and A2E related molecules), that is toxic
towards retinal cells and causes retinal degeneration. In certain
embodiments, administration of the 3-phenylpropylamine derivative
compound lessens the production of waste products, e.g., lipofuscin
pigment, A2E (and A2E related molecules), ameliorate the
development of AMD (e.g., dry-form) and Stargardt's disease, and
subsequently reduce or slow vision loss (e.g., choroidal
neovascularization and/or chorioretinal atrophy). In previous
studies, with 13-cis-retinoic acid (Accutane.RTM. or Isotretinoin),
a drug commonly used for the treatment of acne and an inhibitor of
11-cis-retinol dehydrogenase, has been administered to patients to
prevent A2E accumulation in the RPE. However, a major drawback in
this proposed treatment is that 13-cis-retinoic acid can easily
isomerize to all-trans-retinoic acid. All-trans-retinoic acid is a
very potent teratogenic compound that adversely affects cell
proliferation and development. Retinoic acid also accumulates in
the liver and may be a contributing factor in liver diseases.
[0395] In yet other embodiments, the 3-phenylpropylamine derivative
compound described herein is administered to a subject such as a
human with a mutation in the ABCA4 transporter in the eye. The
3-phenylpropylamine derivative compound described herein is
optionally administered to an aging subject. As used herein, an
aging human subject is typically at least 45, or at least 50, or at
least 60, or at least 65 years old. In Stargardt's disease, which
is associated with mutations in the ABCA4 transporter, the
accumulation of all-trans-retinal has been proposed to be
responsible for the formation of a lipofuscin pigment, A2E (and A2E
related molecules), that is toxic towards retinal cells and causes
retinal degeneration and consequently loss of vision. The
3-phenylpropylamine derivative compound described herein is a
strong inhibitor of an isomerase involved in the visual cycle.
Treating patients with a 3-phenylpropylamine derivative compound as
described herein may prevent or slow the formation of A2E (and A2E
related molecules) and have protective properties for normal
vision.
[0396] As used herein, a patient (or subject) may be any mammal,
including a human, that may have or be afflicted with a
neurodegenerative disease or condition, including an ophthalmic
disease or disorder, or that may be free of detectable disease.
Accordingly, the treatment may be administered to a subject who has
an existing disease, or the treatment may be prophylactic,
administered to a subject who is at risk for developing the disease
or condition. Treating or treatment refers to any indicia of
success in the treatment or amelioration of an injury, pathology or
condition, including any objective or subjective parameter such as
abatement; remission; diminishing of symptoms or making the injury,
pathology, or condition more tolerable to the patient; slowing in
the rate of degeneration or decline; making the final point of
degeneration less debilitating; or improving a subject's physical
or mental well-being.
[0397] The treatment or amelioration of symptoms is based on
objective or subjective parameters; including the results of a
physical examination. The term "therapeutic effect" refers to the
reduction, elimination, or optionally, prevention of the disease,
symptoms of the disease, or sequelae of the disease in the subject.
Treatment also includes restoring or improving retinal neuronal
cell functions (including photoreceptor function) in a vertebrate
visual system, for example, such as visual acuity and visual field
testing etc., as measured over time (e.g., as measured in weeks or
months). Treatment also includes stabilizing disease progression
(i.e., slowing, minimizing, or halting the progression of an
ophthalmic disease and associated symptoms) and minimizing
additional degeneration of a vertebrate visual system. Treatment
also optionally includes prophylaxis and refers to the
administration of a 3-phenylpropylamine derivative compound as
described herein to a subject to prevent degeneration or further
degeneration or deterioration or further deterioration of the
vertebrate visual system of the subject and to prevent or inhibit
development of the disease and/or related symptoms and
sequelae.
[0398] Various methods and techniques practiced by a person skilled
in the medical and ophthalmological arts to determine and evaluate
a disease state and/or to monitor and assess a therapeutic regimen
include, for example, fluorescein angiogram, fundus photography,
indocyanine green dye tracking of the choroidal circulatory system,
opthalmoscopy, optical coherence tomography (OCT), and visual
acuity testing.
[0399] A fluorescein angiogram involves injecting a fluorescein dye
intravenously and then observing any leakage of the dye as it
circulates through the eye. Intravenous injection of indocyanine
green dye may also be used to determine if vessels in the eye are
compromised, particularly in the choroidal circulatory system that
is just behind the retina. Fundus photography may be used for
examining the optic nerve, macula, blood vessels, retina, and the
vitreous. Microaneurysms are visible lesions in diabetic
retinopathy that may be detected in digital fundus images early in
the disease (see, e.g., U.S. Patent Application Publication No.
2007/0002275). An ophthalmoscope may be used to examine the retina
and vitreous. Opthalmoscopy is usually performed with dilated
pupils, to allow the best view inside the eye. Two types of
ophthalmoscopes may be used: direct and indirect. The direct
ophthalmoscope is generally used to view the optic nerve and the
central retina. The periphery, or entire retina, may be viewed by
using an indirect ophthalmoscope. Optical coherence tomography
(OCT) produces high resolution, high speed, non-invasive,
cross-sectional images of body tissue. OCT is noninvasive and
provides detection of microscopic early signs of disruption in
tissues.
[0400] A subject or patient refers to any vertebrate or mammalian
patient or subject to whom the compositions described herein is
administered. The term "vertebrate" or "mammal" includes humans and
non-human primates. Subjects in need of treatment using the methods
described herein are identified according to accepted screening
methods in the medical art that are employed to determine risk
factors or symptoms associated with an ophthalmic disease or
condition described herein or to determine the status of an
existing ophthalmic disease or condition in a subject. These and
other routine methods allow the clinician to select patients in
need of therapy using the methods and formulations described
herein.
[0401] Other embodiments and uses will be apparent to one skilled
in the art in light of the present disclosures. The following
examples are provided merely as illustrative of various embodiments
and shall not be construed to limit the invention in any way.
EXAMPLES
I. Chemical Synthesis
[0402] Unless otherwise noted, reagents and solvents were used as
received from commercial suppliers. Anhydrous solvents and
oven-dried glassware were used for synthetic transformations
sensitive to moisture and/or oxygen. Yields were not optimized.
Reaction times are approximate and were not optimized. Flash column
chromatography and thin layer chromatography (TLC) were performed
on silica gel unless otherwise noted. Proton and carbon nuclear
magnetic resonance spectra were obtained with a Varian VnmrJ 400 at
400 MHz for proton and 100 MHz for carbon. Spectra are given in ppm
(.delta.) and coupling constants, J are reported in Hertz. For
proton spectra the solvent peak was used as the reference peak. For
carbon spectra the solvent peak was used as the reference.
HPLC/LC-MS was performed using the following method: Agilent HP
1100 system with diode array detection at 220 nm on Phenomenex
Gemini 4.6.times.150 mm 5.mu. column, mobile phase 0.05% TFA
CH.sub.3CN/H.sub.2O gradient with mass-spectral detection using
electrospray ionization (ES+) mode.
Intermediate I--Preparation of (R)-tert-Butyl
(3-hydroxy-3-(3-hydroxyphenyl)propyl)-carbamate
##STR00128##
[0404] (R)-tert-Butyl
(3-hydroxy-3-(3-hydroxyphenyl)propyl)carbamate was prepared
following the method shown in Scheme 1:
##STR00129##
[0405] Step 1: K.sub.2CO.sub.3 (66.8 g, 0.48 mol) was added to a
stirred solution of ethyl 3-hydroxybenzoate (1) (40.0 g, 0.24 mol)
and (chloromethyl)benzene (33.5 g, 0.26 mol) in DMF (256 mL) and
the reaction mixture was heated at 90 OC for 3 h. The reaction
mixture was filtered through Celite, the filtrate was diluted with
water (500 mL), extracted with EtOAc (500 mL). The organic layer
was washed with brine (500 mL), dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure to give
ethyl 3-(benzyloxy)benzoate (2) as colorless liquid. Yield (61.0 g,
98%); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.56-7.53 (m,
2H), 7.47-7.44 (m, 3H), 7.39 (t, J=7.2 Hz, 2H), 7.35-7.29 (m, 2H),
5.17 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H).
[0406] Step 2: n-BuLi (1.6 M in hexanes, 146 mL, 234 mmol) was
added dropwise at -78.degree. C. to a solution of CH.sub.3CN (10.39
mL, 199 mmol) in THF (600 mL) and the reaction mixture was stirred
for 30 min. A solution of ester (2) (30.0 g, 117 mmol) in THF (50
mL) was added and the mixture was further stirred for 30 min at
-78.degree. C. The reaction mixture was quenched at -78.degree. C.
by addition of aqueous NH.sub.4Cl (200 mL), diluted with EtOAc (500
mL), the organic layer was dried over anhydrous Na.sub.2SO.sub.4
and concentrated under reduced pressure to give
3-(3-(benzyloxy)phenyl)-3-oxopropanenitrile (3) as a pale yellow
solid. Yield (25.0 g, 85%); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.53 (s, 1H), 7.48-7.36 (m, 6H), 7.35-7.33 (m, 1H),
7.27-7.26 (m, 1H), 5.12 (s, 2H), 4.05 (s, 2H).
[0407] Step 3: HCOOH (30.75 mL, 795 mmol) was added dropwise to a
cooled (0.degree. C.) solution of Et.sub.3N (41.0 mL, 318 mmol) in
EtOAc (400 mL) while maintaining the temperature at 0.degree. C.
(R,R)--RuCl-TsDPEN(p-cymene) (100 mg, 0.2 mol %) was added to the
reaction mixture followed by the addition of oxonitrile (3) (40.0
g, 159 mmol) and the reaction mixture was stirred at room
temperature for 24 h. NaHCO.sub.3 (10%, 500 mL) was added and the
mixture was extracted with EtOAc (500 mL). Organic layer was dried
over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced
pressure to give (R)-3-(3
-(benzyloxy)phenyl)-3-hydroxypropanenitrile (4) as a pale yellow
solid. Yield (38.0 g, 95%); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.46-7.44 (m, 2H), 7.41-7.37 (m, 2H), 7.33 (t, J=7.2 Hz,
1H), 7.26 (t, J=8.0 Hz, 1H), 7.07 (s, 1H), 6.99 (d, J=7.6 Hz, 1H),
6.92 (d, J=8.0 Hz, 1H), 5.95 (d, J=4.4 Hz, 1H), 5.09 (s, 2H), 4.86
(d, J=5.2 Hz, 1H), 2.90 (dd, J=16.8, 4.8 Hz, 1H), 2.80 (dd, J=16.8,
6.8 Hz, 1H).
[0408] Step 4: BH.sub.3-Me.sub.2S complex (35.5 mL, 355.7 mmol) was
added to the solution of (R)-hydroxynitrile (4) (30.0 g, 118.6
mmol) in THF (150 mL) and the reaction mixture was heated at 70 OC
under reflux for 18 h. The reaction mixture was quenched with MeOH
(50 mL), dioxane/HCl (30 mL) was added and the reaction mixture was
further heated under reflux for 1 h. The reaction mixture was
concentrated under reduced pressure to give
(R)-3-amino-1-(3-(benzyloxy)phenyl)propan-1-ol hydrochloride (5) as
a white solid. Yield (31.0 g, 89%); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.87 (bs, 3H), 7.45 (d, J=7.2 Hz, 2H), 7.39
(t, J=7.2 Hz, 2H), 7.34-7.31 (m, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.0
(s, 1H), 6.92-6.88 (m, 2H), 5.56 (d, J=4.4 Hz, 1H), 5.09 (s, 2H),
4.66 (q, J=4.0 Hz, 1H), 3.56 (s, 2H), 2.87-2.82 (m, 2H), 1.89-1.76
(m, 2H).
[0409] Step 5: Et.sub.3N (24.27 mL, 174.84 mmol) was added at 0 OC
to a mixture of amine (5) (30 g, 116.6 mmol) and CH.sub.2Cl.sub.2
(150 mL) and the resulting mixture was stirred for 1 h. Boc.sub.2O
(32.13 mL, 139.9 mmol) was added to the reaction mixture and the
latter was further stirred for 18 h at rt. The reaction mixture was
diluted with H.sub.2O (100 mL), extracted with CH.sub.2Cl.sub.2
(500 mL), organic layer was dried over anhydrous Na.sub.2SO.sub.4
and concentrated under reduced pressure to give (R)-tert-butyl
3-(3-(benzyloxy)phenyl)-3-hydroxypropylcarbamate (6) as colorless
oil. Yield (41.0 g, 98%); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.45 (d, J=7.2 Hz, 2H), 7.39 (t, J=7.2 Hz, 2H), 7.34-7.30
(m, 1H), 7.21 (t, J=8.0 Hz, 1H), 6.98 (s, 1H), 6.90-6.84 (m, 2H),
6.76 (s, 1H), 5.20 (d, J=4.8 Hz, 1H), 5.11 (s, 2H), 4.53-4.49 (m,
1H), 2.99-2.94 (m, 2H), 1.67 (q, J=6.8 Hz, 2H), 1.37 (s, 9H).
[0410] Step 6: A solution of carbamate (6) (41.0 g, 115 mmol) in
EtOH (500 mL) was degassed by applying vacuum once. Pd/C (10% wt,
20.0 g) was added and the mixture was degassed by alternating
vacuum/H.sub.2 three times. The reaction mixture was stirred under
H.sub.2 pressure of 50 psi for 4 h. The reaction mixture was
filtered through Celite, the filtrate was concentrated in vacuum
and the residue was purified by crystallization (10% EtOAc in
hexane) to give (R)-tert-butyl
3-hydroxy-3-(3-hydroxyphenyl)propyl-carbamate (Intermediate I) as a
white solid. Yield (24.0 g, 78%); .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 9.25 (s, 1H), 7.07 (t, J=7.6 Hz, 1H),
6.75-6.69 (m, 3H), 6.59 (d, J=8.0 Hz, 1H), 5.11 (d, J=4.0 Hz, 1H),
4.46-4.42 (m, 1H), 2.96 (t, J=6.8 Hz, 2H), 1.66-1.61 (m, 2H), 1.36
(s, 9H); RP-HPLC: t.sub.R=1.51 min, 98.13% (AUC); ESI MS m/z
266.28[M-H]+; Chiral HPLC 97.5% (R)-isomer.
Stereochemical Correlation of Intermediate I--Preparation of
(R)-3-amino-1-phenylpropan-1-ol from Intermediate I NH.sub.2
##STR00130##
[0412] (R)-3-Amino-1-phenylpropan-1-ol was prepared following the
method shown below:
##STR00131##
[0413] Step 1: Et.sub.3N (1.5 mL, 10.76 mmol) was added to a
suspension of Intermediate I (1.00 g, 3.74 mmol) in anhydrous
CH.sub.2Cl.sub.2 (20 mL), and a clear solution resulted. The
reaction mixture was cooled to 0 OC under N.sub.2 and Tf.sub.2O
(0.7 mL, 4.14 mmol) was added slowly via syringe. The reaction
mixture was stirred for 2 h, water was added and the mixture was
extracted with CH.sub.2Cl.sub.2 twice. Combined organic layers were
washed with brine and concentrated under reduced pressure.
Purification by flash chromatography (10%-50% EtOAc-hexanes
gradient) gave
(R)-3-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenyl
trifluoromethanesulfonate as a colorless oil. Yield (1.10 g, 74%);
.sup.1H NMR (400 MHz, DMSO-d.sub.6); .delta. 7.45-7.52 (m, 1H),
7.39-7.43 (m, 1H), 7.33-7.38 (m, 1H), 7.27-7.32 (m, 1H), 6.72 (br.
t, 1H), 5.45 (d, J=4.7 Hz, 1H), 4.56-4.66 (m, 1H), 2.86-3.2 (m,
2H), 1.60-1.70 (m, 2H), 1.33 (s, 9H).
[0414] Step 2: Et.sub.3N (2.0 mL, 14.35 mmol) and HCOOH (0.4 mL,
10.60 mmol) were added to a solution of
(R)-3-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenyl
trifluoromethanesulfonate (1.05 g, 2.63 mmol) and Ar was bubbled
through the mixture for one minute.
1,3-Bis(diphenylphosphino)propane (1,3-dppp) (0.080 g, 0.194 mmol)
and Pd(OAc).sub.2 (0.050 g, 0.223 mmol) were added to the reaction
mixture and the later was degassed by applying vacuum/Ar cycle
three times. The reaction mixture was heated at +60.degree. C. for
5 h and concentrated under reduced pressure. Aqueous NH.sub.4Cl
(25%) was added to the residue and the mixture was extracted with
MTBE twice. Combined organic layers were washed with brine and
concentrated under reduced pressure. Purification by flash
chromatography (10%-50% EtOAc-hexanes gradient) gave (R)-tert-butyl
(3-hydroxy-3-phenylpropyl)carbamate as a colorless oil. Yield (0.64
g, 97%); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.22-7.30 (m,
4H), 7.14-7.21 (m, 1H), 6.72 (br. t, 1H), 5.14 (d, J=4.4 Hz, 1H),
4.51 (dd, J=6.5, 10.9 Hz, 1H), 2.87-2.98 (m, 2H), 1.60-1.70 (m,
2H), 1.33 (s, 9H).
[0415] Step 3: Deprotection of (R)-tert-butyl
(3-hydroxy-3-phenylpropyl)carbamate following the method used in
Example 1 (method 2, step 2) gave (R)-3-amino-1-phenylpropan-1-ol
hydrochloride. The salt was dissolved in MeOH and treated with 7N
NH.sub.3/MeOH. The mixture was concentrated under reduced pressure.
Purification by flash chromatography (4%-20% 4N
NH.sub.3/MeOH--CH.sub.2Cl.sub.2 gradient) gave
(R)-3-amino-1-phenylpropan-1-ol. Yield (0.18 g, 47%); .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 7.26-7.38 (m, 4H), 7.18-7.25 (m, 1H),
4.71 (dd, J=5.4, 8.3 Hz, 1H), 2.65-2.77 (m, 2H), 1.77-1.94 (m, 2H);
[.alpha.].sub.D=+43.3.degree. (23.degree. C., c=1.6 g/100 mL in
EtOH, 1.0 dm path, 589 nM). Literature (Mitchell, D.; Koenig, T. M.
Synthetic Communications, 1995, 25(8), 1231-1238.): +40.50.
Conclusion: The optical rotation of (R)-3-amino-1-phenylpropan-1-ol
matched the value reported in the literature, thus Intermediate I
and Example 1 are of (R)-configuration.
Example 1
Preparation of
(R)-3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-propan-1-ol
by method 1
##STR00132##
[0417]
(R)-3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-
-ol was prepared following the method shown in Scheme 2:
##STR00133##
[0418] Step 1: Ethyl tetrahydro-2H-pyran-4-carboxylate (5.0 g, 34.7
mmol) was added to a stirred solution of LiAlH.sub.4 (4.0 g, 104
mmol) in THF (100 mL) at 0 OC and the reaction mixture was stirred
for 1 h. Ethyl acetate (20 mL) was added dropwise to the reaction
mixture followed by addition of 10% aq.NaOH and the resulting
mixture was stirred for additional 30 min. Reaction mass was
filtered through Celite and the filtrate was concentrated under
reduced pressure to give (tetrahydro-2H-pyran-4-yl)methanol (9) as
a colorless oil. Yield (3.9 g, 96%); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 4.46 (bs, 1H), 3.82 (dd, J=10.8, 8.0 Hz, 2H),
3.25-3.22 (m, 4H), 1.62-1.52 (m, 3H), 1.18-1.04 (m, 1H).
[0419] Step 2: TsCl (7.22 g, 37.9 mmol) was added portionwise to a
solution of alcohol (9) (4.0 g, 34.44 mmol), Et.sub.3N (7.0 g, 69
mmol) and DMAP (0.05 g, 0.35 mmol) in dry DCM (50 mL) at 0.degree.
C. The reaction mixture was allowed to warm to room temperature and
further stirred for 1 h. The reaction mixture was diluted with
water, extracted with EtOAc, dried over anhydrous Na.sub.2SO.sub.4
and concentrated under reduced pressure to give
(tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzene-sulfonate (10) as
white solid. Yield (8.5 g, 91%); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.78 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz,
2H), 3.87 (d, J=6.4 Hz, 2H), 3.78 (dd, J=11.2, 4.2 Hz, 2H), 3.22
(dt, J=11.6, 1.6 Hz, 2H), 2.42 (s, 3H), 1.88-1.79 (m, 1H), 1.46
(dd, J=12.8, 1.6 Hz, 2H), 1.18-1.07 (m, 2H).
[0420] Step 3: K.sub.2CO.sub.3 (8.2 g, 59.2 mmol) was added to a
stirred solution of methyl 3-hydroxybenzoate (11) (3.0 g, 19.72
mmol) sulfonate (10) (5.33 g, 19.72 mmol) in DMF (30 mL) and the
reaction mixture was stirred at 90 OC for 16 h. The reaction
mixture was concentrated under reduced pressure. Purification by
column chromatography (100-200 silica mesh, 30% EtOAc in hexanes)
gave methyl 3-((tetrahydro-2H-pyran-4-yl)methoxy)benzoate (12) as a
light yellow solid. Yield (4.8 g, 97%); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.53 (d, J=7.6 Hz, 1H), 7.44-7.40 (m, 2H),
7.22 (dd, J=8.4, 2.4 Hz, 1H), 3.88-3.82 (m, 7H), 3.32 (t, J=1.2 Hz,
2H), 2.02-1.96 (m, 1H), 1.69-1.66 (m, 2H), 1.38-1.28 (m, 2H).
[0421] Step 4: The solution of CH.sub.3CN (0.37 g, 8.9 mmol) in THF
(40 mL) was added to n-BuLi (1.6 M in hexanes, 0.58 g, 8.9 mmol) at
-78.degree. C. and the reaction mixture was stirred for 30 min.
Solution of ester (12) (1.5 g, 5.9 mmol) in THF (10 mL) was added
to the reaction mixture and the resulting solution was further
stirred for 30 min. The reaction mixture was quenched by addition
of aq.NH.sub.4Cl (200 mL) and extracted with EtOAc (100 mL). Drying
over anhydrous Na.sub.2SO.sub.4 and concentration under reduced
pressure gave
3-oxo-3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propanenitrile
(13). Yield (1.5 g, 96%); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.43-7.37 (m, 3H), 7.26-7.21 (m, 1H), 4.75 (bs, 2H),
3.89-3.83 (m, 4H), 3.32 (t, J=11.6 Hz, 2H), 2.03-1.98 (m, 1H),
1.69-1.66 (m, 2H), 1.38-1.28 (m, 2H).
[0422] Step 5: The solution of Et.sub.3N (0.78 g, 7.6 mmol) in
EtOAc (50 mL) was cooled to 0.degree. C. for 15 min. HCOOH (0.88 g,
19 mmol) was added dropwise to the reaction mixture and the
solution was stirred for 20 min at same temperature. The solution
of 0.2 mol % (R,R)RuCl-TsDPEN(p-cymene) (10 mg) in EtOAc was added
to the reaction mixture, followed by addition of ketonitrile (13)
(1.0 g, 3.8 mmol) in EtOAc at 0 OC. The reaction mixture was
stirred for 18 h at rt. After completion of the reaction (as
monitored by TLC) the reaction mixture was diluted with water,
extracted with EtOAc, dried over anhydrous Na.sub.2SO.sub.4, and
concentrated under reduced pressure. Purification by column
chromatography (100-200 silica mesh, 20-25% EtOAc in hexanes) gave
(R)-3-hydroxy-3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propane-
nitrile (14) as a white solid. Yield (0.75 g, 75%); .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.24 (t, J=8.0 Hz, 1H), 6.98-6.95
(m, 2H), 6.83 (dd, J=8.0, 4.0 Hz, 1H), 5.92 (d, J=4.8 Hz, 1H), 4.85
(dd, J=11.2, 4.8 Hz, 1H), 3.89-3.81 (m, 4H), 3.35-3.30 (m, 2H),
2.84 (dq, J=16.8, 4.8 Hz, 2H), 2.04-1.96 (m, 1H), 1.69-1.66 (m,
2H), 1.37-1.27 (m, 2H).
[0423] Step 6: BH.sub.3-DMS (0.56 g, 7.4 mmol) was added dropwise
to a solution of hydroxynitrile (14) (0.65 g, 2.4 mmol) in dry THF
(50 mL). The reaction mixture was refluxed 18 h at 65.degree. C.
After completion of the reaction (as monitored by TLC) the MeOH (15
mL) was added to the reaction mixture which was stirred at rt for
an additional 1 h. The mixture was then concentrated under reduced
pressure followed by purification by column chromatography (100-200
silica mesh, 4-6% MeOH in DCM) to give Example 1 as a white solid.
Yield (0.75 g, 99%); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.80 (bs, 3H), 7.24 (t, J=8.0 Hz, 1H), 6.89-6.87 (m, 2H), 6.82-6.80
(m, 1H), 5.54 (bs, 1H), 4.65 (bs, 1H), 3.87 (dd, J=11.4, 2.8 Hz,
2H), 3.81 (d, J=6.4 Hz, 2H), 3.37-3.30 (m, 2H), 2.87-2.79 (m, 2H),
2.02-1.96 (m, 1H), 1.88-1.80 (m, 2H), 1.69-1.65 (m, 2H), 1.34-1.27
(m, 2H); RP HPLC t.sub.R=1.10 min, 94.5% (AUC); ESI MS m/z 266.27
[M+H].sup.+.
Example 1
Preparation of
(R)-3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-propan-1-ol
by method 2
##STR00134##
[0425]
(R)-3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propa-
n-1-ol was prepared following the method shown below.
##STR00135##
[0426] Step 1: Cs.sub.2CO.sub.3 (2.34 g, 7.18 mmol) was added to a
solution of (tetrahydro-2H-pyran-4-yl)methyl methanesulfonate (1.05
g, 5.41 mmol) and Intermediate I (1.13 g, 4.23 mmol) in anhydrous
DMF (11 mL) and the reaction mixture was heated at +70 OC under Ar
for 22 hrs. Aqueous NH.sub.4Cl (25%) was added and the reaction
mixture was extracted with MTBE twice. Combined organic layers were
washed with brine, concentrated under reduced pressure.
Purification by flash chromatography (25%-100% EtOAc-hexanes
gradient) gave (R)-tert-butyl
(3-hydroxy-3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propyl)carbamat-
e as a colorless oil. Yield (0.47 g, 30%); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.18 (t, J=8.0 Hz, 1H), 6.85-6.84 (m, 2H),
6.76-6.74 (m, 2H), 5.15 (d, J=4.4 Hz, 1H), 4.49 (q, J=4.4 Hz, 1H),
3.88-3.84 (m, 2H), 3.79 (d, J=6.4 Hz, 2H), 2.94 (q, J=6.4 Hz, 2H),
1.70-1.62 (m, 4H), 1.38-1.26 (m, 11H).
[0427] Step 2: HCl/i-PrOH (5.5 M, 3 mL) was added to a solution of
(R)-tert-butyl
(3-hydroxy-3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propyl)carbamat-
e (0.45 g, 1.23 mmol) in EtOAc (5 mL). The reaction mixture was
stirred for 5.5 hrs at room temperature, concentrated under reduced
pressure. The residue was dissolved in boiling 25% i-PrOH/EtOAc,
cooled to room temperature and sonicated. White precipitate was
collected by filtration, washed with EtOAc and hexanes, dried to
give Example 1 hydrochloride as a white solid. Yield (0.244 g,
66%); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.85 (s, 3H),
7.20 (t, J=7.8 Hz, 1H), 6.82-6.90 (m, 2H), 6.75-6.80 (m, 1H), 5.49
(d, J=4.4 Hz, 1H), 4.62 (m, 1H), 3.84 (dd, J=3.0, 11.3 Hz, 2H),
3.78 (d, J=6.3 Hz, 2H), 3.24-3.35 (m, 2H), 2.78 (br. s, 2H),
1.90-2.05 (m, 1H), 1.74-1.88 (m, 2H), 1.60-1.68 (m, 2H), 1.23-1.35
(m, 2H); [.alpha.].sub.D=+30.9.degree. (23.degree. C., c=1.5 g/100
mL in EtOH, 1.0 dm path, 589 nM).
Example 2
Preparation of
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
##STR00136##
[0429]
3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
was prepared following method 1 used in Example 1:
[0430] Step 1: BH.sub.3-Me.sub.2S (0.43 g, 5.8 mmol) was added
dropwise to a solution of ketonitrile (13) (0.5 g, 1.9 mmol) in THF
(50 mL). The reaction mixture was heated at 65.degree. C. under
reflux for 18 h. After completion of the reaction (as monitored by
TLC) the reaction mixture was quenched by MeOH (15 mL) and stirred
at rt for an additional 1 h. The reaction mixture was concentrated
and purification by column chromatography (100-200 silica mesh,
4-6% MeOH in DCM) gave Example 2 as a pale yellow semi-solid. Yield
(0.48 g, 96%); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.80
(bs, 3H), 7.24 (t, J=8.0 Hz, 1H), 6.89-6.87 (m, 2H), 6.82-6.80 (m,
1H), 5.54 (bs, 1H), 4.65 (bs, 1H), 3.87 (dd, J=11.4, 2.8 Hz, 2H),
3.81 (d, J=6.4 Hz, 2H), 3.37-3.30 (m, 2H), 2.87-2.79 (m, 2H),
2.02-1.96 (m, 1H), 1.88-1.80 (m, 2H), 1.69-1.65 (m, 2H), 1.34-1.27
(m, 2H); RP HPLC: t.sub.R=3.89 min, 95% (AUC); ESI MS m/z 266.27
[M+H].sup.+.
Example 3
Preparation of
(1R)-3-amino-1-(3-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)propan-1-ol
##STR00137##
[0432]
(1R)-3-Amino-1-(3-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)propan--
1-ol was prepared following the method used in Example 1:
[0433] Step 1: Reaction between (tetrahydro-2H-pyran-3-yl)methyl
4-methylbenzenesulfonate and phenol (11) following the method used
in Example 1 gave methyl
3-((tetrahydro-2H-pyran-3-yl)methoxy)benzoate as a white solid.
Yield (88%); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.53 (d,
J=7.6 Hz, 1H), 7.44-7.38 (m, 2H), 7.22 (dd, J=8.4, 2.0 Hz, 1H),
3.91-3.86 (m, 3H), 3.84 (s, 3H), 3.75-3.71 (m, 1H), 3.38-3.35 (m,
1H), 3.29-3.24 (m, 1H), 2.00-1.99 (m, 1H), 1.85-1.82 (m, 1H),
1.60-1.58 (m, 1H), 1.52-1.49 (m, 1H), 1.41-1.38 (m, 1H).
[0434] Step 2: Reaction between methyl
3-((tetrahydro-2H-pyran-3-yl)methoxy)benzoate and CH.sub.3CN
following the method used in Example 1 gave
3-oxo-3-(3-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)propanenitrile
as a white solid. Yield (84%); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.52-7.45 (m, 2H), 7.43 (s, 1H), 7.29-7.26 (m, 1H), 4.75
(s, 2H), 3.93-3.87 (m, 3H), 3.75-3.71 (m, 1H), 3.39-3.36 (m, 1H),
3.28-3.25 (m, 1H), 2.01-1.98 (m, 1H), 1.86-1.83 (m, 1H), 1.60-1.58
(m, 1H), 1.53-1.49 (m, 1H), 1.42-1.39 (m, 1H).
[0435] Step 3: Reduction of
3-oxo-3-(3-((tetrahydro-2H-pyran-3-yl)methoxy)phenyl)propanenitrile
following the method used in Example 1 gave Example 3 as a mixture
of diastereomers as a white solid. Yield (81%); .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 7.73 (bs, 3H), 7.24 (t, J=7.6 Hz, 1H),
6.89-6.88 (m, 2H), 6.81 (dd, J=8.4, 2.0 Hz, 1H), 5.54 (bs, 1H),
4.85 (dd, J=8.0, 4.8 Hz, 1H), 3.89-3.81 (m, 3H), 3.75-3.72 (m, 1H),
3.38-3.35 (m, 1H), 3.28-3.23 (m, 1H), 2.85-2.80 (m, 2H), 1.98 (bs,
1H), 1.86-1.80 (m, 3H), 1.59-1.52 (m, 2H), 1.40-1.37 (m, 1H); RP
HPLC: t.sub.R=1.31 min, 98.8% (AUC); ESI MS m/z 266.31
[M+H].sup.+.
Example 4
Preparation of
(R)-3-amino-1-(3-(pyridin-4-ylmethoxy)phenyl)propan-1-ol
##STR00138##
[0437] (R)-3-amino-1-(3-(pyridin-4-ylmethoxy)phenyl)propan-1-ol was
prepared following the method shown in Scheme 3:
##STR00139##
[0438] Step 1: 4-(Bromomethyl)pyridine (298 mg, 1.17 mmol) and
K.sub.2CO.sub.3 (774 mg, 5.61 mmol) were added to a solution of
phenol (7, Intermediate I) (300 mg, 1.12 mmol) in acetone (20 mL).
The reaction mixture was stirred overnight at ambient temperature,
diluted with EtOAc and water. The organic layer was washed with 5%
aq. NaOH, dried over anhydrous Na.sub.2SO.sub.4 and concentrated
under reduced pressure. Purification by flash chromatography (50%
EtOAc:hexane) gave (R)-tert-butyl
(3-hydroxy-3-(3-(pyridin-4-ylmethoxy)phenyl)propyl)carbamate (15)
as dark brown solid. Yield (0.183 g, 46%); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.61 (d, J=5.2 Hz, 2H), 7.36 (d, J=5.2 Hz,
2H), 7.28-7.24 (m, 1H), 7.03 (s, 1H), 6.96 (d, J=8.0 Hz, 1H),
6.85-6.83 (m, 1H), 5.10 (s, 2H), 4.86 (bs, 1H), 4.74-4.71 (m, 1H),
3.52-3.49 (m, 1H), 3.39 (bs, 1H), 3.19-3.12 (m, 1H), 1.86-1.77 (m,
2H), 1.45 (s, 9H); MS: m/z 359.19 [M+H].sup.+.
[0439] Step 2: HCl/dioxane (4M, 3 mL) was added at 0.degree. C. to
a solution of carbamate (15) (0.16 g, 0.44 mmol) in methanol (5 mL)
and the reaction mixture was stirred at ambient temperature for 2
h. The reaction mixture was concentrated under reduced pressure to
give after trituration in diethyl ether Example 4 hydrochloride as
a white solid. Yield (0.130 g, 98%); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.83 (d, J=6.0 Hz, 2H), 7.89-7.85 (m, 5H),
7.29 (t, J=8.0 Hz, 1H), 7.05 (s, 1H), 6.97-6.91 (m, 2H), 5.39 (s,
2H), 4.69-4.66 (m, 1H), 2.83 (bs, 2H), 1.92-1.79 (m, 2H); MS: m/z
259.22 [M+H].sup.+.
Example 5
Preparation of
(R)-3-amino-1-(3-(pyridin-3-ylmethoxy)phenyl)propan-1-ol
##STR00140##
[0441] (R)-3-Amino-1-(3-(pyridin-3-ylmethoxy)phenyl)propan-1-ol was
prepared following the method used in Example 4:
[0442] Step 1: Reaction between 3-(bromomethyl)pyridine and phenol
(7, Intermediate I) following the method used in Example 4 gave
after purification by flash chromatography (50% EtOAc:hexane)
(R)-tert-butyl
(3-hydroxy-3-(3-(pyridin-3-ylmethoxy)phenyl)propyl)carbamate as a
pale yellow solid. Yield (0.17 g, 41%); .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.68 (s, 1H), 8.58 (s, 1H), 7.78 (d, J=8.0 Hz,
1H), 7.34-7.31 (m, 1H), 7.29-7.26 (m, 1H), 7.04 (s, 1H), 6.96 (d,
J=8.0 Hz, 1H), 6.88-6.85 (m, 1H), 5.09 (s, 2H), 4.86 (bs, 1H),
4.73-4.71 (m, 1H), 3.50-3.49 (m, 1H), 3.32 (bs, 1H), 3.20-3.12 (m,
1H), 1.87-1.82 (m, 2H), 1.45 (s, 9H); MS: m/z 359.26
[M+H].sup.+.
[0443] Step 2: Deprotection of (R)-tert-butyl
(3-hydroxy-3-(3-(pyridin-3-ylmethoxy)phenyl)propyl)carbamate
following the method used in Example 4 gave Example 5 hydrochloride
as a yellow semi-solid. Yield (0.12 g, 98%); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.80 (s, 1H), 8.68 (d, J=6.0 Hz, 1H), 8.14
(bs, 1H), 7.72 (br.s., 4H), 7.29 (t, J=1.6 Hz, 1H), 7.02 (s, 1H),
6.94 (d, J=8.0 Hz, 2H), 5.21 (s, 2H), 4.68-4.65 (m, 1H), 2.84
(br.s., 2H), 1.86-1.80 (m, 2H); MS: m/z 259.26 [M+H].sup.+.
Example 6
Preparation of
(R)-3-amino-1-(3-(pyridin-2-ylmethoxy)phenyl)propan-1-ol
##STR00141##
[0445] (R)-3-amino-1-(3-(pyridin-2-ylmethoxy)phenyl)propan-1-ol was
prepared following the method used in Example 4:
[0446] Step 1: Reaction between 2-(bromomethyl)pyridine and phenol
(7, Intermediate I) following the method used in Example 4 gave
after purification by flash chromatography (40% EtOAc:hexane)
(R)-tert-butyl
(3-hydroxy-3-(3-(pyridin-2-ylmethoxy)phenyl)propyl)carbamate as a
pale yellow solid. Yield (0.26 g, 88%); .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 8.59 (d, J=4.8 Hz, 1H), 7.71 (t, J=7.6, 1.6
Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.27-7.20 (m, 2H), 7.03 (s, 1H),
6.96 (d, J=10.4 Hz, 1H), 6.87 (d, J=5.6 Hz, 1H), 5.21 (s, 2H), 4.87
(bs, 1H), 4.73-4.70 (m, 1H), 3.50-3.48 (m, 1H), 3.21-3.11 (m, 1H),
1.84-1.61 (m, 2H), 1.45 (s, 9H); MS: m/z 359.26 [M+H].sup.+.
[0447] Step 2: Deprotection of (R)-tert-butyl
(3-hydroxy-3-(3-(pyridin-2-ylmethoxy)phenyl)propyl)carbamate
following the method used in Example 4 gave after purification by
flash chromatography (5% MeOH: CH.sub.2Cl.sub.2) followed by
trituration in diethyl ether Example 5 hydrochloride as a white
solid. Yield (0.25 g, 96%); .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.64 (d, J=4.8 Hz, 1H), 7.96 (t, J=8.4 Hz, 1H), 7.75 (s,
3H), 7.61 (d, J=8.0 Hz, 1H), 7.47-7.44 (m, 1H), 7.27 (t, J=8.0 Hz,
1H), 7.02 (s, 1H), 6.94-6.90 (m, 2H), 5.22 (s, 2H), 4.67-4.64 (m,
1H), 2.83 (bs, 2H), 1.87-1.80 (m, 2H); MS: m/z 259.26
[M+H].sup.+.
Example 7
Preparation of
(1R)-3-amino-1-(3-((tetrahydro-2H-thiopyran-3-yl)methoxy)phenyl)propan-1--
ol
##STR00142##
[0449]
(1R)-3-Amino-1-(3-((tetrahydro-2H-thiopyran-3-yl)methoxy)phenyl)pro-
pan-1-ol was prepared following the method below.
[0450] Step 1: K.sub.2CO.sub.3 (0.72 g, 5.24 mmol) and phenol (7,
Intermediate I) (0.3 g, 1.05 mmol) were added to a solution of
(tetrahydro-2H-thiopyran-3-yl)methyl 4-methylbenzenesulfonate (0.29
g, 1.10 mmol) in DMF (10 mL). The reaction mixture was heated at
100 OC under reflux overnight and then cooled. The reaction mixture
was extracted with EtOAc, organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Purification by flash chromatography (EtOAc:hexane 10-40% gradient)
gave tert-butyl
((3R)-3-hydroxy-3-(3-((tetrahydro-2H-thiopyran-3-yl)methoxy)phenyl)propyl-
)carbamate as a light green solid. Yield (0.21 g, 52%); .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 7.24 (t, J=8.0 Hz, 1H), 6.91 (d,
J=8.0 Hz, 2H), 6.78 (d, 1H), 4.87 (bs, 1H), 4.71 (bs, 1H),
3.84-3.80 (m, 2H), 3.49 (bs, 1H), 3.21-3.13 (m, 2H), 2.82-2.77 (m,
1H), 2.62-2.47 (m, 3H), 2.18 (bs, 1H), 2.08-2.04 (m, 1H), 1.91-1.74
(m, 4H), 1.45 (s, 9H), 1.30-1.20 (m, 3H); MS: m/z 382.2
[M+H].sup.+.
[0451] Step 2: HCl/dioxane (4M, 2 mL) was added to a solution of
tert-butyl
((3R)-3-hydroxy-3-(3-((tetrahydro-2H-thiopyran-3-yl)methoxy)phenyl)propyl-
)carbamate (0.20 g, 0.52 mmol) in CH.sub.2Cl.sub.2 (10 mL) at
0.degree. C. and the reaction mixture was stirred at room
temperature for 2 h. After completion of the reaction (as monitored
by TLC) the solvent was removed under vacuo. The residue was
triturated in diethyl ether to give Example 10 hydrochloride as a
mixture of diastereomers as a white solid. Yield (0.15 g, 78%);
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.64 (bs, 2H),
7.26-7.23 (m, 1H), 6.88 (d, J=12.0 Hz, 2H), 6.82 (d, J=8.0 Hz, 1H),
5.55-5.54 (s, 1H), 4.63 (bs, 1H), 3.86-3.82 (m, 2H), 2.83 (m, 2H),
2.67 (m, 1H), 2.5 (m, 2H), 2.07-1.97 (m, 3H), 1.83-1.81 (m, 3H),
1.62-1.56 (m, 1H), 1.24-1.19 (m, 1H); MS: m/z 282.14
[M+H].sup.+.
Example 8
Preparation of
(R)-3-amino-1-(3-((tetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)propan-1-o-
l
##STR00143##
[0453]
(R)-3-Amino-1-(3-((tetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)prop-
an-1-ol was prepared following the method used in Example 7:
[0454] Step 1: Pyridine (7.6 mL, 98.4 mmol) was added at 0 OC to a
solution of (tetrahydro-2H-thiopyran-4-yl)methanol (1.3 g, 9.84
mmol) in CH.sub.2Cl.sub.2 (20 mL) followed by the addition of TsCl
(2.0 g, 10.83 mmol). The reaction mixture was stirred at ambient
temperature for 18 h, diluted with H.sub.2O (200 mL) and extracted
with CH.sub.2Cl.sub.2 (200 mL). Drying over anhydrous
Na.sub.2SO.sub.4 followed by concentration in vacuo gave
(tetrahydro-2H-thiopyran-4-yl)methyl 4-methylbenzenesulfonate as an
off white solid. The crude was carried forward to the next step
without additional purification. Yield (0.75 g, 30%).
[0455] Step 2: Reaction between
(tetrahydro-2H-thiopyran-4-yl)methyl 4-methylbenzenesulfonate and
phenol (7, Intermediate I) following the method used in Example 7
gave after purification by flash chromatography (40% ethyl
acetate/hexanes) (R)-tert-butyl
(3-hydroxy-3-(3-((tetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)-propyl)car-
bamate as a brown oil. Yield (58%); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.20 (t, J=8.0 Hz, 1H), 6.86 (d, J=8.0 Hz,
2H), 6.78-6.76 (m, 1H), 5.20-5.17 (m, 1H), 4.50-4.49 (bs, 1H),
4.05-3.98 (m, 2H), 2.96-2.89 (m, 3H), 2.80-2.75 (m, 1H), 2.62-2.61
(m, 1H), 2.26-2.25 (m, 1H), 2.16-2.11 (m, 1H), 1.86-1.77 (m, 2H),
1.67-1.64 (m, 2H), 1.36 (s, 9H).
[0456] Step 3: Deprotection of (R)-tert-butyl
(3-hydroxy-3-(3-((tetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)propyl)carb-
amate following the method used in Example 7 gave Example 8
hydrochloride as a white solid. Yield (92%); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): 37.79 (bs, 2H), 7.26-7.21 (m, 1H), 6.89 (d, J=4.0
Hz, 2H), 6.83-6.79 (m, 1H), 5.5 (s, 1H), 4.65 (bs, 1H), 4.02-3.99
(m, 2H), 3.78 (d, J=6.4 Hz, 1H), 2.93-2.89 (m, 1H), 2.84-2.80 (m,
3H), 2.66-2.61 (m, 1H), 2.20-2.35 (m, 1H), 2.14-2.10 (m, 1H),
1.88-1.79 (m, 4H), 1.60-1.57 (m, 1H).
Example 9
Preparation of
(R)-4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thiopyran
1,1-dioxide
##STR00144##
[0458]
(R)-4-((3-(3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thi-
opyran 1,1-dioxide was prepared following the method used in
Example 7:
[0459] Step 1: Reaction between
(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl
4-methylbenzenesulfonate and phenol (7, Intermediate I) following
the method used in Example 7 gave (R)-tert-butyl
(3-(3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)-3-hydroxy-
propyl)carbamate as colorless oil. Yield (58%); .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 7.20 (t, J=8.0 Hz, 1H), 6.87 (d, J=8.0
Hz, 2H), 6.78 (d, J=4.0 Hz, 1H), 5.19 (d, J=4.4 Hz, 1H), 4.51-4.49
(bs, 1H), 3.87-3.85 (d, J=8.0 Hz, 1H), 3.22-3.15 (m, 2H), 3.08-3.05
(m, 2H), 2.96-2.94 (m, 2H), 2.15-2.11 (m, 3H), 1.79-1.74 (m, 2H),
1.67-1.65 (m, 2H), 1.36 (s, 9H).
[0460] Step 2: Deprotection of (R)-tert-butyl
(3-(3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)-3-hydroxy-
propyl)carbamate following the method used in Example 7 gave
Example 9 hydrochloride as a white solid. Yield (86%); .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 7.66 (bs, 2H), 7.25 (t, J=8.0 Hz,
1H), 6.90-6.88 (m, 2H), 6.82 (d, J=8.0 Hz, 1H), 5.55 (d, J=4.0 Hz,
1H), 4.64 (bs, 1H), 3.85 (d, J=4.0 Hz, 2H), 3.19-3.16 (m, 2H),
3.09-3.06 (m, 2H), 2.85-2.80 (m, 2H), 2.14-2.11 (m, 3H), 1.85-1.74
(m, 4H).
Example 10
Preparation of
3-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thiopyran
1,1-dioxide
##STR00145##
[0462]
3-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H--
thiopyran 1,1-dioxide was prepared following the method used in
Example 7:
[0463] Step 1: Reaction between methyl
3-(bromomethyl)tetrahydro-2H-thiopyran 1,1-dioxide and phenol (7,
Intermediate I) following the method used in Example 7 gave
tert-butyl
((3R)-3-(3-((1,1-dioxidotetrahydro-2H-thiopyran-3-yl)methoxy)phenyl)-3-hy-
droxypropyl)carbamate as a light pink semi-solid. Yield (0.43 g,
65%); .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.24 (t, J=8.0 Hz,
1H), 6.93 (d, J=8.0 Hz, 2H), 6.77-6.75 (m, 1H), 4.86 (bs, 1H),
4.72-4.70 (m, 1H), 3.95-3.92 (m, 1H), 3.90-3.88 (m, 1H), 3.38 (s,
1H), 3.26-3.22 (m, 1H), 3.18-3.13 (m, 1H), 3.06 (d, J=4.0 Hz 1H),
2.97-2.88 (m, 2H), 2.65 (bs, 1H), 2.20-2.04 (m, 2H), 1.99-1.95 (m,
1H), 1.84-1.81 (m, 2H), 1.45 (s, 9H). MS: m/z 414.43
[M+H].sup.+.
[0464] Step 2: Deprotection of tert-butyl
((3R)-3-(3-((1,1-dioxidotetrahydro-2H-thiopyran-3-yl)methoxy)phenyl)-3-hy-
droxypropyl)carbamate following the method used in Example 7 gave
Example 10 hydrochloride as a mixture of diastereomers as a white
solid. Yield (0.36 g, 99%); .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 7.79 (bs, 2H), 7.25 (t, J=8.0 Hz, 1H), 6.91-6.90 (m, 2H),
6.84-6.81 (m, 1H), 5.57 (bs, J=12.0 Hz, 1H), 4.65 (dd, J=8.0, 4.0
Hz, 1H), 3.96-3.84 (m, 2H), 3.18-3.15 (m, 1H), 3.11-3.02 (m, 3H),
2.84-2.81 (m, 2H), 2.38 (bs, 1H), 2.10-2.07 (dd, J=10.8, 3.6 Hz,
1H), 1.86-1.79 (m, 4H); MS: m/z 314 [M+H].sup.+.
Example 11
Preparation of
(R)-1-(4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidin-1-yl)ethan-
one
##STR00146##
[0466]
(R)-1-(4-((3-(3-Amino-1-hydroxypropyl)phenoxy)methyl)piperidin-1-yl-
)ethanone was prepared following the method below.
[0467] Step 1: Et.sub.3N (0.16 g, 1.60 mmol) and DMAP (0.39 g, 0.32
mmol) were added to a solution of methyl
4-(hydroxymethyl)piperidine-1-carboxylate (1.0 g, 3.20 mmol) in DCM
(20 mL). The reaction mixture was cooled to 0.degree. C. and TsCl
(0.73 g, 3.80 mmol) was added. The reaction mixture was stirred for
1 h at room temperature, diluted with EtOAc, washed with water,
dried over anhydrous Na.sub.2SO.sub.4 and concentrated under
reduced pressure. Purification by flash chromatography (50%
EtOAc:hexane) gave (1-acetylpiperidin-4-yl)methyl
4-methylbenzenesulfonate as a pale yellow semi-solid. Yield (1.2 g,
63%); .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.77 (d, J=8.4 Hz,
2H), 7.63 (d, J= 7.6 Hz, 2H), 4.64 (d, J=14.4 Hz, 2H), 3.92 (dd,
J=6.0, 2.4 Hz, 2H), 3.84 (t, J=3.2 Hz, 4H), 3.02 (d, J=13.6 Hz,
2H), 2.54-2.49 (m, 2H), 2.45 (s, 3H), 1.72-1.62 (m, 1H), 1.16 (dt,
J=12.4, 3.6 Hz, 1H); MS: m/z 312.05 [M+H]+.
[0468] Step 2: Phenol (7, Intermediate I) (0.850 g, 3.20 mmol) and
K.sub.2CO.sub.3 (1.32 g, 9.60 mmol) were added to a solution of
(1-acetylpiperidin-4-yl)methyl 4-methylbenzenesulfonate (1.0 g,
3.20 mmol) in DMF (10 mL). The reaction mixture was heated at
90.degree. C. overnight. The reaction mixture was diluted with
EtOAc and washed with water and brine. Organic layer was dried over
anhydrous Na.sub.2SO.sub.4) and concentrated under reduced pressure
to give after purification by column chromatography to give
(R)-tert-butyl
(3-(3-((1-acetylpiperidin-4-yl)methoxy)phenyl)-3-hydroxypropyl)carbamate
as a colorless semi solid. Yield (600 mg, 46%); .sup.1H NMR (400
MHz, DMSO-d.sub.6); .delta. 7.18 (d, J=4.0 Hz, 1H), 6.93 (s, 1H),
6.86 (d, J=7.6 Hz, 1H), 6.76 (d, J=6.0 Hz, 1H), 5.17 (d, J=4.4 Hz,
1H), 4.50 (d, J=4.8 Hz, 1H), 4.39 (d, J=11.6 Hz, 1H), 3.81 (d,
J=6.4 Hz, 2H), 3.06-2.94 (m, 4H), 1.99 (s, 3H), 1.78 (t, J=14 Hz,
2H), 1.65 (t, J=7.2, 2H), 1.36 (s, 9H), 1.23 (s, 3H), 1.55-0.88 (m,
1H); MS: m/z 407.05 [M+H].
[0469] Step 3: HCl/dioxane (4M, 2 mL) was added to a solution of
(R)-tert-butyl
(3-(3-((1-acetylpiperidin-4-yl)methoxy)phenyl)-3-hydroxypropyl)carbamate
(0.60 g, 1.40 mmol) in CH.sub.2Cl.sub.2 (10 mL) at 0.degree. C. and
the reaction mixture was stirred at room temperature for 2 h. The
reaction mixture was concentrated under reduced pressure to give
after purification by triturating in diethyl ether Example 11
hydrochloride as a white solid. Yield (0.40 g, 88%); .sup.1H NMR
(400 MHz, DMSO-d.sub.6); .delta. 7.18 (t, J=7.8 Hz, 1H), 6.84 (d,
J=7.6 Hz, 2H), 6.75 (d, J=7.6 Hz, 1H), 4.60 (t, J=6.4 Hz, 1H), 4.38
(d, J=14.8 Hz, 1H), 4.11 (s, 2H), 3.79 (d, J=6 Hz, 3H), 3.02 (t,
J=11.2, 1H), 2.64 (d, J=3.2 Hz, 2H), 2.54 (s, 1H), 1.97 (s, 4H),
1.76 (t, J=16.0 Hz, 2H), 1.66-1.61 (m, 2H), 1.26-1.04 (m, 2H); MS:
m/z 307.01 [M+H]+.
Example 12
Preparation of
(R)-3-Amino-1-(3-((6-methylpyridin-2-yl)methoxy)phenyl)propan-1-ol
##STR00147##
[0471]
(R)-3-Amino-1-(3-((6-methylpyridin-2-yl)methoxy)phenyl)propan-1-ol
was prepared following the method described below.
[0472] Step 1: Phenol (7, Intermediate I) (0.50 g, 1.87 mmol) and
K.sub.2CO.sub.3 (1.29 g, 9.35 mmol) were added to a solution of
(6-methylpyridin-2-yl)methyl methanesulfonate (412 mg, 2.05 mmol)
in DMF (20 mL) and the reaction mixture was heated under reflux at
90.degree. C. for 18 h. The reaction mixture was diluted with EtOAc
and washed with water and brine. Drying over anhydrous
Na.sub.2SO.sub.4 and concentration under reduced pressure gave
(R)-tert-butyl
(3-hydroxy-3-(3-((6-methylpyridin-2-yl)methoxy)phenyl)propyl)-carbamate
as pale yellow liquid. Yield (200 mg, 72%); .sup.1H NMR (400 MHz,
CDCl.sub.3); .delta. 7.59 (t, J=8.0 Hz, 1H), 7.32 (d, J=7.2 Hz,
1H), 7.23 (s, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.03 (s, 1H), 6.95 (d,
J=7.6 Hz, 1H), 6.87 (dd, J=8.0, 2.4 Hz, 1H), 5.17 (s, 2H), 4.86
(bs, 1H), 4.71 (bs, 1H), 3.49-3.48 (m, 1H), 3.19-3.11 (m, 2H), 2.57
(s, 3H), 1.88-1.82 (m, 2H), 1.45 (s, 9H); MS: m/z 373.20
[M+H].sup.+.
[0473] Step 2: HCl/dioxane (4M, 2 mL) was added at 0.degree. C. to
a solution of (R)-tert-butyl
(3-hydroxy-3-(3-((6-methylpyridin-2-yl)methoxy)phenyl)propyl)carbamate
(200 mg, 0.54 mmol) in MeOH (3 mL) and the reaction mixture was
stirred at room temperature for 2 h. The reaction mixture was
concentrated under reduced pressure to give after purification by
triturating in diethyl ether Example 12 hydrochloride as a white
solid. Yield (0.15 g, 52%); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.92 (bs, 1H), 7.74 (bs, 3H), 7.47 (bs, 1H), 7.40 (bs, 1H),
7.28 (t, J=8.0 Hz, 1H), 7.02 (s, 1H), 6.95-6.90 (m, 2H), 5.20 (s,
2H), 4.68-4.65 (m, 1H), 2.84 (bs, 2H), 2.56 (s, 3H), 1.88-1.83 (m,
2H); MS: m/z 273.20 [M+H].sup.+.
Example 13
Preparation of (1R)-3-amino-1-(3-((2,3-dihydrobenzo
furan-2-yl)methoxy)phenyl)propan-1-ol
##STR00148##
[0475] (1R)-3-Amino-1-(3-((2,3-dihydrobenzo
furan-2-yl)methoxy)phenyl)propan-1-ol was prepared following the
method used in Example 12.
[0476] Step 1: Reaction between ((2,3-dihydrobenzofuran-2-yl)methyl
4-methylbenzenesulfonate and phenol (7, Intermediate I) following
the method used in Example 12 gave tert-butyl
((3R)-3-(3-((2,3-dihydrobenzofuran-2-yl)methoxy)phenyl)-3-hydroxypropyl)c-
arbamate as a white solid. Yield (65%); .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.24-7.18 (m, 2H), 7.12 (t, J=8 Hz, 1H), 6.94
(t, J=8.4 Hz, 2H), 6.88-6.81 (m, 3H), 5.16-5.13 (m, 1H), 4.87 (s,
1H), 4.71 (s, 1H), 4.20 (dd, J=10.0, 6.8 Hz m, 1H), 4.10 (dd,
J=6.0, 4.8 Hz, 1H), 3.41 (s, 1H), 3.39-3.35 (m, 1H), 3.25 (s, 1H),
3.17-3.11 (m, 2H), 1.85-1.80 (m, 2H), 1.45 (s, 9H); MS: m/z 400
[M+H].sup.+.
[0477] Step 2: Deprotection of tert-butyl
((3R)-3-(3-((2,3-dihydrobenzofuran-2-yl)methoxy)phenyl)-3-hydroxypropyl)c-
arbamate following the method used in Example 12 gave Example 13
hydrochloride as a mixture of diastereomers as a white solid. Yield
(91%); .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.81 (s, 3H),
7.27-7.24 (m, 2H), 7.09 (t, J=7.6 Hz, 1H), 6.91 (d, J=7.2 Hz, 2H),
6.82-6.81 (m, 2H), 6.77 (d, J=8 Hz, 1H), 5.54 (d, J=12 Hz, 1H),
5.31 (t, J=3.6 Hz m, 1H), 4.65 (t, J=3.6 Hz, 1H), 4.20-4.10 (m,
2H), 3.07 (dd, J=16.0, 7.6 Hz, 1H), 2.81 (s, 2H), 1.88-1.81 (m,
2H); MS: m/z 300 [M+H].sup.+.
Example 14
Preparation of
(1R)-3-amino-1-(3-((tetrahydrofuran-2-yl)methoxy)phenyl)propan-1-ol
##STR00149##
[0479]
(1R)-3-Amino-1-(3-((tetrahydrofuran-2-yl)methoxy)phenyl)propan-1-ol
was prepared following the method used in Example 12.
[0480] Step 1: tert-Butyl
((3R)-3-hydroxy-3-(3-((tetrahydrofuran-2-yl)methoxy)phenyl)propyl)carbama-
te was prepared by the reaction between
rac-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate and
phenol (7, Intermediate I) at +100.degree. C. following the method
used in Example 12 with the following exception. After the reaction
was complete (as judged by TLC), the reaction mixture was diluted
with EtOAc, dried over anhydrous Na.sub.2SO.sub.4 and concentrated
under reduced pressure. Purification by flash chromatography
(EtOAc: hexane 10-40% gradient) gave the product as an off-white
semi-solid. Yield (0.36 g, 66%); .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta. 7.23 (t, J=8.0 Hz, 1H), 6.95 (s, 1H), 6.91 (d, J=8.0 Hz,
1H), 6.82 (d, 1H), 4.88 (bs, 1H), 4.71 (bs, 1H), 4.28-4.25 (m, 1H),
3.96-3.90 (m, 3H), 3.85-3.82 (m, 1H), 3.49 (bs, 1H), 3.19-3.13 (m,
2H), 1.97-1.92 (m, 2H), 1.83-1.74 (m, 3H), 1.60 (s, 1H), 1.45 (s,
9H); MS: m/z 352.8 [M+H].sup.+.
[0481] Step 2: HCl/dioxane (4M, 2.5 mL) was added at 0.degree. C.
to a solution of tert-butyl
((3R)-3-hydroxy-3-(3-((tetrahydrofuran-2-yl)methoxy)phenyl)propyl)carbama-
te (0.25 g, 0.71 mmol) in DCM (10 mL) and the reaction mixture was
stirred at room temperature for 2 h. After completion of the
reaction the solvent was removed under reduced pressure.
Purification by column chromatography (MeOH:DCM with 1% aq.
NH.sub.4OH, 1-10% gradient) gave Example 14 as a mixture of
diastereomers as an off white semi-solid. Yield (0.22 g, 95%);
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 7.20 (t, J=8.0 Hz,
1H), 6.87 (d, J=8.0 Hz, 2H), 6.78-6.76 (m, 1H), 4.64-4.61 (m, 1H),
4.15-4.11 (dd, 1H), 3.93-3.87 (m, 2H), 3.78-3.75 (m, 1H), 3.70-3.64
(m, 1H), 2.69-2.66 (m, 2H), 2.01-1.95 (m, 1H), 1.88-1.79 (m, 2H),
1.70-1.65 (dd, J=6.8 Hz, 3H); MS: m/z 252.14 [M+H].sup.+.
Example 15
Preparation of
(R)-3-amino-1-(3-(piperidin-4-ylmethoxy)phenyl)propan-1-ol
##STR00150##
[0483] (R)-3-Amino-1-(3-(piperidin-4-ylmethoxy)phenyl)propan-1-ol
was prepared following the method used in Example 11.
[0484] Step 1: Reaction between phenol (7, Intermediate I) and
tert-butyl 4-((tosyloxy)methyl)piperidine-1-carboxylate following
the method used in Example 11 gave (R)-tert-butyl
4-((3-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)pipe-
ridine-1-carboxylate as a colorless oil. Yield (53%); .sup.1H NMR
(400 MHz, CDCl.sub.3): .delta. 3.49 (d, J=2.0 Hz, 2H), 2.69 (t,
J=11.6 Hz, 2H), 1.72 (s, 2H), 1.70 (d, J=14.0 Hz, 1H), 1.51-1.49
(m, 2H), 1.44 (s, 9H), 1.13 (dq, J=4.40, 8.0 Hz, 2H); MS: m/z
317.18 [M+H].sup.+.
[0485] Step 2: Deprotection of (R)-tert-butyl
4-((3-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)pipe-
ridine-1-carboxylate following the method used in Example 11 gave
Example 15 dihydrochloride as a white solid. Yield (98%); .sup.1H
NMR (400 MHz, DMSO-d.sub.6); .delta. 8.74 (d, J=20.8 Hz, 1H), 8.58
(d, J=35 Hz, 2H), 7.79 (s, 2H), 7.25 (t, J=8 Hz, 1H), 6.89 (d,
J=7.2 Hz, 1H), 6.82 (d, J=7.2 Hz, 1H), 5.53 (d, J=4.4 Hz, 1H), 4.65
(t, J=4.4 Hz, 1H), 3.84 (d, J=6.4 Hz, 1H), 3.25 (s, 3H), 3.16-2.83
(m, 4H), 2.65 (s, 1H), 1.98-1.75 (m, 3H), 1.52-1.44 (m, 1H),
1.36-1.14 (s, 1H); MS: m/z 265.05 [M+H].sup.+.
Example 16
Preparation of
(R)-3-amino-1-(3-((1-methylpiperidin-4-yl)methoxy)phenyl)propan-1-ol
##STR00151##
[0487]
(R)-3-Amino-1-(3-((1-methylpiperidin-4-yl)methoxy)phenyl)propan-1-o-
l was prepared following the method used in Example 11.
[0488] Step 1: Tosylation of tert-butyl
4-(hydroxymethyl)piperidine-1-carboxylate following the method used
in Example 11 gave tert-butyl
4-((tosyloxy)methyl)piperidine-1-carboxylate as a colorless oil.
Yield (1.5 g, 88%).
[0489] Step 2: Alkylation of phenol (7, Intermediate I) with
tert-butyl 4-((tosyloxy)methyl)piperidine-1-carboxylate following
the method used in Example 11 gave (R)-tert-butyl
4-((3-(3-((tert-butoxycarbonyl)amino)-1
-hydroxypropyl)phenoxy)methyl)piperidine-1-carboxylate as a
colorless oil. Yield (0.70 g, 80%).
[0490] Step 3: (R)-tert-Butyl
4-((3-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)pipe-
ridine-1-carboxylate (0.70 g, 1.50 mmol) was added at 0.degree. C.
to a suspension of LiAlH.sub.4 (0.171 g, 4.5 mmol) in anhydrous THF
(10 mL) and the reaction mixture was stirred at room temperature
for 1 h. After completion of the reaction as judged by TLC, the
reaction mixture was quenched with EtOAc (10 mL) and 10% aqueous
NaOH, filtered through Celite, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Purification by column chromatography (CH.sub.2Cl.sub.2-10%
MeOH:CH.sub.2Cl.sub.2, 0-5% gradient) gave (R)-tert-butyl
(3-hydroxy-3-(3-((1-methylpiperidin-4-yl)methoxy)phenyl)propyl)carbamate
as a pale yellow semi-solid. Yield (0.50 g, 87%); .sup.1H NMR (400
MHz, CDCl.sub.3): .delta. 7.22 (t, J=4.40 Hz, 1H), 6.92 (s, 2H),
6.76 (d, J=8.0 Hz, 1H), 4.31 (s, 1H), 3.85 (d, J=5.6 Hz, 2H), 3.69
(s, 1H), 3.27 (d, J=6.8 Hz, 2H), 2.58 (s, 2H), 2.46 (s, 2H),
2.04-1.91 (m, 4H), 1.84 (t, J=5.20 Hz, 4H), 1.70-1.67 (m, 1H), 1.45
(s, 9H); MS: m/z 379.28 [M+H].sup.+.
[0491] Step 4: Deprotection of (R)-tert-butyl
(3-hydroxy-3-(3-((1-methylpiperidin-4-yl)methoxy)phenyl)propyl)carbamate
following the method used in Example 11 gave Example 16
hydrochloride as a white solid. Yield (0.40 g, 97%); .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 7.99 (bs, 2H), 7.24 (t, J=7.6 Hz,
1H), 6.89 (d, J=7.6 Hz, 2H), 6.81 (d, J=7.60 Hz, 1H), 4.65 (dd,
J=7.2, 4.4 Hz, 1H), 3.82 (d, J=6 Hz, 2H), 3.38 (t, J=7.2 Hz, 2H),
3.09 (s, 2H), 2.81 (s, 2H), 2.45 (s, 3H), 1.84 (d, J=10 Hz, 5H),
1.86 (d, J=10.8 Hz, 2H), 1.08 (t, J=7.2 Hz, 1H).
Example 17
Preparation of (R)-methyl
4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidine-1-carboxylate
##STR00152##
[0493] (R)-Methyl
4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidine-1-carboxylate
was prepared following the method used in Examples 16 and 11.
[0494] Step 4: Deprotection of (R)-methyl
4-((3-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)pipe-
ridine-1-carboxylate following the method used in Example 11 gave
Example 17 hydrochloride as a white solid. Yield (89%); .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta.7.18 (t, J=8.0 Hz, 1H), 6.86 (d,
J=7.6 Hz, 2H), 6.75 (d, J=7.2 Hz, 1H), 4.62 (t, J=6.0 Hz, 1H), 4.00
(s, 2H), 3.80 (d, J=6.4 Hz, 2H), 3.58 (s, 3H), 2.80 (s, 2H),
2.66-2.60 (m, 2H), 1.92 (s, 1H), 1.76 (d, J=13.2 Hz, 2H), 1.62 (dd,
J=12.4, 6.4 Hz, 2H), 1.16 (dd, J=20.4, 8.8 Hz, 2H); MS: m/z 323.13
[M+H].sup.+.
Example 18
Preparation of
(R)-3-amino-1-(3-(pyrimidin-5-ylmethoxy)phenyl)propan-1-ol
##STR00153##
[0496] (R)-3-Amino-1-(3-(pyrimidin-5-ylmethoxy)phenyl)propan-1-ol
was prepared following the method below and described in Example
6.
[0497] Step 1: A solution of pyrimidin-5-ylmethanol (1.0 g, 9.08
mmol) in DCM (20 mL) was cooled to 0.degree. C. PPh.sub.3 (2.61 g,
9.99 mmol) and CBr.sub.4 (3.3 g, 9.99 mmol) were added to the
reaction mixture and the latter was stirred for 1 h at room
temperature. The reaction mixture was extracted with EtOAc, dried
over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Purification by flash chromatography (80% EtOAc in
hexane) gave 5-(bromomethyl)pyrimidine as a pale yellow liquid.
Yield (1.2 g, 60%); .sup.1H NMR (400 MHz, DMSO-d.sub.6); .delta.
9.13 (s, 1H), 8.92 (s, 2H), 4.74 (s, 2H).
[0498] Step 2: Alkylation of phenol (7, Intermediate I) with
5-(bromomethyl)pyrimidine following the method used in Example 6
gave after purification by flash chromatography (50-60% EtOAc in
hexane gradient) (R)-tert-butyl
(3-hydroxy-3-(3-(pyrimidin-5-ylmethoxy)phenyl)propyl)carbamate as a
yellow semi-solid. Yield (1.4 g, 63%); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 9.21 (s, 1H), 8.83 (s, 2H), 7.28 (m, 1H), 7.05
(s, 1H), 6.98 (d, J=7.6 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 5.09 (s,
2H), 4.88 (bs, 1H), 4.74 (d, J=6.0 Hz, 1H), 3.52 (bs, 2H),
3.19-3.14 (m, 1H), 1.86-1.81 (m, 2H), 1.45 (s, 9H).
[0499] Step 3: Deprotection of (R)-tert-butyl
(3-hydroxy-3-(3-(pyrimidin-5-ylmethoxy)phenyl)propyl)carbamate
following the method used in Example 6 gave after trituration in
diethyl ether Example 18 hydrochloride as a white solid. Yield
(0.36 g, 100%); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.18
(s, 1H), 8.92 (s, 2H), 7.73 (bs, 3H), 7.29 (t, J=8.0 Hz, 1H), 7.02
(s, 1H), 6.94 (d, J=8.0 Hz, 2H), 5.18 (s, 2H), 4.67 (s, 1H), 2.84
(bs, 2H), 1.86-1.81 (m, 2H).
Example 19
Preparation of
(1R)-3-amino-1-(3-(chroman-3-ylmethoxy)phenyl)propan-1-ol
##STR00154##
[0501] (1R)-3-Amino-1-(3-(chroman-3-ylmethoxy)phenyl)propan-1-ol
was prepared following the method used in Example 12.
[0502] Step 1: Alkylation of phenol (7, Intermediate I) with
chroman-3-ylmethyl 4-methylbenzenesulfonate following the method
used in Example 12 gave tert-butyl
((3R)-3-(3-(chroman-3-ylmethoxy)phenyl)-3-hydroxypropyl)carbamate
as a colorless oil. Yield (71%); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.21 (t, J=7.6 Hz, 1H), 7.10-7.05 (m, 2H),
6.91 (s, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.85-6.83 (m, 1H), 6.81-6.79
(m, 1H), 6.75 (d, J=8.4 Hz, 1H), 5.19 (d, J=4.8 Hz, 1H), 4.53-4.48
(m, 1H), 4.31-4.28 (m, 1H), 3.99-3.91 (m, 2H), 2.98-2.93 (m, 2H),
2.92-2.90 (m, 1H), 2.71-2.69 (m, 2H), 1.66 (q, J=6.8 Hz, 2H), 1.36
(s, 9H).
[0503] Step 2: Deprotection of tert-butyl
((3R)-3-(3-(chroman-3-ylmethoxy)phenyl)-3-hydroxypropyl)carbamate
following the method used in Example 12 gave Example 19
hydrochloride as a mixture of diastereomers as a white solid. Yield
(99%); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.66 (bs, 3H),
7.25 (t, J=8.0 Hz, 1H), 7.09 (t, J=7.2 Hz, 1H), 7.05 (s, 1H),
6.93-6.89 (m, 2H), 6.86-6.82 (m, 2H), 6.76 (d, J=8.4 Hz, 1H), 5.53
(d, J=4.4 Hz, 1H), 4.66-4.64 (m, 1H), 4.29 (d, J=10.4 Hz, 1H),
4.05-3.92 (m, 3H), 2.96-2.95 (m, 1H), 2.92-2.81 (m, 2H), 2.73-2.65
(m, 2H), 1.87-1.80 (m, 2H).
Example 20
Preparation of
(R)-4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thiopyran
1-oxide
##STR00155##
[0505]
R)-4-((3-(3-Amino-1-hydroxypropyl)phenoxy)methyl)tetrahydro-2H-thio-
pyran-1-oxide was prepared following the method used in Example
8.
[0506] Step 1: FeCl.sub.3 (3.0 mg, 0.023 mmol) was added at room
temperature to a stirred solution of (R)-tert-butyl
(3-hydroxy-3-(3-((tetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)-propyl)car-
bamate (0.22 g, 0.576 mmol) in CH.sub.3CN (3 mL) followed by
HIO.sub.4 (0.132 g, 0.691 mmol). The reaction mixture was stirred
for 2 min, quenched by the addition of an aqueous solution of
sodium thiosulfate (20%, 5 mL), extracted with EtOAc (50 mL) and
dried over Na.sub.2SO.sub.4. Concentration in vacuo gave
(R)-tert-butyl
(3-hydroxy-3-(3-((1-oxidotetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)prop-
yl)carbamate as a pale yellow semi-solid. Yield (0.13 g, 57%). The
crude was carried forward to the next step without additional
purification.
[0507] Step 2: HCl/dioxane (4M, 1 mL) was added at 0.degree. C. to
a solution of (R)-tert-butyl
(3-hydroxy-3-(3-((1-oxidotetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)prop-
yl)carbamate (0.12 g, 0.30 mmol) in CH.sub.2Cl.sub.2 (2 mL) and the
reaction mixture was stirred at room temperature for 30 min. After
completion of the reaction (as judged by TLC) the solvent was
removed in vacuo. The compound was purified by preparative HPLC to
give Example 20 as a colorless semi-solid. Yield (70.7 mg, 77%);
MS: m/z 298.14 [M+H].sup.+.
Example 21
Preparation of
(R)-3-amino-1-(3-(((S)-1-methylpyrrolidin-2-yl)methoxy)phenyl)propan-1-ol
##STR00156##
[0509]
(R)-3-Amino-1-(3-(((S)-1-methylpyrrolidin-2-yl)methoxy)phenyl)propa-
n-1-ol was prepared following the method described below.
[0510] Step 1: A mixture of (S)-tert-butyl
2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (1.6 g, 5.4 mmol),
phenol (7, Intermediate I) (0.8 g, 2.9 mmol), t-BuO.sup.-K.sup.+
(0.5 g, 4.5 mmol) in anhydrous DMF (5 mL) was heated at +45.degree.
C. for 16 hrs. The reaction mixture was concentrated under reduced
pressure, partitioned between EtOAc and 5% NaOH, organic layer was
dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced
pressure. Purification by column chromatography gave (S)-tert-butyl
2-((3-((R)-3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)-
pyrrolidine-1-carboxylate as a light yellow oil. Yield (0.8 g,
59%).
[0511] Step 2: Anhydrous THF (5 mL) was cooled to 0 OC and
LiAlH.sub.4 (0.016 g, 0.44 mmol) was added. (S)-tert-butyl
2-((3-((R)-3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)-
pyrrolidine-1-carboxylate (0.1 g, 0.22 mmol) was slowly added to
reaction mixture and then kept at room temperature for 4 hrs. After
completion of reaction as judged by TLC (10% MeOH/CH.sub.2Cl.sub.2)
the reaction mixture was quenched with EtOAc followed by saturated
Na.sub.2SO.sub.4, extracted with EtOAc and organic layer was
concentrated under reduced pressure to give tert-butyl
((R)-3-hydroxy-3-(3-(((S)-1-methylpyrrolidin-2-yl)methoxy)phenyl)propyl)c-
arbamate as a light yellow oil which was used in the next step
without additional purification. Yield (0.060 g, 75%).
[0512] Step 3: To a solution of tert-butyl
((R)-3-hydroxy-3-(3-(((S)-1-methylpyrrolidin-2-yl)methoxy)phenyl)propyl)c-
arbamate (0.32 g, 0.87 mmol) in DCM (10 mL) was added HCl/dioxane
(4 mL) at 0.degree. C. and the reaction mixture was stirred at rt
for 2 h. After completion of the reaction the solvent was removed
in vacuo. The compound was purified by prep HPLC to obtain
(R)-3-Amino-1-(3-(((S)-1-methylpyrrolidin-2-yl)methoxy)phenyl)propan-1-ol
(Example 21) as a yellow semi solid. Yield (0.18 g, 68%); .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 7.29 (t, J=8.0 Hz, 1H), 7.01-6.97
(m, 2H), 6.89-6.87 (m, 1H), 4.82-4.80 (m, 1H), 4.10-4.04 (m, 2H),
3.10-3.02 (m, 3H), 2.68 (s, 3H), 2.65-2.58 (m, 1H), 2.18-2.15 (m,
1H), 2.03-2.01 (m, 2H), 1.99-1.94 (m, 3H), 1.84-1.77 (m, 1H). MS:
m/z 265.22 [M+H].sup.+.
Example 22
Preparation of
(R)-3-amino-1-(3-((S)-pyrrolidin-2-ylmethoxy)phenyl)propan-1-ol
hydrochloride
##STR00157##
[0514]
(R)-3-Amino-1-(3-((S)-pyrrolidin-2-ylmethoxy)phenyl)propan-1-ol was
prepared following the method used in Example 21 and below.
##STR00158##
[0515] Step 1: To a solution of (S)-tert-butyl
2-((3-((R)-3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)-
pyrrolidine-1-carboxylate (0.3 g, 0.66 mmol) in DCM (10 mL) was
added HCl/dioxane (3 mL) at 0.degree. C. and the reaction mixture
was stirred at rt for 2 h. After completion of the reaction the
solvent was removed in vacuo. The residue was purified by prep HPLC
to give
(R)-3-Amino-1-(3-((S)-pyrrolidin-2-ylmethoxy)phenyl)propan-1-ol
(Example 22) as a white solid. Yield (0.18 g, 89%); .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 7.31 (t, J=8.0 Hz, 1H), 7.07 (s, 1H),
7.03 (d, J=7.6 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 4.83-4.82 (m, 1H),
4.35 (dd, J=10.4, 3.2 Hz, 1H), 4.17-4.12 (m, 1H), 4.05-4.03 (m,
1H), 3.39-3.36 (m, 2H), 3.14-3.01 (m, 2H), 2.32-2.18 (m, 1H),
2.16-2.08 (m, 2H), 2.06-1.87 (m, 3H). MS: m/z 251.28 [M+H]+.
Example 23
Preparation of
(R)-3-amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)propan-1-
-ol
##STR00159##
[0517]
(R)-3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl-
)propan-1-ol was prepared following the method below.
[0518] Step 1: CH.sub.3COOH (1 mL) was added to a solution of
tetrahydro-2H-pyran-4-carbaldehyde (0.7 g, 6.12 mmol) and
(R)-3-(3-aminophenyl)-3-hydroxypropanenitrile (1.0 g, 6.12 mmol) in
CH.sub.2Cl.sub.2 (20 mL) at 0.degree. C. followed by the addition
of Na(OAc).sub.3BH (3.89 g, 18.34 mmol). The reaction mixture was
stirred at room temperature overnight. The reaction mixture was
diluted with NaHCO.sub.3 (50 mL), extracted with EtOAc (200 mL),
organic layer was dried over anhydrous Na.sub.2SO.sub.4 and
concentrated under reduced pressure. Purification by flash
chromatography (50% EtOAc: hexanes) gave
(R)-3-hydroxy-3-(3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)propan-
enitrile as a pale yellow liquid. Yield (1.0 g, 63%); .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.02 (t, J=8.0 Hz, 1H), 6.62 (s,
1H), 6.51 (d, J=7.2 Hz, 1H), 6.47 (d, J=7.6 Hz, 1H), 5.77 (d, J=4.4
Hz, 1H), 5.68 (t, J=5.2 Hz, 1H), 4.73 (dd, J=10.8, 4.8 Hz, 1H),
3.85 (dd, J=10.8, 2.8 Hz, 2H), 3.26 (t, J=11.2 Hz, 2H), 2.89 (t,
J=6.0 Hz, 2H), 2.82 (dd, J=16.8, 4.8 Hz, 1H), 2.73 (dd, J=16.8, 6.8
Hz, 1H), 1.81-1.75 (m, 1H), 1.66 (d, J=12.8 Hz, 2H), 1.23-1.19 (m,
2H).
[0519] Step 2: BH.sub.3-Me.sub.2S complex (0.4 mL) was added to a
solution of
(R)-3-hydroxy-3-(3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)pro-
panenitrile (0.5 g, 1.92 mmol 1) in THF (20 mL). The reaction
mixture was heated at 80.degree. C. under reflux for 18 h. The
reaction mixture was quenched with MeOH (10 mL) followed by
HCl/dioxane (4N, 0.5 mL). The mixture was heated at 60.degree. C.
for 1 h and concentrated under reduced pressure to give Example 23
hydrochloride as a pale yellow oil. Yield (0.4 g, 80%); .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 7.59-7.51 (m, 3H), 7.42 (d, J=8.0 Hz,
1H), 4.93-4.91 (m, 2H), 3.97 (dd, J=11.2, 3.6 Hz, 2H), 3.42 (t,
J=10.4 Hz, 2H), 3.33-3.29 (m, 2H), 3.12 (q, J=6.8 Hz, 2H),
2.11-2.03 (m, 2H), 2.01-1.93 (m, 1H), 1.75 (d, J=13.2 Hz, 1H), 1.43
(dq, J=12.0, 4.4 Hz, 2H).
Intermediate II--Preparation of
S-(3-(3-((tert-butoxycarbonyl)amino)propanoyl)phenyl)benzothioate
##STR00160##
[0521]
S-(3-(3-((tert-butoxycarbonyl)amino)propanoyl)phenyl)benzothioate
was prepared following the method shown in Scheme 4:
##STR00161##
[0522] Step 1: Molecular sieves (20.0 g) and PCC (28.0 g, 127 mmol)
were added portionwise to a stirred solution of tert-butyl
(3-hydroxy-3-(3-iodophenyl)propyl)carbamate (16) (40.0 g, 106 mmol)
in anhydrous CH.sub.2Cl.sub.2 (500 mL) under argon atmosphere at 0
OC. The reaction mixture was allowed to warm to room temperature
and stirred for 20 min. The reaction mixture was concentrated under
reduced pressure, the residue was dissolved in water (300 mL),
extracted with EtOAc (2.times.300 mL), washed with brine (300 mL),
dried over anhydrous Na.sub.2SO.sub.4 and concentrated under
reduced pressure. Purification by flash chromatography (100-200
silica mesh, 15-20% EtOAc-hexane) gave tert-butyl
(3-(3-iodophenyl)-3-oxopropyl)carbamate (17) as a pale yellow oil.
Yield (21.0 g, 54%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.27
(s, 1H), 7.95-7.91 (m, 2H), 7.21 (t, J=8.0 Hz, 1H), 3.57-3.51 (m,
2H), 3.18-3.12 (m, 2H), 1.83-1.76 (m, 1H), 1.45 (s, 9H); MS: m/z
378.12 [M+H].sup.+.
[0523] Step 2: BzSH (8.84 g, 63.9 mmol), 1,10-phenanthroline (1.92
g, 10.7 mmol) and i-Pr.sub.2NEt (13.8 g, 106 mmol) were added to a
stirred solution of aryl iodide (17) (20.0 g, 53.3 mmol) in toluene
(200 mL) and the reaction mixture was degassed by bubbling argon
for 10 min. CuI (1.0 g, 5.3 mmol) was added to the resulting
reaction mixture and the mixture was heated at 110.degree. C. for
18 h. After the completion of the reaction (monitored by TLC), the
reaction mixture was concentrated under reduced pressure.
Purification by column chromatography (100-200 silica mesh, 10-20%
EtOAc-hexanes) gave
S-(3-(3-((tert-butoxycarbonyl)-amino)propanoyl)phenyl)benzothioate
(18, Intermediate II) as an off white solid. Yield (18.0 g, 87%);
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.07-8.05 (m, 2H),
8.01-7.99 (m, 2H), 7.81-7.74 (m, 2H), 7.69-7.60 (m, 3H), 6.82 (bs,
1H), 3.31-3.27 (m, 2H), 3.20-3.17 (m, 2H), 1.35 (s, 9H); MS: m/z
385.66 [M+H].sup.+.
Example 24
Preparation of
3-amino-1-(3-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)sulfonyl)p-
henyl)propan-1-one
##STR00162##
[0525]
3-Amino-1-(3-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)s-
ulfonyl)phenyl)propan-1-one was prepared following the method used
in Example 8, Intermediate II and below.
[0526] Step 1: K.sub.2CO.sub.3 (1.61 g, 11.67 mmol) was added at
0.degree. C. to a solution of thioester (18, Intermediate II) (1.5
g, 3.89 mmol) in MeOH (20 mL) followed by NaBH.sub.4 (222 mg, 5.84
mmol). The reaction mixture was allowed to warm to room temperature
and stirred for 30 min. The solvent was removed under reduced
pressure. The residue was dissolved in DMF (10 mL), K.sub.2CO.sub.3
(1.16 g, 11.67 mmol), NaBH.sub.4 (222 mg, 5.84 mmol) and
(tetrahydro-2H-thiopyran-4-yl)methyl 4-methylbenzenesulfonate (1.15
g, 4.27 mmol) were added and the resulting mixture was heated at
90.degree. C. under reflux overnight. The reaction mixture was
diluted with EtOAc and washed with water and brine solution, dried
over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced
pressure. Purification by column chromatography (40% EtOAc-hexanes)
gave tert-butyl
(3-hydroxy-3-(3-(((tetrahydro-2H-thiopyran-4-yl)methyl)thio)phenyl)propyl-
)carbamate as a dark brown liquid. Yield (0.67 g, 45%); .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.37-7.32 (m, 1H), 7.23-7.22 (m, 1H),
7.20 (s, 1H), 7.17-7.14 (m, 1H), 4.71 (s, 1H), 4.65 (s, 1H),
3.48-3.46 (m, 1H), 3.38 (s, 1H), 3.18-3.15 (m, 1H), 2.84-2.81 (m,
2H), 2.22-2.19 (m, 2H), 2.09-2.04 (m, 2H), 1.85-1.80 (m, 2H), 1.57
(s, 1H), 1.45 (s, 9H), 1.41-1.37 (m, 2H), 1.37-1.27 (m, 2H); MS:
m/z 398.16 [M+H].sup.+.
[0527] Step 2: Ammonium molybdate (0.99 g, 0.50 mmol) was added to
a solution of tert-butyl
(3-hydroxy-3-(3-(((tetrahydro-2H-thiopyran-4-yl)methyl)thio)phenyl)propyl-
)carbamate (670 mg, 1.68 mmol) in EtOH (10 mL) followed by hydrogen
peroxide (0.2 mL) at 0.degree. C. and the reaction mixture was
stirred at rt for 2 h. The reaction mixture was concentrated under
reduced pressure to give after purification by column
chromatography (50-60% EtOAc-hexanes) tert-butyl
(3-(3-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)sulfonyl)phenyl)--
3-hydroxypropyl)carbamate as a pale yellow liquid. Yield (0.65 g,
97%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.93 (s, 1H), 7.79
(d, J=7.2 Hz, 1H), 7.71 (s, 1H), 7.58-7.53 (s, 1H), 4.86-4.82 (m,
2H), 4.29 (s, 1H), 3.65-3.52 (m, 1H), 3.29-3.20 (m, 2H), 2.91-2.79
(m, 1H), 2.36 (m, 4H), 2.04 (s, 3H), 1.84 (bs, 1H), 1.75-1.72 (m,
1H), 1.46 (s, 9H), 1.42 (s, 1H), 1.31-1.25 (m, 1H); MS: m/z 462.03
[M+H].sup.+.
[0528] Step 3: Pyridinium chlorochromate (218 mg, 1.01 mmol) and
molecular sieves were added to a solution of tert-butyl
(3-(3-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)sulfonyl)phenyl)--
3-hydroxypropyl)carbamate (650 mg, 1.40 mmol) in CH.sub.2Cl.sub.2
(20 mL) and the reaction mixture was stirred at room temperature
for 2 h. The reaction mixture was filtered through a Celite, the
filtrate was diluted with EtOAc, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Purification by flash chromatography (60% EtOAc-hexanes gradient)
gave tert-butyl
(3-(3-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)sulfonyl)phenyl)--
3-oxopropyl)carbamate as a colorless liquid. Yield (0.438 g, 67%);
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.36 (s, 1H), 8.28 (d,
J=7.6 Hz, 1H), 8.16 (d, J=7.6 Hz, 1H), 7.83 (t, J=8.0 Hz, 1H), 6.87
(s, 1H), 3.51 (d, J=6.4 Hz, 2H), 3.32-3.28 (m, 4H), 3.28-3.23 (m,
2H), 3.20-3.13 (m, 1H), 3.04-3.01 (m, 1H), 2.32 (bs, 1H), 2.17-2.14
(m, 2H), 1.85-1.76 (m, 2H), 1.35 (s, 9H); MS: m/z 460.23
[M+H].sup.+.
[0529] Step 4: HCl/dioxane (4N, 5 mL) was added at 0.degree. C. to
a solution of tert-butyl
(3-(3-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)sulfonyl)phenyl)--
3-oxopropyl)carbamate (0.40 g, 0.87 mmol) in CH.sub.2Cl.sub.2 (10
mL) and the reaction mixture was stirred at room temperature for 2
h. The reaction mixture was concentrated under reduced pressure to
give after purification by preparative HPLC Example 24 as a white
solid. Yield (200 mg, 50%); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.39 (s, 1H), 8.31 (d, J=7.6 Hz, 1H), 8.20 (d, J=7.6 Hz,
1H), 7.88 (m, 4H), 3.56-3.52 (m, 2H), 3.50-3.47 (m, 2H), 3.20-3.17
(m, 4H), 3.05-3.02 (m, 2H), 2.31 (bs, 1H), 2.17-2.14 (m, 2H),
1.85-1.77 (m, 2H); MS: m/z 360.18 [M+H].sup.+.
Example 25
Preparation of
3-amino-1-(3-(((tetrahydro-2H-pyran-3-yl)methyl)sulfonyl)phenyl)propan-1--
one
##STR00163##
[0531]
3-Amino-1-(3-(((tetrahydro-2H-pyran-3-yl)methyl)sulfonyl)phenyl)pro-
pan-1-one was prepared following the method used in Example 24 and
below.
[0532] Step 1: Reaction between (tetrahydro-2H-pyran-3-yl)methyl
4-methylbenzenesulfonate and thioester (18, Intermediate II)
following the method used in Example 24 gave after purification by
flash chromatography using 50%-60% EtOAc-hexanes tert-butyl
(3-hydroxy-3-(3-(((tetrahydro-2H-pyran-3-yl)methyl)thio)phenyl)propyl)car-
bamate as a pale yellow liquid. Yield (512 mg, 35%); .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.01 (s, 1H), 7.34 (s, 1H), 7.23 (s,
1H), 7.21 (s, 1H), 7.19-7.14 (m, 1H), 4.90 (s, 1H), 4.75 (s, 1H),
3.95 (s, 1H), 3.83-3.80 (m, 1H), 3.41-3.38 (m, 3H), 3.24-3.11 (m,
2H), 2.82 (d, J=8.0 Hz, 2H), 2.02 (m, 1H), 1.84-1.80 (m, 1H),
1.64-1.55 (m, 2H), 1.45 (s, 9H), 1.36-1.34 (m, 2H); MS: m/z 382.18
[M+H].sup.+.
[0533] Step 2: Oxidation of tert-butyl
(3-hydroxy-3-(3-(((tetrahydro-2H-pyran-3-yl)methyl)thio)phenyl)propyl)car-
bamate following the method used in Example 24 gave after
purification by flash chromatography using 60%-70% EtOAc-hexanes
tert-butyl
(3-hydroxy-3-(3-(((tetrahydro-2H-pyran-3-yl)methyl)sulfonyl)phenyl)propyl-
)carbamate as a pale yellow solid. Yield (0.42 g, 83%); .sup.1H NMR
(400 MHz, CDCl.sub.3), 7.91 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.71
(d, J=4.0 Hz, 1H), 7.56-7.54 (m, 1H), 2.26 (bs, 2H), 1.98-1.96 (m,
2H), 1.86-1.82 (m, 2H), 1.76-1.72 (m, 2H), 1.60-1.58 (m, 2H),
1.58-1.57 (m, 2H), 1.45 (s, 9H), 1.39 (m, 2H), 1.33 (m, 1H), 1.30
(s, 1H), 1.28-1.25 (m, 2H); MS: m/z 414.10 [M+H].sup.+.
[0534] Step 3: Oxidation of tert-butyl
(3-hydroxy-3-(3-(((tetrahydro-2H-pyran-3-yl)methyl)sulfonyl)phenyl)propyl-
)carbamate following the method used in Example 24 gave after
purification by flash chromatography using 60% EtOAc-hexanes
tert-butyl
(3-oxo-3-(3-(((tetrahydro-2H-pyran-3-yl)methyl)sulfonyl)phenyl)propyl)car-
bamate as a colorless oil. Yield (0.18 g, 42%); .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.36 (s, 1H), 8.28 (d, J=8.4 Hz, 1H),
8.16 (d, J=7.6 Hz, 1H), 7.83 (t, J=4.0 Hz, 1H), 6.86 (s, 1H),
3.79-3.75 (m, 1H), 3.67-3.64 (m, 1H), 3.27-3.23 (m, 5H), 3.18-3.13
(m, 1H), 2.08 (s, 1H), 1.82 (bs, 1H), 1.61 (s, 1H), 1.55-1.51 (m,
1H), 1.44-1.42 (m, 1H), 1.35 (s, 9H), 1.27-1.24 (m, 2H); MS: m/z
412.01 [M+H].sup.+.
[0535] Step 4: Deprotection of tert-butyl
(3-oxo-3-(3-(((tetrahydro-2H-pyran-3-yl)methyl)sulfonyl)phenyl)propyl)car-
bamate following the method used in Example 24 gave Example 25 as a
pale yellow solid. Yield (0.150 g, 83%); .sup.1H NMR (400 MHz,
DMSO-d.sub.6), 8.38 (s, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.21 (d,
J.sup.=7.6 Hz, 1H), 7.88 (t, J=7.6 Hz, 2H), 7.82 (bs, 2H), 3.77 (m,
2H), 3.67-3.63 (m, 1H), 3.49-3.46 (m, 2H), 3.37-3.31 (m, 3H),
3.18-3.16 (m, 3H), 1.98-1.93 (m, 1H), 1.84-1.81 (m, 1H), 1.53-1.51
(m, 1H), 1.45-1.35 (m, 1H); MS: m/z 312.28 [M+H].sup.+.
Example 26
Preparation of
3-amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)propan-1--
one
##STR00164##
[0537]
3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)pro-
pan-1-one was prepared following the method used in Example 24 and
below.
[0538] Step 1: A mixture of (tetrahydro-2H-pyran-4-yl)methyl
methanesulfonate (0.33 g, 1.7 mmol), thioester (18, Intermediate
II) (0.65 g, 1.65 mmol) and Cs.sub.2CO.sub.3 (1.40 g, 4.2 mmol) in
DMF (10 ml) and MeOH (5 ml) was degassed and saturated with argon.
The resulting mixture was stirred at 65.degree. C. under argon for
18 hr. Reaction mixture was concentrated under vacuum, partitioned
between H.sub.2O and EtOAc. Organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure to give
tert-butyl
(3-oxo-3-(3-(((tetrahydro-2H-pyran-4-yl)methyl)thio)phenyl)propyl)carbama-
te which directly used in next step without further
purification.
[0539] Step 2: Oxidation of tert-butyl
(3-oxo-3-(3-(((tetrahydro-2H-pyran-4-yl)methyl)thio)phenyl)propyl)carbama-
te using ammonium molybdate and H.sub.2O.sub.2 following the method
used in Example 24 except that the reaction was carried overnight
gave tert-butyl
(3-oxo-3-(3-(((tetrahydro-2H-pyran-4-yl)methyl)-sulfonyl)phenyl)propyl)ca-
rbamate in quantitative yield. The product was used in the next
step without further purification.
[0540] Step 3: Deprotection of tert-butyl
(3-oxo-3-(3-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)propyl)car-
bamate following method described in Example 24 gave Example 26 as
a white solid. Yield (0.48 g, 84%); .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.51 (s, 1H), 8.36 (d, J=7.6 Hz, 1H), 8.22 (d,
J=8.0 Hz, 1H), 7.84 (t, J=7.6 Hz, 1H), 3.91-3.84 (m, 2H), 3.53 (t,
J=6.0 Hz, 2H), 3.44-3.34 (m, 4H), 3.26 (t, J=6.4 Hz, 2H), 2.24-2.14
(m, 1H), 1.82-1.74 (m, 2H), 1.51-1.39 (m, 2H); MS: m/z 312.1
[M+H].sup.+.
Example 27
Preparation of
3-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)piperidin-2-one
##STR00165##
[0542]
3-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)piperidin-2-one
was prepared following the method below.
[0543] Step 1: 6-(Hydroxymethyl)piperidin-2-one (1.0 g, 7.8 mmol)
and Et.sub.3N (1.1 ml, 7.8 mmol) in DCM (5 ml) was added into mesyl
chloride (0.88 g, 7.8 mmol) in DCM (20 ml) at 0.degree. C. The
reaction mixture was stirred at room temperature for 15 mins. The
reaction mixture was washed with 1 N HCl (20 ml) and brine (40 ml),
dried over anhydrous Na.sub.2SO.sub.4 and concentrated under
reduced pressure to give (6-oxopiperidin-2 -yl)methyl
methanesulfonate which was used in the next step without additional
purification. Yield (quant.).
[0544] Step 2: To a mixture of (6-oxopiperidin-2-yl)methyl
methanesulfonate (0.44 g, 2.2 mmol) in DMF (15 ml) was added
Cs.sub.2CO.sub.3 (3.5 g, 11 mmol) and phenol (Intermediate I) (0.88
g, 3.3 mmol). The reaction mixture was stirred at room temperature
for 40 hours and partitioned between water and ethyl acetate.
Organic layer was washed with brine, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure.
Purification by flash chromatography (20% MeOH-EtOAc) gave
tert-butyl
((3R)-3-hydroxy-3-(3-((6-oxopiperidin-2-yl)methoxy)phenyl)propyl)carbamat-
e as a yellow oil. Yield (0.17 g, 20%); .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.24 (t, J=8.0 Hz, 1H), 6.97-6.93 (m, 2H), 6.84
(d, J=8.0 Hz, 1H), 4.64 (t, J=7.2 Hz, 1H), 4.06-4.02 (m, 1H),
3.94-3.90 (m, 1H), 3.86-3.76 (m, 1H), 3.15-3.06 (m, 2H), 2.37-2.30
(m, 2H), 2.05-1.92 (m, 3H), 1.86-1.75 (m, 3H), 1.43 (s, 9H).
[0545] Step 3: To a solution of tert-butyl
((3R)-3-hydroxy-3-(3-((6-oxopiperidin-2-yl)methoxy)phenyl)propyl)carbamat-
e (0.08 g, 0.21 mmol) in EtOAc (2 ml) was added HCl/i-PrOH (5.5 M,
27.5 mmol). The reaction mixture was stirred at room temperature
for 2 hours and concentrated under reduced pressure. Hexane was
added to the residue and the resulting mixture was sonicated and
deasted. The residue was dried under reduced pressure to give
Example 27 as a colorless oil. Yield (0.04 g, 60%); .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 7.28 (t, J=7.6 Hz, 1H), 7.01-6.97 (m,
2H), 6.88 (d, J=8.0 Hz, 1H), 4.85-4.80 (m, 1H), 4.09-4.05 (m, 1H),
3.95 (t, J=6.8 Hz, 1H), 3.90-3.82 (m, 1H), 3.12-3.0 (m, 2H),
2.44-2.36 (m, 2H), 2.06-1.94 (m, 4H), 1.86-1.66 (m, 2H); MS: m/z
279.2 [M+H].sup.+.
Example 28
Preparation of
(R)-3-amino-1-(3-(thiophen-2-ylmethoxy)phenyl)propan-1-ol
##STR00166##
[0547] (R)-3-Amino-1-(3-(thiophen-2-ylmethoxy)phenyl)propan-1-ol
was prepared following the method below.
[0548] Step 1: Alkylation of phenol (1) with
2-(bromomethyl)thiophene following the method used in Example 4
gave after flash column chromatography ethyl
3-(thiophen-2-ylmethoxy)benzoate as a colorless oil. Yield (2.80 g,
97%); .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.66 (d, J=1.2 Hz,
2H), 7.35-7.33 (m, 2H), 7.18-7.02 (m, 2H), 7.01 (d, J= 4.0 Hz, 1H),
5.26 (s, 2H), 4.37 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H); MS:
m/z 247 [M+H].sup.+.
[0549] Step 2: Condensation between ethyl
3-(thiophen-2-ylmethoxy)benzoate and acetonitrile following the
method used in the preparation of phenol (Intermediate I) gave
after flash column chromatography
3-oxo-3-(3-(thiophen-2-ylmethoxy)phenyl)propanenitrile as a
colorless oil. Yield (2.80 g, 95%); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.53 (d, J=2.0 Hz, 1H), 7.49-7.41 (m, 2H), 7.35
(d, J=4.8 Hz, 1H), 7.28 (d, J=1.6 Hz, 1H), 7.14 (d, J=3.2 Hz, 1H),
7.02 (dd, J=4.8, 1.2 Hz, 1H), 5.28 (s, 1H), 4.05 (s, 1H); MS: m/z
258.06 [M+H].sup.+.
[0550] Step 3: Chiral reduction of
3-oxo-3-(3-(thiophen-2-ylmethoxy)phenyl)propanenitrile following
the method used in the preparation of phenol (7, Intermediate I)
gave after flash column chromatography
(R)-3-hydroxy-3-(3-(thiophen-2-ylmethoxy)phenyl)propanenitrile as a
white solid. Yield (2.6 g, 82%); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.55 (d, J=4.8 Hz, 1H), 7.25 (t, J=8.0 Hz,
1H), 7.21 (d, J=3.2 Hz, 1H), 7.06-6.99 (m, 3H), 6.94 (dd, J=8.0,
2.0 Hz, 1H), 5.95 (d, J=4.4 Hz, 1H), 5.27 (s, 2H), 4.85 (dd,
J=11.2, 4.8 Hz, 1H), 2.92-2.77 (m, 2H). Yield (2.6 g, 92%); MS: m/z
260.06 [M+H].sup.+.
[0551] Step 4: Borane-dimethylsulfide (1.0 mL, 10.5 mmol) was added
to a stirred solution of
(R)-3-hydroxy-3-(3-(thiophen-2-ylmethoxy)phenyl)propanenitrile
(1.00 g, 3.856 mmol) in anhydrous THF (10 mL) and the reaction
mixture was stirred under reflux at +80.degree. C. for 1 hour, then
at room temperature for 16 hrs, then again at +80.degree. C. for 2
h. MeOH was added to the reaction mixture followed by HCl/MeOH
(1.25 M, 5 mL). The mixture was stirred under reflux at +80.degree.
C. for 1 h then concentrated under reduced pressure. The residue
was partitioned between EtOAc and IN NaOH, organic layer was washed
with brine, dried over anhydrous dried over anhydrous MgSO.sub.4
and concentrated under reduced pressure. Purification by flash
chromatography (5%-20% of 20% 7N
NH.sub.3/MeOH/CH.sub.2Cl.sub.2--CH.sub.2Cl.sub.2 gradient) gave
Example 44 as a colorless oil. Yield (0.76 g, 75%); .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta.7.38 (d, J=5.10 Hz, 1H), 7.23 (t,
J=8.02 Hz, 1H), 7.12 (m, 1H), 6.97-7.02 (m, 2H), 6.94 (d, J=8.0 Hz,
1H), 6.85-6.90 (m, 1H), 5.25 (s, 2H), 4.69 (t, J=7.2 Hz, 1H),
2.65-2.78 (m, 2H), 1.76-1.90 (m, 2H); MS: m/z 264.1
[M+H].sup.+.
Example 29
Preparation of
(R)-3-amino-1-(3-(thiophen-3-ylmethoxy)phenyl)propan-1-ol
##STR00167##
[0553] (R)-3-Amino-1-(3-(thiophen-3-ylmethoxy)phenyl)propan-1-ol
was prepared following the method used in Example 28.
[0554] Step 1: Alkylation of phenol (1) with
3-(bromomethyl)thiophene gave after flash column chromatography
ethyl 3-(thiophen-3-ylmethoxy)benzoate as a pale yellow waxy solid.
Yield (3.0 g, 96%); .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
7.66-7.64 (m, 2H), 7.36-7.26 (m, 3H), 7.17-7.14 (m, 2H), 5.11 (s,
2H), 4.37 (q, J=7.2 Hz, 2H), 1.41-1.36 (m, 3H); MS: m/z 247.09.
[0555] Step 2: Condensation between ethyl
3-(thiophen-2-ylmethoxy)benzoate and acetonitrile gave after flash
column chromatography
3-oxo-3-(3-(thiophen-2-ylmethoxy)phenyl)propanenitrile as a pale
yellow solid. Yield (2.60 g, 83%); .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 7.52 (s, 1H), 7.48-7.41 (m, 2H), 3.73 (d,
J=3.2 Hz, 2H), 7.27 (s, 1H), 7.15 (d, J=4.8 Hz, 1H), 5.13 (s, 2H),
4.05 (s, 2H); MS: m/z 258.0.
[0556] Step 3: Chiral reduction of
3-oxo-3-(3-(thiophen-2-ylmethoxy)phenyl)propanenitrile gave after
flash column chromatography
(R)-3-hydroxy-3-(3-(thiophen-2-ylmethoxy)phenyl)propanenitrile as a
white solid. Yield (1.7 g, 80%); .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 7.58 (s, 2H), 7.26 (t, J=7.6 Hz, 1H), 7.18
(s, 1H), 6.98 (d, J=17.6 Hz, 1H), 6.92 (d, J=7.6 Hz, 2H), 5.94 (s,
1H), 5.07 (s, 2H), 4.86 (s, 1H), 2.90-2.77 (m, 2H); MS: m/z
260.25.
[0557] Step 4: Reduction of
(R)-3-hydroxy-3-(3-(thiophen-3-ylmethoxy)phenyl)propanenitrile
following the method used in Example 28 gave Example 29 as a
colorless oil. Yield (0.45 g, 74%); .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.37-7.42 (m, 2H), 7.23 (t, J=7.83 Hz, 1H),
7.11-7.16 (m, 1H), 7.01 (s, 1H), 6.93 (d, J=7.63 Hz, 1H), 6.84-6.89
(m, 1H), 5.09 (s, 2H), 4.69 (t, J=7.24 Hz, 1H), 2.64-2.76 (m, 2H),
1.76-1.92 (m, 2H); MS: m/z 264.1 [M+H].sup.+.
Example 30
Preparation of (R)-tert-butyl
4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidine-1-carboxylate
##STR00168##
[0559] (R)-tert-Butyl
4-((3-(3-amino-1-hydroxypropyl)phenoxy)methyl)piperidine-1-carboxylate
was prepared following the method below.
[0560] Step 1: A mixture of tert-butyl
4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (1.91 g,
6.51 mmol), phenol (11) (1.25 g, 8.22 mmol), K.sub.2CO.sub.3 (1.11
g, 8.03 mmol) in anhydrous DMF (10 mL) was stirred under inert
atmosphere at +80.degree. C. for 18 hrs. The reaction mixture was
partitioned between aqueous 25% NH.sub.4Cl and EtOAc. Aqueous layer
was extracted with EtOAc and combined organic layers were washed
with brine, dried over anhydrous MgSO.sub.4, and concentrated under
reduced pressure to give tert-butyl
4-((3-(methoxycarbonyl)phenoxy)methyl)piperidine-1-carboxylate as a
light yellow oil which was used in the next step without further
purification. Yield (2.02 g, 89%).
[0561] Step 2: CH.sub.3CN (0.25 mL, 4.79 mmol) was added to a cold
(-78.degree. C.) solution of t-BuO.sup.-K.sup.+ in THF (1M, 5.0 mL,
5.0 mmol) under Ar and the reaction mixture was stirred for 5 mins.
Solution of tert-butyl
4-((3-(methoxycarbonyl)phenoxy)methyl)piperidine-1-carboxylate
(1.01 g, 2.86 mmol) in anhydrous THF (7 mL) was added to the
reaction mixture and the resulting mixture was stirred at
-78.degree. C. for 10 min, then warmed to room temperature over 30
mins. The reaction mixture was quenched with 5% aqueous NaHSO4 and
extracted twice with tert-butyl methyl ether. Combined organic
layers were washed with brine and concentrated under reduced
pressure. Purification by flash chromatography (20%-80%
EtOAc-hexanes gradient) gave tert-butyl
4-((3-(2-cyanoacetyl)phenoxy)methyl)piperidine-1-carboxylate as a
white solid. Yield (0.55 g, 54%); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.39-7.51 (m, 3H), 7.23-7.28 (m, 1H), 4.73
(s, 2H), 3.84-4.00 (m, 2H), 3.90 (d, J=6.26 Hz, 2H), 2.60-2.80 (m,
2H), 1.86-1.97 (m, 1H), 1.70-1.78 (m, 2H), 1.38 (s, 9H), 1.08-1.23
(m, 2H).
[0562] Step 3: Chiral hydrogenation of tert-butyl
4-((3-(2-cyanoacetyl)phenoxy)methyl)piperidine-1-carboxylate in
EtOH (10 mL) following the method used in Example 1 using
HCOOH.Et.sub.3N mixture in EtOH (4.1M) gave after flash
chromatography purification (25%-100% EtOAc-hexanes gradient)
(R)-tert-butyl
4-((3-(2-cyano-1-hydroxyethyl)phenoxy)methyl)piperidine-1-carboxylate
as a light brown oil. Yield (0.47 g, 94%); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.23 (t, J=7.83 Hz, 1H), 6.92-6.98 (m, 2H),
6.79-6.84 (m, 1H), 5.89 (m, 1H), 4.83 (m, 1H), 3.66-4.00 (m, 2H),
3.81 (d, J=6.26 Hz, 2H), 2.60-2.90 (m, 4H), 1.84-1.96 (m, 1H),
1.68-1.78 (m, 2H), 1.38 (s, 9H), 1.08-1.18 (m, 2H).
[0563] Step 4: Reduction of (R)-tert-butyl
4-((3-(2-cyano-1-hydroxyethyl)phenoxy)methyl)piperidine-1-carboxylate
was done following the method used in Example 28. After the
reaction was complete, it was quenched with addition of 10%
NaHCO.sub.3. The mixture was stirred over 3 days and extracted with
MTBE. Organic layer was washed with brine, concentrated under
reduced pressure. Flash chromatography purification (10%-50% of 20%
7N NH.sub.3/MeOH/CH.sub.2Cl.sub.2--CH.sub.2Cl.sub.2 gradient) gave
Example 30 as a free base. HCl/i-PrOH (5.5 N) was added to solution
of Example 30 in EtOAc (5 mL), the mixture was concentrated under
reduced pressure, re-evaporated with EtOAc and some EtOAc was
added. The mixture was sonicated until white precipitate formed;
the latter was collected by filtration, washed with EtOAc, hexanes
and dried on filter to give Example 30 hydrochloride as a white
solid. Yield (0.187 g, 39%); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.22 (t, J=7.43 Hz, 1H), 6.84-6.90 (m, 2H), 6.76-6.81 (m,
1H), 4.63 (dd, J=4.50, 7.63 Hz, 1H), 3.90-4.00 (m, 2H), 3.80 (d,
J=6.26 Hz, 2H), 2.60-2.85 (m, 4H), 1.77-1.95 (m, 3H), 1.68-1.77 (m,
2H), 1.38 (s, 9H), 1.07-1.20 (m, 2H); MS: m/z 365.3
[M+H].sup.+.
Example 31
Preparation of
(E)-3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)prop-2-en-1-amine
##STR00169##
[0565]
(E)-3-(3-((Tetrahydro-2H-pyran-4-yl)methoxy)phenyl)prop-2-en-1-amin-
e was prepared following the method below.
[0566] Step 1: Alkylation of 3-bromophenol with
(tetrahydro-2H-pyran-4-yl)methyl methanesulfonate following the
method used in preparation of phenol (7, Intermediate I) gave
4-((3-bromophenoxy)methyl)tetrahydro-2H-pyran as a white solid
which was used in the next step without additional purification.
Yield (quant.).
[0567] Step 2: A mixture of
4-((3-bromophenoxy)methyl)tetrahydro-2H-pyran (1.86 g, 6.86 mmol),
N-allyl-2,2,2-trifluoroacetamide (1.14 g, 7.45 mmol),
P(o-Tol).sub.3 (0.31 g, 1.02 mmol), Pd(OAc).sub.2 (0.12 g, 0.534
mmol), Et.sub.3N (2.0 mL, 14.35 mmol) and anhydrous DMF (10 mL) was
degassed by bubbling Ar for at least 5 mins, then applying
vacuum/Ar once. The reaction mixture was heated under Ar at
+90.degree. C. for 20 hrs then concentrated under reduced pressure.
Aqueous NH.sub.4Cl was added to the residue and extracted twice
with EtOAc. Combined organic layers were washed with brine, treated
with activated charcoal and dried over anhydrous MgSO.sub.4 and
concentrated under reduced pressure. Purification by flash
chromatography (20%-50% EtOAc-hexanes gradient) gave
(E)-2,2,2-trifluoro-N-(3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)pheny-
l)allyl)acetamide as a light yellow oil. Yield (2.01 g, 85%);
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.70 (m, 1H), 7.21 (t,
J=7.63 Hz, 1H), 6.94-7.00 (m, 2H), 6.78-6.83 (m, 1H), 6.48 (d,
J=15.85 Hz, 1H), 6.25 (dt, J=15.85, 5.87 Hz, 1H), 3.90-4.00 (m,
2H), 3.75-3.90 (m, 4H), 3.31 (t, J=11.74 Hz, 2H), 1.90-2.04 (m,
1H), 1.60-1.70 (m, 2H), 1.24-1.37 (m, 2H).
[0568] Step 3: A mixture of
(E)-2,2,2-trifluoro-N-(3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)all-
yl)acetamide (1.05 g, 3.06 mmol), K.sub.2CO.sub.3 (1.51 g, 10.93
mmol), MeOH (25 mL) and H.sub.2O (10 mL) was stirred at room
temperature over 3 days then concentrated under reduced pressure.
Water was added and the mixture was extracted twice with MTBE.
Combined organic layers were washed with brine, dried over
anhydrous MgSO.sub.4, concentrated under reduced pressure. The
residue was dissolved in EtOAc and HCl/i-PrOH (5.5 M, 0.7 mL) was
added. The precipitate was collected by filtration, washed with
EtOAc and dried to give Example 31 hydrochloride as a white solid.
Yield (0.604 g, 70%); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.17 (br. s, 3H), 7.26 (t, J=7.83 Hz, 1H), 6.93-7.00 (m, 2H),
6.83-6.88 (m, 1H), 6.68 (d, J=16.04 Hz, 1H), 6.28 (dt, J=16.04,
6.06 Hz, 1H), 3.80-3.90 (m, 4H), 3.54-3.60 (m, 2H), 3.27-3.36 (m,
2H), 1.97 (m, 1H), 1.62-1.70 (m, 2H), 1.25-1.38 (m, 2H); MS: m/z
231.2 [M-NH.sub.3].sup.+.
Example 32
Preparation of
3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-amine
##STR00170##
[0570]
3-(3-((Tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-amine was
prepared following the method below.
[0571] Step 1: Hydrogenation of Example 31
((E)-3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)prop-2-en-1-amine
hydrochloride) at 1 atm H.sub.2 pressure using Pd/C (10% wt, 0.020
g) catalyst in EtOH (absolute, degassed, 20 mL) for 1.5 hrs gave
after filtration through Celite and concentration of the filtrate
under reduced pressure Example 32 hydrochloride as a white solid.
Yield (0.150 g, 73%); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.98 (br. s, 3H), 7.18 (t, J=7.83 Hz, 1H), 6.72-6.80 (m, 3H),
3.750-3.90 (m, 4H), 3.26-3.36 (m, 2H), 2.72 (t, J=7.24 Hz, 2H),
2.59 (t, J=7.43 Hz, 1H), 1.96 (m, 1H), 1.78-1.88 (m, 2H), 1.61-1.69
(m, 2H), 1.24-1.36 (m, 2H); MS: m/z 250.2 [M+H].sup.+.
Example 33
Preparation of
(R)-3-(methylamino)-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-
-1-ol
##STR00171##
[0573]
(R)-3-(Methylamino)-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-
propan-1-ol was prepared following the method below.
[0574] Step 1: (Boc).sub.2O (0.22 g, 3.80 mmol) was added to a
solution of
(R)-3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(Example 1) (1.0 g, 3.80 mmol) in DCM (20 mL) at room temperature.
The reaction mixture was stirred at room temperature for 18 hrs and
concentrated under reduced pressure. Purification by flash
chromatography (60% EtOAc-hexane) gave tert-butyl
(3-hydroxy-3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propyl)carbamat-
e as a colorless oil. Yield (1.1 g, 80%); .sup.1H NMR (400 MHz,
DMSO-d.sub.6); .delta. 7.18 (t, J=8.0 Hz, 1H), 6.85-6.84 (m, 2H),
6.76-6.74 (m, 2H), 5.15 (d, J=4.4 Hz, 1H), 4.49 (q, J=4.4 Hz, 1H),
3.88-3.84 (m, 2H), 3.79 (d, J=6.4 Hz, 2H), 2.94 (q, J=6.4 Hz, 2H),
1.70-1.62 (m, 4H), 1.38-1.26 (m, 11H).
[0575] Step 2: LiAlH.sub.4 (1 M in THF, 7.50 mmol) was added to a
solution of tert-butyl
(3-hydroxy-3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propyl)carbamat-
e (1.1 g, 3.00 mmol) in anhydrous THF (20 mL) at room temperature.
The reaction mixture was stirred at 65.degree. C. for 18 hours and
cooled to room temperature. The reaction mixture was quenched by
slow addition of saturated Na.sub.2SO.sub.4. MTBE was added and the
mixture stirred for 30 min. Layers were separated and organic
portion was dried over anhydrous Na.sub.2SO.sub.4 and concentrated
under reduced pressure. The residue was dissolved in methanol (10
ml) and HCl/MeOH was added (1.25 M, 3.75 mmol), the mixture was
concentrated under reduced pressure. EtOAc was added to the residue
and the mixture was sonicated to give white solid which was
collected by filtration and dried in vacuum to give Example 33 as a
white solid. Yield (0.65 g, 6%); .sup.1H NMR (400 MHz,
DMSO-d.sub.6); .delta. 7.26 (t, J=8.0 Hz, 1H), 6.95-6.93 (m, 2H),
6.83 (d, J=8.0 Hz, 1H), 4.82-4.79 (m, 1H), 4.0-3.86 (m, 2H), 3.84
(d, J=6.4 Hz, 2H), 3.49-3.46 (m, 2H), 3.20-3.04 (m, 2H), 2.70 (s,
3H), 2.12-1.96 (m, 3H), 1.77-1.74 (m, 2H), 1.50-1.38 (m, 2H); MS:
m/z 280.2 [M+H].sup.+.
Example 34
Preparation of
1-((S)-2-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)pyrrolidin-1-yl)-
ethanone
##STR00172##
[0577]
1-((S)-2-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)pyrroli-
din-1-yl)ethanone is prepared following the method used in Example
11.
[0578] Step 1: Sulphonation of
(S)-1-(2-(hydroxymethyl)pyrrolidin-1-yl)ethanone with TsCl gives
(S)-(1-acetylpyrrolidin-2-yl)methyl 4-methylbenzenesulfonate.
[0579] Step 2: Alkylation of phenol (7, Intermediate I) with
(S)-(1-acetylpyrrolidin-2-yl)methyl 4-methylbenzenesulfonate gives
tert-butyl
((R)-3-(3-(((S)-1-acetylpyrrolidin-2-yl)methoxy)phenyl)-3-hydroxypropyl)c-
arbamate.
[0580] Step 3: Deprotection of
((R)-3-(3-(((S)-1-acetylpyrrolidin-2-yl)methoxy)phenyl)-3-hydroxypropyl)c-
arbamate gives Example 34.
Example 35
Preparation of
5-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)piperidin-2-one
##STR00173##
[0582]
5-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)piperidin-2-one
is prepared following the method used in Example 27.
[0583] Step 1: Sulphonation of 5-(hydroxymethyl)piperidin-2-one
with MsCl gives (6-oxopiperidin-3-yl)methyl methanesulfonate.
[0584] Step 2: Alkylation of phenol (7, Intermediate I) with
(6-oxopiperidin-3-yl)methyl methanesulfonate gives tert-butyl
((3R)-3-hydroxy-3-(3-((6-oxopiperidin-3-yl)methoxy)phenyl)propyl)carbamat-
e.
[0585] Step 3: Deprotection of tert-butyl
((3R)-3-hydroxy-3-(3-((6-oxopiperidin-3-yl)methoxy)phenyl)propyl)carbamat-
e gives Example 35.
Example 36
Preparation of
4-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)piperidin-2-one
##STR00174##
[0587]
4-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)piperidin-2-one
is prepared following the method used in Example 27.
[0588] Step 1: Sulphonation of 4-(hydroxymethyl)piperidin-2-one
with MsCl gives (2-oxopiperidin-4-yl)methyl methanesulfonate.
[0589] Step 2: Alkylation of phenol (7, Intermediate I) with
(2-oxopiperidin-4-yl)methyl methanesulfonate gives tert-butyl
((3R)-3-hydroxy-3-(3-((2-oxopiperidin-4-yl)methoxy)phenyl)propyl)carbamat-
e.
[0590] Step 3: Deprotection of tert-butyl
((3R)-3-hydroxy-3-(3-((2-oxopiperidin-4-yl)methoxy)phenyl)propyl)carbamat-
e gives Example 36.
Example 37
Preparation of
6-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)-1-methylpiperidin-2-on-
e
##STR00175##
[0592]
6-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)-1-methylpiperidi-
n-2-one is prepared following the method used in Example 27.
[0593] Step 1: Sulphonation of
6-(hydroxymethyl)-1-methylpiperidin-2-one with MsCl gives
(1-methyl-6-oxopiperidin-2-yl)methyl methanesulfonate.
[0594] Step 2: Alkylation of phenol (7, Intermediate I) with
(1-methyl-6-oxopiperidin-2-yl)methyl methanesulfonate gives
tert-butyl
((3R)-3-hydroxy-3-(3-((1-methyl-6-oxopiperidin-2-yl)methoxy)phenyl)propyl-
)carbamate.
[0595] Step 3: Deprotection of tert-butyl
((3R)-3-hydroxy-3-(3-((1-methyl-6-oxopiperidin-2-yl)methoxy)phenyl)propyl-
)carbamate gives Example 37.
Example 38
Preparation of
5-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)pyrrolidin-2-one
##STR00176##
[0597]
5-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)pyrrolidin-2-one
is prepared following the method used in Example 27.
[0598] Step 1: Alkylation of phenol (7, Intermediate I) with
(5-oxopyrrolidin-2-yl)methyl methanesulfonate gives tert-butyl
((3R)-3-hydroxy-3-(3-((5-oxopyrrolidin-2-yl)methoxy)phenyl)propyl)carbama-
te.
[0599] Step 2: Deprotection of tert-butyl
((3R)-3-hydroxy-3-(3-((5-oxopyrrolidin-2-yl)methoxy)phenyl)propyl)carbama-
te gives Example 38.
Example 39
Preparation of
5-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)-1-methylpyrrolidin-2-o-
ne
##STR00177##
[0601]
5-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)-1-methylpyrrolid-
in-2-one is prepared following the method used in Example 38.
[0602] Step 1: Alkylation of phenol (7, Intermediate I) with
(1-methyl-5-oxopyrrolidin-2-yl)methyl methanesulfonate gives
tert-butyl
((3R)-3-hydroxy-3-(3-((1-methyl-5-oxopyrrolidin-2-yl)methoxy)phenyl)propy-
l)carbamate.
[0603] Step 2: Deprotection of tert-butyl
((3R)-3-hydroxy-3-(3-((1-methyl-5-oxopyrrolidin-2-yl)methoxy)phenyl)propy-
l)carbamate gives Example 39.
Example 40
Preparation of
N-(3-(3-amino-1-hydroxypropyl)phenyl)-6-oxopiperidine-3-carboxamide
##STR00178##
[0605]
N-(3-(3-Amino-1-hydroxypropyl)phenyl)-6-oxopiperidine-3-carboxamide
is prepared following the method below.
[0606] Step 1: Condensation between 6-oxopiperidine-3-carboxylic
acid and tert-butyl (3-(3-aminophenyl)-3-hydroxypropyl)carbamate
gives tert-butyl
(3-hydroxy-3-(3-(6-oxopiperidine-3-carboxamido)phenyl)propyl)carbamate.
[0607] Step 2: Deprotection of tert-butyl
(3-hydroxy-3-(3-(6-oxopiperidine-3-carboxamido)phenyl)propyl)carbamate
gives Example 40.
Example 41
Preparation of
3-((3-((R)-3-amino-1-hydroxypropyl)phenoxy)methyl)-1,2-thiazinane
1,1-dioxide
##STR00179##
[0609]
3-((3-((R)-3-Amino-1-hydroxypropyl)phenoxy)methyl)-1,2-thiazinane
1,1-dioxide was prepared following the method used in Example
27.
[0610] Step 1: Sulphonation of 3-(hydroxymethyl)-1,2-thiazinane
1,1-dioxide with MsCl gives (1,1-dioxido-1,2-thiazinan-3-yl)methyl
methanesulfonate.
[0611] Step 2: Alkylation of phenol (7, Intermediate I) with
(1,1-dioxido-1,2-thiazinan-3-yl)methyl methanesulfonate gives
tert-butyl
((3R)-3-(3-((1,1-dioxido-1,2-thiazinan-3-yl)methoxy)phenyl)-3-hydroxyprop-
yl)carbamate.
[0612] Step 3: Deprotection of tert-butyl
((3R)-3-(3-((1,1-dioxido-1,2-thiazinan-3-yl)methoxy)phenyl)-3-hydroxyprop-
yl)carbamate gives Example 41.
Example 42
Preparation of
(R)-1-(3-((1H-pyrrol-2-yl)methoxy)phenyl)-3-aminopropan-1-ol
##STR00180##
[0614] (R)-1-(3-((1H-Pyrrol-2-yl)methoxy)phenyl)-3-aminopropan-1-ol
is prepared following the method used in Example 15.
[0615] Step 1: Alkylation of phenol (7, Intermediate I) with
tert-butyl 2-(((methylsulfonyl)oxy)methyl)-1H-pyrrole-1-carboxylate
gives (R)-tert-butyl
2-((3-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)-1H--
pyrrole-1-carboxylate.
[0616] Step 2: Deprotection of (R)-tert-butyl
2-((3-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)-1H--
pyrrole-1-carboxylate gives Example 42.
Example 43
Preparation of
(R)-3-amino-1-(3-(furan-2-ylmethoxy)phenyl)propan-1-ol
##STR00181##
[0618] (R)-3-Amino-1-(3-(furan-2-ylmethoxy)phenyl)propan-1-ol is
prepared following the method used in Example 27.
[0619] Step 1: Alkylation of phenol (7, Intermediate I) with
furan-2-ylmethyl methanesulfonate gives (R)-tert-butyl
(3-(3-(furan-2-ylmethoxy)phenyl)-3-hydroxypropyl)carbamate.
[0620] Step 2: Deprotection of (R)-tert-butyl
(3-(3-(furan-2-ylmethoxy)phenyl)-3-hydroxypropyl)carbamate gives
Example 43.
Example 44
Preparation of
(R)-3-amino-1-(3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)propan-
-1-ol
##STR00182##
[0622]
R)-3-Amino-1-(3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)p-
ropan-1-ol is prepared following the method used in Example 4.
[0623] Step 1: Reaction between
(1-(methylsulfonyl)piperidin-4-yl)methyl methanesulfonate and
phenol (7, Intermediate I) gives (R)-tert-butyl
(3-hydroxy-3-(3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)propyl)-
carbamate.
[0624] Step 2: Deprotection of (R)-tert-butyl
(3-hydroxy-3-(3-((1-(methylsulfonyl)piperidin-4-yl)methoxy)phenyl)propyl)-
carbamate gives Example 44.
Example 45
Preparation of
(R)-1-(3-(((1H-indol-6-yl)methyl)amino)phenyl)-3-aminopropan-1-ol
##STR00183##
[0626]
(R)-1-(3-(((1H-Indol-6-yl)methyl)amino)phenyl)-3-aminopropan-1-ol
is prepared following the method used in Example 23.
[0627] Step 1: Reaction between 1H-indole-6-carbaldehyde and
(R)-3-(3-aminophenyl)-3-hydroxypropanenitrile gives
(R)-3-(3-(((1H-indol-6-yl)methyl)amino)phenyl)-3-hydroxypropanenitrile.
[0628] Step 2: Reduction of
(R)-3-(3-(((1H-indol-6-yl)methyl)amino)phenyl)-3-hydroxypropanenitrile
gives Example 45.
Example 46
Preparation of
(R)-1-(3-((1H-indol-6-yl)methoxy)phenyl)-3-aminopropan-1-ol
##STR00184##
[0630] (R)-1-(3-((1H-Indol-6-yl)methoxy)phenyl)-3-aminopropan-1-ol
is prepared following the method used in Example 42.
[0631] Step 1: Sulphonation of tert-butyl
6-(hydroxymethyl)-1H-indole-1-carboxylate with mesyl chloride gives
tert-butyl
6-(((methylsulfonyl)oxy)methyl)-1H-indole-1-carboxylate.
[0632] Step 2: Alkylation of phenol (7, Intermediate I) with
tert-butyl 6-(((methylsulfonyl)oxy)methyl)-1H-indole-1-carboxylate
gives (R)-tert-butyl
6-((3-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)-1H--
indole-1-carboxylate.
[0633] Step 3: Deprotection of (R)-tert-butyl
6-((3-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)-1H--
indole-1-carboxylate gives Example 46.
Example 47
Preparation of
(R)-3-amino-1-(3-(benzofuran-2-ylmethoxy)phenyl)propan-1-ol
##STR00185##
[0635] (R)-3-Amino-1-(3-(benzofuran-2-ylmethoxy)phenyl)propan-1-ol
is prepared following the method used in Example 13.
[0636] Step 1: Sulphonation of benzofuran-2-ylmethanol with mesyl
chloride gives benzo furan-2-ylmethyl methanesulfonate.
[0637] Step 2: Alkylation of phenol (7, Intermediate I) with
benzofuran-2-ylmethyl methanesulfonate gives (R)-tert-butyl
(3-(3-(benzofuran-2-ylmethoxy)phenyl)-3-hydroxypropyl)carbamate.
[0638] Step 3: Deprotection of (R)-tert-butyl
(3-(3-(benzofuran-2-ylmethoxy)phenyl)-3-hydroxypropyl)carbamate
gives Example 47.
Example 48
Preparation of
3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)prop-2-yn-1-amine
##STR00186##
[0640]
3-(3-((Tetrahydro-2H-pyran-4-yl)methoxy)phenyl)prop-2-yn-1-amine is
prepared following the method below.
[0641] Step 1: Sonogashira coupling between
4-((3-bromophenoxy)methyl)tetrahydro-2H-pyran and tert-butyl
prop-2-yn-1-ylcarbamate gives tert-butyl
(3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)prop-2-yn-1-yl)carbamate.
[0642] Step 2: Deprotection of tert-butyl
(3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)prop-2-yn-1-yl)carbamate
gives Example 48.
Example 49
Preparation of
3-amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)thio)phenyl)propan-1-ol
##STR00187##
[0644]
3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)thio)phenyl)propan--
1-ol is prepared following the method used in Example 26 and
below.
[0645] Step 1: Reduction of tert-butyl
(3-oxo-3-(3-(((tetrahydro-2H-pyran-4-yl)methyl)thio)-phenyl)propyl)carbam-
ate with NaBH.sub.4 gives tert-butyl
(3-hydroxy-3-(3-(((tetrahydro-2H-pyran-4-yl)methyl)thio)phenyl)propyl)car-
bamate.
[0646] Step 2: Deprotection of tert-butyl
(3-hydroxy-3-(3-(((tetrahydro-2H-pyran-4-yl)methyl)thio)phenyl)propyl)car-
bamate gives Example 49.
Example 50
Preparation of
3-amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)propan-1--
ol
##STR00188##
[0648]
3-Amino-1-(3-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)pro-
pan-1-ol is prepared following the method used in Examples 24, 26
and below.
[0649] Step 1: Oxidation of tert-butyl
(3-hydroxy-3-(3-(((tetrahydro-2H-pyran-4-yl)methyl)thio)phenyl)propyl)car-
bamate following the method used in Example 40 gives tert-butyl
(3-hydroxy-3-(3-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonyl)phenyl)-propy-
l)carbamate.
[0650] Step 2: Deprotection of tert-butyl
(3-hydroxy-3-(3-(((tetrahydro-2H-pyran-4-yl)methyl)-sulfonyl)phenyl)propy-
l)carbamate gives Example 50.
Example 51
Preparation of
3-amino-1-(3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)phenyl)propan-1-ol
##STR00189##
[0652]
3-Amino-1-(3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)phenyl)propan-1-ol
is prepared following the method below.
[0653] Step 1: Sonogashira coupling between
4-ethynyltetrahydro-2H-pyran and tert-butyl
(3-(3-bromophenyl)-3-hydroxypropyl)carbamate gives tert-butyl
(3-hydroxy-3-(3-((tetrahydro-2H-pyran-4-yl)ethynyl)phenyl)propyl)carbamat-
e.
[0654] Step 2: Deprotection of tert-butyl
(3-hydroxy-3-(3-((tetrahydro-2H-pyran-4-yl)ethynyl)phenyl)propyl)carbamat-
e gives
3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)ethynyl)phenyl)propan-1-ol-
.
[0655] Step 3: Hydrogenation of gives
3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)ethynyl)phenyl)propan-1-ol
gives Example 51.
Example 52
Preparation of
3-amino-1-(3-(2-(pyridin-3-yl)ethyl)phenyl)propan-1-ol
##STR00190##
[0657] 3-Amino-1-(3-(2-(pyridin-3-yl)ethyl)phenyl)propan-1-ol is
prepared following the method below.
[0658] Step 1: Sonogashira coupling between 3-ethynylpyridine and
tert-butyl (3-(3-bromophenyl)-3-hydroxypropyl)carbamate gives
tert-butyl
(3-hydroxy-3-(3-(pyridin-3-ylethynyl)phenyl)propyl)carbamate.
[0659] Step 2: Deprotection of tert-butyl
(3-hydroxy-3-(3-(pyridin-3-ylethynyl)phenyl)propyl)-carbamate gives
3-Amino-1-(3-(pyridin-3-ylethynyl)phenyl)propan-1-ol.
[0660] Step 3: Hydrogenation of
3-Amino-1-(3-(pyridin-3-ylethynyl)phenyl)propan-1-ol gives Example
71.
Example 53
Preparation of
3-amino-1-(3-(2-(thiophen-3-yl)ethyl)phenyl)propan-1-ol
##STR00191##
[0662] 3-Amino-1-(3-(2-(thiophen-3-yl)ethyl)phenyl)propan-1-ol is
prepared following the method below.
[0663] Step 1: Sonogashira coupling between 3-ethynylthiophene and
tert-butyl (3-(3-bromophenyl)-3-hydroxypropyl)carbamate gives
tert-butyl
(3-hydroxy-3-(3-(thiophen-3-ylethynyl)phenyl)propyl)carbamate.
[0664] Step 2: Deprotection of tert-butyl
(3-hydroxy-3-(3-(thiophen-3-ylethynyl)phenyl)propyl)carbamate gives
3-Amino-1-(3-(thiophen-3-ylethynyl)phenyl)propan-1-ol.
[0665] Step 3: Hydrogenation of
3-Amino-1-(3-(thiophen-3-ylethynyl)phenyl)propan-1-ol gives Example
53.
Example 54
Preparation of
(E)-1-(3-(3-amino-1-hydroxypropyl)styryl)pyrrolidin-2-one
##STR00192##
[0667] (E)-1-(3-(3-Amino-1-hydroxypropyl)styryl)pyrrolidin-2-one is
prepared following the method used in Example 31 and below.
[0668] Step 1: Heck coupling between 1-vinylpyrrolidin-2-one and
tert-butyl (3-(3-bromophenyl)-3-hydroxypropyl)carbamate gives
(E)-tert-butyl
(3-hydroxy-3-(3-(2-(2-oxopyrrolidin-1-yl)vinyl)phenyl)propyl)carbamate.
[0669] Step 2: Deprotection of (E)-tert-butyl
(3-hydroxy-3-(3-(2-(2-oxopyrrolidin-1-yl)vinyl)phenyl)propyl)carbamate
give Example 54.
Example 55
Preparation of
1-(3-(3-amino-1-hydroxypropyl)phenethyl)pyrrolidin-2-one
##STR00193##
[0671] 1-(3-(3-Amino-1-hydroxypropyl)phenethyl)pyrrolidin-2-one is
prepared following the method below.
[0672] Step 1: Heck coupling between 1-vinylpyrrolidin-2-one and
tert-butyl (3-(3-bromophenyl)-3-hydroxypropyl)carbamate gives
(E)-tert-butyl
(3-hydroxy-3-(3-(2-(2-oxopyrrolidin-1-yl)vinyl)phenyl)propyl)carbamate.
[0673] Step 2: Deprotection of (E)-tert-butyl
(3-hydroxy-3-(3-(2-(2-oxopyrrolidin-1-yl)vinyl)phenyl)propyl)carbamate
give (E)-1-(3-(3-Amino-1-hydroxypropyl)styryl)pyrrolidin-2-one.
[0674] Step 3: Hydrogenation of
(E)-1-(3-(3-Amino-1-hydroxypropyl)styryl)pyrrolidin-2-one gives
Example 55.
Example 56
Preparation of
3-amino-1-(3-(2-(pyrrolidin-1-yl)ethyl)phenyl)propan-1-ol
##STR00194##
[0676] 3-Amino-1-(3-(2-(pyrrolidin-1-yl)ethyl)phenyl)propan-1-ol is
prepared following the method used in Example 55 and below.
[0677] Step 1: Reduction of Example 55 with an appropriate reducing
agent gives Example 56.
Example 57
Preparation of
(E)-1-(3-(2-(1H-imidazol-1-yl)vinyl)phenyl)-3-aminopropan-1-ol
##STR00195##
[0679]
(E)-1-(3-(2-(1H-Imidazol-1-yl)vinyl)phenyl)-3-aminopropan-1-ol is
prepared following the method below.
[0680] Step 1: Coupling between 1-vinyl-1H-imidazole and tert-butyl
(3-(3-bromophenyl)-3-hydroxypropyl)carbamate gives (E)-tert-butyl
(3-(3-(2-(1H-imidazol-1-yl)vinyl)phenyl)-3-hydroxypropyl)carbamate.
[0681] Step 2: Deprotection of (E)-tert-butyl
(3-(3-(2-(1H-imidazol-1-yl)vinyl)phenyl)-3-hydroxypropyl)carbamate
gives Example 57.
Example 58
Preparation of
1-(3-(2-(1H-imidazol-1-yl)ethyl)phenyl)-3-aminopropan-1-ol
##STR00196##
[0683] 1-(3-(2-(1H-Imidazol-1-yl)ethyl)phenyl)-3-aminopropan-1-ol
is prepared following the method below.
[0684] Step 1: Hydrogenation of Example 57 gives Example 58.
Example 59
Preparation of
(E)-3-amino-1-(3-(2-(pyridin-2-yl)vinyl)phenyl)propan-1-ol
##STR00197##
[0686] (E)-3-Amino-1-(3-(2-(pyridin-2-yl)vinyl)phenyl)propan-1-ol
is prepared following the method below.
[0687] Step 1: Coupling between 2-vinylpyridine and tert-butyl
(3-(3-bromophenyl)-3-hydroxypropyl)carbamate gives (E)-tert-butyl
(3-hydroxy-3-(3-(2-(pyridin-2-yl)vinyl)phenyl)propyl)carbamate.
[0688] Step 2: Deprotection of (E)-tert-butyl
(3-hydroxy-3-(3-(2-(pyridin-2-yl)vinyl)phenyl)propyl)carbamate
gives Example 59.
Example 60
Preparation of
3-amino-1-(3-(2-(pyridin-2-yl)ethyl)phenyl)propan-1-ol
##STR00198##
[0690] 3-Amino-1-(3-(2-(pyridin-2-yl)ethyl)phenyl)propan-1-ol is
prepared following the method below.
[0691] Step 1: Hydrogenation of Example 59 gives Example 60.
Example 61
Preparation of
(E)-3-amino-1-(3-(2-(tetrahydro-2H-pyran-4-yl)vinyl)phenyl)propan-1-ol
##STR00199##
[0693]
(E)-3-Amino-1-(3-(2-(tetrahydro-2H-pyran-4-yl)vinyl)phenyl)propan-1-
-ol is prepared following the method below.
[0694] Step 1: Coupling between 4-vinyltetrahydro-2H-pyran and
tert-butyl (3-(3-bromophenyl)-3-hydroxypropyl)carbamate gives
(E)-tert-butyl
(3-hydroxy-3-(3-(2-(tetrahydro-2H-pyran-4-yl)vinyl)phenyl)propyl)carbamat-
e.
[0695] Step 2: Deprotection of (E)-tert-butyl
(3-hydroxy-3-(3-(2-(tetrahydro-2H-pyran-4-yl)vinyl)phenyl)propyl)carbamat-
e gives Example 61.
Example 62
Preparation of
3-amino-1-(3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)phenyl)propan-1-ol
##STR00200##
[0697]
3-Amino-1-(3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)phenyl)propan-1-ol
is prepared following the method below.
[0698] Step 1: Hydrogenation of Example 61 gives Example 62.
II. Biological Evaluation
Example 1
In Vitro Isomerase Inhibition
[0699] The capability of compounds disclosed herein to inhibit the
activity of a visual cycle isomerase was determined. In particular,
the human in vitro isomerase assay was performed essentially as in
Golczak et al. Proc. Natl. Acad. Sci. (2005) 102, 8162-8167, and in
Imanishi, et al. J. Cell Biol. (2004), 164, 373-383.
Isolation of Human Apo Cellular Retinaldehyde-Binding Protein
(CRALBP)
[0700] Recombinant human apo cellular retinaldehyde-binding protein
(CRALBP) was cloned and expressed according to standard molecular
biology methods (see Crabb et al., Protein Science 7:746-57 (1998);
Crabb et al., J. Biol. Chem. 263:18688-92 (1988)). Briefly, total
RNA was prepared from confluent ARPE19 cells (American Type Culture
Collection, Manassas, Va.), cDNA was synthesized using an
oligo(dT).sub.12-18 primer, and then DNA encoding CRALBP was
amplified by two sequential polymerase chain reactions (see Crabb
et al., J. Biol. Chem. 263:18688-92 (1988); Intres, et al., J.
Biol. Chem. 269:25411-18 (1994); GenBank Accession No. L34219.1).
The PCR product was sub-cloned into pTrcHis2-TOPO TA vector
according to the manufacturer's protocol (Invitrogen Inc.,
Carlsbad, Calif.; catalog no. K4400-01), and then the sequence was
confirmed according to standard nucleotide sequencing techniques.
Recombinant 6.times.His-tagged human CRALBP was expressed in One
Shot TOP 10 chemically competent E. coli cells (Invitrogen), and
the recombinant polypeptide was isolated from E. coli cell lysates
by nickel affinity chromatography using nickel (Ni) Sepharose
XK16-20 columns for HPLC (Amersham Bioscience, Pittsburgh, Pa.;
catalog no. 17-5268-02). The purified 6.times.His-tagged human
CRALBP was dialyzed against 10 mM bis-tris-Propane (BTP) and
analyzed by SDS-PAGE. The molecular weight of the recombinant human
CRALBP was approximately 39 kDal.
Isomerase Assay
[0701] Compounds disclosed herein and control compounds were
reconstituted in ethanol to 0.1 M. Ten-fold serial dilutions
(10.sup.-2, 10.sup.-3, 10.sup.-4, 10.sup.-5, 10.sup.-6 M) in
ethanol of each compound were prepared for analysis in the
isomerase assay.
[0702] A homogenate of HEK293 cell clone co-expressing recombinant
human RPE65 and LRAT were the source of the visual enzymes, and
exogenous all-trans-retinol (about 20 .mu.M) was used as the
substrate. Recombinant human CRALBP (about 80 ug/mL) was added to
enhance the formation of 11-cis-retinal. The 200 .mu.L Bis-Tris
Phosphate buffer (10 mM, pH 7.2) based reaction mixture also
contains 0.5% BSA, and 1 mM NaPPi. In this assay, the reaction was
carried out at 37.degree. C. in duplicates for one hour and was
terminated by addition of 300 .mu.L methanol. The amount of
reaction product, 11-cis-retinol, was measured by HPLC analysis
following Heptane extraction of the reaction mixture. The Peak Area
Units (PAUs) corresponding to 11-cis-retinol in the HPLC
chromatograms were recorded and concentration dependent curves
analyzed by GraphPad Prism for IC.sub.50 values. The ability of the
compounds disclosed herein to inhibit isomerization reaction was
quantified and the respective IC.sub.50 value was determined. Table
2 below provides the IC.sub.50 values of various compounds
disclosed herein determined by the above methods. In the human in
vitro isomerase inhibition assay described herein, compound
(R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol (described
in US Patent Application Publication US 2009/0326074) had an
IC.sub.50 of 4.4 nM, compound
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(described in US Patent Application Publication US 2009/0326074)
had an IC.sub.50 of 24 nM, and compound
(R)-3-amino-1-(3-(cyclohexylmethylamino)phenyl)propan-1-ol
(described in US Patent Application Publication US 2010/0113539)
had an IC.sub.50 of 6.3 nM.
TABLE-US-00002 TABLE 2 Human in vitro Inhibition data IC.sub.50
(.mu.M) Compound/Example Number .ltoreq.0.1 .mu.M 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 17, 19, 23, 25, 26, 27, 28, 29, 30,
31, 32 >0.1 .mu.M-.ltoreq.1 .mu.M 16, 18, 20, 21, 22, 24, 33
>1 .mu.M-.ltoreq.10 .mu.M 15 >10 .mu.M No detectable
activity
Example 2
In Vivo Murine Isomerase Assay
[0703] The capability of compounds described herein to inhibit
isomerase was determined by an in vivo murine isomerase assay.
Brief exposure of the eye to intense light ("photobleaching" of the
visual pigment or simply "bleaching") is known to photo-isomerize
almost all 11-cis-retinal in the retina. The recovery of
11-cis-retinal after bleaching can be used to estimate the activity
of isomerase in vivo. Delayed recovery, as represented by lower
11-cis-retinal oxime levels, indicates inhibition of isomerization
reaction. Procedures were performed essentially as described by
Golczak et al., Proc. Natl. Acad. Sci. USA 102:8162-67 (2005). See
also Deigner et al., Science, 244: 968-71 (1989); Gollapalli et
al., Biochim Biophys Acta. 1651: 93-101 (2003); Parish, et al.,
Proc. Natl. Acad. Sci. USA, 14609-13 (1998); Radu, et al., Proc
Natl Acad Sci USA 101: 5928-33 (2004).
[0704] Six-week old dark-adapted CD-1 (albino) male mice were
orally gavaged with compound (0.03-3 mg/kg) dissolved in 100 .mu.l
corn oil containing 10% ethanol (five animals per group). Mice were
gavaged with the test compound. After 2-24 hours in the dark, the
mice were exposed to photobleaching of 5,000 lux of white light for
10 minutes. The mice were allowed to recover 2 hours in the dark.
The animals were then sacrificed by carbon dioxide inhalation.
Retinoids were extracted from the eye and the regeneration of
11-cis-retinal was assessed at various time intervals.
Eye Retinoid Extraction
[0705] All steps were performed in darkness with minimal redlight
illumination (low light darkroom lights and redfiltered flashlights
for spot illumination as needed) (see, e.g., Maeda et al., J.
Neurochem 85:944-956, 2003; Van Hooser et al., J Biol Chem
277:19173-82, 2002). After the mice were sacrificed, the eyes were
immediately removed and placed in liquid nitrogen for storage.
[0706] The eyes were placed in 500 .mu.L of bis-tris propane buffer
(10 mM, pH.about.7.3) and 20 .mu.L of 0.8M hydroxile amine
(pH.about.7.3). The eyes were cut up into small pieces with small
iris scissors and then thoroughly homogenized at 30000 rpm with a
mechanical homogenizer (Polytron PT 1300 D) in the tube until no
visible tissue remained. 500 .mu.L of methanol and 500 .mu.L of
heptane were added to each tube. The tubes were attached to a
vortexer so that the contents were mixed thoroughly for 15 minutes
in room temperature. The organic phase was separated from the
aqueous phase by centrifugation for 10 min at 13K rpm, 4.degree. C.
240 .mu.L of the solution from the top layer (organic phase) was
removed and transferred to clean 300 .mu.l glass inserts in HPLC
vials using glass pipette and the vials were crimped shut
tightly.
[0707] The samples were analyzed on an Agilent 1100 HPLC system
with normal phase column: SILICA (Beckman Coutlier, dp 5 .mu.m, 4.6
mM.times.250 mM). The running method has a flow rate of 1.5 ml/min;
solvent components were 15% solvent 1 (1% isopropanol in ethyl
acetate), and 85% solvent 2 (100% hexanes). Loading volume for each
sample was 100 .mu.l; detection wavelength was 360 nm. The area
under the curve for 11-cis retinal oxime was calculated by Agilent
Chemstation software and was recorded manually. Data processing was
performed using Prizm software. Results from the in vivo murine
isomerase assay are provided in Table 3.
[0708] Positive control mice (no compound administered) were
sacrificed fully dark-adapted and the eye retinoids analyzed. Light
(bleached) control mice (no compound administered) were sacrificed
and retinoids isolated and analyzed immediately after light
treatment.
[0709] A time course study was performed to determine the isomerase
inhibitory activity of the test compound. Male Balb/c mice
(4/group) received test compound orally by gavage. The animals were
then "photo-bleached" (5000 Lux white light for 10 minutes) at 2,
4, 8, 16 and 24 hours after dosing, and returned to darkness to
allow recovery of the 11-cis-retinal content of the eyes. Mice were
sacrificed 2 hours after bleaching, eyes were enucleated, and
retinoid content is analyzed by HPLC. FIG. 1 provides one example
of the outcome of a time course experiment. In FIG. 1, compound A
is
(R)-3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(Example 1 as described herein), compound B is
(R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol (described
in US Patent Application Publication US 2009/0326074), and compound
C is
3-amino-1-(3-((4,4-difluorocyclohexyl)methoxy)phenyl)propan-1-ol
(described in US Patent Application Publication US 2009/0326074).
Further examples of time course experiments are provided in Table
3.
[0710] Recovery control mice (vehicle-only treated) were
light-treated and left to recover for 2 hours in the dark before
sacrifice and analysis. Light control mice (vehicle only treated)
were sacrificed for analysis immediately after photo-bleaching.
[0711] An in vivo dose response isomerase inhibition study was
performed with test compound. Male Balb/c mice (8/group) were dosed
orally with 0.03, 0.1, 0.3, 1 and 3 mg/kg of test compound in
sterile water as solution, and photobleached 2 hours after dosing.
Recovery and retinoid analysis were performed as described above.
Dark control mice were vehicle-only treated, sacrificed fully dark
adapted without light treatment, and analyzed. Recovery control
mice and light control mice were included in the study as per the
initial phase. Examples of dose response experiments are provided
in Table 3.
[0712] In another experiment, male Balb/c mice are dosed with test
compound as above but the dosing is repeated twice daily for 7
consecutive days. The animals are photobleached 4 hours after the
last dose. Recovery and retinoid analysis is as per the initial
phase and the ED.sub.50 is estimated.
[0713] In the in vivo isomerase inhibition assay described herein,
compound (R)-3-amino-1-(3-(cyclohexylmethoxy)phenyl)propan-1-ol
(described in US Patent Application Publication US 2009/0326074)
had 98-100% inhibition at 1 mg/kg concentration and 4 h time point,
compound
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(described in US Patent Application Publication US 2009/0326074)
had 57% inhibition at 1 mg/kg concentration and 4 h time point, and
compound (R)-3-amino-1-(3-(cyclohexylmethylamino)phenyl)propan-1-ol
(described in US Patent Application Publication US 2010/0113539)
had 96% inhibition at 1 mg/kg concentration and 4 h time point.
[0714] Table 3 provides in vivo inhibition data for the indicted
compounds disclosed herein.
TABLE-US-00003 TABLE 3 in vivo isomerase inhibition Dose % Example
(mg/kg) Time (h) Inhibition St. Dev. 1 0.03 2 -2.7 7.2 0.1 2 3.4
6.6 0.3 2 58.4 10.0 0.3 2 40.2 16.1 0.3 4 15.7 9.6 0.3 8 10.4 7.2
0.3 16 -2.7 8.6 0.3 24 -4.4 6.0 0.5 2 89.9 2.2 0.81 2 98.2 0.7 0.81
4 87.9 6.2 0.81 6 75.8 5.9 0.81 8 51.8 4.2 0.81 16 5.5 8.9 0.81 24
-4.8 6.4 1 2 96.9 0.7 1 2 96.7 0.8 1 4 91.1 2.3 1 4 92.8 1.8 1 8
62.0 18.2 1 16 -1.2 11.4 1 24 3.8 9.8 3 2 100.9 1.8 2 1 4 89.9 4.7
3 0.01 2 1.2 9.3 0.03 2 2.7 9.8 0.1 2 4.2 10.0 0.3 2 75.2 7.1 0.3 2
75.1 6.3 0.3 4 59.7 4.6 0.3 8 14.8 12.0 0.3 16 1.6 8.6 0.3 24 4.1
8.3 1 2 98.7 1.1 1 4 94.2 3.6 3 2 101.9 0.6 4 1 4 -8.7 8.6 5 1 4
3.1 17.4 7 1 2 60.5 12.1 1 4 68.0 6.0 1 8 40.3 6.0 8 1 4 33.2 9.3 9
1 4 -8.2 9.2 10 1 4 -7.6 8.4 11 1 2 -4.7 9.4 1 4 2.6 11.3 1 8 -3.8
9.5 12 1 4 11.2 8.1 13 1 2 62.1 5.6 14 1 2 79.2 4.3 1 4 59.8 14.0 1
8 0.8 14.5 17 0.01 2 0 6.8 0.03 2 -2 8.0 0.1 2 9 4.2 0.3 2 8 12.1 1
2 93 2.3 1 2 93 2.6 1 4 88 2.9 1 4 85 3.7 1 8 25 5.9 1 16 -1 9.0 1
24 -8 7.7 3 2 100 1.2 19 0.3 2 49.4 9.2 0.3 4 40.0 11.6 0.3 8 15.5
9.8 1 4 91.4 1.2 23 1 2 4.4 5.3 1 4 -1.4 8.7 1 8 1.5 5.3 27 1 4 9.0
3.7 28 1 4 50.6 3.2 29 1 4 27.4 12.7 31 1 2 11.3 10.6 32 1 2 14.2
3.6 33 1 2 65.2 11.3 1 4 54.5 12.9 1 8 10.9 8.4 1 16 -0.8 5.3 1 24
1.8 10.4
Comparative In Vivo Murine Isomerase Assay--Dose Response
Comparison of
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
and
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
Introduction
[0715] Light is essential for vision but can also generate
photochemical damage to the retina (Boulton et al., 2001).
Protective effects against photo damage were observed when
rhodopsin regeneration was reduced due to mutations in RPE65, a
protein necessary for the regeneration of the retinoid chromophore
11-cis-retinal in the visual cycle (Grimm et al., 2000). Likewise,
it is expected that drugs that inhibit regeneration of 11-cis
retinal will have a protective effect against light mediated
retinal damage and degenerative disorders. 11-cis-retinal is
generated by oxidation of 11-cis retinol in the retina pigment
epithelium (RPE). The isomerization reaction that forms
11-cis-retinol from all-trans retinylesters is rate limiting in the
visual cycle and it can be expected that compounds that inhibit
this reaction will limit the generation of 11-cis-retinal and thus
have a therapeutic potential in the treatment of light-mediated
retinal degenerative disorders. The rate of regeneration of
11-cis-retinal will affect the rate of functional photoreceptor
recovery from bleaching light. The regeneration of 11-cis-retinal
after bleach is used to screen for active cycle modulators.
Purpose
[0716] This study is intended to assess the effects of multiple
dose levels of
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-
-ol and
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
on retinal isomerase activity in BALB/c mice 2 hours after oral
doses of 0.03, 0.1, 0.3, 9.5, 1 and 3 mg/kg.
Materials and Methods
[0717] The test compounds were
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A and Example 1 described herein) and
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(compound D and described in US Patent Application Publication US
2009/0326074). All test compounds were stored at room temperature,
dessicated.
[0718] On the day prior to dose administration compound A and
compound D were weighed into new empty glass vials. The compounds
were dissolved in di-water at the concentration of 0.833 mg/mL
compound A and 0.892 mg/mL compound D, serially diluted into
various concentrations, and stored overnight at 4 OC.
[0719] 56 Male BALB/c mice (Charles River Laboratories) were used
for this study. The mice were approximately 8 weeks at the
initiation of dosing with an average body weight of 24 grams.
Assay
[0720] The day prior to dose administration 56 BALB/c mice were
placed into a dark room and dark adapted for a minimum of 12 hours
prior to dose administration. The mice were maintained in the dark
for the duration of the study.
[0721] Each animal was removed from its cage and dosed accordingly
to the study design in Table 4 (see below). Each animal was
administered 0.1 mL of the appropriate compound or vehicle via oral
gavage using a 1 mL syringe fitted with a 23 gauge oral gavage
needle. Two hours following dose administration, animals were
removed from the dark and exposed to 5000 Lux white light for 10
minutes to photobleach their eyes.
[0722] Following the completion of the photobleach the animals were
returned to the dark for 2 hours to allow for the regeneration of
11-cis-retinal in the eyes. Two hours after photobleaching each
animal was euthanized with carbon dioxide followed by cervical
dislocation, in the dark under red light. The light control group
was euthanized immediately following photobleaching. Immediately
following the cervical dislocation both eyes of each animal were
removed and transferred into separate tubes, flash frozen in liquid
nitrogen and stored in the dark at -80.degree. C. until processing
and analysis.
TABLE-US-00004 TABLE 4 Study Design Total Num- Num- Dose Dose ber
ber Level Conc. Vol. Bleach of of Treat- (mg/ (mg/ (mL/ Time Ani-
Ani- Group ment kg) mL) animal) (Hours) mals mals 1 cmpdA 3 0.83
0.1 2 4 56 2 cmpdA 1 0.28 0.1 2 4 3 cmpdA 0.5 0.14 0.1 2 4 4 cmpdA
0.3 0.08 0.1 2 4 5 cmpdA 0.1 0.03 0.1 2 4 6 cmpdA 0.03 0.008 0.1 2
4 7 cmpdD 3 0.89 0.1 2 4 8 cmpdD 1 0.30 0.1 2 4 9 cmpdD 0.5 0.15
0.1 2 4 10 cmpdD 0.3 0.09 0.1 2 4 11 cmpdD 0.1 0.03 0.1 2 4 12
cmpdD 0.03 0.009 0.1 2 4 RC.sup.1 Vehicle.sup.3 0 0 0.1 2 4
LC.sup.2 Vehicle 0 0 0.1 2 4 .sup.1RC = Recovery control .sup.2LC =
Light control .sup.3Vehicle = di-water
Eye Sample Analysis
[0723] The right eye of each animal was processed according to the
method listed in Table 5 (see below). All sample processing
procedures were performed in the dark under red light.
TABLE-US-00005 TABLE 5 Eye Sample Processing Reagent/Step
Volume/Time 10 mM Bis-Tris-Propane 500 .mu.L 0.8M Hydroxylamine 20
.mu.L Homogenized 2x 20 seconds @ 6000 RPM Methanol 500 .mu.L
Heptane 500 .mu.L Vortex 15 minutes Centrifuge 10 minutes @ 13,200
RP< Transfer to HPLC vial 250 .mu.L
[0724] Extracted samples were analyzed using an Agilent 1100 HPLC
system according to the procedure outlined in Table 6 (see
below)
TABLE-US-00006 TABLE 6 HPLC Conditions HPLC Conditions Column:
Normal Phase Silica column Beckman Coulter, 5 .mu.M, 4.6 .times.
250 mm Mobile Phase A (85%) 100% Hexanes Mobile Phase B (15%) Ethyl
Acetate with 1% Isopropyl Alcohol Flow Rate 1.5 mL/min
Data Analysis
[0725] HPLC analysis of the eyes measures the peak area units of
the 110 cis-Ral-Oxime_syn. Signal.
[0726] Data analysis % inhibition (drug vs. recovery control). %
control (drug vs. light control), and One-way ANOVA (followed by
Tukey's Multiple Comparison) were performed using peak area units
and performed by Prism software. Data are represented as mean and
standard deviation.
Results
[0727]
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A) percent inhibition of 11-cis-retinal at 2 hours
following oral administration of 0.03, 0.1, 0.3, 0.5, 1 and 3 mg/kg
dose are listed in Table 7 (see below). There was a statistically
significant difference, P<0.001 for 0.3, 0.5, 1 and 3 mg/kg dose
levels from the recovery control group (see Table 9).
[0728]
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(compound D) percent inhibition of 11-cis-retinal at 2 hours
following oral administration of 0.03, 0.1, 0.3, 0.5, 1 and 3 mg/kg
dose are also listed in Table 7 (see below). There was a
statistically significant difference, P<0.001 for 1 and 3 mg/kg
dose levels from the recovery control group.
Conclusions
[0729]
3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A) had a significant inhibitory effect at 0.3 mg/kg, 0.5
mg/kg, 1 mg/kg and 3 mg/kg dose levels on the recovery of
11-cis-retinal following a single oral dose, see FIG. 2(a).
[0730]
3-Amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(compound D) had a significant inhibitory effect at 1 mg/kg and 3
mg/kg dose levels on the recovery of 11-cis-retinal following a
single oral dose, see FIG. 2(b).
[0731] The dose at which 11-cis-retinal recovery was inhibited by
50% was 0.17 mg/kg for
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A) and 0.59 mg/kg for
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(compound D) (see FIGS. 3 (a) and (b)).
[0732] In this dose response experiment,
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A) had an IC50 of 0.17 mg/kg, and
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(compound D) had an IC50 of 0.59 mg/kg. Thus, within this
parameter,
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A) is approximately 3-4.times. more active than
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(compound D).
[0733] In this same dose response experiment,
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A) showed nearly 100% inhibition at a dose of 0.5 mg/kg,
whereas
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-o-
l (compound D) required a dose of 3.0 mg/kg to show the same level
of inhibition. Thus, within this parameter,
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A) is approximately 6.times. more active than
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(compound D).
[0734] In this same dose response experiment,
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A) showed greater than 90% inhibition at a dose of 0.3
mg/kg, whereas
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-o-
l (compound D) showed no inhibition at this same dose. Thus, within
this parameter,
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A) was greater than 10.times. more active than
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(compound D).
TABLE-US-00007 TABLE 7 Percent Inhibition at 2 Hours Dose Level
Avg. % Standard Number of Compound ID (mg/kg) Inhibition Deviation
Animals cmpd A 0.03 -44.1 -53.6 3 cmpd A 0.1 -9.8 -3.5 4 cmpd A 0.3
92.4 -1.5 4 cmpd A 0.5 99.3 -3.9 3 cmpd A 1 100.4 -1.8 4 cmpd A 3
105.2 -1.9 4 cmpd D 0.03 -5.3 -8.8 3 cmpd D 0.1 -23.9 -22.1 4 cmpd
D 0.3 -2.1 -24.8 2 cmpd D 0.5 41.4 -10.4 4 cmpd D 1 70.2 -14.9 4
cmpd D 3 100 -2.8 4
TABLE-US-00008 TABLE 8 Percent control at 2 Hours Dose Level Avg. %
Standard Number of Compound ID (mg/kg) Inhibition Deviation Animals
cmpd A 0.03 144.1 53.6 3 cmpd A 0.1 109.8 3.5 4 cmpd A 0.3 7.6 1.5
4 cmpd A 0.5 0.7 3.9 3 cmpd A 1 -0.4 1.8 4 cmpd A 3 -5.2 2.0 4 cmpd
D 0.03 105.3 8.8 3 cmpd D 0.1 123.9 22.1 4 cmpd D 0.3 102.1 24.8 2
cmpd D 0.5 58.6 10.4 4 cmpd D 1 29.8 14.8 4 cmpd D 3 0 2.8 4
TABLE-US-00009 TABLE 9 One-way ANOVA Tukey's Multiple Comparison
Test Mean Diff. q P Value Vehicle vs. 0.03 mg/kg -7.4 4.2 P <
0.05 cmpd A Vehicle vs. 0.1 mg/kg -1.7 1.0 P < 0.05 cmpd A
Vehicle vs. 0.3 mg/kg 15.6 9.6 P < 0.001 cmpd A Vehicle vs. 0.5
mg/kg 16.7 9.5 P < 0.001 cmpd A Vehicle vs. 1 mg/kg 16.9 10.4 P
< 0.001 cmpd A Vehicle vs. 3 mg/kg 17.7 10.9 P < 0.001 cmpd A
Vehicle vs. 0.03 mg/kg -0.9 0.6 P < 0.05 cmpd D Vehicle vs. 0.1
mg/kg -4.0 3.0 P < 0.05 cmpd D Vehicle vs. 0.3 mg/kg -0.4 0.2 P
< 0.05 cmpd D Vehicle vs. 0.5 mg/kg 7.0 5.2 P < 0.05 cmpd D
Vehicle vs. 1 mg/kg 11.8 8.9 P < 0.001 cmpd D Vehicle vs. 3
mg/kg 16.9 12.6 P < 0.001 cmpd D
Single Dose Time Course of
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(example 1, compound A) and
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(compound D) in the in Vivo Isomerase Assay at 0.3 mg/kg in BALB/c
Mice
Introduction
[0735] Light is essential for vision but can also generate
photochemical damage to the retina (Boulton et al., 2001).
Protective effects against photo damage were observed when
rhodopsin regeneration was reduced due to mutations in RPE65, a
protein necessary for the regeneration of the retinoid chromophore
11-cis-retinal in the visual cycle (Grimm et al., 2000). Likewise,
it is expected that drugs that inhibit regeneration of 11-cis
retinal will have a protective effect against light mediated
retinal damage and degenerative disorders. 11-cis-retinal is
generated by oxidation of 11-cis retinol in the retina pigment
epithelium (RPE). The isomerization reaction that forms
11-cis-retinol from all-trans retinylesters is rate limiting in the
visual cycle and it can be expected that compounds that inhibit
this reaction will limit the generation of 11-cis-retinal and thus
have a therapeutic potential in the treatment of light-mediated
retinal degenerative disorders. The rate of regeneration of
11-cis-retinal will affect the rate of functional photoreceptor
recovery from bleaching light. The regeneration of 11-cis-retinal
after bleach is used to screen for active cycle modulators.
Purpose
[0736] The purpose of this study was to assess the effect over time
of
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A) and
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(compound D), on the regeneration of 11-cis-retinal following a
single oral dose at 0.3 mg/kg to BALB/c mice.
Materials and Methods
[0737] The test compounds
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A, example 1) and
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(compound D and described in US Patent Application Publication US
2009/0326074). All test compounds were stored at room temperature,
dessicated.
[0738] On the day prior to dose administration
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A) and 3-amino-1-(3-((tetrahydro-2H-pyran-
2-yl)methoxy)phenyl)propan-1-ol (compound D) were weighed into new
empty glass vials. The compounds were dissolved in di-water at the
concentration of 0.068 mg/mL and stored overnight at 4.degree.
C.
[0739] 52 Male BALB/c mice (Charles River Laboratories) were used
for this study. The mice were approximately 8 weeks at the
initiation of dosing with an average body weight of 23 grams.
Assay
[0740] The day prior to dose administration 52 BALB/c mice were
placed into a dark room and dark adapted for a minimum of 12 hours
prior to dose administration. The mice were maintained in the dark
for the duration of the study.
[0741] Each animal was removed from its cage and dosed accordingly
to the study design in Table 10 (see below). Each animal was
administered 0.1 mL of the appropriate test article or vehicle
orally using a 1 mL syringe fitted with a 23 gauge oral gavage
needle. At 2, 4, 6, 8, 16 or 24 hours following dose
administration, animals were removed from the dark and exposed to
5000 Lux white light for 10 minutes to photobleach their eyes.
Following the completion of the photobleach the animals were
returned to the dark for 2 hours to allow for the regeneration of
11-cis-retinal in the eyes. Two hours after photobleaching each
animal was euthanized with carbon dioxide followed by cervical
dislocation, in the dark under red light. The light control group
was euthanized immediately following photobleaching. Immediately
following the cervical dislocation both eyes of each animal were
removed and transferred into separate tubes, flash frozen in liquid
nitrogen and stored in the dark at -80.degree. C. until processing
and analysis.
TABLE-US-00010 TABLE 10 Study Design Dose Bleach Number Level Conc.
Dose Vol. Time of Group Treatment (mg/kg) (mg/mL) (mL/animal)
(Hours) Animals 1 cmpd A 0.3 0.068 0.1 2 4 2 cmpd A 0.3 0.068 0.1 4
4 3 cmpd A 0.3 0.068 0.1 6 4 4 cmpd A 0.3 0.068 0.1 8 4 5 cmpd A
0.3 0.068 0.1 16 4 6 cmpd A 0.3 0.068 0.1 24 4 7 cmpd D 0.3 0.068
0.1 2 4 8 cmpd D 0.3 0.068 0.1 4 4 9 cmpd D 0.3 0.068 0.1 6 4 10
cmpd D 0.3 0.068 0.1 8 4 11 cmpd D 0.3 0.068 0.1 16 4 12 cmpd D 0.3
0.068 0.1 24 4 RC.sup.1 Vehicle.sup.3 0 0 0.1 4 2 LC.sup.2 Vehicle
0 0 0.1 4 2 .sup.1RC = Recovery Control .sup.2LC = Light Control
.sup.3Vehicle = di-water
Eye Sample Analysis
[0742] The right eye of each animal was processed according to the
method listed in Table 11 (see below). All sample processing
procedures were performed in the dark under red light.
TABLE-US-00011 TABLE 11 Eye Sample Processing Reagent/Step
Volume/Time 10 mM Bis-Tris-Propane 500 .mu.L 0.8M Hydroxylamine 20
.mu.L Homogenized 2 .times. 20 seconds @ 6000 RPM Methanol 500
.mu.L Heptane 500 .mu.L Vortex 15 minutes Centrifuge 10 minutes @
13,200 RPM Transfer to HPLC vial 250 .mu.L
[0743] Extracted samples were analyzed using an Agilent 1100 HPLC
system according to the procedure outlined in Table 12 (see
below)
TABLE-US-00012 TABLE 12 HPLC Conditions HPLC Conditions Column:
Normal Phase Silica column Beckman Coulter, 5 .mu.M, 4.6 .times.
250 mm Mobile Phase A (85%) 100% Hexanes Mobile Phase B (15%)
Ethyle Acetate with 1% Isopropyl alcohol Flow Rate 1.5 mL/min
Data Analysis
[0744] HPLC analysis of the eyes measures the peak area units of
the 110 cis-Ral-Oxime_syn. Signal.
[0745] Data analysis % inhibition (drug vs. recovery control). %
control (drug vs. light control), and One-way ANOVA (followed by
Tukey's Multiple Comparison) were performed using peak area units
and performed by Prism software. Data are represented as mean and
standard deviation.
Results
[0746]
3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A) percent inhibition of 11-cis-retinal at 2, 4, 6, 8, 16
and 24 hours following oral administration of a 0.3 mg/kg dose are
listed in Table 13 (see below). There was a statistically
significant difference, P<0.001, from the recovery control group
for the 2, 4 and 6 hour time points (see Table 15). There was not a
statistically significant difference, P>0.05 for the 8, 16 and
24 time points from the recovery control group.
[0747]
3-Amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(compound D) percent inhibition of 11-cis-retinal at 2, 4, 6, 8, 16
and 24 hours following oral administration of a 0.3 mg/kg dose are
listed in Table 16 (see below). There was not a statistically
significant difference, P>0.05 for any time points from the
recovery control group. (see table 18)
Conclusions
[0748]
3-Amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A) had a significant inhibitory effect at 2, 4 and 6
hours on the recovery of 11-cis-retinal following single dose
administration at a dose level of 0.3 mg/kg. There was no
significant effect on the recovery of 11-cis-retinal at the 8, 16
and 24 hour time points, see FIG. 4(a).
[0749]
3-Amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(compound D) had no significant inhibitory effect at any time
points on the recovery of 11-cis-retinal following single dose
administration at a dose level of 0.3 mg/kg, see FIG. 4(b).
[0750] The recovery control and the light control data were
consistent with the historical data for both experiments.
[0751] In this time course experiment, determinations were made at
2, 4, 6, 8, 16 and 24 hours after dosing level of 0.3 mg/kg. The
activity of
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A) was statistically significant from the control group
at the 2, 4, and 6 hour time points, whereas
3-amino-1-(3-((tetrahydro- 2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(compound D) did not exhibit a significant difference from the
control group at any time point. Thus within these parameters,
3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(compound A) was greater than 10.times. more active than
3-amino-1-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propan-1-ol
(compound D).
TABLE-US-00013 TABLE 13 Percent Inhibition, 0.3 mg/kg,
3-amino-1-(3-((tetrahydro-2H-pyran-4- yl)methoxy)phenyl)propan-1-ol
(compound A) Time Point Avg. % Standard Number of Compound ID
(Hours) Inhibition Deviation Animals cmpd A 2 98.0 1.9 4 cmpd A 4
88.5 3.5 4 cmpd A 6 56.3 9.7 4 cmpd A 8 20.2 8.8 4 cmpd A 16 1.5
4.9 4 cmpd A 24 4.2 4.6 4
TABLE-US-00014 TABLE 14 Percent Control, 0.3 mg/kg,
3-amino-1-(3-((tetrahydro-2H-pyran-4- yl)methoxy)phenyl)propan-1-ol
(compound A) Time Point Standard Number of Compound ID (Hours) Avg.
% Control Deviation Animals cmpd A 2 2.0 1.9 4 cmpd A 4 11.5 3.5 4
cmpd A 6 43.7 9.7 4 cmpd A 8 79.8 8.8 4 cmpd A 16 98.5 4.8 4 cmpd A
24 95.8 4.6 4
TABLE-US-00015 TABLE 15 One-way ANOVA, 0.3 mg/kg,
3-amino-1-(3-((tetrahydro-2H-pyran-4- yl)methoxy)phenyl)propan-1-ol
(compound A) Tukey's Multiple Comparison Test Mean Diff. q P value
Vehicle vs. 2 Hr 46.9 21.4 P < 0.001 Vehicle vs. 4 Hr 42.3 19.4
P < 0.001 Vehicle vs. 6 Hr 26.9 12.3 P < 0.001 Vehicle vs. 8
Hr 9.7 4.4 P > 0.05 Vehicle vs. 16 Hr 0.73 0.33 P > 0.05
Vehicle vs. 24 Hr 2.0 0.91 P > 0.05
TABLE-US-00016 TABLE 16 Percent Inhibition, 0.3 mg/kg,
3-amino-1-(3-((tetrahydro-2H-pyran-2- yl)methoxy)phenyl)propan-1-ol
(compound D) Time Point Avg. % Standard Number of Compound ID
(Hours) Inhibition Deviation Animals cmpd D 2 13.2 10.0 4 cmpd D 4
-1.8 6.4 4 cmpd D 6 12.1 4.6 4 cmpd D 8 5.4 6.0 4 cmpd D 16 -4.1
4.5 4 cmpd D 24 10.5 4.8 4
TABLE-US-00017 TABLE 17 Percent Control, 0.3 mg/kg,
3-amino-1-(3-((tetrahydro-2H-pyran-2- yl)methoxy)phenyl)propan-1-ol
(compound D) Time Point Avg. % Standard Number of Compound ID
(Hours) Inhibition Deviation Animals cmpd D 2 86.8 10.0 4 cmpd D 4
101.8 6.5 4 cmpd D 6 87.9 4.6 4 cmpd D 8 94.6 6.0 4 cmpd D 16 104.1
4.5 4 cmpd D 24 89.5 4.8 4
TABLE-US-00018 TABLE 18 One-way ANOVA, 0.3 mg/kg,
3-amino-1-(3-((tetrahydro-2H-pyran-2- yl)methoxy)phenyl)propan-1-ol
(compound D) Tukey's Multiple Comparison Test Mean Diff. q P value
Vehicle vs. 2 Hr 6.3 2.9 P > 0.05 Vehicle vs. 4 Hr -0.88 0.40 P
> 0.05 Vehicle vs. 6 Hr 5.8 2.6 P > 0.05 Vehicle vs. 8 Hr 2.6
1.2 P > 0.05 Vehicle vs. 16 Hr -2.0 0.88 P > 0.05 Vehicle vs.
24 Hr 5.0 2.3 P > 0.05
Example 3
A2E Accumulation Model
[0752] The purpose of this study was to assess the ability of test
compounds to inhibit the accumulation of A2E in the eyes of
abca4.sup.-/-, RPE65 Leu450Leu mice (ABCR) following 91 days of
continuous dosing.
[0753] The test compound
(R)-3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-propan-1-ol
(Example 1) was stored in a freezer set to maintain at
approximately -20.degree. C.
[0754] On the day prior to dosing and once weekly for 13 weeks the
test articles were weighed into new empty glass scintillation
vials. The compound was dissolved in ethanol (10% of final volume)
and then diluted with deionized water (90% of total final volume)
resulting in a concentrations of 0.2 mg/mL. This dosing solution
was administered to the high dose groups (1 mg/kg). For the low
dose groups (0.1 mg/kg) a 0.2 mg/mL dosing solution was prepared by
diluting with vehicle (10% ethanol 90% water) to the appropriate
concentration. The dosing solutions were stored in a refrigerator
set to maintain between 2 to 8.degree. C. and used for dose
administration once per day for one week. The vehicle used for
dosing control groups was 10% ethanol 90% deionized water.
[0755] Male and female abca4.sup.-/-, and RPE65 Leu450Leu, mice
(Charles River Laboratories) were used for this study. The mice
were approximately 8-12 week old at the initiation of dosing with a
starting average body weight of 19 grams for females and 27 grams
for males.
[0756] Group 1 animals (Time zero for A2E accumulation) were
euthanized with carbon dioxide followed by cervical dislocation on
the first day of dosing. Immediately following the cervical
dislocation both eyes of the animal was removed and transferred
into separate tubes, flash frozen in liquid nitrogen and stored in
the dark at -80.degree. C. until processing and analysis.
[0757] The remaining groups (2-4) were dosed once each day for 13
weeks. When dosed each animal was administered a 5 mL/kg dose of
the appropriate test compound or vehicle via oral gavage using a 1
mL syringe fitted with a 20 gauge oral gavage needle. Upon the
completion of the study, animals were euthanized with carbon
dioxide followed by cervical dislocation. Immediately following the
cervical dislocation both eyes of the animal was removed and
transferred into separate tubes, flash frozen in liquid nitrogen
and stored in the dark at -80.degree. C. until processing and
analysis for A2E concentration.
TABLE-US-00019 TABLE 19 Study Design Dose Test Article Level Conc.
Dose Vol. Number of Group Treatment (mg/kg) (mg/mL) (mL/kg) Animals
1 No Dose 0 N/A N/A 8 2 Vehicle.sup.1 0 0 5 8 3 Test cmpd 0.1 0.02
5 8 4 Test cmpd 1 0.2 5 8 .sup.1Vehicle = 10% Ethanol, 90%
Deionized Water
[0758] The left eye of each animal was analyzed for A2E
concentration and was processed according to the method listed in
Table 20 (See Below). All sample processing procedures were
performed in the dark under red light.
TABLE-US-00020 TABLE 20 Eye Sample Extraction Reagent/Step
Volume/Time Phosphate Buffered Saline 500 .mu.L Homogenized 30
seconds @ 30,000 RPM Methanol 600 .mu.L Chloroform 750 .mu.L Vortex
5 minutes Equilibrate 15 minutes Vortex 5 minutes Centrifuge 10
minutes @ 13,200 RPM Speed Vac. 1 hour Reconstitution Methanol 25
.mu.L 72% Acetonitrile/28% Water, 0.05% 20 .mu.L Trifluoroacetic
acid (TFA) Transfer to HPLC vial 45 .mu.L
[0759] Extracted samples were analyzed using an Agilent 1100 HPLC
system according to the procedure outlined in Table 21 (See
Below)
TABLE-US-00021 TABLE 21 HPLC Conditions HPLC Conditions Column:
Luna 2.5 .mu.m C18, 100 A 250 mm .times. 2.0 mm (Phenomenex) Flow
Rate 0.4 mL/min Injection Volume 30 .mu.L Mobile Phase A
Acetonitrile with (0.05% TFA) Mobile Phase B Water with 0.05% TFA
Gradient Profile Time (minutes) Mobile Phase A Mobile Phase B 0 72
28 10 77 23 30 80 20 40 90 10
[0760] HPLC analysis of the eyes looks at the peak area units of
the A2E present in the eyes following extraction as described
above.
[0761] Data analysis % inhibition (drug vs. recovery control), %
control (drug vs. light control), and One-way ANOVA (followed by
Tukey's Multiple Comparison) were performed using peak area units
and performed by Prism software. Data are represented as mean and
standard deviation. A summary of the data collected is provided in
Table 22.
TABLE-US-00022 TABLE 22 Day 91 A2E Concentrations Concentration
Pico Moles/eye Compound Animal # ID 1 2 3 4 5 6 7 8 T0 (no Dose)
4.67 6.27 5.38 5.52 4.93 5 4.67 4.52 Vehicle 13.24 14.1 14.7 14.35
13.91 13.2 11.05 14.24 Test cmpd, 9.64 8.97 10.23 8.42 8.49 9.6
11.68 10.27 0.1 mg/kg Test cmpd, 6.49 7.68 7.75 8.87 7.56 8.01 8.86
9.49 1.0 mg/kg
[0762] At a dose level of 0.1 mg/kg,
(R)-3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-propan-1-ol
(Example 1) inhibited A2E accumulation at 46.4% (sd 12.7) following
daily oral administration for 91 days. This was a statistically
significant difference, P<0.001, from the vehicle control
group.
[0763] At a dose level of 1 mg/kg,
(R)-3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-propan-1-ol
(Example 1) inhibited A2E accumulation at 65.0% (sd 11.2) following
daily oral administration for 91 days. This was a statistically
significant difference, P<0.001, from the vehicle control
group.
Conclusions
[0764]
(R)-3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)-propan--
1-ol (Example 1) had statistically significant inhibitory effects
on the accumulation of A2E following 91 days of oral dosing at 0.1
mg/kg and 1.0 mg/kg. The vehicle control and the time zero A2E data
were consistent with historical data for A2E accumulation in this
assay.
Example 4
In Vivo Light Mouse Model
[0765] This Example describes the effect of a compound disclosed
herein in an in vivo light damage mouse model.
[0766] Exposure of the eye to intense white light can cause
photo-damage to the retina. The extent of damage after light
treatment can be evaluated by measuring cytoplasmic
histone-associated-DNA-fragment (mono- and oligonucleosomes)
content in the eye (see, e.g., Wenzel et al., Prog. Retin. Eye Res.
24:275-306 (2005)).
[0767] Dark adapted male Balb/c (albino, 10/group) mice are gavaged
with test compound at various doses (0.03, 0.1, 0.3, 1, and 3
mg/kg) or vehicle only is administered. Six hours after dosing, the
animals are subjected to light treatment (8,000 lux of white light
for 1 hour). Mice are sacrificed after 40 hours of recovery in
dark, and retinas are dissected. A cell death detection ELISA assay
is performed according to the manufacturer's instructions (ROCHE
APPLIED SCIENCE, Cell Death Detection ELISA plus Kit). Contents of
fragmented DNA in the retinas are measured to estimate the
retinal-protective activity of the test compound.
Example 5
Electroretinographic (ERG) Study
[0768] ERG experiments are performed using 11-16 week old BALB/c
mice of both genders (n=5). All studies involve the pharmacodynamic
assessment of dark-adapted (scotopic, rod-dominated) and
light-adapted (photopic, cone-dominated) ERG responses. Experiments
are performed using test compound. All recording procedures are
performed according to the same protocol and with the same
equipment. Data are aggregated across individual studies to
generate summary graphs.
[0769] Results from four independent studies are combined to build
the dose-response function between administration of test compound
and changes in the amplitude of the scotopic b-wave (0.01
cd.s/m.sup.2), 4 hours after single oral administration of the test
compound (dissolved in corn oil).
[0770] The effect on the cone system is estimated based on
recording and measurement of the ERG b-wave intensity-response
function under photopic conditions. In such studies, two parameters
are typically evaluated: maximal response (V.sub.max), measured in
microvolts, and semi-saturation constant (k), measured in
cd.s/m.sup.2.
[0771] Results from three independent studies are combined to
estimate the effect of single dosing of test compound on the
photopic ERG (11-16 week old BALB/c mice of both genders, n=5).
III. Preparation of Dosage Forms
Example 1
Parenteral Composition
[0772] To prepare a parenteral pharmaceutical composition suitable
for administration by injection, 100 mg of a water-soluble salt of
a 3-phenylpropylamine derivative compound as described herein such
as
(R)-3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(example 1) is dissolved in sterile water and then mixed with 10 mL
of 0.9% sterile saline. The mixture is incorporated into a dosage
unit form suitable for administration by injection.
Example 2
Oral Composition
[0773] To prepare a pharmaceutical composition for oral delivery,
100 mg of a 3-phenylpropylamine derivative compound as described
herein such as
(R)-3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(example 1) is mixed with 750 mg of starch. The mixture is
incorporated into an oral dosage unit, such as a hard gelatin
capsule, which is suitable for oral administration.
Example 3
Ophthalmic Solution Composition
[0774] To prepare a pharmaceutical ophthalmic solution composition,
100 mg of a 3-phenylpropylamine derivative compound as described
herein such as
(R)-3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(example 1) is mixed with 0.9 g of NaCl in 100 mL of purified water
and filtered using a 0.2 micron filter. The resulting isotonic
solution is then incorporated into ophthalmic delivery units, such
as eye drop containers, which are suitable for ophthalmic
administration.
IV. Clinical Trial
Example 1
Phase 1A Study of Safety and Pharmacodynamics Effect
[0775] A single-center, randomized, double masked, placebo
controlled, dose-escalating Phase 1A study to determine the safety
and pharmacodynamic effect of single oral dose of a compound as
described herein, such as
(R)-3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(example 1), measured by dark-adapted electroretinogram (ERG), is
performed. Study participants are healthy volunteers of both
genders, aged 55-80, weighing between 50 and 110 kg. Major
exclusion criteria include other ocular conditions (e.g. cataracts,
glaucoma, uveitis, diabetic retinopathy, active conjunctivitis),
change in prescription chronic medications within the preceding 28
days, treatment with a retinoid compound within the last year,
treatment with sildenafil citrate, tadalafil, or vardenafil citrate
within the last week, or concomitant treatment with hypnotics,
anti-depressants, psychoactive substances, digitalis glycosides,
L-DOPA, chloroquine, hydroxychloroquine, systemic corticosteroids,
topical anti-glaucoma medications, or medications for the treatment
of wet AMD. Eight cohorts are randomized 5:1/drug:placebo and
assigned to dosage cohorts of 2 mg, 7 mg, 10 mg, 20 mg, 40 mg, 60
mg, and 75 mg. Plasma concentration versus time is determined. Peak
plasma concentrations (C.sub.max), time of peak plasma
concentration (T.sub.max) and mean terminal elimination half-life
(t.sub.1/2) will be determined across all doses.
[0776] ERG studies are performed prior to dosing, 4-6 hours
post-dose (Day 1 ERG), 24 hours post-dose (Day 2 ERG), Day 4, and
on Day 7. For patients given placebo, the ERG readout will be
monitored for a rapid rise in amplitude such that the response is
90% recovered by about 20 minutes. For patients given a test
compound, such as
(R)-3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(example 1), the ERG readout will be monitored for a clear
dose-related slowing of the rate of recovery; i.e. the slope of the
recovery function became slower with increasing dose.
Example 2
Treatment of Dry-Form Age Related Macular Degeneration
[0777] An individual diagnosed with dry-form age related macular
degeneration is treated with an oral dose of 5 mg of a compound as
described herein, such as
(R)-3-amino-1-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)propan-1-ol
(example 1). On days 2, 4, 6, 8, 12, 18, 24 and 30 the individual
is subjected to an electroretinogram determination to evaluate
treatment response and the individual is monitored for instances of
delayed dark adaptation and achromatopsia, as well as systemic
adverse effects.
[0778] When ranges are used herein for physical properties, such as
molecular weight, or chemical properties, such as chemical
formulae, all combinations and subcombinations of ranges and
specific embodiments therein are intended to be included.
[0779] The various embodiments described herein can be combined to
provide further embodiments. All U.S. patents, U.S. patent
application publications, U.S. patent applications, foreign
patents, foreign patent applications, and non-patent publications
referred to in this specification and/or listed in the Application
Data Sheet, are incorporated herein by reference in their
entireties.
[0780] From the foregoing it will be appreciated that, although
specific embodiments have been described herein for purposes of
illustration, various modifications may be made. Those skilled in
the art will recognize, or be able to ascertain, using no more than
routine experimentation, many equivalents to the specific
embodiments described herein. Such equivalents are intended to be
encompassed by the following claims. In general, in the following
claims, the terms used should not be construed to limit the claims
to the specific embodiments disclosed in the specification and the
claims, but should be construed to include all possible embodiments
along with the full scope of equivalents to which such claims are
entitled. Accordingly, the claims are not limited by the
disclosure.
[0781] While preferred embodiments of the present invention have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
invention. It should be understood that various alternatives to the
embodiments of the invention described herein may be employed in
practicing the invention. It is intended that the following claims
define the scope of the invention and that methods and structures
within the scope of these claims and their equivalents be covered
thereby.
* * * * *