U.S. patent application number 10/360580 was filed with the patent office on 2004-01-29 for dimer-selective rxr modulators and methods for their use.
Invention is credited to Badea, Beth Ann, Boehm, Marcus F., Canan-Koch, Stacie, Dardashti, Laura J., Farmer, Luc J., Heyman, Richard A., Hwang, Chan K., Lala, Deepak S., Mukherjee, Ranjan, Nadzan, Alex M., Zhang, Lin.
Application Number | 20040019072 10/360580 |
Document ID | / |
Family ID | 27485410 |
Filed Date | 2004-01-29 |
United States Patent
Application |
20040019072 |
Kind Code |
A1 |
Canan-Koch, Stacie ; et
al. |
January 29, 2004 |
Dimer-selective RXR modulators and methods for their use
Abstract
Dimer-selective RXR modulator compounds having agonist, partial
agonist and/or antagonist activity in the context of an RXR
homodimer and/or RXR heterodimers are provided. Also provided are
pharmaceutical compositions incorporating such dimer-selective RXR
modulator compounds and methods for their therapeutic use.
Inventors: |
Canan-Koch, Stacie; (San
Diego, CA) ; Hwang, Chan K.; (Boulder, CO) ;
Boehm, Marcus F.; (San Diego, CA) ; Badea, Beth
Ann; (San Diego, CA) ; Dardashti, Laura J.;
(Santa Anna, CA) ; Zhang, Lin; (San Diego, CA)
; Nadzan, Alex M.; (San Diego, CA) ; Heyman,
Richard A.; (Encinitas, CA) ; Mukherjee, Ranjan;
(San Diego, CA) ; Lala, Deepak S.; (San Diego,
CA) ; Farmer, Luc J.; (La Jolla, CA) |
Correspondence
Address: |
Richard H. Pagliery
Brobeck, Phleger & Harrison LLP
12390 El Camino Real
San Diego
CA
92130-2081
US
|
Family ID: |
27485410 |
Appl. No.: |
10/360580 |
Filed: |
February 5, 2003 |
Related U.S. Patent Documents
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Application
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10360580 |
Feb 5, 2003 |
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09388888 |
Sep 2, 1999 |
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6545049 |
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09388888 |
Sep 2, 1999 |
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08710427 |
Sep 17, 1996 |
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60004897 |
Oct 6, 1995 |
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60009884 |
Jan 11, 1996 |
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60018318 |
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60021839 |
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Current U.S.
Class: |
514/290 ;
514/567; 514/569; 514/570; 546/79; 552/271; 562/440; 562/490 |
Current CPC
Class: |
A61K 31/425 20130101;
A61K 31/192 20130101; C07C 2603/24 20170501; A61P 17/00 20180101;
A61P 43/00 20180101; A61P 35/00 20180101; C07C 63/66 20130101; C07C
57/50 20130101; C07D 311/92 20130101; C07C 65/36 20130101; C07C
59/72 20130101; A61P 3/04 20180101; A61P 17/02 20180101; C07C
251/48 20130101; C07C 2602/10 20170501; C07D 221/08 20130101; C07C
65/28 20130101; A61P 29/00 20180101; A61K 38/28 20130101; A61P 9/00
20180101; C07C 63/49 20130101; A61P 5/10 20180101; A61P 3/10
20180101; A61P 31/12 20180101; C07D 265/34 20130101; A61K 45/06
20130101; A61P 37/02 20180101; A61P 17/14 20180101; A61P 27/02
20180101; C07D 317/30 20130101; A61P 25/00 20180101; A61K 31/44
20130101; A61K 31/4418 20130101; A61P 5/06 20180101; A61K 31/192
20130101; A61K 2300/00 20130101; A61K 31/425 20130101; A61K 2300/00
20130101; A61K 31/44 20130101; A61K 2300/00 20130101; A61K 31/4418
20130101; A61K 2300/00 20130101; A61K 38/28 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/290 ;
514/567; 514/569; 514/570; 546/79; 552/271; 562/440; 562/490 |
International
Class: |
C07D 221/22; C07C
251/48; C07C 063/44; A61K 031/473; A61K 031/195; A61K 031/198 |
Claims
What is claimed is:
1. A compound of the formula: 35wherein, R.sub.1 through R.sub.4
each independently are hydrogen, a C.sub.1-C.sub.6 alkyl or a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl; R.sub.5 is a
C.sub.5-C.sub.10 alkyl, heteroalkyl, aryl, heteroaryl, a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl, N.sub.6R.sub.7, or
OR.sub.8, where R.sub.6 and R.sub.7 each independently are a
C.sub.7-C.sub.10 alkyl, heteroalkyl, a C.sub.7-C.sub.15 arylalkyl
or heteroarylalkyl, a C.sub.3-C.sub.10 acyl, provided that only one
of R.sub.6 or R.sub.7 can be acyl, or R.sub.6 and R.sub.7 taken
together are C.sub.3-C.sub.6 cycloalkyl, and where R.sub.8 is a
C.sub.7-C.sub.10 alkyl, heteroalkyl, aryl, heteroaryl, or a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl; R.sub.9 and R.sub.10
each independently are hydrogen, a C.sub.1-C.sub.10 alkyl, halogen,
heteroalkyl, NR.sub.11R.sub.12, NO.sub.2 or OR.sub.13, where
R.sub.11 and R.sub.12 each independently are hydrogen, a
C.sub.1-C.sub.10 alkyl, heteroalkyl, a C.sub.7-C.sub.15 arylalkyl
or heteroarylalkyl, a C.sub.1-C.sub.8 acyl, provided that only one
of R.sub.11 or R.sub.12 can be acyl, or R.sub.11 and R.sub.12 taken
together are a C.sub.3-C.sub.6 cycloalkyl, and where R.sub.13 is
hydrogen or a C.sub.1-C.sub.10 alkyl, heteroalkyl or a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl; R.sub.14 and
R.sub.15 each independently are hydrogen, a C.sub.1-C.sub.10 alkyl,
a C.sub.1-C.sub.8 acyl, or OR.sub.16 where R.sub.16 is hydrogen or
a C.sub.1-C.sub.10 alkyl; or R.sub.14 and R.sub.15 taken together
are keto, methano, optionally substituted oxime, optionally
substituted hydrazone, optionally substituted epoxy, 1,3-dioxolane,
1,3-dioxane, 1,3-dithiolane, 1,3-dithiane, oxazolidine or: 36where
R.sub.17 through R.sub.23 have the definitions given below and the
dashed lines crossing the bonds indicate the attachment bonds to
the rings adjacent to R.sub.14 and R.sub.15; R.sub.17 and R.sub.18
each independently are hydrogen, a C.sub.1-C.sub.10 alkyl,
heteroalkyl, aryl, a C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl
or R.sub.17 and R.sub.18 taken together are a C.sub.3-C.sub.6
cycloalkyl; R.sub.19 is hydrogen, a C.sub.1-C.sub.10 alkyl,
heteroalkyl, aryl, heteroaryl, a C.sub.7-C.sub.15 arylalkyl or
heteroarylalkyl; R.sub.20 through R.sub.23 each independently are
hydrogen, halogen, a C.sub.1-C.sub.10 alkyl, heteroalkyl, aryl,
heteroaryl, a C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl,
NR.sub.24R.sub.25, NO.sub.2, or OR.sub.26, where R.sub.24 and
R.sub.25 each independently are hydrogen, a C.sub.1-C.sub.10 alkyl,
heteroalkyl, a C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl or a
C.sub.1-C.sub.8 acyl, provided that only one of R.sub.24 or
R.sub.25 can be acyl, and where R.sub.26 is hydrogen or a
C.sub.1-C.sub.10 alkyl, heteroalkyl, aryl, heteroaryl, or a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl; R.sub.27 through
R.sub.31 each independently are hydrogen, a C.sub.1-C.sub.10 alkyl,
heteroalkyl, halogen, NR.sub.32R.sub.33, NO.sub.2 or OR.sub.34,
where R.sub.32 and R.sub.33 each independently are hydrogen, a
C.sub.1-C.sub.10 alkyl, a C.sub.7-C.sub.15 arylalkyl or
heteroarylalkyl, a C.sub.1-C.sub.8 acyl, provided that only one of
R.sub.32 or R.sub.33 can be acyl, or R.sub.32 and R.sub.33 taken
together are a C.sub.3-C.sub.6 cycloalkyl, and where R.sub.34 is
hydrogen or a C.sub.1-C.sub.10 alkyl, heteroalkyl or a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl and can only exist
when W is C; R.sub.35 through R.sub.38 each independently are
hydrogen, a C.sub.1-C.sub.2 alkyl or OR.sub.39 where R.sub.39 is
hydrogen or a C.sub.1-C.sub.10 alkyl, or R.sub.35 and R.sub.36 or
R.sub.37 and R.sub.38 taken together are keto, or R.sub.35 and
R.sub.36, R.sub.37 and R.sub.38, R.sub.35 and R.sub.37 or R.sub.36
and R.sub.38 taken together are epoxy; COR.sub.40 can originate
from any W, when the originating W is C, and R.sub.40 is OR.sub.41
or NR.sub.42R.sub.43, with R.sub.41 being hydrogen, a
C.sub.1-C.sub.6 alkyl or a C.sub.7-C.sub.15 arylalkyl or
heteroarylalkyl, and with R.sub.42 and R.sub.43 each independently
being hydrogen, a C.sub.1-C.sub.6 alkyl, a C.sub.7-C.sub.15
arylalkyl or heteroarylalkyl, aryl, ortho-, meta-, or
para-substituted hydroxyaryl, or taken together are a
C.sub.3-C.sub.6 cycloalkyl; R.sub.44 and R.sub.45 each
independently-are hydrogen, a C.sub.1-C.sub.4 alkyl or
CH.sub.2OR.sub.46, where R.sub.46 is hydrogen or a C.sub.1-C.sub.6
alkyl, or R.sub.44 and R.sub.45 taken together are a
C.sub.3-C.sub.6 cycloalkyl or cycloheteroalkyl; R.sub.47 is
hydrogen, a C.sub.1-C.sub.4 alkyl, or when n=1, R.sub.47 taken
together with R.sub.44 or R.sub.45 are a C.sub.3-C.sub.6 cycloalkyl
or cycloheteroalkyl; R.sub.48 and R.sub.49 each independently are
C.sub.1-C.sub.4 alkyl; R.sub.50 is a C.sub.4-C.sub.10 alkyl,
heteroalkyl, aryl, heteroaryl, a C.sub.7-C.sub.15 arylalkyl or
heteroarylalkyl, NR.sub.51R.sub.52, or OR.sub.53, where R.sub.51
and R.sub.52 each independently are a C.sub.2-C.sub.10 alkyl,
heteroalkyl, a C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl, a
C.sub.3-C.sub.10 acyl, provided that only one of R.sub.51 or
R.sub.52 can be acyl, or R.sub.51 and R.sub.52 taken together are
C.sub.3-C.sub.6 cycloalkyl, and where R.sub.53 is a
C.sub.7-C.sub.10 alkyl, heteroalkyl, aryl, heteroaryl, a
C.sub.3-C.sub.6 alkyl, heteroalkyl, aryl or heteroalkyl or a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl; R.sub.54 represents:
37where R.sub.9, R.sub.10, R.sub.14, R.sub.15 and R.sub.40 have the
definitions given above; R.sub.55 through R.sub.58 each
independently are hydrogen, halogen, a C.sub.1-C.sub.10 alkyl,
heteroalkyl, aryl, heteroaryl, a C.sub.7-C.sub.15 arylalkyl or
heteroarylalkyl, NR.sub.59R.sub.60 or OR.sub.61, where R.sub.59 and
R.sub.60 each independently are hydrogen, a C.sub.1-C.sub.10 alkyl
or heteroalkyl, a C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl, a
C.sub.1-C.sub.8 acyl, provided that only one of R.sub.59 or
R.sub.60 can be acyl, or R.sub.59 and R.sub.60 taken together are
C.sub.3-C.sub.6 cycloalkyl, and where R.sub.61 is hydrogen or a
C.sub.1-C .sub.10 alkyl, heteroalkyl, aryl, heteroaryl, or a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl, or where R.sub.55
and R.sub.56 or R.sub.57 and R.sub.58 taken together are keto,
methano, a C.sub.1-C.sub.10 alkyl methylene, a C.sub.1-C.sub.10
dialkylmethylene, C.sub.7-C.sub.15 arylalkyl or
heteroarylalkylmethylene, oxime, O-alkyl oxime, hydrazone,
1,3-dioxolane, 1,3-dioxane, 1,3-dithiolane, 1,3-dithiane,
oxazolidine, or R.sub.55 and R.sub.57 or R.sub.56 and R.sub.58
taken together are epoxy; R.sub.62 through R.sub.64 each
independently are hydrogen, aryl, heteroaryl, CF.sub.3, a C.sub.2
-C.sub.6 alkyl, C.sub.2-C.sub.6 heteroalkyl or NR.sub.51R.sub.52,
where R.sub.51 and R.sub.52 have the definitions given above;
R.sub.65 is hydrogen, a C.sub.1-C.sub.2 alkyl or OR.sub.66, where
R.sub.66 is a C.sub.1-C.sub.2 alkyl; R.sub.67 is a C.sub.4-C.sub.10
alkyl, heteroalkyl, aryl, heteroaryl, a C.sub.7-C.sub.15 arylalkyl
or heteroarylalkyl, NR.sub.51R.sub.52, or OR.sub.68, where R.sub.51
and R.sub.52 have the definitions described above, and where
R.sub.68 is a C.sub.3-C.sub.10 alkyl, heteroalkyl, aryl,
heteroaryl, or a C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl; X
and Y each independently represent C, O, S, N, SO or SO.sub.2,
provided, however, that when X or Y are O, S, SO or SO.sub.2, then
either R.sub.1 and R.sub.2 or R.sub.3 and R.sub.4 respectively do
not exist, and further provided, that when X or Y is N, then one
each of R.sub.1 and R.sub.2 or R.sub.3 and R.sub.4 respectively, do
not exist; M is N or C; Q is N or C; Z is O, S, SO, SO.sub.2,
CR.sub.69R.sub.70 or NR.sub.71, where R.sub.69 through R.sub.71
each independently are hydrogen or a C.sub.1-C.sub.10 alkyl,
heteroalkyl, aryl, heteroaryl, a C.sub.7-C.sub.15 arylalkyl or
heteroarylalkyl, or R.sub.69 and R.sub.70 each independently are
OR.sub.71, or R.sub.69 and R.sub.70 taken together are a
cycloalkyl; each W is independently C, N, S or O, or a
pharmaceutically acceptable salt, but is not O or S if attached by
a double bond to another W or if attached to another such W which
is O or S, and is not N if attached by a single bond to another
such W which is N; m is 0, 1 or 2 carbon atoms; n is 0 or 1 carbon
atoms; k is 1 to 5 carbon atoms; the dashed lines in the
structures, other than at R.sub.14 and R.sub.15, represent optional
double bonds, provided, however, that the double bonds cannot be
contiguous, and further provided that when such optional double
bonds exist then the substitution patterns around such bonds cannot
violate double bond valency; and the wavy lines represent olefin
geometry that is either cis (Z) or trans (E), and unless otherwise
indicated, for substituents R.sub.1 through R.sub.71, all olefin
geometric Isomers (i.e., cis (Z) or trans (E)) of the above
compounds are included.
2. A compound according to claim 1, wherein the compound is a
dimer-selective RXR modulator.
3. A compound according to claim 2, wherein the compound is
effective in modulating RXR homodimer interactions.
4. A compound according to claim 3, wherein the compound is a RXR
homodimer antagonist.
5. A compound according to claim 2, wherein the compound is
effective in modulating RXR heterodimer interactions, and wherein
the RXR heterodimer comprises an RXR complexed with another
intracellular receptor that forms a heterodimer with RXR.
6. A compound according to claim 5, wherein the compound is a RXR,
heterodimer antagonist.
7. A compound according to claim 5, wherein the RXR is selected
from the group consisting of RXR.alpha., RXR.beta. and
RXR.gamma..
8. A compound according to claim 5, wherein the other intracelluar
receptor is selected from the group consisting of PPAR.alpha.,
PPAR.beta., PPAR.gamma.1, PPAR.gamma.2, TR.alpha., TR.beta., VDRs,
RAR.alpha., RAR.beta., RAR.gamma., NGFIBs, NURR1s, LXR.alpha.,
LXR.beta. and DAXs.
9. A compound according to claim 2, wherein the compound is
effective in treating skin-related diseases and conditions,
cancerous and pre-cancerous conditions, diseases of the eye,
cardiovascular diseases, metabolic diseases, obesity, inflammatory
diseases, neurodegenerative diseases, diseases involving modulation
of apoptosis, diseases involving modulation of cellular
proliferation, diseases involving modulation of cellular
differentiation, diseases of the immune system, improper pituitary
function, diseases involving human papilloma virus, wound healing
br restoration of hair growth.
10. A compound according to claim 9, wherein the compound is
effective in treating non-insulin dependent diabetes mellitus and
insulin dependent diabetes mellitus.
11. A compound according to claim 2 selected from the group
consisting of
4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl-
]benzoic acid (Compound 101);
4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-te-
tramethyl-2-naphthyl)ethenyl]benzoic acid (Compound 102);
4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)cyclopro-
pyl] benzoic acid (Compound 103);
4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,-
8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime (Compound
104);
4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic
acid O-benzyloxime (Compound 105);
4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetr-
ahydro-2-naphthyl)carbonyl]benzoic acid O-hexyloxime (Compound
106);
4-[(3-ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethenyl]be-
nzoic acid (Compound 107);
4-[(3-ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetrame-
thyl-2-naphthyl)carbonyl]benzoic acid O-methyloxime (Compound 108);
4-[(3-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]-
benzoic acid oxime (Compound 109);
4-[(3-propoxy-5,6,7,8-tetrahydro-5,5,8,-
8-tetramethyl-2-naphthyl)carbonyl]benzoic acid O-methyloxime
(Compound 110);
4-[(3-butyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ca-
rbonyl]benzoic acid (Compound 111);
4-[(3-butyloxy-5,6,7,8-tetrahydro-5,5,-
8,8-tetramethyl-2-naphthyl)ethenyl]benzoic acid (Compound 112);
4-[(3-butyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl-
]benzoic acid O-methyloxime (Compound 113);
4-[(3-hexyloxy-5,6,7,8-tetrahy- dro-5,5,8,8
-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime (Compound 114);
4-[(3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)c-
arbonyl]benzoic acid oxime (Compound 115);
4-[(3-heptyloxy-5,6,7,8-tetrahy-
dro-5,5,8,8-tetramethyl-2-naphthyl)ethenyl]benzoic acid (Compound
116);
cis-4-[(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)car-
bonyl]benzoic acid oxime (Compound 117);
trans-4-[(3-benzyloxy-5,6,7,8-tet-
rahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime
(Compound 118); (2E, 4E,
6E)-7-[3-butyl-5,6,7,8-tetrahydro-5,5,8,8-tetram-
ethyl-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound
119); (2Z, 4E,
6E)-7-[3-(butyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth-
alen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 120); (2E,
4E,
6E)-7-[3-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalen-2-yl-
]-3-methylocta-2,4,6-trienoic acid (Compound 121); (2E, 4E,
6Z)-7-[3-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalen-2-yl-
]-3-methylocta-2,4,6-trienoic acid (Compound 122); (2Z, 4E,
6E)-7-(3-ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl)-
-3-methylocta-2,4,6-trienoic acid (Compound 123); (2E, 4E,
6Z)-7-[3-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-y-
l]-3-methylocta-2,4,6-trienoic acid (Compound 124); (2E, 4E,
6E)-7-[3-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-y-
l]-3-methylocta-2,4,6-trienoic acid (Compound 125); (2E, 4E,
6E)-7-[3-(3-methylbutyl-2-enyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-
-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound
126); (2E, 4E,
6E)-7-[3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthale-
n-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 127); (2E, 4E,
6Z)-7-[3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2--
yl]-3-methylocta-2,4,6-trienoic acid (Compound 128); (2E, 4E,
6E)-7-[3-(4-methylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-nap-
hthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 129); (2E,
4E,
6Z)-7-[3-(4-methylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-nap-
hthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 130);
4-(3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-anthracen-1-ylmethyl)-benzoi-
c acid (Compound 131);
4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3H-cyclop-
enta[b]naphthalen-1-ylmethyl)-benzoic acid (Compound 132);
4-(6,7,8,9-tetrahydro-6,6,9,9-tetramethyl-2H-benzo[g]chromen-4-ylmethyl)--
benzoic acid (Compound 133);
4-(3,4,6,7,8,9-hexahydro-2-oxo-6,6,9,9-tetram-
ethyl-2H-benzo[g]quinolin-1-ylmethyl-)-benzoic acid (Compound 134);
4-(3,4,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-2H-benzo[g]quinolin-1-ylmeth-
yl)-benzoic acid (Compound 135);
4-(2,3,6,7,8,9-hexahydro-6,6,9,9-tetramet-
hyl-naphtho[2,3-b][1,4]oxazin-4-ylmethyl)-benzoic acid (Compound
136);
4-(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracene-1-carbonyl-
)-benzoic acid (Compound 137);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl--
anthracen-1-yl)-hydroxymethyl]-benzoic acid (Compound 138);
4(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracen-1-ylmethyl)-benzoic
acid (Compound 139);
4-[1-hydroxy-1-(5,6,7,8-tetrahydro-5,5,8,8-tetrameth-
yl-anthracen-1-yl)-ethyl)-benzoic acid (Compound 140);
4-[1-methoxy-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracen-1-yl)-et-
hyl)-benzoic acid (Compound 141);
4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetrame-
thyl-anthracen-1-yl)-vinyl)-benzoic acid (Compound 142);
(trans)4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracene-1-carbonyl
oxime)-benzoic acid. (Compound 143);
(cis)-4-(5,6,7,8-tetrahydro-5,5,8,8--
tetramethyl-anthracene-1-carbonyl oxime)-benzoic acid (Compound
144);
(trans)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracene-1-carbonyl
O-methyloxime)-benzoic acid (Compound 145); (2E, 4E,
6E)-7-(3,5-diisopropyl-2-n-heptyloxyphenyl)-3-methylocta-2,4,6-trienoic
acid (Compound 146); (2E, 4E,
6Z)-7-(3,5-diisopropyl-2-n-heptyloxyphenyl)-
-3-methylocta-2,4,6-trienoic acid (Compound 147); (2E,
4E,)-7-(3,5-diisopropyl-2-n-heptyloxyphenyl)-3-methylocta-2,4-dienoic
acid (Compound 148); (2Z,
4E,)-7-(3,5-diisopropyl-2-n-heptyloxyphenyl)-3--
methylocta-2,4,dienoic acid (Compound 149); (2E, 4E,
6E)-7-(3,5-diisopropyl-2-benzyloxyphenyl)-3-methylocta-2,4,6-trienoic
acid (Compound 150); (2E, 4E,
6E)-7-(3,5-diisopropyl-2-n-butyloxyphenyl)--
3-methylocta-2,4,6-trienoic acid (Compound 151); (2E,
4E)-6-[2-(5,5,8,8-Tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2--
yl) cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 152);
(2E,
4E)-6-[2-(5,5,8,8-Tetramethyl-3-heptyloxy-5,6,7,8-tetrahydronaphthalen-2--
yl) cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 153);
(2E,
4E)-6-[2-(5,5,8,8-Tetramethyl-3-benzyloxy-5,6,7,8-tetrahydronaphthalen-2--
yl) cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 154);
(2E,
4E)-7-[(5,5,8,8-Tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphtha-len-2-y-
l) cyclopropan-1-yl]-3-methyl heptadienoic acid (Compound 155);
(2E,
4E)-7-[(5,5,8,8-Tetramethyl-3-heptyloxy-5,6,7,8-tetrahydronaphtha-len-2-y-
l) cyclopropan-1-yl]-3-methyl heptadienoic acid (Compound 156);
(2E,
4E)-7-[(5,5,8,8-Tetramethyl-3-benzyloxy-5,6,7,8-tetrahydronaphtha-len-2-y-
l) cyclopropan-1-yl]-3-methyl heptadienoic acid (Compound 157);
(2E,
4E)-5-[2-(5,5,8,8-Tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2--
yl) cyclopent-1-en-1-yl]-3-methyl pentadienoic acid (Compound 158);
cis (2E,
4E)-5-[2-(5,5,8,8-Tetramethyl-3-propyloxy-5,6,7,8-tetrahydro-2-napht-
hyl) cyclopentan-1-yl]-3-methyl pentadienoic acid (Compound 159);
4-[(3-(4-t-Butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napht-
hyl)carbonyl]benzoic acid oxime (Compound 160);
4-[(3-(4-Bromobenzyloxy)-5-
,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic
acid oxime (Compound 161);
cis-4-[(3-Benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetr-
amethyl-2-naphthyl)carbonyl]benzoic acid O-methyloxime (Compound
162);
trans-4-[(3-Benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)c-
arbonyl]benzoic acid O-methyloxime (Compound 163);
4-[2-(3-Benzyloxy-5,6,7-
,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-[1,3]dioxolan-2-yl]benzoic
acid (Compound 164);
4-[2-Methyl-1-(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,-
8-tetramethyl-2-naphthyl)propenyl]benzoic acid (Compound 165); (2E,
4E,
6E)-7-[3-(4-tert-butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound
166); (2E, 4E,
6Z)-7-[3-(4-tert-butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetrameth-
yl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound
167); (2E, 4E,
6E)-7-[3-isobutyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-na-
phthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 168);
(2E, 4E,
6Z)-7-[3-isobutyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen--
2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 169); (2E, 4E,
6E)-7-[3-pentyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2--
yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 170); (2E, 4E,
6Z)-7-[3-pentyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2--
yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 171); (2E, 4E,
6E)-7-[3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2--
yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 172); (2E, 4E,
6Z)-7-[3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2--
yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 173); (2E, 4E,
6E)-7-[3-(4-methoxybenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-na-
phthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 174)
and (2E,
4E)-7-[3-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl-
]-3-methyl-octa-2,4-dienoic acid. (Compound 175).
12. A pharmaceutical composition comprising a pharmaceutically
effective amount of a compound according to claim 2 and a
pharmaceutically acceptable carrier.
13. A pharmaceutical composition according to claim 12, wherein the
composition is formulated for oral, topical, intravenous,
suppository or parental administration.
14. A pharmaceutical composition according to claim 13, wherein the
composition is effective to treat skin-related diseases and
conditions, cancerous and pre-cancerous conditions, diseases of the
eye, cardiovascular diseases, metabolic diseases, obesity,
inflammatory diseases, neurodegenerative diseases, diseases
involving modulation of apoptosis, diseases involving modulation of
cellular proliferation, diseases involving modulation of cellular
differentiation, diseases of the immune system, improper pituitary
function, diseases involving human papilloma virus, wound healing
or restoration of hair growth.
15. A compound according to claim 14, wherein the compound is
effective in treating non-insulin dependent diabetes mellitus and
insulin dependent diabetes mellitus.
16. A pharmaceutical composition according to claim 12, wherein the
composition is administered to a patient as a dosage unit at from
about 1 .mu.g/kg of body weight to about 500 mg/kg of body
weight.
17. A pharmaceutical composition according to claim 12, wherein the
composition is administered to a patient as a dosage unit at from
about 10 .mu.g/kg of body weight to about 250 mg/kg of body
weight.
18. A pharmaceutical composition according to claim 12, wherein the
composition is administered to a patient as a dosage unit at from
about 20 .mu.g/kg of body weight to about 100 mg/kg of body
weight.
19. A method of modulating processes mediated by RXR homodimers
and/or RXR heterodimers comprising administering to a patient an
effective amount a dimer-selective RXR modulator compound of the
formula: 38wherein, R.sub.1 through R.sub.71, M, Q, W, X, Y, Z, k,
m and n each have the definitions provided in claim 1; R.sub.72 is
a C.sub.3-C.sub.10 alkyl, heteroalkyl, aryl, heteroaryl, a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl, NR.sub.73R.sub.74,
or OR.sub.75, where R.sub.73 and R.sub.74 each independently are a
C.sub.7-C.sub.10 alkyl, heteroalkyl, a C.sub.7-C.sub.15 arylalkyl
or heteroarylalkyl, a C.sub.3-C.sub.10 acyl, provided that only one
of R.sub.73 or R.sub.74 can be acyl, or R.sub.73 and R.sub.74 taken
together are C.sub.3-C.sub.6 cycloalkyl, and where R.sub.72 is a
C.sub.2-C.sub.10 alkyl, heteroalkyl, aryl, heteroaryl, or a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl; the dashed lines in
the structures, other than at R.sub.14 and R.sub.15, represent
optional double bonds, provided, however, that the double bonds
cannot be contiguous, and further provided that when such optional
double bonds exist then the substitution patterns around such bonds
cannot violate double bond valency; and the wavy lines represent
olefin geometry that is either cis (Z) or trans (E), and unless
otherwise indicated, for substituents R.sub.1 through R.sub.75, all
olefin geometric isomers (i.e., cis (Z) or trans (E)) of the above
compounds are included.
20. A method of modulating according to claim 19, wherein the
process is mediated by RXR homodimers.
21. A method of modulating according to claim 19, wherein the
process is mediated by RXR heterodimers.
22. A method of modulating according to claim 19, wherein the
process is selected from the group consisting of skin-related
diseases and conditions, cancerous and pre-cancerous conditions,
diseases of the eye, cardiovascular diseases, metabolic diseases,
obesity, inflammatory diseases, neurodegenerative diseases,
diseases involving modulation of apoptosis, modulation of diseases
involving cellular proliferation, modulation of diseases involving
cellular differentiation, diseases of the immune system, improper
pituitary function, diseases involving human papilloma virus, wound
healing and restoration of hair growth.
23. A method of modulating according to claim 22, wherein the
metabolic disease process is selected from the group consisting of
non-insulin dependent diabetes mellitus and insulin dependent
diabetes mellitus.
24. A method of modulating according to claim 19, wherein the
dimer-selective RXR modulator compound is combined with a
pharmaceutically acceptable carrier to form a pharmaceutical
composition.
25. A method of modulating according to claim 24, wherein the
pharmaceutical composition is formulated for oral, topical,
intravenous, suppository or parental administration.
26. A method of modulating according to claim 24, wherein the
pharmaceutical composition is effective to treat processes selected
from the group consisting of skin-related diseases and conditions,
cancerous and pre-cancerous conditions, diseases of the eye,
cardiovascular diseases, metabolic diseases, obesity, inflammatory
diseases, neurodegenerative diseases, diseases involving modulation
of apoptosis, diseases involving modulation of cellular
proliferation, diseases involving modulation of cellular
differentiation, diseases of the immune system, improper pituitary
function, diseases involving human papilloma virus, wound healing
and restoration of hair growth.
27. A method of modulating according to claim 26, wherein the
metabolic disease process is selected from the group consisting of
non-insulin dependent diabetes mellitus and insulin dependent
diabetes mellitus.
28. A method of modulating according to claim 24, wherein the
composition is administered to a patient as a dosage unit at from
about 1 .mu.g/kg of body weight to about 500 mg/kg of body
weight.
29. A method of modulating according to claim 24, wherein the
composition is administered to a patient as a dosage unit at from
about 10 .mu.g/kg of body weight to about 250 mg/kg of body
weight.
30. A method of modulating according to claim 24, wherein the
composition is administered to a patient as a dosage unit at from
about 20 .mu.g/kg of body weight to about 100 mg/kg of body
weight.
31. A method of modulating a process mediated by RXR homodimers
and/or RXR heterodimers comprising administering to a patient an
effective amount of a dimer-selective RXR modulator compound of the
formula: 39wherein, R.sub.44 through R.sub.47 and R.sub.62 through
R.sub.68, M, W and n each have the definitions given in claim 1, or
R.sub.62 and R.sub.63, R.sub.63 and R.sub.65, or R.sub.65 and
R.sub.64 taken together are: 40where R.sub.1 through R.sub.4,
R.sub.35 through R.sub.39, X, Y and m have the definitions given in
claim 1 and the dashed lines crossing the bonds adjacent X and Y
indicate the points of attachment at R.sub.62 and R.sub.63,
R.sub.63 and R.sub.65, or R.sub.65 and R.sub.64; 41where R.sub.27
through R.sub.34, R.sub.40 through R.sub.43, R.sub.49, W and n have
the same definitions given in claim 1 and the dashed lines crossing
the bonds adjacent R.sub.49 and R.sub.27/R.sub.31 indicate the
points of attachment at R.sub.76; other than as indicated above for
points of attachment, the dashed lines in the structures represent
optional double bonds, provided, however, that the double bonds
cannot be contiguous, and further provided that when such optional
double bonds exist then the substitution patterns around such bonds
cannot violate double bond valency; and the wavy lines represent
olefin geometry that is either cis (Z) or trans (E), and unless
otherwise indicated, for substituents R.sub.1 through R.sub.76, all
olefin geometric isomers (i.e., cis (Z) or trans (E)) of the above
compounds are included.
32. A method of modulating according to claim 31, wherein the
process is mediated by RXR homodimers.
33. A method of modulating according to claim 31, wherein the
process is mediated by RXR heterodimers.
34. A method of modulating according to claim 31, wherein the
process is selected from the group consisting of skin-related
diseases and conditions, cancerous and pre-cancerous conditions,
diseases of the eye, cardiovascular diseases, metabolic diseases,
obesity, inflammatory diseases. neurodegenerative diseases,
diseases involving modulation of apoptosis, diseases involving
modulation of cellular proliferation, diseases involving modulation
of cellular differentiation, diseases of the immune system,
improper pituitary function, diseases involving human papilloma
virus, wound healing and restoration of hair growth.
35. A method of modulating according to claim 34, wherein the
metabolic disease process is selected from the group consisting of
non-insulin dependent diabetes mellitus and insulin dependent
diabetes mellitus.
36. A method of modulating according to claim 31, wherein the
dimer-selective RXR modulator compound is combined with a
pharmaceutically acceptable carrier to form a pharmaceutical
composition.
37. A method of modulating according to claim 36, wherein the
pharmaceutical composition is formulated for oral, topical,
intravenous, suppository or parental administration.
38. A method of modulating according to claim 36, wherein the
pharmaceutical composition is effective to treat processes selected
from the group consisting of skin-related diseases and conditions,
cancerous and pre-cancerous conditions, diseases of the eye,
cardiovascular diseases, metabolic diseases, obesity, inflammatory
diseases, neurodegenerative diseases, diseases involving modulation
of apoptosis, diseases involving modulation of cellular
proliferation, diseases involving modulation of cellular
differentiation, diseases of the immune system, improper pituitary
function, diseases involving human papilloma virus, wound healing
and restoration of hair growth.
39. A method of modulating according to claim 38, wherein the
metabolic disease process is selected from the group consisting of
non-insulin dependent diabetes mellitus insulin dependent diabetes
mellitus.
40. A RXR homodimer antagonist compound.
41. A RXR homodimer antagonist according to claim 40, wherein the
compound also antagonizes a RXR heterodimer.
42. A RXR homodimner antagonist according to claim 40, wherein the
compound antagonizes a RXR homodimner, but does not antagonize a
RXR heterodimer.
43. A RXR homodimer antagonist according to claim 42, wherein the
compound activates RXR heterodimers.
44. A RXR homodimer antagonist according to claim 43, wherein the
compound activates RXR hetrodimers comprising a RXR selected from
the group consisting of RXR.alpha., RXR.beta. and RXR.gamma.
complexed with another intracellular receptor selected from the
group consisting of PPAR.alpha., PPAR.beta., PPAR.gamma.1,
PPAR.gamma.2, TR.alpha., TR.beta., VRDs, RAR.alpha., RAR.beta.,
RAR.gamma., NGFIBs, NURR1s, LXR.alpha., LXR.beta. and DAXs.
45. A RXR homodimer antagonist according to claim 44, wherein the
compound activates the RXR heterodimer in the absence of an
activator for the other intracellular receptor complexed with
RXR.
46. A RXR homodimer antagonist according to claim 45, wherein the
compound activates a RXR:RAR heterodimer in the absence of a RAR
activator.
47. A RXR homodimer antagonist according to claim 44, wherein the
compound and an activator for the other intracellular receptor
complexed with RXR activate the RXR heterodimer to a significantly
greater extent than either the compound or activator alone.
48. A RXR homodimer antagonist according to claim 44, wherein the
compound activates the RXR heterodimer in the presence or absence
of an activator for the other intracellular receptor complexed with
RXR.
49. A RXR homodimer antagonist according to claim 48, wherein the
other intracellular receptor is selected from the group consisting
of PPAR.alpha., PPAR.beta., PPAR.gamma.1, PPAR.gamma.2, NGFIBs
LXR.alpha. and LXR.beta..
50. A RXR homodimer antagonist compound of the formula: 42wherein,
R.sub.44 through R.sub.47 and R.sub.62 through R.sub.68, M, W and n
each have the definitions given in claim 1, or R.sub.62 and
R.sub.63, R.sub.63 and R.sub.65, or R.sub.65 and R.sub.64 taken
together are: 43where R.sub.1 through R.sub.4, R.sub.35 through
R.sub.39, X, Y and m have the definitions given in claim 1 and the
dashed lines crossing the bonds adjacent X and Y indicate the
points of attachment at R.sub.62 and R.sub.63, R.sub.63 and
R.sub.65, or R.sub.65 and R.sub.64; R76 is: 44where R.sub.27
through R.sub.34, R.sub.40 through R.sub.43, R.sub.49, W and n have
the same definitions given in claim 1 and the dashed lines crossing
the bonds adjacent R.sub.49 and R.sub.27/R.sub.31 indicate the
points of attachment at R.sub.76; other than as indicated above for
points of attachment, the dashed lines in the structures represent
optional double bonds, provided, however, that the double bonds
cannot be contiguous, and further provided that when such optional
double bonds exist then the substitution patterns around such bonds
cannot violate double bond valency; and the wavy lines represent
olefin geometry that is either cis (Z) or trans (E), and unless
otherwise indicated, for substituents R.sub.1 through R.sub.76, all
olefin geometric isomers (i.e., cis (Z) or trans (E)) of the above
compounds are included.
51. A RXR homodimer antagonist according to claim 50, wherein the
compound antagonizes a RXR homodimer, but does not antagonize a RXR
heterodimer.
52. A RXR homodimer antagonist according to claim 51, wherein the
compound activates RXR heterodimers.
53. A RXR homodimner antagonist according to claim 52, wherein the
compound activates RXR hetrodimers comprising a RXR selected from
the group consisting of RXR.alpha., RXR.beta. and RXR.gamma.
complexed with another intracellular receptor selected from the
group consisting of PPAR.alpha., PPAR.beta., PPAR.gamma.1,
PPAR.gamma.2, TR.alpha., TR.beta., VRDs, RAR.alpha., RAR.beta.,
RAR.gamma., NGFIBs, NURR1s, LXR.alpha., LXR.beta. and DAXs.
54. A RXR homodimer antagonist according to claim 53, wherein the
compound activates the RXR heterodimer in the absence of an
activator for the other intracellular receptor complexed with
RXR.
55. A RXR homodimer antagonist according to claim 54, wherein the
compound activates a RXR:RAR heterodimer in the absence of a RAR
activator.
56. A RXR homodimer antagonist according to claim 53, wherein the
compound and an activator for the other intracellular receptor
complexed with RXR activate the RXR heterodimer to a significantly
greater extent than either the compound or activator alone.
57. A RXR homodimer anatagonist according to claim 50, wherein a
pharmaceutically effective amount of the compound is combined with
a pharmaceutically acceptable carrier to form a pharmaceutical
composition.
58. A pharmaceutical composition according to claim 57, wherein the
composition is formulated for oral, topical, intravenous,
suppository or parental administration.
59. A pharmaceutical composition according to claim 58, wherein the
composition is effective to treat skin-related diseases and
conditions, cancerous and pre-cancerous conditions, diseases of the
eye, cardiovascular diseases, metabolic diseases, obesity,
inflammatory diseases, neurodegenerative diseases, diseases
involving modulation of apoptosis, diseases involving modulation of
cellular proliferation, diseases involving modulation of cellular
differentiation, diseases of the immune system, improper pituitary
function, diseases involving human papilloma virus, wound healing
or restoration of hair growth.
60. A compound according to claim 59, wherein the compound is
effective in treating non-insulin dependent diabetes mellitus or
insulin dependent diabetes mellitus.
61. A pharmaceutical composition according to claim 57, wherein the
composition is administered to a patient as a dosage unit at from
about 1 .mu.g/kg of body weight to about 500 mg/kg of body
weight.
62. A pharmaceutical composition according to claim 57, wherein the
composition is administered to a patient as a dosage unit at from
about 10 .mu.g/kg of body weight to about 250 mg/kg of body
weight.
63. A pharmaceutical composition according to claim 57, wherein the
composition is administered to a patient as a dosage unit at from
about 20 .mu.g/kg of body weight to about 100 mg/kg of body
weight.
64. A method of modulating a process mediated by a RXR homodimer
comprising administering an effective amount of a RXR homodimer
antagonist.
65. A method of modulating a process mediated by a RXR heterodimer
comprising administering an effective amount of a RXR homodimer
antagonist.
66. A method of modulating a process mediated by a RXR heterodimer
comprising administering an effective amount of a RXR heterodimer
antagonist.
67. A method of treating a disease process mediated by RXR
heterodimers comprising administering to a patient a
therapeutically effective amount of a RXR homodimer antagonist.
68. A method of treating a disease according to claim 67, wherein
the RXR homodimer antagonist activates the RXR heterodimer in the
absence of an activator for the other intracellular receptor
complexed with RXR.
69. A method of treating a disease according to claim 68, wherein
the RXR homodimer antagonist activates a RXR:RAR heterodimer in the
absence of a RAR activator.
70. A method of treating a disease according to claim 67, wherein
the RXR homodimer antagonist and an activator for the other
intracellular receptor complexed with RXR activate the RXR
heterodimer to a significantly greater extent than either the RXR
homodimer antagonist or activator alone.
71. A method of treating a disease according to claim 67, wherein
the disease process is selected from the group consisting of
skin-related diseases and conditions, cancerous and pre-cancerous
conditions, diseases of the eye, cardiovascular diseases, metabolic
diseases, obesity inflammatory diseases, neurodegenerative
diseases, diseases involving modulation of apoptosis, diseases
involving modulation of cellular proliferation, diseases involving
modulation of cellular differentiation, diseases of the immune
system, improper pituitary function, diseases involving human
papilloma virus, wound healing and restoration of hair growth.
72. A method of treating a disease according to claim 71, wherein
the disease process is selected from the group consisting of
non-insulin dependent diabetes mellitus and insulin dependent
diabetes mellitus.
73. A method of treating a disease according to claim 68, wherein
the disease process is selected from the group consisting of
skin-related diseases and conditions, cancerous and pre-cancerous
conditions, diseases of the eye, cardiovascular diseases, metabolic
diseases, obesity inflammatory diseases, neurodegenerative
diseases, diseases involving modulation of apoptosis, diseases
involving modulation of cellular proliferation, diseases involving
modulation of cellular differentiation, diseases of the immune
system, improper pituitary function, diseases involving human
papilloma virus, wound healing and restoration of hair growth.
74. A method of treating a disease according to claim 73, wherein
the disease process is selected from the group consisting of
non-insulin dependent diabetes mellitus and insulin dependent
diabetes mellitus.
75. A method of treating a disease according to claim 67, wherein
the RXR homodimer antagonist is a compound according to claim 1.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/004,897, filed Oct. 6, 1995; U.S. Provisional
Application No. 60/009,884, filed Jan. 10, 1996; U.S. Provisional
Application No. 60/018,318, filed May 21, 1996, and U.S.
Provisional Application No. 60/021,839, filed Jul. 10, 1996.
FIELD OF THE INVENTION
[0002] The present invention relates to compounds having agonist,
partial agonist and antagonist activity for retinoid X receptors,
and to methods for the production and therapeutic use of such
compounds.
BACKGROUND OF THE INVENTION
[0003] The vitamin A metabolite, retinoic acid, has long been
recognized to induce a broad spectrum of biological effects. For
example, retinoic acid-containing products, such as Retin-A.RTM.
and Accutane.RTM., have found utility as therapeutic agents for the
treatment of various pathological conditions. In addition, a
variety of structural analogues of retinoic acid have been
synthesized that also have been found to be bioactive. Many of
these synthetic retinoids have been found to mimic many of the
pharmacological actions of retinoic acid, and thus have therapeutic
potential for the treatment of numerous disease states.
[0004] Medical professionals have become very interested in the
therapeutic applications of retinoids. Among their uses approved by
the FDA is the treatment of severe forms of acne and psoriasis. A
large body of evidence also exists that these compounds can be used
to arrest and, to an extent, reverse the effects of skin damage
arising from prolonged exposure to the sun. Other evidence exists
that these compounds have clear effects on cellular proliferation,
differentiation and programmed cell death (apoptosis), and thus,
may be useful in the treatment and prevention of a variety of
cancerous and pre-cancerous conditions, such as acute promyleocytic
leukemia (APL), epithelial cancers, squamous cell carcinomas,
including cervical and skin cancers and renal cell carcinoma.
Furthermore, retinoids may have beneficial activity in treating and
preventing diseases of the eye, cardiovascular disease and other
skin disorders.
[0005] Major insight into the molecular mechanism of retinoic acid
signal transduction was gained in 1988, when a member of the
steroid/thyroid hormone intracellular receptor superfamily was
shown to transduce a retinoic acid signal. Giguere et al., Nature,
330:624-29 (1987); Petkovich et al., Nature, 330: 444-50 (1987);
for review, See Evans, Science, 240:889-95 (1988). It is now known
that retinoids regulate the activity of two distinct intracellular
receptor subfamilies; the Retinoic Acid Receptors (RARs) and the
Retinoid X Receptors (RXRs), including their subtypes, RAR.alpha.,
.beta., .gamma. and RXR.alpha., .beta., .gamma.. All-trans-retinoic
acid (ATRA) is an endogenous low-molecular-weight ligand which
modulates the transcriptional activity of the RARs, while 9-cis
retinoic acid (9-cis) is the endogenous ligand for the RXRs. Heyman
et al., Cell, 68:397-406 (1992) and Levin et al. Nature, 355:359-61
(1992).
[0006] Although both the RARs and RXRs respond to ATRA in vivo, due
to the in vivo conversion of some of the ATRA to 9-cis, the
receptors differ in several important aspects. First, the RARs and
RXRs are significantly divergent in primary structure (e.g., the
ligand binding domains of RAR.alpha. and RXR.alpha. have only
approximately 30% amino acid identity). These structural
differences are reflected in the different relative degrees of
responsiveness of RARs and RXRs to various vitamin A metabolites
and synthetic retinoids. In addition, distinctly different patterns
of tissue distribution are seen for RARs and RXRs. For example,
RXR.alpha. mRNA is expressed at high levels in the visceral
tissues, e.g., liver, kidney, lung, muscle and intestine, while
RAR.alpha. mRNA is not. Finally, the RARs and RXRs have different
target gene specificity. In this regard, RARs and RXRs regulate
transcription by binding to response elements in target genes that
generally consist of two direct repeat half-sites of the consensus
sequence AGGTCA. RAR:RXR heterodimers activate transcription ligand
by binding to direct repeats spaced by five base pairs (a DR5) or
by two base pairs (a DR2). However, RXR:RXR homodimers bind to a
direct repeat with a spacing of one nucleotide (a DR1). See
Mangelsdorf et al., "The Retinoid Receptors" in The Retinoids:
Biology, Chemistry and Medicine, M. B. Sporn, A. B. Roberts and D.
S. Goodman, Eds., Raven Press, New York, N.Y., Second Addition
(1994). For example, response elements have been identified in the
cellular retinal binding protein type II (CRBPII), which consists
of a DR1, and Apolipoprotein AI genes which confer responsiveness
to RXR, but not RAR. Further, RAR has also been recently shown to
repress RXR-mediated activation through the CRBPII RXR response
element (Manglesdorf et al., Cell, 66:555-61 (1991)). Also, RAR
specific target genes have recently been identified, including
target genes specific for RAR.beta. (e.g. .beta.RE), which consists
of a DR5. These data indicate that two retinoic acid responsive
pathways are not simply redundant, but instead manifest a complex
interplay.
[0007] RXR agonists in the context of an RXR:RXR homodimer display
unique transcriptional activity in contrast to the activity of the
same compounds through an RXR heterodimer. Activation of a RXR
homodimer is a ligand dependent event, i.e., the RXR agonist must
be present to bring about the activation of the RXR homodimer. In
contrast, RXR working through a heterodimer (e.g., RXR:RAR,
RXR:VDR) is often the silent partner, i.e., no RXR agonist will
activate the RXR-containing heterodimer without the corresponding
ligand for the heterodimeric partner. However, for other
heterodimers, (e.g., PPAR:RXR) a ligand for either or both of the
heterodimer partners can activate the heterodimeric complex.
Furthermore, in some instances, the presence of both an RXR agonist
and the agonist for the other heterodimeric partner (e.g.,
gemfibrizol for PPAR.alpha. and TTNPB for RAR.alpha.) leads to at
least an additive, and often a synergistic enhancement of the
activation pathway of the other IR of the heterodimer pair (e.g.,
the PPAR.alpha. pathway). See e.g., PCT Application No.
PCT/US93/10204, filed Oct. 22, 1993, published as PCT Publication
No. WO 94/15902 on Jul. 21, 1994, R. Mukherjee et al., 51 J.
Steroid Biochem. Molec Biol., 157-166 (1994) and L. Jow and R.
Mukherjee, 270 Journ. Biol. Chem., 3836-3840 (1995).
[0008] RAR and RXR retinoid agonists, including both RAR specific
and RXR specific agonists have been previously identified. See
e.g., PCT Publication Nos. WO 94/15902 WO93/21146, WO94/15901,
WO94/12880, WO94/17796, WO94/20093, WO96/05165 and PCT Application
No. PCT/US93/10166; EPO Patent Application Nos. 87110303.2,
87309681.2 and EP 0718285, U.S. Pat. Nos. 4,193,931, 4,539,134,
4,801,733, 4,831,052, 4,833,240, 4,874,747, 4,879,284, 4,898,864,
4,925,979, 5,004,730, 5,124,473, 5,198,567, 5,391,569 and Re
33,533; and H. Kagechika et al., "Retinobenzoic Acids. 2.
Structure-Activity Relationship of Chalcone-4-carboxylic Acids and
Flavone-4'-carboxylic Acids", 32 J. Med. Chem., 834 (1989); H.
Kagechika et al., "Retinobenzoic Acids. 3. Structure-Activity
Relationships of Retinoidal Azobenzene-4-carboxylic Acids and
Stilbene-4-carboxylic Acids", 32 J. Med. Chem., 1098 (1989); H.
Kagechika et al., "Retinobenzoic Acids 4. Conformation of Aromatic
Amides with Retinoidal Activity. Importance of trans-Amide
Structure for the Activity", 32 J. Med. Chem. 2292 (1989): M. Boehm
et al., 37 J. Med. Chem., 2930 (1994); M. Boehm et al., 38 J. Med.
Chem., 3146 (1995); E. Allegretto et al., 270 Journal of Biol.
Chem., 23906 (1995); R. Bissonnette et al., 15 Mol. & Cellular
Bio., 5576 (1995); R. Beard et al., 38 J. Med. Chem., 2820 (1995)
and M. I. Dawson et al., "Effect of Structural Modifications in the
C7-C11 Region of the Retinoid Skeleton on Biological Activity in a
Series of Aromatic Retinoids", 32 J. Med. Chem., 1504 (1989).
Further, antagonists to the RAR subfamily of receptors have
recently been identified. See e.g., C. Apfel et al., 89 Proc. Natl.
Acad. Sci., 7129 (1992); S. Keidel et al., 14 Mol. Cell. Biol., 287
(1994); S. Kaneko et al., 1 Med. Chem. Res., 220 (1991); L.
Eyrolles et al., 2 Med. Chem. Res., 361 (1992); J. Eyrolles et al.,
37 J. Med. Chem., 1508 (1994); M-O Lee et al., 91 Proc. Natl. Acad.
Sci., 5632 (1994); Yoshimura et al., 38 J. Med. Chem., 3163 (1995)
and U.S. Pat. No. 5,391,766. In addition, various polyene compounds
have been disclosed to be useful in the treatment of inflammatory
conditions, psoriasis, allergic reactions, and for use in
sunscreens in cosmetic preparations. See e.g., U.S. Pat. Nos.
4,534,979 and 5,320,833. Also, trienediolates of hexadienoic acids
have proved useful in the synthesis of retinoic and nor-retinoic
acids. See M. J. Aurell, et al., 49 Tetrahedron, 6089 (1993).
However, to date, compounds that are RXR antagonist (e.g., that
bind to RXR and do not activate, but antagonize transcription)
and/or RXR selective compounds that have distinct heterodimer
selective properties, such that they are capable of manifesting
agonist, partial agonist and antagonist properties, have not been
identified or characterized.
SUMMARY OF THE INVENTION
[0009] The present invention provides novel RXR modulators that
selectively bind to RXR receptors in preference to RAR receptors
and that, depending upon the receptor and/or cellular context,
display activity as full agonists, partial agonists and/or full
antagonists on RXR homodimers and/or RXR heterodimers. Thus, these
compounds display unique selectivity for RXR heterodimers, and are
referred to herein as dimer-selective RXR modulators. The present
invention also provides pharmaceutical compositions incorporating
these novel compounds and methods for the therapeutic use of such
compounds and pharmaceutical compositions.
[0010] These and various other advantages and features of novelty
which characterize the invention are pointed out with particularity
in the claims annexed hereto and forming a part hereof. However,
for a better understanding of the invention, its advantages, and
objects obtained by its use, reference should be had to the
accompanying drawings and descriptive matter, in which there is
illustrated and described preferred embodiments of the
invention.
[0011] Definitions
[0012] In accordance with the present invention and as used herein,
the following terms are defined with the following meanings, unless
explicitly stated otherwise.
[0013] The term alkyl refers a straight-chain, branched-chain,
cyclic and combination alkyls, including optional unsaturation
(thereby resulting in alkenyls and alkynyls).
[0014] The term heteroalkyl refers to an optionally substituted
straight-chain, branched-chain, cyclic and combination C.sub.1 to
C.sub.10 alkyls containing one or more heteroatoms selected from
the group consisting of halogen (i.e., F, Cl, Br, I) (including
perfluoro alkyls), oxygen, nitrogen and sulfur, including optional
unsaturation.
[0015] The term cycloalkyl refers to an optionally substituted
C.sub.3 to C.sub.6 group which forms a ring, including optional
unsaturation and optional heteroatom (e.g., O, N or S) substitution
in or on the cycloalkyl ring.
[0016] The term aryl refers to optionally substituted phenyl,
biphenyl, naphthyl or anthracenyl ring systems.
[0017] The term heteroaryl refers to an optionally substituted
five-membered or six-membered heterocyclic or other aryl ring
containing one or more heteroatoms selected from the group
consisting of oxygen, nitrogen and sulfur, including, without
limitation, furyl, pyrrolyl, pyrrolidinyl, thienyl, pyridyl,
piperidyl, indolyl, quinolyl, thiazole, benzthiazole and
triazole.
[0018] The term arylalkyl or heteroarylalkyl refers to optionally
substituted alkyls containing one or more aryl and/or heteroaryl
groups.
[0019] The term acyl refers to alkyl, aryl or arylalkyl or
heteroarylalkyl substituents attached to a compound via a carbonyl
functionality (e.g., --CO-alkyl, --CO-aryl, --CO-arylalkyl or
heteroarylalkyl etc . . . ).
[0020] The term dimer-selective RXR modulator refers to a compound
that binds to one or more Retinoid X Receptors and modulates (i.e.,
increases or decreases the transcriptional activity and/or
biological properties of the given receptor dimer) the
transcriptional activity of an RXR homodimer (i.e., RXR:RXR) and/or
RXR in the context of a heterodimer, including but not limited to
heterodimer formation with peroxisome proliferator activated
receptors (e.g., RXR:PPAR.alpha., .beta., .gamma.1 or .gamma.2),
thyroid receptors (e.g., RXR:TR.alpha. or .beta.), vitamin D
receptors (e.g., RXR:VDR), retinoic acid receptors (e.g.,
RXR:RAR.alpha., .beta. or .gamma.), NGFIB receptors (e.g.,
RXR:NGFIB), NURR1 receptors (e.g., RXR:NURR1) LXR receptors (e.g.,
RXR:LXR.alpha., .beta.), DAX receptors (e.g., RXR:DAX), as well as
other orphan receptors that form heterodimers with RXR, as either
an agonist, partial agonist and/or antagonist. The particular
effect of a dimer-selective RXR modulator as an agonist, partial
agonist and/or antagonist will depend upon the cellular context as
well as the heterodimer partner in which the modulator compounds
acts. In this regard, the present invention describes
dimer-selective RXR modulators, i.e., modulators that are selective
activators and/or repressors through Retinoid X Receptors (i.e.,
RXR.alpha., RXR.beta., and/or RXR.gamma.) rather than Retinoic Acid
Receptors (i.e., RAR.alpha., RAR.beta., and/or RAR.gamma.).
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] The invention may be further illustrated by reference to the
accompanying Drawings wherein:
[0022] FIG. 1A is a dose response curve showing that Compound 122
of the present invention (.box-solid.) fails to activate RXR:RXR
homodimers, while the known RXR agonist, LG100268 (.diamond-solid.)
(Ligand Pharmaceuticals, Inc.), does activate the RXR:RXR
homodimer;
[0023] FIG. 1B is a dose response curve showing that Compound 122
of the present invention (.box-solid.) functions as an RXR
homodimer antagonist of a fixed concentration of LGD1069
(.circle-solid.; 100 nM);
[0024] FIG. 1C is a bar graph showing that 1 mM of Compound 122 of
the present invention also antagonizes the RXR activators 9-cis
retinoic acid (100 nM) and LG100268 (100 nM);
[0025] FIG. 2A is a dose response curve showing that Compound 122
of the present invention (.box-solid.) activates
RXR.alpha.:PPAR.alpha. heterodimers to a greater extent than the
known RXR agonist LG100268 (.diamond-solid.);
[0026] FIG. 2B is a bar graph showing that 1 mM of Compound 122 of
the present invention and the known RAR agonist TTNPB (100 nM;
Hoffman La-Roche, Inc.) activate RXR.alpha.:RAR.alpha.
heterodimers, whereas the known RXR agonist LG100268 (100 nM;
Ligand Pharmaceuticals, Inc.) is inactive, and further that TTNPB
added with Compound 122 leads to a greater than additive response
than either compound added alone;
[0027] FIG. 3 is a bar graph showing that, a concentration of 1 mM
of Compound 122 of the present invention, as well as TTNBP (100 nM)
and 9-cis retinoic acid (100 nM) stimulate NB4 cells to
differentiate, whereas LG100268 (100 nM) does not.
DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION
[0028] In accordance with a first aspect of the present invention,
we have developed compounds of the formula: 1
[0029] wherein,
[0030] R.sub.1 through R.sub.4 each independently are hydrogen, a
C.sub.1-C.sub.6 alkyl or a C.sub.7-C.sub.15 arylalkyl or
heteroarylalkyl;
[0031] R.sub.5 is a C.sub.5-C.sub.10 alkyl, heteroalkyl, aryl,
heteroaryl, a C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl,
NR.sub.6R.sub.7, or OR.sub.8, where R.sub.6 and R.sub.7 each
independently are a C.sub.7-C.sub.10 alkyl, heteroalkyl, a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl, a C.sub.3-C.sub.10
acyl, provided that only one of R.sub.6 or R.sub.7 can be acyl, or
R.sub.6 and R.sub.7 taken together are C.sub.3-C.sub.6 cycloalkyl,
and where R.sub.8 is a C.sub.7-C.sub.10 alkyl, heteroalkyl, aryl,
heteroaryl, or a C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl;
[0032] R.sub.9 and R.sub.10 each independently are hydrogen, a
C.sub.1-C.sub.10 alkyl, halogen, heteroalkyl, NR.sub.11R.sub.12,
NO.sub.2 or OR.sub.13, where R.sub.11 and R.sub.12 each
independently are hydrogen, a C.sub.1-C.sub.10 alkyl, heteroalkyl,
a C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl, a C.sub.1-C.sub.8
acyl, provided that only one of R.sub.11 or R.sub.12 can be acyl,
or R.sub.11 and R.sub.12 taken together are a C.sub.3-C.sub.6
cycloalkyl, and where R.sub.13 is hydrogen or a C.sub.1-C.sub.10
alkyl, heteroalkyl or a C.sub.7-C.sub.15 arylalkyl or
heteroarylalkyl;
[0033] R.sub.14 and R.sub.15 each independently are hydrogen, a
C.sub.1-C.sub.10 alkyl, a C.sub.1-C.sub.8 acyl, or OR.sub.16 where
R.sub.16 is hydrogen or a C.sub.1-C.sub.10 alkyl; or R.sub.14 and
R.sub.15 taken together are keto, methano, optionally substituted
oxime, optionally substituted hydrazone, optionally substituted
epoxy, 1,3-dioxolane, 1,3-dioxane, 1,3-dithiolane, 1,3-dithiane,
oxazolidine or: 2
[0034] where R.sub.17 through R.sub.23 have the definitions given
below and the dashed lines crossing the bonds indicate the
attachment bonds to the rings adjacent to R.sub.14 and
R.sub.15;
[0035] R.sub.17 and R.sub.18 each independently are hydrogen, a
C.sub.1-C.sub.10 alkyl, heteroalkyl, aryl, a C.sub.7-C.sub.15
arylalkyl or heteroarylalkyl, or R.sub.17 and R.sub.18 taken
together are a C.sub.3-C.sub.6 cycloalkyl;
[0036] R.sub.19 is hydrogen, a C.sub.1-C.sub.10 alkyl, heteroalkyl,
aryl, heteroaryl, a C.sub.7-C.sub.15 arylalkyl or
heteroarylalkyl;
[0037] R.sub.20 through R.sub.23 each independently are hydrogen,
halogen, a C.sub.1-C.sub.10 alkyl, heteroalkyl, aryl, heteroaryl, a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl, NR.sub.24R.sub.25,
NO.sub.2, or OR.sub.26, where R.sub.24 and R.sub.25 each
independently are hydrogen, a C.sub.1-C.sub.10 alkyl, heteroalkyl,
a C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl or a
C.sub.1-C.sub.8 acyl, provided that only one of R.sub.24 or
R.sub.25 can be acyl, and where R.sub.26 is hydrogen or a
C.sub.1-C.sub.10 alkyl, heteroalkyl, aryl, heteroaryl, or a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl;
[0038] R.sub.27 through R.sub.31 each independently are hydrogen, a
C.sub.1-C.sub.10 alkyl, heteroalkyl, halogen, NR.sub.32R.sub.33,
NO.sub.2 or OR.sub.34, where R.sub.32 and R.sub.33 each
independently are hydrogen, a C.sub.1-C.sub.10 alkyl, a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl, a C.sub.1-C.sub.8
acyl, provided that only one of R.sub.32 or R.sub.33 can be acyl,
or R.sub.32 and R.sub.33 taken together are a C.sub.3-C.sub.6
cycloalkyl, and where R.sub.34 is hydrogen or a C.sub.1-C.sub.10
alkyl, heteroalkyl or a C.sub.7-C.sub.15 arylalkyl or
heteroarylalkyl and can only exist when W is C;
[0039] R.sub.35 through R.sub.38 each independently are hydrogen, a
C.sub.1-C.sub.2 alkyl or OR.sub.39 where R.sub.39 is hydrogen or a
C.sub.1-C.sub.10 alkyl, or R.sub.35 and R.sub.36 or R.sub.37 and
R.sub.38 taken together are keto, or R.sub.35 and R.sub.36,
R.sub.37 and R.sub.38, R.sub.35 and R.sub.37 or R.sub.36 and
R.sub.38 taken together are epoxy;
[0040] COR.sub.40 can originate from any W, when the orginating W
is C, and R.sub.40 is OR.sub.41 or NR.sub.42R.sub.43, with R.sub.41
being hydrogen, a C.sub.1-C.sub.6 alkyl or a C.sub.7-C.sub.15
arylalkyl or heteroarylalkyl, and with R.sub.42 and R.sub.43 each
independently being hydrogen, a C.sub.1-C.sub.6 alkyl, a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl, aryl, ortho-, meta-,
or para-substituted hydroxyaryl, or taken together are a
C.sub.3-C.sub.6 cycloalkyl;
[0041] R.sub.44 and R.sub.45 each independently are hydrogen, a
C.sub.1-C.sub.4 alkyl or CH.sub.2OR.sub.46, where R.sub.46 is
hydrogen or a C.sub.1-C.sub.6 alkyl, or R.sub.44 and R.sub.45 taken
together are a C.sub.3-C.sub.6 cycloalkyl or cycloheteroalkyl;
[0042] R.sub.47 is hydrogen, a C.sub.1-C.sub.4 alkyl, or when n=1,
R.sub.47 taken together with R.sub.44 or R.sub.45 are a
C.sub.3-C.sub.6 cycloalkyl or cycloheteroalkyl;
[0043] R.sub.48 and R.sub.49 each independently are C.sub.1-C.sub.4
alkyl;
[0044] R.sub.50 is a C.sub.4-C.sub.10 alkyl, heteroalkyl, aryl,
heteroaryl, a C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl,
NR.sub.51R.sub.52, or OR.sub.53, where R.sub.51 and R.sub.52 each
independently are a C.sub.2-C.sub.10 alkyl, heteroalkyl, a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl, a C.sub.3-C.sub.10
acyl, provided that only one of R.sub.51 or R.sub.52 can be acyl,
or R.sub.51 and R.sub.52 taken together are C.sub.3-C.sub.6
cycloalkyl, and where R.sub.53 is a C.sub.7-C.sub.10 alkyl,
heteroalkyl, aryl, heteroaryl, a C.sub.3-C.sub.6 alkyl,
heteroalkyl, aryl or heteroalkyl or a C.sub.7-C.sub.15 arylalkyl or
heteroarylalkyl;
[0045] R.sub.54 represents: 3
[0046] where R.sub.9, R.sub.10, R.sub.14, R.sub.15 and R.sub.40
have the definitions given above;
[0047] R.sub.55 through R.sub.58 each independently are hydrogen,
halogen, a C.sub.1-C.sub.10 alkyl, heteroalkyl, aryl, heteroaryl, a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl, NR.sub.59R.sub.60 or
OR.sub.61, where R.sub.59 and R.sub.60 each independently are
hydrogen, a C.sub.1-C.sub.10 alkyl or heteroalkyl, a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl, a C.sub.1-C.sub.8
acyl, provided that only one of R.sub.59 or R.sub.60 can be acyl,
or R.sub.59 and R.sub.60 taken together are C.sub.3-C.sub.6
cycloalkyl, and where R.sub.61 is hydrogen or a C.sub.1-C.sub.10
alkyl, heteroalkyl, aryl, heteroaryl, or a C.sub.7-C.sub.15
arylalkyl or heteroarylalkyl, or where R.sub.55 and R.sub.56 or
R.sub.57 and R.sub.58 taken together are keto, methano, a
C.sub.1-C.sub.10alkyl methylene, a C.sub.1-C.sub.10
dialkylmethylene, C.sub.7-C.sub.15 arylalkyl or
heteroarylalkylmethylene, oxime, O-alkyl oxime, hydrazone,
1,3-dioxolane, 1,3-dioxane, 1,3-dithiolane, 1,3-dithiane,
oxazolidine, or R.sub.55 and R.sub.57 or R.sub.56 and R.sub.58
taken together are epoxy;
[0048] R.sub.62 through R.sub.64 each independently are hydrogen,
aryl, heteroaryl, CF.sub.3, a C.sub.2-C.sub.6 alkyl,
C.sub.2-C.sub.6 heteroalkyl or NR.sub.51R.sub.52, where R.sub.51
and R.sub.52 have the definitions given above;
[0049] R.sub.65 is hydrogen, a C.sub.1-C.sub.2 alkyl or OR.sub.66,
where R.sub.66 is a C.sub.1-C.sub.2 alkyl;
[0050] R.sub.67 is a C.sub.4-C.sub.10 alkyl, heteroalkyl, aryl,
heteroaryl, a C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl,
NR.sub.51R.sub.52, or OR.sub.68, where R.sub.51 and R.sub.52 have
the definitions described above, and where R.sub.68 is a
C.sub.3-C.sub.10 alkyl, heteroalkyl, aryl, heteroaryl, or a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl;
[0051] X and Y each independently represent C, O, S, N, SO or
SO.sub.2, provided, however, that when X or Y are O, S, SO or
SO.sub.2, then either R.sub.1 and R.sub.2 or R.sub.3 and R.sub.4
respectively do not exist, and further provided, that when X or Y
is N, then one each of R.sub.1 and R.sub.2 or R.sub.3 and R.sub.4
respectively, do not exist;
[0052] M is N or C;
[0053] Q is N or C;
[0054] Z is O, S, SO, SO.sub.2, CR.sub.69R.sub.70 or NR.sub.71,
where R.sub.69 through R.sub.71 each independently are hydrogen or
a C.sub.1-C.sub.10 alkyl, heteroalkyl, aryl, heteroaryl, a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl, or R.sub.69 and
R.sub.70 each independently are OR.sub.71, or R.sub.69 and R.sub.70
taken together are a cycloalkyl;
[0055] each W is independently C, N, S or O, or a pharmaceutically
acceptable salt, but is not O or S if attached by a double bond to
another W or if attached to another shuch W which is O or S, and is
not N if attached by a single bond to another such W which is
N;
[0056] m is 0, 1 or 2 carbon atoms;
[0057] n is 0 or 1 carbon atoms;
[0058] k is 1 to 5 carbon atoms;
[0059] the dashed lines in the structures, other than at R.sub.14
and R.sub.15, represent optional double bonds, provided, however,
that the double bonds cannot be contiguous, and further provided
that when such optional double bonds exist then the substitution
patterns around such bonds cannot violate double bond valency;
and
[0060] the wavy lines represent olefin geometry that is either cis
(Z) or trans (E), and unless otherwise indicated, for substituents
R.sub.1 through R.sub.71, all olefin geometric isomers (i.e., cis
(Z) or trans (E)) of the above compounds are included.
[0061] The compounds of the present invention will find particular
application as RXR modulators, and in particular, as
dimer-selective R modulators, including, but not limited to RXR
homodimer antagonists and agonist, partial agonist and antagonists
of RXRs in the context of a heterodimer.
[0062] In a second aspect, the present invention provides a method
of modulating processes mediated by RXR homodimers and/or RXR
heterodimers comprising administering to a patient an effective
amount a dimer-selective RXR modulator compound of the formula:
4
[0063] wherein,
[0064] R.sub.1 through R.sub.71, M, Q, W, X, Y, Z, k, m and n each
have the definitions given above;
[0065] R.sub.72 is a C.sub.3-C.sub.10 alkyl, heteroalkyl, aryl,
heteroaryl, a C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl,
NR.sub.73R.sub.74, or OR.sub.75, where R.sub.73 and R.sub.74 each
independently are a C.sub.7-C.sub.10 alkyl, heteroalkyl, a
C.sub.7-C.sub.15 arylalkyl or heteroarylalkyl, a C.sub.3-C.sub.10
acyl, provided that only one of R.sub.73 or R.sub.74 can be acyl,
or R.sub.73 and R.sub.74 taken together are C.sub.3-C.sub.6
cycloalkyl, and where R.sub.75 is a C.sub.2-C.sub.10 alkyl,
heteroalkyl, aryl, heteroaryl, or a C.sub.7-C.sub.15 arylalkyl or
heteroarylalkyl;
[0066] the dashed Lines in the structures, other than at R.sub.14
and R.sub.15, represent optional double bonds, provided, however,
that the double bonds cannot be contiguous, and further provided
that when such optional double bonds exist then the substitution
patterns around such bonds cannot violate double bond valency;
and
[0067] the wavy lines represent olefin geometry that is either cis
(Z) or trans (E), and unless otherwise indicated, for substituents
R.sub.1 through R.sub.75, all olefin geometric isomers (i.e., cis
(Z) or trans (E)) of the above compounds are included.
[0068] In a third aspect, the present invention further provides a
method of modulating processes mediated by RXR homodimers and/or
RXR heterodimers comprising administering to a patient an effective
amount a dimer-selective RXR modulator compound of the formula:
5
[0069] wherein,
[0070] R.sub.44 through R.sub.47 and R.sub.62 through R.sub.68, M,
W and n each have the definitions given above, or R.sub.62 and
R.sub.63, R.sub.63 and R.sub.65, or R.sub.65 and R.sub.64 taken
together are: 6
[0071] where R.sub.1 through R.sub.4, R.sub.35 through R.sub.39, X,
Y and m have the definitions given above and the dashed lines
crossing the bonds adjacent X and Y indicate the points of
attachment at R.sub.62 and R.sub.63, R.sub.63 and R.sub.65, or
R.sub.65 and R.sub.64;
[0072] R.sub.76 is: 7
[0073] where R.sub.27 through R.sub.34, R.sub.40 through R.sub.43,
R.sub.49, W and n have the same definitions given above and the
dashed lines crossing the bonds adjacent R.sub.49 and
R.sub.27/R.sub.31 indicate the points of attachment at
R.sub.76;
[0074] other than as inicated above for points of attachment, the
dashed lines in the structures represent optional double bonds,
provided, however, that the double bonds cannot be contiguous, and
further provided that when such optional double bonds exist then
the substitution patterns around such bonds cannot violate double
bond valency; and
[0075] the wavy lines represent olefin geometry that is either cis
(Z) or trans (E), and unless otherwise indicated, for substituents
R.sub.1 through R.sub.76, all olefin geometric isomers (i.e., cis
(Z) or trans (E)) of the above compounds are included.
[0076] In a fourth aspect, the present invention provides
antagonists of a RXR homodimer and/or a RXR heterodimer.
Preferably, the anagonists are selective RXR homodimer antagonists,
i.e., the compounds antagonize a RXR homodimer, but do not
antagonize RXR in the context of a heterodimer (e.g., an RXR:RAR or
RXR:PPAR heterodimer). More preferably, the present invention
provides RXR homodimer and and/or heterodimer antagonists of the
formula: 8
[0077] (VII)
[0078] wherein,
[0079] R.sub.44 through R.sub.47 and R.sub.62 through R.sub.68, M,
W and n each have the definitions given above, or R.sub.62 and
R.sub.63, R.sub.63 and R.sub.65, or R.sub.65 and R.sub.64 taken
together are: 9
[0080] where R.sub.1 through R.sub.4, R.sub.35 through R.sub.39, X,
Y and m have the definitions given above and the dashed lines
crossing the bonds adjacent X and Y indicate the points of
attachment at R.sub.62 and R.sub.63, R.sub.63 and R.sub.65, or
R.sub.65 and R.sub.64;
[0081] R76 is: 10
[0082] where R.sub.27 through R.sub.34, R.sub.40 through R.sub.43,
R.sub.49, W and n have the same definitions given above and the
dashed lines crossing the bonds adjacent R.sub.49 and
R.sub.27/R.sub.31 indicate the points of attachment at
R.sub.76;
[0083] other than as inicated above for points of attachment, the
dashed lines in the structures represent optional double bonds,
provided, however, that the double bonds cannot be contiguous, and
further provided that when such optional double bonds exist then
the substitution patterns around such bonds cannot violate double
bond valency; and
[0084] the wavy lines represent olefin geometry that is either cis
(Z) or trans (E), and unless otherwise indicated, for substituents
R.sub.1 through R.sub.76, all olefin geometric isomers (i.e., cis
(Z) or trans (E)) of the above compounds are included.
[0085] The compounds of the present invention, as well as the
compounds utilized in the methods of the present invention, also
include all pharmaceutically acceptable salts, as well as esters
and amides. As used in this disclosure, pharmaceutically acceptable
salts include, but are not limited to: pyridine, ammonium,
piperazine, diethylamine, nicotinamide, formic, urea, sodium,
potassium, calcium, magnesium, zinc, lithium, cinnamic,
methylamino, methanesulfonic, picric, tartaric, triethylamino,
dimethylamino, and tris(hydoxymethyl) aminomethane. Additional
pharmaceutically acceptable sats are known to those skilled in the
art.
[0086] The compounds of the present invention are useful in the
modulation of transcriptional activity through an RXR homodimer
(i.e., RXR:RXR), as well as through RXR in the context of a
heterodimer (e.g., RXR:PPAR.alpha., .beta., .gamma.; RXR:TR;
RXR:VDR; RXR:RAR.alpha., .beta., .gamma.; RXR:NGFIB; RXR:NURR1;
RXR:LXR.alpha., .beta.; RXR:DAX), including any other intracellular
receptors (IRs) which form a heterodimer with RXR. For example,
application of the compounds of the present invention to modulate a
RXR.alpha.:PPAR.alpha. heterodimer is useful to modulate, i.e.
increase HDL cholesterol levels and reduce triglyceride levels.
Yet, application of many of the same compounds of the present
invention to a RXR.alpha.:PPAR.gamma. heterodimer modulates a
distinct activity, i.e., modulation of adipocyte biology, including
effects on the differentiation and apoptosis of adipocytes which
will have implications in the treatment and/or prevention of
diabetes and obesity. In addition, use of the modulator compounds
of the present invention with activators of the other heterodimer
partner (e.g., fibrates for PPAR.alpha. and thiazolidinediones for
PPAR.gamma.) can lead to a synergistic enhancement of the desired
response. Likewise, application of the modulator compounds of the
present invention in the contexts of a RXR.alpha.:RAR.alpha. and/or
RXR.alpha.:VDR heterodimers will be useful to modulate skin related
processes (e.g., photoaging, acne, psoriasis), malignant and
pre-malignant conditions and programmed cell death (apoptosis).
Further, it will be understood by those skilled in the art that the
modulator compounds of the present invention will also prove useful
in the modulation of other heteromer interactions that include RXR,
e.g., trimers, tetramers and the like.
[0087] Thus, the present inventors have discovered novel
dimer-selective RXR modulators with multifunctional activity, that
selectively bind to RXRs in preference to RARs and that, depending
upon the cellular and/or receptor context, can modulate processes
as full agonists, partial agonists and/or full antagonists. For
example, in the context of an RXR homodimer, the compounds of the
present invention function as RXR antagonists, the first
demonstration of such RXR antagonism to date. In addition, many of
these same compounds show a surprisingly different biology when
exerting their effects through an RXR heterodimer. For example, in
the context of a RXR:RAR or RXR:PPAR heterodimer, many of the same
RXR homodimer antagonist compounds will serve as partial or full
agonists, both alone, and in the presence of a corresponding RAR
modulator (e.g., all-trans retinoic acid (ATRA or TTNPB) or PPAR
modulator (e.g., gemfibrizol). In other instances, the compounds of
the present invention will also antagonize RXR in the context of a
heterodimer.
[0088] Importantly, the dimer-selective RXR modulators of the
present invention activate the transcriptional activity of RXRs in
the context of heterodimers without the presence of a corresponding
modulator of the other heterodimeric partner (e.g., clofibric acid
or gemfibrizol for PPAR.alpha.; ATRA or TTNPB for RAR.alpha.). In
fact, and in contrast to heterodimers with PPAR, RAR suppresses RXR
ligand binding and transactivation for typical RXR agonists (e.g.,
LGD1069) in the absence of a RAR ligand. However, many of the
modulator compounds of the present invention escape suppression by
RAR on RXR (e.g., Compounds 122 and 130), and as such, can activate
and RAR:RXR heterodimer alone or in the presence of a RAR ligand.
While not being bound to a theory of operation, one possible
explanation arises from the fact that these unique modulator
compounds mechanistically interact with an RXR:RAR heterodimer in a
different manner than pure RXR agonists (e.g., LGD 1069). Unlike
typical RXR agonists, which require an intact activation domain of
an RXR receptor in the context of a RAR:RXR heterodimer, the
modulator compounds of the present invention require an intact
activation domain for the heterodimeric partner (e.g., RAR), but
not for the RXR receptor. Accordingly, the modulator compounds of
the present invention will, in certain contexts, serve as RAR
mimics, activating a subset of the genes activated by typical RAR
compounds (e.g., ATRA or TTNPB) and/or activating distinct genes
from those activated by typical RAR compounds. In this regard, the
modulator compounds of the present invention display many of the
benefits of RAR compounds in animals without the typical RAR
retinoid-associated toxicities.
[0089] Further, when the modulator compounds of the present
invention are combined with a corresponding modulator of the other
heterodimeric partner, a surprising synergistic enhancement of the
activation of the heterodimer pathway can occur. For example, with
respect to a RXR.alpha.:PPAR.alpha. heteodimer, the combination of
a compound of the present invention with clofibric acid or
gemfibrozil unexpectedly leads to a greater than additive (i.e.
synergistic) activation of PPAR.alpha. responsive genes, which in
turn is useful to modulate serum cholesterol and triglyceride
levels and other conditions associated with lipid metabolism.
[0090] Whether acting on an RXR heterodimer pathway, or the RXR
homodimer pathway, it will also be understood by those skilled in
the art that the dimer-selective RXR modulator compounds of the
present invention will prove useful in any therapy in which
agonists, partial agonists and/or full antagonists of such pathways
will find application. Importantly, because the compounds of the
present invention can differentially activate RXR homodimers and
RXR heterodimers, their effects will be tissue and/or cell type
specific, depending upon the cellular context of the different
tissue types in a given patient. For example, compounds of the
present invention will exert an RXR antagonists effect in tissues
where RXR homodimers prevail, and partial agonist or full agonist
activity on the PPAR pathway where RXR.alpha.:PPAR.alpha.
heterodimers prevail (e.g., in liver tissue). Thus, the compounds
of the present invention will exert a differential effect in
various tissues in an analogous fashion to the manner in which
various classes of estrogens and antiestrogens (e.g., Estrogen,
Tamoxifen, Raloxifen) exert differential effects in different
tissue and/or cell types (e.g., bone, breast, uterus). See e.g.,
Maty T. Tzukerman et al., 8 Mol. Endo, 21-30 (1994); Donald P.
McDonnell et al., 9 Mol. Endo, 659-669 (1995). However, in the
present case, it is believed that the differential effects of the
compounds of the present invention is based upon the particular
dimer pair through which the compound acts, rather than through
different transactiving regions of the estrogen receptor in the
case of estrogens and antiestrogens.
[0091] The particular conditions that may be treated with the
compounds of the present invention include, skin-related diseases,
such as actinic keratoses, arsenic keratoses, inflammatory and
non-inflammatory acne, psoriasis, ichthyoses and other
keratinization and hyperproliferative disorders of the skin,
eczema, atopic dermatitis, Darriers disease, lichen planus,
prevention and reversal of glucocorticoid damage (steroid atrophy),
as a topical anti-microbial, as skin pigmentation agents and to
treat and reverse the effects of age and photo damage to the skin.
With respect to the modulation of malignant and pre-malignant
conditions, the compounds may also prove useful for the prevention
and treatment of cancerous and pre-cancerous conditions, including,
premalignant and malignant hyperproliferative diseases and cancers
of epithelial origin such as cancers of the breast, skin, prostate,
cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx,
oral cavity, blood and lymphatic system, metaplasias, dysplasias,
neoplasias, leukoplakias and papillomas of the mucous membranes and
in the treatment of Kaposis sarcoma. In addition, the present
compounds may be used as agents to treat and prevent various
cardiovascular diseases, including, without limitation, diseases
associated with lipid metabolism such as dyslipidemias, prevention
of restenosis and as an agent to increase the level of circulating
tissue plasminogen activator (TPA), metabolic diseases such as
obesity and diabetes (i.e., non-insulin dependent diabetes mellitus
and insulin dependent diabetes mellitus), the modulation of
differentiation and proliferation disorders, as well as the
prevention and treatment of neurodegenerative diseases such as
Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral
Sclerosis (ALS), and in the modulation of apoptosis, including both
the induction of apoptosis and inhibition of T-Cell activated
apoptosis.
[0092] Furthermore, it will be understood by those skilled in the
art that the compounds of the present invention, including
pharmaceutical compositions and formulations containing these
compounds, can be used in a wide variety of combination therapies
to treat the conditions and diseases described above. Thus, the
compounds of the present invention can be used in combination with
modulators of the other heterodimeric partner with RXR (i.e., in
combination with PPAR.alpha. modulators, such as fibrates, in the
treatment of cardiovascular disease, and in combination with
PPAR.gamma. modulators, such thiazolidinediones, in the treatment
of diabetes, including non-insulin dependent diabetes mellitus and
insulin dependent diabetes mellitus, and with agents used to treat
obesity) and with other therapies, including, without limitation,
chemotherapeutic agents such as cytostatic and cytotoxic agents,
immunological modifiers such as interferons, interleukins, growth
hormones and other cytokines, hormone therapies, surgery and
radiation therapy. By utilizing the compounds of the present
invention with modulators of the other heterodimeric partner one is
able to utilize lower dosages of either or both modulators, thereby
leading to a significant decrease is the side-effects associated
with such modulators when employed alone at the strengths required
to achieve the desired effect. Thus, the modulator compounds of the
present invention, when utilized in combination therapies, provide
an enhanced therapeutic index (i.e., signficantly enhanced efficacy
and/or decrease side-effect profiles) over utilization of the
compounds by themselves.
[0093] Representative modulator compounds of the present invention
include, without limitation,
4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-te-
tramethyl-2-naphthyl)carbonyl] benzoic acid (Compound 101);
4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethenyl]-
benzoic acid (Compound 102);
4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tet-
ramethyl-2-naphthyl)cyclopropyl] benzoic acid (Compound 103);
4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl-
]benzoic acid oxime (Compound 104),
4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetr-
ahydro-2-naphthyl)carbonyl]benzoic acid O-benzyloxime (Compound
105);
4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic
acid O-hexyloxime (Compound 106);
4-[(3-ethoxy-5,6,7,8-tetrahydro-5,5,8,8-
-tetramethyl-2-naphthyl)ethenyl]benzoic acid (Compound 107),
4-[(3-ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]b-
enzoic acid O-methyloxime (Compound 108);
4-[(3-propoxy-5,6,7,8-tetrahydro-
-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime
(Compound 109),
4-[(3-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)car-
bonyl]benzoic acid O-methyloxime (Compound 110),
4-[(3-butyloxy-5,6,7,8-te-
trahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid
(Compound 111);
4-[(3-butyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)et-
henyl]benzoic acid (Compound 112),
4-[(3-butyloxy-5,6,7,8-tetrahydro-5,5,8-
,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid O-methyloxime
(Compound 113);
4-[(3-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ca-
rbonyl]benzoic acid oxime (Compound 114);
4-[(3-heptyloxy-5,6,7,8-tetrahyd-
ro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime
(Compound 115);
4-[(3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)e-
thenyl]benzoic acid (Compound 116);
cis-4-[(3-benzyloxy-5,6,7,8-tetrahydro-
-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime
(Compound 117);
trans-4-[(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naph-
thyl)carbonyl]benzoic acid oxime (Compound 118); (2E, 4E,
6E)-7-[3-butyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]--
3-methylocta-2,4,6-trienoic acid (Compound 119); (2Z, 4E,
6E)-7-[3-(butyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl-
]-3-methylocta-2,4,6-trienoic acid (Compound 120); (2E, 4E,
6E)-7-[3-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalen-2-yl-
]-3-methylocta-2,4,6-trienoic acid (Compound 121); (2E, 4E,
6Z)-7-[3-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalen-2-yl-
]-3-methylocta-2,4,6-trienoic acid (Compound 122); (2Z, 4E,
6E)-7-(3-ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl)-
-3-methylocta-2,4,6-trienoic acid (Compound 123); (2E, 4E,
6Z)-7-[3-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-y-
l]-3-methylocta-2,4,6-trienoic acid (Compound 124); (2E, 4E,
6E)-7-[3-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-y-
l]-3-methylocta-2,4,6-trienoic acid (Compound 125); (2E, 4E,
6E)-7-[3-(3-methylbut-2-enyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 126);
(2E, 4E,
6E)-7-[3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthale-
n-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 127); (2E, 4E,
6Z)-7-[3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2--
yl]-3-methylocta-2,4,6-trienoic acid (Compound 128); (2E, 4E,
6E)-7-[3-(4-methylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-nap-
hthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 129); (2E,
4E,
6Z)-7-[3-(4-methylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-nap-
hthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 130);
4-(3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-anthracen-1-ylmethyl)-benzoi-
c acid (Compound 131);
4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3H-cyclop-
enta[b]naphthalen-1-ylmethyl)-benzoic acid (Compound 132);
4-(6,7,8,9-tetrahydro-6,6,9,9-tetramethyl-2H-benzo[g]chromen-4-ylmethyl)--
benzoic acid (Compound 133);
4-(3,4,6,7,8,9-hexahydro-2-oxo-6,6,9,9-tetram-
ethyl-2H-benzo[g]quinolin-1-ylmethyl)-benzoic acid (Compound 134);
4-(3,4,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-2H-benzo[g]quinolin-1-ylmeth-
yl)-benzoic acid (Compound 135),
4-(2,3,6,7,8,9-hexahydro-6,6,9,9-tetramet-
hyl-naphtho[2,3-b][1,4]oxazin-4-ylmethyl)-benzoic acid (Compound
136);
4-(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracene-1-carbonyl-
)-benzoic acid (Compound 137);
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl--
anthracen-1-yl)-hydroxymethyl]-benzoic acid (Compound 138),
4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracen-1-ylmethyl)-benzoic
acid (Compound 139),
4-[1-hydroxy-1-(5,6,7,8-tetrahydro-5,5,8,8-tetrameth-
yl-anthracen-1-yl)-ethyl)-benzoic acid (Compound 140);
4-[1-methoxy-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracen-1-yl)-et-
hyl)-benzoic acid (Compound 141);
4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetrame-
thyl-anthracen-1-yl)-vinyl)-benzoic acid (Compound 142);
(trans)4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracene
1-carbonyl oxime)-benzoic acid (Compound 143),
(cis)-4-(5,6,7,8-tetrahydro-5,5,8,8-t-
etramethyl-anthracene-1-carbonyl oxime)-benzoic acid (Compound
144);
(trans)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracene-1-carbonyl
O-methyloxime)-benzoic acid (Compound 145); (2E, 4E,
6E)-7-(3,5-diisopropyl-2-n-heptyloxyphenyl)-3-methylocta-2,4,6-trienoic
acid (Compound 146); (2E, 4E,
6Z)-7-(3,5-diisopropyl-2-n-heptyloxyphenyl)-
-3-methylocta-2,4,6-trienoic acid (Compound 147); (2E,
4E,)-7-(3,5-diisopropyl-2-n-heptyloxyphenyl)-3-methylocta-2,4-dienoic
acid (Compound 148); (2Z,
4E,)-7-(3,5-diisopropyl-2-n-heptyloxyphenyl)-3--
methylocta-2,4,dienoic acid (Compound 149); (2E, 4E,
6E)-7-(3,5-diisopropyl-2-benzyloxyphenyl)-3-methylocta-2,4,6-trienoic
acid (Compound 150); (2E, 4E,
6E)-7-(3,5-diisopropyl-2-n-butyloxyphenyl)--
3-methylocta-2,4,6-trienoic acid (Compound 151); (2E,
4E)-6-[2-(5,5,8,8-Tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2--
yl)cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 152); (2E,
4E)-6-[2-(5,5,8,8-Tetramethyl-3-heptyloxy-5,6,7,8-tetrahydronaphthalen-2--
yl)cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 153); (2E,
4E)-6-[2-(5,5,8,8-Tetramethyl-3-benzyloxy-5,6,7,8-tetrahydronaphthalen-2--
yl)cyclopropan-1-yl]-3-methyl hexadienoic acid (Compound 154); (2E,
4E)-7-[(5,5,8,8-Tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphtha-len-2-y-
l)cyclopropan-1-yl]-3-methyl heptadienoic acid (Compound 155); (2E,
4E)-7-[(5,5,8,8-Tetramethyl-3-heptyloxy-5,6,7,8-tetrahydronaphtha-len-2-y-
l)cyclopropan-1-yl]-3-methyl heptadienoic acid (Compound 156); (2E,
4E)-7-[(5,5,8,8-Tetramethyl-3-benzyloxy-5,6,7,8-tetrahydronaphtha-len-2-y-
l)cyclopropan-1-yl]-3-methyl heptadienoic acid (Compound 157); (2E,
4E)-5-[2-(5,5,8,8-Tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2--
yl)cyclopent-1-en-1-yl]-3-methyl pentadienoic acid (Compound 158);
cis (2E,
4E)-5-[2-(5,5,8,8-Tetramethyl-3-propyloxy-5,6,7,8-tetrahydro-2-napht-
hyl)cyclopentan-1-yl]-3-methyl pentadienoic acid (Compound 159);
4-[(3-(4-t-Butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napht-
hyl)carbonyl]benzoic acid oxime (Compound 160);
4-[(3-(4-Bromobenzyloxy)-5-
,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic
acid oxime (Compound 161),
cis-4-[(3-Benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetr-
amethyl-2-naphthyl)carbonyl]benzoic acid O-methyloxime (Compound
162),
trans-4-[(3-Benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)c-
arbonyl]benzoic acid O-methyloxime (Compound 163);
4-[2-(3-Benzyloxy-5,6,7-
,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-[1,3]dioxolan-2-yl]benzoic
acid (Compound 164);
4-[2-Methyl-1-(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,-
8-tetramethyl-2-naphthyl)propenyl]benzoic acid (Compound 165); (2E,
4E,
6E)-7-[3-(4-tert-butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound
166); (2E, 4E,
6Z)-7-[3-(4-tert-butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetrameth-
yl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound
167); (2E, 4E,
6E)-7-[3-isobutyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-na-
phthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 168);
(2E, 4E,
6Z)-7-[3-isobutyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen--
2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 169); (2E, 4E,
6E)-7-[3-pentyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2--
yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 170), (2E, 4E,
6Z)-7-[3-pentyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2--
yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 171); (2E, 4E,
6E)-7-[3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-4--
yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 172); (2E, 4E,
6Z)-7-[3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2--
yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 173); (2E, 4E,
6E)-7-[3-(4-methoxybenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-na-
phthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid. (Compound 174)
and (2E,
4E)-7-[3-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl-
]-3-methyl-octa-2,4-dienoic acid. (Compound 175).
[0094] The compounds of the present invention can be obtained by
modification of the compounds disclosed or by a total synthesis
approach, by techniques known to those skilled in the art. In this
regard, the synthesis of the dimer-specific RXR modulator compounds
of the present invention follow established retinoid synthesis
schemes and techniques as described in M. I. Dawson and W. H.
Okamura, "Chemistry and Biology of Synthetic Retinoids", Chapters
3, 8, 14 and 16, CRC Press, Inc., Florida (1990); M. I. Dawson and
P. D. Hobbs, The Synthetic Chemistry of Retinoids, In Chapter 2:
"The Retinoids, Biology, Chemistry and Medicine", M. B. Sporn et
al., Eds. (2nd ed.), Raven Press, New York, N.Y., pp. 5-178 (1994);
R. S. H. Liu and A. E. Asato, "Photochemistry and Synthesis of
Stereoisomers of Vitamin A," 40 Tetrahedron, 1931 (1984), 43 Cancer
Res., 5268 (1983); 15 Eur. J. Med. Chem., 9 (1980); M. Boehm et
al., 37 J. Med. Chem., 2930 (1994); M. Boehm et al., 38 J. Med.
Chem., 3146 (1995); E. Allegretto et al., 270 Journal of Biol.
Chem., 23906 (1995); R. Bissonette et al., 15 Mol. & Cellular
Bio., 5576 (1995), R. Beard et al., 38 J. Med. Chem., 2820 (1995),
S. Canan Koch et al., 39 J. Med. Chem., 3229 (1996) and U.S. Pat.
Nos. 4,326,055 and 4,578,498, the disclosures of which are herein
incorporated by reference. The sequence of steps of the general
schemes of synthesizing the compounds of the present invention are
shown below. In addition, more detailed and illustrative synthetic
schemes for specific compounds of the present invention will be
found in the Examples included herein. 11
[0095] In Scheme 1, the compound 3, a common precursor to the
compounds of the present invention, 5-12, may be prepared by
Friedel-Crafts acylation of an appropriately substituted
tetrahydrotetramethylnaphthalene 1 with an acid chloride 2, such as
monomethyl teraphthalate acid chloride, under Lewis acid (such as
aluminum trichloride) and/or protic acid (such as H.sub.2SO.sub.4)
catalyzed conditions in solvents such as dichloromethane or
dichloroethane. In cases such that the naphthalene has a hydroxy
functionality, an O-alkylation of the naphthol may be achieved by
treatment with a base, such as NaH or K.sub.2CO.sub.3, and an alkyl
halide to provide the keto ether 4. The acid 5 is readily
obtainable from the corresponding ester by hydrolysis in an alkanol
solvent at ambient temperature with about a three molar excess of
base, for example, potassium hydroxide. Alternatively, the ester 4
may be hydrolyzed in THF/water or acetone/water at ambient
temperature with, for example, excess lithium hydroxide. The
hydrolysis solution is acidified and the hydrolysate recovered by
conventional means to provide the keto acid 5. 12
[0096] In accordance with reaction Scheme 2, treatment of the
ketone 3 with a phosphonium ylide, such as methyl
triphenylphosphonium bromide-sodium amide in solvents such as THF
or ether at room temperature or at elevated temperatures affords
the ethenyl compound 6 where R.sub.38 is OCH.sub.3. Hydrolysis to
afford the olefin acid is conducted in the same fashion as
described in Scheme 1 above. The cyclopropyl derivatives such as 7
can be prepared in a Simmons-Smith reaction as shown in Scheme 2 by
treatment of the ethenyl compound 6 (R38.dbd.OCH.sub.3) with
CH.sub.2ClI, Et.sub.2Zr, and CuCl in solvents such as
dichloromethane at reflux temperature, followed by the same
standard hydrolysis processes as employed in the preparation
process of Scheme 1. 13
[0097] In accordance with reaction Scheme 3, the ketone 3 may also
be treated with hydroxylamine hydrochloride in ethanol and pyridine
and heated at reflux to afford, after standard hydrolysis, the
oxime acid 8. Other O-substituted oximes may also be prepared as
shown in Scheme 3. These compounds are synthesized from the
corresponding free oxime 8 by treatment of the oxime with a base,
such as sodium hydride, in solvents such as THF or ether or DMF at
ambient temperature, followed by alkylation with the appropriate
alkylhalide (R--Br or R--I), and standard hydrolysis by the same
processes as employed in the preparation process of Scheme 1 to
provide the O-alkylated oxime 9. 14
[0098] Similar to the reaction process of reaction Scheme 3, the
ketone 3 may be condensed with methoxylamine hydrochloride in
ethanol and pyridine and heated at reflux to afford, after standard
hydrolysis by the same processes as employed in the preparation
process of Scheme 1, the O-methyl oxime acid 10. 15
[0099] In accordance with reaction Scheme 5, ketal and dithioketal
derivatives such as compound 11 can be obtained by condensation of
the ketone 3 with ethylene glycol, 1,3-propanediol or
1,3-propanedithiol in solvents such as benzene and acid catalysis
with acids such as p-toluenesulfonic acid, followed by standard
hydrolysis by the same processes as employed in the preparation
process of Scheme 1, to afford the ketal or dithioketal 11. 16
[0100] In accordance with reaction Scheme 6, other substituted
olefin derivatives such as compound 12 may be derived by Grignard
addition of alkyl magnesium halides, such as isopropyl magnesium
bromide, with ketone 3, followed by dehydration with acid
catalysis, such as p-toluenesulfonic acid or sulfuric acid, and
standard hydrolysis by the same processes as employed in the
preparation process of Scheme 1 to afford the olefin analogues 12.
1718
[0101] The bicyclic derivatives of the present invention, that is
compounds of general structures 19, may be prepared in accordance
with reaction Scheme 7. The starting materials for this sequence,
substituted tetrahydrotetramethylnaphthalenes of general structure
1, may be prepared by Friedel-Crafts alkylation/cyclization of an
appropriately substituted benzene with a dichloroalkane 13, such as
2,5-dimethyl-2,5-dichlorohexane- , under Lewis acid catalyzed
conditions in solvents such as dichloromethane or dichloroethane.
Treatment of 1 with an acid chloride, such as acetyl chloride, and
a Lewis acid, such as aluminum trichloride, provides the acylated
naphthalene 14. In cases such that the naphthalene has a hydroxy
functionality, an O-alkylation of the naphthol may be achieved by
treatment with a base, such as KOH, and an alkyl halide to provide
the keto ether 14 (where R.sub.47.dbd.OR.sub.50). Further, in
accordance with this sequence of reactions aryl ketones of general
structure 14 are condensed with a phosphonate, such as the sodium
or lithium salt of diethyl cyanomethylphosphonate, in THF at
ambient or reduced temperatures in a Horner-Wadsworth-Emmons
olefination reaction to provide cyano olefin 15. The cyano olefin
15 is reduced with DIBAL at -78.degree. C. to provide the
intermediate enals 16 and 17. The solvent to be used in the
reduction includes methylene chloride, hexanes, and THF. The trans
and cis isomers 16 and 17 may be separated at this stage via
thin-layer chromatography (TLC), or other recognized procedures
known to those skilled in the art. These separated aldehydes 16 and
17 are then treated with a phosphonate, such as the lithium salt of
diethyl 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (mixture of
double bond isomers), in THF at reduced temperatures in a
Horner-Wadsworth-Emmons olefination reaction to provide the
trienoate esters 18 where R.sub.38 is OEt. The olefination reaction
is preferably conducted in the presence of
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU). The
acids and salts 19 are readily obtainable from the corresponding
esters by hydrolysis in an alkanol solvent at ambient temperature
with about a three molar excess of base, for example, potassium
hydroxide. Alternatively, the ethyl esters may be hydrolyzed in
THF/water or acetone/water at ambient temperature with, for
example, excess lithium hydroxide. The hydrolysis solution is
acidified and the hydrolysate recovered by conventional means to
give as the major product the (2E, 4E, 6E)-bicyclic triene
carboxylic acid derivatives of structure 19 where R.sub.38 is OH.
The minor (2E, 4E, 6Z)-bicyclic triene and (2Z, 4E, 6E)-bicyclic
triene geometric isomers, by-products of the olefination reaction,
are readily isolated by silica gel chromatography or HPLC
purification of the hydrolysate mixture. 19
[0102] An alternative means for making the (2E, 4E, 6Z)-bicyclic
triene derivatives of general structure 23 is in accordance with
reaction Scheme 8 The aryl ketone 14 is treated with phosphorous
oxychloride in solvents such as DMF and the intermediate chloroenal
is treated with a strong base, such as sodium hydroxide, to provide
the aryl alkyne 20. The aryl alkyne is then treated with a suitable
nitrile source, such as PhOCN, in the presence of a base, such as
ethylmagnesium bromide, to give alkyne nitrile 21, which is then
subjected to reductive methylation to provide as the major product
the cis isomer, nitrile 22. Nitrile 22 is then reduced to the
corresponding aldehyde 17 and homologated in the same fashion as
described in Scheme 7 to yield the (2E, 4E, 6Z)-bicyclic triene 23.
20
[0103] The tricyclic derivatives of the present invention, that is
compounds of general structure 29, may be prepared in accordance
with reaction Scheme 9. The starting materials for this sequence,
ketones of general structure 24, may be prepared from the
appropriately substituted octahydroanthracene by oxidation with
chromium trioxide in acetic acid at ambient temperature or with
chromium trioxide in methylene chloride/pyridine at 0.degree. C.
The tricyclic ketones are reduced with sodium borohydride in
methanol at low temperature and the resultant benzylic alcohols are
reacted with triphenylphosphine hydrobromide in methanol at
elevated temperature to provide phosphonium salts of general
structure 25. Compounds of general structure 27 may be prepared
from the lithium salt of the phosphonium bromide of general
structure 25 and aldehyde of general structure 26 by a
Horner-Wadsworth-Emmons olefination reaction in THF at reduced
temperatures. The olefination reaction is preferably conducted in
the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2-
(1M)-pyrimidinone (DMPU). The exocyclic olefin product 27 may be
isomerized to the endocyclic olefin analogue of general structure
28 by treatment with methanolic HCl at elevated temperatures. The
acids and salts 29 are readily obtainable from the corresponding
esters by hydrolysis in an alkanol solvent at ambient temperature
with about a three molar excess of base, for example, potassium
hydroxide. Alternatively, the ethyl esters may be hydrolyzed in
THF/water or acetone/water at ambient temperature with, for
example, excess lithium hydroxide. The hydrolysis solution is
acidified and the hydrolysate recovered by conventional means to
give the tricyclic carboxylic acid derivatives of structure 29.
21
[0104] The tricyclic derivatives of general structure 35 can be
prepared in accordance with reaction Scheme 10. The tricyclic
amides 31 can be prepared from quinolone of general structure 30
and 2,5-dichloro-2,5-dialkylhexanes of general structure 13 by
aluminum trichloride catalyzed Friedel-Crafts
alkylation/cyclization in dichloromethane at ambient temperature.
Amides of general structure 31 can be reduced with agents such as
LAH or DIBAL in solvents such as THF or methylene chloride at
25.degree. C. to provide the corresponding amines 32. The amines of
general structure 32 are deprotonated with NaH at reduced
temperatures in THF and alkylated at ambient temperature with alkyl
or benzylhalides, such as methyl bromomethylbenzoate 33, to give
substituted amines of general structure 34. The acids and salts
derived from general structure 34 are readily obtainable from the
corresponding esters by the same processes as those employed in the
preparation process of Scheme 9 to give the acid analogues 35.
22
[0105] The tricyclic derivatives of general structure 37 and 38 can
be prepared in accordance with reaction Scheme 11. The tricyclic
ketone 24 (from Scheme 9) can be condensed with
p-toluenesulfonhydrazide in alcoholic solvents, such as ethanol or
methanol, with catalysis by acids such as hydrochloric acid or
sulfuric acid at elevated temperatures to provide the hydrazones of
general structure 36. The hydrazones can undergo a Shapiro-type
reaction in the presence of two equivalents of a strong base, such
as n-butyl lithium, in solvents such as THF or ether at reduced
temperatures, and the vinyl anion thus generated can be reacted
with carbonyl compounds, such as 4-formyl benzoates 26, to provide
the anthracenyl-hydroxymethyl benzoic acid derivatives of general
structure 37. The hydroxy functionality in compound 37 can be
oxidized by agents such as manganese dioxide in dichloromethane to
provide the keto derivatives of general structure 38. The acids and
salts 37 and 38 are readily obtainable from the corresponding
esters by hydrolysis in an alkanol solvent at ambient temperature
with about a three molar excess of base, for example, potassium
hydroxide. Alternatively, the ethyl esters may be hydrolyzed in
THF/water or acetone/water at ambient temperature with, for
example, excess lithium hydroxide. The hydrolysis solution is
acidified and the hydrolysate recovered by conventional means to
give as the major product the tricyclic-carbonyl benzoic acid
derivatives of general structure 37 and 38 where R.sub.38 is OH.
23
[0106] Additional tricyclic derivatives of general structure 39 can
be prepared in accordance with reaction Scheme 12. The
tricyclic-carbonyl derivatives 38 (from Scheme 11) can be reduced
to the hydroxy functionalized derivatives of general structue 37
with agents such as sodium borohydride in alcoholic solvents such
as methanol, and further reduced to the methylene derivatives of
general structure 39 with agents such as triethylsilane and boron
triflouride-etherate in dichloromethane at reduced temperatures.
The acids and salts 39 are readily obtainable from the
corresponding esters by the same processes as those employed in the
preparation process of Scheme 9 to give the acid analogues of
general structure 39 where R.sub.38 is OH. 24
[0107] Other substituted tricyclic derivatives of general
structures 40-42 can be prepared in accordance with reaction Scheme
13. Addition of trimethylaluminum to the keto compound 38 and
treatment of the intermediate tertiary alcohol 40 with acids such
as hydrochloric acid in solvents such as methanol or ethanol at
elevated tempertures provides the alkoxy substituted and
methylene-linked tricyclic derivatives of general structures 41 and
42. The acids and salts are readily obtainable from the
corresponding esters by hydrolysis following the standard
conditions outlined in Scheme 9 to give the acid analogues where
R.sub.38 is OH. 25
[0108] The keto tricylic derivatives of general structue 38 may
also be treated with hydroxylamine hydrochloride or alkoxyamines in
alcoholic solvents, such as ethanol, with pyridine and heated at
reflux to afford the oxime acids of general structure 43 in
accordance with reaction Scheme 14. Other O-substituted oximes may
also be synthesized from the corresponding free oxime 43 (where
R.sub.19 is H) by treatment of the oxime with a base, such as
sodium hydride, in solvents such as THF or ether or DMF at ambient
temperature, followed by alkylation with the appropriate
alkylhalide or arylalkylhalide (R--Br or R--I). The acids and salts
are readily obtainable from the corresponding esters by hydrolysis
following the standard conditions provided in Scheme 9 to give the
acid analogues where R.sub.38 is OH. 2627
[0109] The aromatic trienes of the present invention, that is
compounds of general structures 50 and 51, may be prepared in
accordance with reaction Scheme 15. The starting materials for this
sequence, substituted benzoic acids of general structure 44, may be
treated with alkyl lithiums, such as methyllithium, at low
temperatures in solvents such as THF or ether to produce alkyl aryl
ketones of general structure 45. In cases where the aryl group
contains a hydroxy functionality, the phenol may be alkylated by
treatment with a base, such as KOH, and an alkyl or benzyl halide
in a solvent such as DMSO to provide the keto ether 46. Further, in
accordance with this sequence of reactions aryl ketones of general
structure 46 are condensed with a phosphonate, such as the sodium
or lithium salt of diethyl cyanomethylphosphonate, in THF at
ambient or reduced temperatures in a Horner-Wadsworth-Emmons
olefination reaction to provide cyano olefin 47. The cyano olefin
47 is reduced with DIBAL at -78.degree. C. to provide the
intermediate enal 48. The solvent to be used in the reduction
includes methylene chloride, hexanes, and THF. The trans and cis
isomers may be separated at this stage via thin-layer
chromatography (TLC), or other recognized procedures known to those
skilled in the art. The aldehyde intermediate is then treated with
a phosphonate, such as the lithium salt of diethyl
3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (mixture of double
bond isomers) in THF at reduced temperatures in a
Horner-Wadsworth-Emmons olefination reaction to provide the
trienoate esters 49 where R.sub.38 is OR.sub.39. The olefination
reaction is preferably conducted in the presence of
1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H)-pyrimidinone (DMPU). The
acids and salts 50 and 51 are readily obtainable from the
corresponding esters by hydrolysis in an alkanol solvent at ambient
temperature with about a three molar excess of base, for example,
potassium hydroxide. Alternatively, the ethyl esters may be
hydrolyzed in THF/water or acetone/water at ambient temperature
with, for example, excess lithium hydroxide. The hydrolysis
solution is acidified and the hydrolysate recovered by conventional
means to give as the major product the (2E, 4E, 6E)-aromatic triene
carboxylic acid derivatives of structure 50. The minor (2E, 4E,
6Z)-aromatic triene geometric isomer, 51, a by-product of the first
olefination reaction, is readily isolated by silica gel
chromatography or HPLC purification of the hydrolysate mixture.
2829
[0110] In accordance with reaction Scheme 16, reduction of the
intermediate cyano olefin 47 under an atmosphere of hydrogen gas
and in the presence of a catalyst, such as 10% palladium on carbon,
provides the saturated nitrile 52. The nitrile can be reduced in
the same fashion as described in reaction Scheme 15 to yield the
saturated aldehyde intermediate 53. The aldehyde 53 is then
homologated in the same fashion as described in Scheme 15 to yield
as the major product the (2E, 4E)-aromatic diene of general
structure 55 and as the minor geometric isomer, the (2Z,
4E)-aromatic diene of general structure 56. 3031
[0111] The bicyclic derivatives of the present invention, that is
compounds of general structures 66, may be prepared in accordance
with Scheme 17. The starting materials for this sequence,
substituted tetrahydrotetramethylnaphthalenes of general structure
58, may be prepared by Friedel-Crafts alkylation/cyclization of an
appropriately substituted benzene with a dichloroalkane 13, such as
2,5-dimethyl-2,5-dichlorohexane, under Lewis acid catalyzed
conditions in solvents such as dichloromethane or dichloroethane.
Treatment of 58 with potassium carbonate and an alkyl halide, such
as iodopropane, in refluxing acetone provides the ether 59.
Halogen-metal exchange of the bromonaphthol 59 with a base, such as
n-BuLi, followed by treatment with trimethyl borate and
acidification with aqueous 10% hydrochloric acid provides the
boronic acid precursor 60. The dienoic acid side chain precursor
was introduced by the Suzuki coupling of boronic acid 60 with
2-bromo-1-propene in the presence of tetrakis triphenylphosphine
palladium (0) and a base, such as sodium carbonate, in toluene at
100.degree. C. to provide compound 61. Allylic oxidation with
catalytic selenium dioxide and t-butyl hydroperoxide in
dichloromethane at room temperature, known as the Sharpless
conditions, provides allylic alcohol 62. Cyclopropanation of
allylic alcohol 62 with reagents such as diethyl zinc and
chloroiodomethane in dichloroethane provides the cyclopropane
compound 63. Oxidation of alcohol 63 with a reagent such as PCC in
dichloromethane, provides aldehyde 64. This aldehyde 64 can be
treated with a phosphonate, such as the lithium salt of diethyl
3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (mixture of double
bond isomers) in THF at reduced temperatures in a
Horner-Wadsworth-Emmons olefination reaction to provide the
dienoate esters 65 where R.sub.38 is OEt. The olefination reaction
is preferably conducted in the presence of
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU). The
acids and salts 66 are readily obtainable from the corresponding
esters by hydrolysis in an alkanol solvent at ambient temperature
with about a three molar excess of base, for example, potassium
hydroxide. Alternatively, the ethyl esters may be hydrolyzed in
THF/water or acetone/water at ambient temperature with, for
example, excess lithium hydroxide. The hydrolysis solution is
acidified and the hydrolysate recovered by conventional means to
give as the major product the (2E, 4E)-bicyclic diene carboxylic
acid derivatives of structure 66 where R.sub.38 is OH. The minor
(2E, 4Z)-bicyclic diene and (2Z, 4E)-bicyclic diene geometric
isomers, by-products of the olefination reaction, are readily
isolated by silica gel chromatography or HPLC purification of the
hydrolysate mixture. 32
[0112] The bicyclic derivatives of the present invention, that is
compounds of general structures 71, may be prepared in accordance
with Scheme 18. The dienoic acid side chain of 71 was introduced by
the Suzuki coupling of boronic acid 60 with 3-bromo-3-buten-1-ol in
the presence of tetrakis triphenylphosphine palladium (0) and a
base such as sodium carbonate in toluene at 100.degree. C. to
provide compound 67. Cyclopropanation of homoallylic alcohol 67
with reagents such as diethyl zinc and chloroiodomethane in
dichloroethane provides the cyclopropane compound 68. Oxidation of
alcohol 68 with reagent such as PCC in dichloromethane, provides
aldehyde 69. The aldehyde 69 can be treated with a phosphonate,
such as the lithium salt of diethyl
3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (mixture of double
bond isomers) in THF at reduced temperatures in
Horner-Wadsworth-Emmons olefination reaction to provide the
dienoate esters 70 where R.sub.38 is OEt. The olefination reaction
is preferably conducted in the presence of
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU). The
acids and salts 71 are readily obtainable from the corresponding
esters by hydrolysis in an alkanol solvent at ambient temperature
with about a three molar excess of base, for example, potassium
hydroxide. Alternatively, the ethyl esters may be hydrolyzed in
THF/water or acetone/water at ambient temperature with, for
example, excess lithium hydroxide. The hydrolysis solution is
acidified and the hydrolysate recovered by conventional means to
give as the major product the (2E, 4E)-bicyclic diene carboxylic
acid derivatives of structure 71 where R.sub.38 is OH. The minor
(2Z, 4E)-bicyclic diene geometric isomer, by-product of the
olefination reaction, is readily isolated by silica gel
chromatography or HPLC purification of the hydrolysate mixture.
33
[0113] The bicyclic derivatives of the present invention, that is
compounds of general structures 75, may be prepared in accordance
with Scheme 19. The side chain of 75 was introduced by the Suzuki
coupling of boronic acid 60 with 1,2-dibromocyclopentene in the
presence of tetrakis triphenylphosphine palladium (0) and a base
such as sodium carbonate in toluene at 100.degree. C. to provide
compound 72. Halogen-metal exchange with a base such as t-BuLi in
ether at -78.degree. C. followed by a treatment with dimethyl
formamide (DMF), provides aldehyde 73. The aldehyde 73 can be
treated with a phosphonate, such as the lithium salt of diethyl
3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (mixture of double
bond isomers) in THF at reduced temperatures in a
Horner-Wadsworth-Emmons olefination reaction to provide the
dienoate esters 74 where R.sub.38 is OEt. The olefination reaction
is preferably conducted in the presence of
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi- dinone (DMPU). The
acids and salts 75 are readily obtainable from the corresponding
esters by hydrolysis in an alkanol solvent at ambient temperature
with about a three molar excess of base, for example, potassium
hydroxide. Alternatively, the ethyl esters may be hydrolyzed in
THF/water or acetone/water at ambient temperature with, for
example, excess lithium hydroxide. The hydrolysis solution is
acidified and the hydrolysate recovered by conventional means to
give as the major product the (2E, 4E)-bicyclic diene carboxylic
acid derivatives of structure 75 where R.sub.38 is OH. The minor
(2Z, 4E)-bicyclic diene geometric isomer, by-product of the
olefination reaction, is readily isolated by silica gel
chromatography or HPLC purification of the hydrolysate mixture.
34
[0114] The bicyclic derivatives of the present invention, that is
compounds of general structures 78, may be prepared in accordance
with Scheme 20. The .alpha.,.beta.-unsaturated aldehyde 73 was
hydrogenated under an atmosphere of hydrogen with palladium on
charcoal in ethyl acetate to provide aldehyde 76. The aldehyde 76
can be treated with a phosphonate, such as the lithium salt of
diethyl 3-ethoxycarbonyl-2-methy- lprop-2-enylphosphonate (mixture
of double bond isomers) in THF at reduced temperatures in a
Horner-Wadsworth-Emmons olefination reaction to provide the
dienoate esters 77 where R.sub.38 is OEt. The olefination reaction
is preferably conducted in the presence of
1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H)-pyrimidinone (DMPU). The
acids and salts 78 are readily obtainable from the corresponding
esters by hydrolysis in an alkanol solvent at ambient temperature
with about a three molar excess of base, for example, potassium
hydroxide. Alternatively, the ethyl esters may be hydrolyzed in
THF/water or acetone/water at ambient temperature with, for
example, excess lithium hydroxide. The hydrolysis solution is
acidified and the hydrolysate recovered by conventional means to
give as the major product the (2E, 4E)-bicyclic diene carboxylic
acid derivatives of structure 78 where R.sub.38 is OH. The minor
(2Z, 4E)-bicyclic diene geometric isomer, by-product of the
olefination reaction, is readily isolated by silica gel
chromatography or HPLC purification of the hydrolysate mixture.
[0115] It will be understood by those skilled in the art that
certain modifications can be made to the above-described methods
that remain within the scope of the present invention. For example,
the modulator compounds of the present invention may also be
produced in the form of the corresponding amides or esters, or
pharmaceutically acceptable salts.
[0116] In another aspect, the dimer-selective RXR modulator
compounds of the present invention are combined in a mixture with a
pharmaceutically acceptable carrier to provide pharmaceutical
compositions useful for treating the biological conditions or
disorders noted herein in mammalian, and more preferably, in human
patients. The particular carrier employed in these pharmaceutical
compositions may take a wide variety of forms depending upon the
type of administration desired, e.g., intravenous, oral, topical,
suppository, parenteral or in a liposomal formulation.
[0117] In preparing the compositions in oral liquid dosage forms
(e.g., suspensions, elixirs and solutions), typical pharmaceutical
media, such as water, glycols, oils, alcohols, flavoring agents,
preservatives, coloring agents and the like can be employed.
Similarly, when preparing oral solid dosage forms (e.g., powders,
tablets and capsules), carriers such as starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and
the like will be employed. Due to their ease of administration,
tablets and capsules represent the most advantageous oral dosage
form for the pharmaceutical compositions of the present
invention.
[0118] For parenteral administration, the carrier will typically
comprise sterile water, although other ingredients that aid in
solubility or serve as preservatives, may also be included.
Furthermore, injectable suspensions may also be prepared, in which
case appropriate liquid carriers, suspending agents and the like
will be employed.
[0119] For topical administration, the compounds of the present
invention may be formulated using bland, moisturizing bases, such
as ointments or creams. Examples of suitable ointment bases are
petrolatum, petrolatum plus volatile silicones, lanolin, and water
in oil emulsions such as Eucerin.TM. (Beiersdorf). Examples of
suitable cream bases are Nivea.TM. Cream (Beiersdorf), cold cream
(USP), Purpose Cream.TM. (Johnson & Johnson), hydrophilic
ointment (USP), and Lubriderm.TM. (Warner-Lambert).
[0120] The pharmaceutical compositions and compounds of the present
invention will generally be administered in the form of a dosage
unit (e.g., tablet, capsule, etc.) at from about 1 .mu.g/kg of body
weight to about 500 mg/kg of body weight, more preferably from
about 10 .mu.g/kg to about 250 mg/kg, and most preferably from
about 20 .mu.g/kg to about 100 mg/kg. As recognized by those
skilled in the art, the particular quantity of pharmaceutical
composition according to the present invention administered to a
patient will depend upon a number of factors, including, without
limitation, the biological activity desired, the condition of the
patient, and tolerance for the drug.
[0121] The compounds of this invention also have utility when
labeled, either with a radio or stable isotope label, and used in
assays to determine the presence of RXRs. They are particularly
useful due to their ability to selectively bind to members of the
RXR subfamily and can therefore be used to determine the presence
of RXR isoforms in the presence of other retinoid receptors or
related intracellular receptors.
[0122] Due to the selective specificity of the compounds of this
invention for binding to retinoid X receptors, these compounds can
also be used to purify samples of RXRs in vitro. Such purification
can be carried out by mixing samples containing retinoid receptors
with one of more of the compounds of the present invention, so that
the modulator compound (ligand) binds to the receptor, and then
separating out the bound ligand/receptor combination by separation
techniques which are known to those of skill in the art. These
techniques include column separation, filtration, centrifugation,
tagging and physical separation, and antibody complexing, among
others.
[0123] The compounds of the present invention also include
racemate, individual stereoisomers, including enantiomers and
mixtures thereof. These isomers are then isolated by standard
resolution techniques, including fractional crystallization and
reverse phase and chiral column chromatography.
[0124] The compounds and pharmaceutical compositions of the present
invention can advantageously be used in the treatment of the
diseases and conditions described herein. In this regard, the
dimer-selective modulator compounds and compositions will prove
particularly useful in the modulation of processes controlled by
RXR homodimers and/or RXR heterodimers, such as apolipoprotein
metabolism, either alone, or in combination with PPARs and/or TR
modulators such as gemfibrozil or thyroid hormone, as well as
modulation of skin-related processes, malignant and pre-malignant
conditions and apoptosis, including combinations with RAR and VDR
modulators. Likewise, the compounds and compositions will also
prove useful in the modulation of processes mediated by RXR
homodimers, including selective modulation of programmed cell death
(apoptosis). Further, all of these treatment pathways can be
triggered without activating the RXR agonist homodimer pathway.
[0125] Furthermore, the modulator compounds and pharmaceutical
compositions of the present invention are extremely potent
antagonists of a RXR homodimer, typically displaying 50% inhibition
of activation of one or more of the retinoid X receptors at a
concentration of less than 500 nM, preferably at a concentration of
less than 100 nM, more preferably at a concentration of less than
50 nM, more preferably yet at a concentration of less than 20 nM,
and most preferably at a concentration of less than 10 nM.
Concurrently, the modulator compounds of the present invention are
also extremely potent agonists in the context of a RXR heterodimer,
typically displaying 50% activation of retinoid X receptors
heterodimers at a concentration of less than 500 nM, preferably at
a concentration of less than 100 nM, more preferably at a
concentration of less than 50 nM, more preferably yet at a
concentration of less than 20 nM, and most preferably at a
concentration of less than 10 nM. Also, the dimer-selective RXR
modulator compounds of the present invention preferentially bind to
and inhibit transactivation of one or more of the RXR subfamily of
retinoid receptors at a level at least 2 times greater, preferably
at least 5 times greater, more preferably at least 10 times
greater, and most preferably at least 100 times greater than on the
RAR subfamily of retinoid receptors.
[0126] The invention will be further illustrated by reference to
the following non-limiting Examples.
EXAMPLE 1
[0127]
4-[(3-n-Propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ca-
rbonyl]benzoic Acid (Compound 101, Prepared as Illustrated and
Described in Scheme 1)
[0128] 3-n-Propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene
(prepared from Friedel-Crafts alkylation/cyclization of
n-propylbenzene with 2,5-dichloro-2,5-dimethylhexane) was combined
with monomethylterephthalate acid chloride in dichloromethane and
treated portionwise at ambient temperature with aluminum chloride
until the spontaneous reflux had subsided and the solution became
dark red/brown in color. After stirring at room temperature for
10-15 min, the reaction was poured into ice water and the layers
were separated. The aqueous layer was extracted with EtOAc. The
combined organic extracts were washed with water and brine, dried
(MgSO.sub.4), filtered, and concentrated to give a yellow oil. The
crude product was crystallized (CH.sub.2Cl.sub.2/hexanes) to give
4-[(3-n-propyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-
carbonyl]benzoic acid methyl ester as white crystals (95%): TLC
(20% ethyl acetate: 80% hexanes) R.sub.f 0.7; mp 112-114.degree.
C., .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.19 (1/2ABq, J=8.0
Hz, 2H, ArH), 7.89 (1/2ABq, J=8.0 Hz, 2H, ArH), 7.22 (s, 1H, ArH),
7.20 (s, 1H, ArH), 3.95 (s, 3H, OCH.sub.3), 2.64 (t, J=8.0 Hz, 2H,
CH.sub.2), 1.69 (s, 4H, 2CH.sub.2), 1.55 (m, 2H, CH.sub.2), 1.31
(s, 6H, 2CH.sub.3), 1.20 (s, 6H, 2CH.sub.3), 0.89 (t, J=7.5 Hz, 3H,
CH.sub.3), Anal. (C.sub.23H.sub.32O.sub.3) C, H. The ester was
hydrolyzed in excess KOH/MeOH at ambient temperature for 24 h. The
methanol was removed in vacuo. The residue was taken-up in water
and the aqueous layer was adjusted to pH=4-5 with 1 M aqueous HCl.
The aqueous solution was extracted 3 times with EtOAc; the organic
layers were combined, and washed with water (2.times.) and brine.
The organic solution was dried (Na.sub.2SO.sub.4), filtered, and
concentrated to give
4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl-
]benzoic acid (101). Crystallization gave a white powder (93%): TLC
(10% MeOH: 90% CHCl.sub.3) R.sub.f 0.3; mp 252-254.degree. C.;
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.20 (1/2ABq, J=8.0 Hz,
2H, ArH), 7.90 (1/2ABq, J=8.0 Hz, 2H, ArH), 7.20 (s, 1H, ArH), 7.25
(s, 1H, ArH), 2.64 (t, J=8.0 Hz, 2H, CH.sub.2), 1.69 (s, 4H,
2CH.sub.2), 1.55 (m, 2H, CH.sub.2), 1.31 (s, 6H, 2CH.sub.3), 1.20
(s, 6H, 2CH.sub.3), 0.89 (t, J=7.5 Hz, 3H, CH.sub.3), Anal
(C.sub.25H.sub.30O.sub.3) C, H.
EXAMPLE 2
[0129]
4-[(3-n-Propyl-5,6,7,8-tetrahydro-5,5,3,8-tetramethyl-2-naphthyl)et-
henyl]benzoic Acid (Compound 102, Prepared as Illustrated and
Described in Scheme 2)
[0130]
4-[(3-n-Propyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)ca-
rbonyl]benzoic acid methyl ester (2.7 mmol) in THF (25 mL) was
treated with methyltriphenylphosphonium bromide/sodium azide (1.2
g, 3.1 mmol) and the solution was allowed to stir at ambient
temperature for 3 h. The reaction was quenched with saturated
aqueous NH.sub.4Cl and diluted with EtOAc. The organic solution was
separated and washed with water and brine, dried (MgSO.sub.4),
filtered, and concentrated to give a yellow oil. The crude product
was crystallized (CH.sub.2Cl.sub.2/hexanes) to give
4-[(3-n-propyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)eth-
enyl]benzoic acid methyl ester as white crystals (78%). TLC (20%
ethyl acetate: 80% hexanes) R.sub.f 0.8; mp 120-121.degree. C.,
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.94 (1/2ABq, J=8.0 Hz,
2H, ArH), 7.33 (1/2ABq, J=8.0 Hz, 2H, ArH), 7.09 (s, 1H, ArH), 7.08
(s, 1H, ArH), 5.80 (s, 1H, olefinic), 5.30 (s, 1H, olefinic), 3.90
(s, 3H, OCH.sub.3), 2.24 (t, J=8.0 Hz, 2H, CH.sub.2), 1.70 (s, 4H,
2CH.sub.2), 1.39 (m, 2H, CH.sub.2), 1.30 (s, 6H, 2CH.sub.3), 1.26
(s, 6H, 2CH.sub.3), 0.73 (t, J=7.5 Hz, 3H, CH.sub.3), Anal.
(C.sub.27H.sub.34O.sub.2) C, H. The ester was hydrolyzed using the
standard conditions of Example 1 to yield
4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethenyl]-
benzoic acid (102). Crystallization gave white crystals (83%): TLC
(10% MeOH-90% CHCl.sub.3) R.sub.f 0.5; mp 263-265.degree. C.,
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.00 (1/2ABq, J=8.0 Hz,
2H, ArH), 7.36 (1/2ABq, J=8.0 Hz, 2H, ArH), 7.09 (s, 1H, ArH), 7.08
(s, 1H, ArH), 5.81 (s, 1H, olefinic), 5:31 (s, 1H, olefinic), 2.23
(t, J=8.0 Hz, 2H, CH.sub.2), 1.70 (s, 4H, 2CH.sub.2), 1.39 (m, 2H,
CH.sub.2), 1.30 (s, 6H, 2CH.sub.3), 1.26 (s, 6H, 2CH.sub.3), 0.73
(t, J=7.5 Hz, 3H, CH.sub.3), FAB-MS m/z 377 (MH+); Anal.
(C.sub.26H.sub.32O.sub.2) C, H.
EXAMPLE 3
[0131]
4-[(3-n-Propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)cy-
clopropyl]benzoic Acid (Compound 103, Prepared as Illustrated and
Described in Scheme 2)
[0132]
4-[(3-n-Propyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)et-
henyl]benzoic acid methyl ester (0.573 mmol) in dichloromethane (10
mL) under a nitrogen atmosphere at 0.degree. C. was combined with
Et.sub.2Zn (0.29 mL, 2.87 mM). To this solution was added
CH.sub.2ClI (0.8 mmol) dropwise via a syringe and the reaction
mixture was stirred at 0.degree. C. for 10 min. The solution was
then heated at 55.degree. C. for 6 h. The solution was cooled to
ambient temperature, water was added, and the mixture was extracted
with EtOAc. The organic solution was washed with water and brine,
dried (MgSO.sub.4), filtered, and concentrated to give a yellow
oil. The crude product was purified by SiO.sub.2 flash
chromatography to give
4-[(3-n-propyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahy-
dro-2-naphthyl)cyclopropyl]benzoic acid methyl ester (14%) as a
white solid: .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.94
(1/2ABq, J=8.0 Hz, 2H, ArH), 7.33 (1/2ABq, J=8.0 Hz, 2H, ArH), 7.09
(s, 1H, ArH), 7.08 (s, 1H, ArH), 3.90 (s, 3H, OCH.sub.3), 2.24 (t,
J=8.0 Hz, 2H, CH.sub.2), 1.70 (s, 4H, 2CH.sub.2), 1.39 (s, 4H,
2CH.sub.2), 1.35 (m, 2H, CH.sub.2), 1.30 (s, 6H, 2CH.sub.3), 1.26
(s, 6H, 2CH.sub.3), 0.73 (t, J=7.5 Hz, 3H, CH.sub.3). The ester was
hydrolyzed using the standard conditions of Example 1 to yield
4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl--
2-naphthyl)cyclopropyl]benzoic acid (103). Crystallization gave
white crystals (88%): .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
8.00 (1/2ABq, J=8.0 Hz, 2H, ArH). 7.36 (1/2ABq, J=8.0 Hz, 2H, ArH),
7.09 (s, 1H, ArH), 7.08 (s, 1H, ArH), 2.23 (t, J=8.0 Hz, 2H,
CH.sub.2), 1.69 (s, 4H, 2CH.sub.2), 1.39 (s, 4H, 2CH.sub.2), 1.35
(m, 2H, CH.sub.2), 1.30 (s, 6H, 2CH.sub.3), 1.26 (s, 6H,
2CH.sub.3), 0.73 (t, J=7.5 Hz, 3H, CH.sub.3).
EXAMPLE 4
[0133]
4-[(3-n-Propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ca-
rbonyl]benzoic Acid Oxime (Compound 104, Prepared as Illustrated
and Described in Scheme 3)
[0134]
4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ca-
rbonyl]benzoic acid (101) (12.6 mmol) in EtOH (10 mL) and pyridine
(15.3 mL) was treated with hydroxylamine hydrochloride (4.38 g, 63
mmol), and the mixture was heated at reflux. After 6 h, the mixture
was cooled to room temperature and the ethanol was removed in
vacuo. The residue was taken-up in water and the aqueous layer was
adjusted to pH=4-5 with 1 M aqueous HCl. The aqueous solution was
extracted with EtOAc, 3.times.. The organic layers were combined
and washed with water (2.times.) and brine. The organic solution
was dried (NaSO.sub.4), filtered, and concentrated to give a foamy
white solid. Recrystallization (CH.sub.2Cl.sub.2/ether/he- xanes)
gave
4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth-
yl)carbonyl]benzoic acid oxime (104), as white crystals (85%): mp
255-257.degree. C.; .sup.1H-NMR (400 M, CDCl.sub.3) .delta. 8.19
(1/2ABq, J=8.3 Hz, 2H, ArH), 7.89 (1/2ABq, J=8.3 Hz, 2H, ArH), 7.23
(s, 1H, ArH), 7.20 (s, 1H, ArH), 2.65 (m, 2H, CH.sub.2), 1.70 (m,
4H, 2CH.sub.2), 1.56 (m, 2H, CH.sub.2), 1.32 (s, 6H, 2CH.sub.3),
1.20 (s, 6H, 2CH.sub.3), 0.88 (t, J=7.3 Hz, 3H, CH.sub.3).
EXAMPLE 5
[0135]
4-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]be-
nzoic Acid O-benzyloxime (Compound 105, Prepared as Illustrated and
Described in Scheme 3)
[0136]
4-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]be-
nzoic acid (4.41 g, 12.6 mmol) in EtOH (10 mL) and pyridine (15.3
mL) was treated with hydroxylamine hydrochloride (4.38 g, 63 mmol),
and the mixture was heated at reflux. After 6 h, the mixture was
cooled to room temperature and the ethanol was removed in vacuo.
The residue was taken-up in water and the aqueous layer was
adjusted to pH=4-5 with 1 M aqueous HCl. The aqueous solution was
extracted with EtOAc, 3.times.. The organic layers were combined
and washed with water (2.times.) and brine. The organic solution
was dried (NaSO.sub.4), filtered, and concentrated.
Recrystallization (CH.sub.2Cl.sub.2/ether/hexanes) gave
4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic
acid oxime 4.05 g (88%) as a white solid: mp 204-209.degree. C.
(d); .sup.1H NMR (CDCl.sub.3/d-4 MeOH) .delta. 7.99 (1/2ABq, J=8.4
Hz, 2H, ArH), 7.53 (1/2 ABq, J=8.4 Hz, 2H, ArH), 7.20 (s, 1H, ArH),
6.99 (s, 1H, ArH), 2.11 (s, 3H, CH.sub.3), 1.69 (s, 4H, 2CH.sub.2),
1.32 (s, 6H, 2CH.sub.3), 1.22 (s, 6H, 2CH.sub.3); HRMS: 366.2060
(MH.sup.+). A solution of
4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)carbo-
nyl]benzoic acid oxime (100 mg, 0.27 mmol) in THF (0.3 mL) and DMPU
(0.3 mL) was added at 0.degree. C. to a suspension of NaH (20 mg,
0.82 mmol) in THF (1.0 mL). The suspension was allowed to warm to
room temperature with stirring over 30 minutes, then a solution of
benzyl bromide (71 mL, 0.82 mmol) was added. The solution was
allowed to warm to room temperature and stirred for 12 h. Aqueous,
saturated NH.sub.4Cl (5.0 mL) was added and the aqueous layer was
adjusted to pH=4-5 with 1 M aqueous HCl. The aqueous solution was
extracted with EtOAc, 3.times.. The organic layers were combined
and washed with water (2.times.) and brine. The organic solution
was dried (Na.sub.2SO.sub.4), filtered, and concentrated to give a
white solid. Purification by radial chromatography
(10:1=hexanes:EtOAc) gave
4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2--
naphthyl)carbonyl]benzoic acid O-benzyloxime (105) 154 mg (61%) as
a white solid: mp 169-172.degree. C.; IR (neat) 2961 m, 2926 m,
1691 s, 1420 w, 1285 w, 1016 w cm.sup.-1; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.03 (1/2ABq, J=8.5 Hz, 2H, ArH), 7.55 (1/2ABq,
J=8.5 Hz, 2H, ArH), 7.31 (m, 5H, ArH), 7.15 (s, 1H, ArH), 6.96 (s,
1H, ArH), 5.25 (s, 2H, OCH.sub.2), 2.00 (s, 3H, Ar--CH.sub.3), 1.69
(s, 4H, 2CH.sub.2), 1.31 (s, 6H, 2CH.sub.3), 1.22 (s, 6H,
2CH.sub.3); .sup.13C NMR (100.8 MHz, CDCl.sub.3) .delta. 171.7,
156.6, 145.3, 142.2, 141.4, 138.2, 132.5, 130.2, 130.1, 129.4,
128.2, 128.1, 127.9, 127.6, 127.0, 126.2, 35.2, 35.1, 34.1, 33.9,
31.9, 19.4; MS (FAB) m/e 456 (MH.sup.+); HRMS (FAB, MH.sup.+) Calcd
for C.sub.30H.sub.33NO.sub.3: 456.2539 Found: 456.2526.
EXAMPLE 6
[0137]
4-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]be-
nzoic Acid O-hexyloxime (Compound 106, Prepared as Illustrated and
Described in Scheme 3)
[0138]
4-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]be-
nzoic acid methyl ester (5 mmol) in MeOH (10 mL) was treated with
hydroxylamine hydrochloride (2 eq) and pyridine (2.1 eq) and the
mixture was heated at reflux for 5 h. The reaction was worked-up in
a manner identical to that described for Example 5. The ester oxime
was alkylated with 1-bromohexane in a manner similar to that
described in Example 5 to give
4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]ben-
zoic acid O-hexyloxime methyl ester (80%): IR (neat) 2957 s, 2930
s, 2862 m, 1726 s, 1589 w, 1435 w, 1363 w, 1275 s, 1107 m, 1018 m,
864 w cm.sup.-1; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.96
(1/2ABq, J=8.5 Hz, 2H, ArH), 7.53 (1/2ABq, J=8.5 Hz, 2H, ArH), 7.15
(s, 1H, Ar--H), 6.96 (s, 1H, Ar--H), 4.18 (t, J=6.7 Hz, 2H,
OCH.sub.2), 3.97 (s, 3H, OCH.sub.3), 2.04 (s, 3H, Ar--CH.sub.3),
1.68 (m, 6H, 3CH.sub.2), 1.31 (s, 6H, 2CH.sub.3), 1.28 (m, 6H,
3CH.sub.2), 1.21 (s, 6H, 2CH.sub.3), 0.86 (t, J=6.8 Hz, 3H,
CH.sub.3). The ester was hydrolyzed using the standard conditions
of Example 1 to yield, after recrystallization (THF/hexanes)
4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic
acid O-hexyloxime (106) (85%): mp 91-95.degree. C.; .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.03 (1/2ABq, J=8.5 Hz, 2H, ArH),
7.57 (1/2ABq, J=8.5 Hz, 2H, ArH), 7.16 (s, 1H, Ar--H), 6.97 (s, 1H,
Ar--H), 4.20 (t, J=6.7 Hz, 2H, OCH.sub.2), 2.05 (s, 3H,
Ar--CH.sub.3), 1.69 (m, 6H, 3CH.sub.2), 1.31 (s, 6H, 2CH.sub.3),
1.29 (m, 6H, 3CH.sub.2), 1.22 (s, 6H, 2CH.sub.3), 0.86 (t, J=6.8Hz,
3H, CH.sub.3).
EXAMPLE 7
[0139]
4-[(3-Ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethe-
nyl]benzoic Acid (Compound 107, Prepared as Illustrated and
Described in Scheme 1 and Scheme 3)
[0140] A solution of
5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-ol (5.09 g,
25.00mmol; prepared by Friedel-Crafts alkylation/cyclization of
phenol with 2,5-dichloro-2,5-dimethylhexane) and monomethyl
terephthalate acid chloride (5.95 g, 29.9 mmol) in CH.sub.2Cl.sub.2
(10 mL) and hexanes (60 mL) was treated portionwise with aluminum
trichloride (10.0 g, 75 mmol) over 30 minutes at ambient
temperature. After the addition was complete, sulfuric acid
(concentrated, 0.5 mL) was added and the orange solution was heated
at reflux for 1 h. The solution was allowed to cool to ambient
temperature and the reaction was quenched by slowly pouring the
solution into ice/water accompanied by vigorous stirring. The
mixture was stirred for an additional 30 min. The aqueous solution
was extracted with EtOAc, 3.times.. The organic layers were
combined and washed with water (2.times.) and brine. The organic
solution was dried (NaSO.sub.4), filtered, and concentrated to give
a red oil. Purification by silica gel flash chromatography
(20:1=hexanes:EtOAc) gave 4-[(3-hydroxy-5,6,7,8-tetr-
ahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl
ester 3.24 g (35%) as a yellow solid: mp 155-159.degree. C. (d);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.18 (1/2ABq, J=8.3 Hz,
2H, ArH), 7.72 (1/2ABq, J=8.3 Hz, 2H, ArH), 7.43 (s, 1H, ArH), 7.01
(s, 1H, ArH), 3.98 (s, 3H, OCH.sub.3), 1.70 (m, 4H, 2CH.sub.2),
1.31 (s, 6H, 2CH.sub.3), 1.16 (s, 6H, 2CH.sub.3). A solution of the
4-[(3-hydroxy-5,6,7,8-tetrahyd-
ro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl
ester (433 mg, 1.18 mmol) in DMF (2 mL) was treated with NaH (1.5
mmol) at 0.degree. C. and allowed to warm to ambient temperature
over 1 h. The yellow solution was cooled again to 0.degree. C. and
treated with a solution of bromoethane (83 mL, 1.30 mmol) in DMF (1
mL) and allowed to warm to ambient temperature and stirred for 10
h. The reaction was quenched with saturated aqueous NH.sub.4Cl. The
aqueous solution was extracted with EtOAc, 3.times.. The organic
layers were combined and washed with water (2.times.) and brine.
The organic solution was dried (NaSO.sub.4), filtered, and
concentrated to give a colorless oil. Purification by silica gel
flash chromatography (20:1=hexanes:Et.sub.2O) gave
4-[3-ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]be-
nzoic acid methyl ester 436 mg (97%) as a white solid: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.07 (1/2ABq, J=8.4 Hz, 2H, ArH),
7.82 (1/2ABq, J=8.4 Hz, 2H, ArH), 7.43 (s, 1H, ArH), 6.82 (s, 1H,
ArH), 3.95 (s, 3H, OCH3), 3.88 (q, J=6.9 Hz, 2H, OCH.sub.2), 1.70
(m, 4H, 2CH.sub.2), 1.31 (s, 6H, 2CH.sub.3), 1.27 (s, 6H,
2CH.sub.3), 0.98 (t, J=6.9 Hz, 3H, CH.sub.3); HRMS calcd. for
C.sub.25H.sub.30O.sub.4 395.2222 (MH.sup.+), found 395.2219. The
ethoxy keto ester was converted to the ethenyl compound by the
method described in Example 2 to give, after preparative silica gel
TLC (1:1:1=hexanes:EtOAc:CH.sub.2Cl.sub.2+5% MeOH),
4-[(3-ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethenyl]be-
nzoic acid (107) (17%) as a white solid: mp 195-200.degree. C. (d);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.01 (1/2ABq, J=8.3 Hz,
2H, ArH), 7.39 (1/2ABq, J=8.3 Hz, 2H, ArH), 7.19 (s, 1H, ArH), 6.74
(s, 1H, ArH), 5.67 (appp s, 1H, methylene). 5.45 (d, J=0.8 Hz, 1H,
methylene), 3.78 (q, J=6.9 Hz, 2H, OCH.sub.2), 1.70 (m, 4H,
2CH.sub.2), 1.30 (s, 6H, 2CH.sub.3), 1.28 (s, 6H, 2CH.sub.3), 0.91
(t, J=6.9 Hz, 3H, CH.sub.3); HRMS calcd. for
C.sub.25H.sub.30O.sub.3 378.2195 (M.sup.+), found 378.2210.
EXAMPLE 8
[0141]
4-[(3-Ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carb-
onyl]benzoic Acid O-methyloxime (Compound 108, Prepared as
Illustrated and Described in Scheme 4)
[0142] The ethoxy keto ester from Example 7 was hydrolyzed as
described in Example 1 to give
4-[(3-ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-n-
aphthyl)carbonyl]benzoic acid: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.15 (1/2ABq, J=8.3 Hz, 2H, ArH), 7.85 (1/2ABq, J=8.3 Hz,
2H, ArH), 7.46 (s, 1H, ArH), 6.83 (s, 1H, ArH), 3.89 (q, J=6.9 Hz,
2H, OCH.sub.2), 1.70 (m, 4H, 2CH.sub.2), 1.32 (s, 6H, 2CH.sub.3),
1.28 (s, 6H, 2CH.sub.3), 0.98 (t, J=6.9 Hz, 3H, CH.sub.3); HRMS
calcd. for C.sub.24H.sub.28O.sub.4 381.2066 (MH.sup.+), found
381.2098. 4-[(3-Ethoxy-5,6,7,8-tetrahydro-5,5,-
8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid (0.41 mmol) in
EtOH (1 mL) was treated with methoxylamine hydrochloride (52 mg,
0.62 mmol) and pyridine (70 mL, 0.82 mmol), and the mixture was
heated at reflux for 5 h. The reaction was worked-up in a manner
identical to that described for Example 5 to give, after
recrystallization (THF/hexanes)
4-[(3-ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]b-
enzoic acid O-methyloxime (108) (90%) as a colorless film: .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.02 (1/2ABq, J=8.4 Hz, 2H, ArH),
7.59 (1/2ABq, J=8.4 Hz, 2H, ArH), 7.08 (s, 1H, ArH), 6.84 (s, 1H,
ArH), 4.00 (s, 3H, OCH3), 3.90 (q, J=7.0 Hz, 2H, OCH.sub.2), 1.69
(m, 4H, 2CH.sub.2), 1.31 (s, 6H, 2CH.sub.3), 1.23 (s, 6H,
2CH.sub.3), 1.08 (t, J=7.0 Hz, 3H, CH.sub.3).
EXAMPLE 9
[0143]
4-[(3-Propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)car-
bonyl]benzoic Acid Oxime (Compound 109, Prepared as Illustrated and
Described in Scheme 1 and Scheme 3)
[0144] A solution of the
4-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramet-
hyl-2-naphthyl)carbonyl]benzoic acid methyl ester (from Example 7,
433 mg, 1.18 mmol) in DMSO (2 mL) was treated with KOH (1.5 mmol)
at 0.degree. C. and allowed to warm to ambient temperature over 1
h. The yellow solution was cooled again to 0.degree. C., and
treated with a solution of bromopropane (118 mL, 1.30 mmol) in DMSO
(1 mL) and allowed to warm to ambient temperature and stirred for
10 h. The reaction was quenched with saturated aqueous NH.sub.4Cl.
The aqueous solution was adjusted to pH=3 with 1M HCl and extracted
with EtOAc, 3.times.. The organic layers were combined and washed
with water (2.times.) and brine. The organic solution was dried
(NaSO.sub.4), filtered, and concentrated. Purification by silica
gel radial chromatography (20:1=hexanes:Et.sub.2O) gave
4-[2-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]b-
enzoic acid 337 mg (75%) as a colorless oil: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8:15 (1/2ABq, J=8.2 Hz, 2H, ArH), 7.85 (1/2ABq,
J=8.2 Hz, 2H, ArH), 7.46 (s, 1H, ArH), 6.82 (s, 1H, ArH), 3.78 (t,
J=6.3 Hz, 2H, OCH.sub.2), 1.70 (m, 4H, 2CH.sub.2), 1.36 (m, 2H,
CH.sub.2), 1.32 (s, 6H, 2CH.sub.3), 1.28 (s, 6H, 2CH.sub.3), 0.62
(t, J=7.4 Hz, 3H, CH.sub.3). The propoxyketo acid (134 mg, 0.33
mmol) in EtOH (2 mL) was converted to the oxime derivative as
described in Example 4 to provide, after recrystallization
(CH.sub.2Cl.sub.2/hexanes)
4-[(3-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]-
benzoic acid oxime (109) (97%) as a white solid: mp 251-255.degree.
C. (d); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.98 (1/2ABq,
J=8.4 Hz, 2H, ArH), 7.54 (1/2ABq, J=8.4 Hz, 2H, ArH), 7.13 (s, 1H,
ArH), 6.86 (s, 1H, ArH), 3.81 (t, J=6.2 Hz, 2H, OCH.sub.2), 1.70
(m, 4H, 2CH.sub.2), 1.51 (m, 2H, CH.sub.2), 1.32 (s, 6H,
2CH.sub.3), 1.24 (s, 6H, 2CH.sub.3), 0.72 (t, J=7.4 Hz, 3H,
CH.sub.3).
EXAMPLE 10
[0145]
4-[(3-Propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)car-
bonyl]benzoic Acid O-methyloxime (Compound 110, Prepared as
Illustrated and Described in Scheme 1 and Scheme 4)
[0146]
p-[2-Propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carb-
onyl]benzoic acid (from Example 9, 28 mg, 0.07 mmol) was converted
to the O-methyloxime derivative as described in Example 8.
Crystallization (CH.sub.2Cl.sub.2/Et.sub.2O/hexanes) gave
4-[(3-propoxy-5,6,7,8-tetrahydr-
o-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid
O-methyloxime (110) 21 mg (70%) as a white solid: mp
202-204.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.98
(1/2ABq, J=8.4 Hz, 2H, ArH), 7.54 (1/2ABq, J=8.4 Hz, 2H, ArH), 7.13
(s, 1H, ArH), 6.86 (s, 1H, ArH), 4.00 (s, 3H, OCH3), 3.81 (t, J=6.2
Hz, 2H, OCH.sub.2), 1.70 (m, 4H, 2CH.sub.2), 1.51 (m, 2H,
CH.sub.2), 1.32 (s, 6H, 2CH.sub.3), 1.24 (s, 6H, 2CH.sub.3), 0.72
(t, J=7.4 Hz, 3H, CH.sub.3).
EXAMPLE 11
[0147]
4-[(3-Butyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ca-
rbonyl]benzoic Acid (Compound 111, Prepared as Illustrated and
Described in Scheme 1)
[0148] A solution of the
4-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramet-
hyl-2-naphthyl)carbonyl]benzoic acid methyl ester (433 mg, 1.18
mmol) in DMF (2 mL) was treated with NaH (1.5 mmol) at 0.degree. C.
and allowed to warm to ambient temperature over 1 h. The yellow
solution was cooled again to 0.degree. C., and treated with a
solution of bromobutane (119 mL, 1.30 mmol) in DMF (1 mL) and
allowed to warm to ambient temperature and stirred for 10 h. The
reaction was quenched with saturated aqueous NH.sub.4Cl. The
aqueous solution was extracted with EtOAc, 3.times.. The organic
layers were combined and washed with water (2.times.) and brine.
The organic solution was dried (NaSO.sub.4), filtered, and
concentrated to give a colorless oil. Purification by silica gel
flash chromatography (20:1=hexanes:Et.sub.2O) gave
4-[3-butyloxy-5,6,7,8-tetrahydro-5,5,8,8-te-
tramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester 275 mg
(55%) as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.07 (1/2ABq, J=8.2 Hz, 2H, ArH), 7.81 (1/2ABq, J=8.2 Hz, 2H, ArH),
7.44 (s, 1H, ArH), 6.82 (s, 1H, ArH), 3.95 (s, 3H, OCH3), 3.81 (t,
J=6.2 Hz, 2H, OCH.sub.2), 1.70 (m, 4H, 2CH.sub.2), 1.34 (m, 2H,
CH.sub.2), 1.32 (s, 6H, 2CH.sub.3), 1.27 (s, 6H, 2CH.sub.3), 1.02
(m, 2H, CH.sub.2), 0.71 (t, J=7.2 Hz, 3H, CH.sub.3); HRMS calcd.
for C.sub.27H.sub.34O.sub.4 423.2535 (MH.sup.+), found 423.2505.
The butyloxy keto ester (150 mg, 0.36 mmol) was hydrolyzed with
excess KOH in MeOH as described in Example 1 to give
4-[(3-butyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl-
]benzoic acid (111) 82 mg (59%) as a white solid: mp
207-210.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.14
(1/2ABq, J=8.2 Hz, 2H, ArH), 7.84 (1/2ABq, J=8.2 Hz, 2H, ArH), 7.46
(s, 1H, ArH), 6.82 (s, 1H, ArH), 3.81 (t, J=6.2 Hz, 2H, OCH.sub.2),
1.71 (m, 4H, 2CH.sub.2), 1.32 (s, 6H, 2CH.sub.3); 1.29 (m, 2H,
CH.sub.2), 1.28 (s, 6H, 2CH.sub.3), 1.00 (m, 2H, CH.sub.2), 0.72
(t, J=7.3 Hz, 3H, CH.sub.3); HRMS calcd. for
C.sub.26H.sub.32O.sub.4 408.2301 (M.sup.+), found 408.2300.
EXAMPLE 12
[0149]
4-[(3-Butyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)et-
henyl]benzoic Acid (Compound 112, Prepared as Illustrated and
Described in Scheme 1 and Scheme 2)
[0150]
4-[3-Butyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)car-
bonyl]benzoic acid methyl ester (from Example 11, 119 mg, 0.28
mmol) was converted to the ethenyl compound as described in Example
2 to afford, after recrystallization (CH.sub.2Cl.sub.2/hexanes)
4-[(3-butyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethenyl]-
benzoic acid methyl ester 43 mg (38%) as a pale yellow solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.94 (1/2ABq, J=8.4 Hz,
2H, ArH), 7.35 (1/2ABq, J=8.4 Hz, 2H, ArH), 7.18 (s, 1H, ArH), 6.72
(s, 1H, ArH), 5.64 (d, J=1.3 Hz, 1H, olefinic), 5.41 (d, J=1.3 Hz,
1H, olefinic), 3.90 (s, 3H, OCH3), 3.71 (t, J=6.2 Hz, 2H,
OCH.sub.2), 1.69 (m, 4H, 2CH.sub.2), 1.30 (s, 6H, 2CH.sub.3), 1.29
(m, 2H, CH.sub.2), 1.27 (s, 6H, 2CH.sub.3), 0.99 (m, 2H, CH.sub.2),
0.71 (t, J=7.3 Hz, 3H, CH.sub.3). The butyloxy ethenyl ester (43
mg, 0.10 mmol) was hydrolyzed with excess KOH in MeOH as described
in Example 1 to give 4-[(3-butyloxy-5,6,7,8-tetrahydro-5,5,8-
,8-tetramethyl-2-naphthyl)ethenyl]benzoic acid (112) 32 mg (79%) as
a white solid: mp 194-196.degree. C., .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.01 (1/2ABq, J=8.4 Hz, 2H, ArH), 7.39 (1/2ABq,
J=8.4 Hz, 2H, ArH), 7.20 (s, 1H, ArH), 6.73 (s, 1H, ArH), 5.66 (d,
J=1.1 Hz, 1H, olefinic), 5.44 (d, J=1.1 Hz, 1H, olefinic), 3.72 (t,
J=6.2 Hz, 2H, OCH.sub.2), 1.70 (m, 4H, 2CH.sub.2), 1.30 (s, 6H,
2CH.sub.3), 1.28 (s, 6H, 2CH.sub.3), 1.27 (m, 2H, CH.sub.2), 0.97
(m, 2H, CH.sub.2), 0.72 (t, J=7.4 Hz, 3H, CH.sub.3); HRMS
(EI.sup.-, 70 ev) calcd. for C.sub.27H.sub.34O.sub.3: 406.2508,
found 406.2467.
EXAMPLE 13
[0151]
4-[(3-Butyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ca-
rbonyl]benzoic Acid O-methyloxime (Compound 113, Prepared as
Illustrated and Described in Scheme 1 and Scheme 4)
[0152]
4-[(3-butyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ca-
rbonyl]benzoic acid (from Example 11) was converted to the
O-methyloxime derivative as described in Example 8. Crystallization
(hexanes/EtOAc) gave
4-[(3-butyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)car-
bonyl]benzoic acid O-methyloxime (113) 14 mg (100%) as a colorless
film: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.06 and 7.55 (d of
ABq, J=8.4 Hz, 4H, Ar--H), 7.40 (s, 1H, Ar--H), 6.98 (s, 1H,
Ar--H), 3.99 (s, 3H, NOCH.sub.3), 3.67 (t, J=6.1 Hz, 2H,
OCH.sub.2), 1.68 (s, 4H, 2CH.sub.2), 1.31 (s, 6H, 2CH.sub.3), 1.25
(s, 6H, 2CH.sub.3), 1.24 (m, 2H, CH.sub.2), 1.01 (m, 2H, CH.sub.2),
0.90 (t, J=7.3 Hz, 3H, CH.sub.3).
EXAMPLE 14
[0153]
4-[(3-Hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ca-
rbonyl]benzoic Acid Oxime (Compound 114, Prepared as Illustrated
and Described in Scheme 1 and Scheme 3)
[0154] A solution of the
4-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramet-
hyl-2-naphthyl)carbonyl]benzoic acid methyl ester (from Example 7,
433 mg, 1.18 mmol) in DMSO (2 mL) was treated with KOH (1.5 mmol)
at 0.degree. C. and allowed to warm to ambient temperature over 1
h. The yellow solution was cooled again to 0.degree. C. and treated
with a solution of bromohexane (156 mL, 1.30 mmol) in DMSO (1 mL)
and allowed to warm to ambient temperature and stirred for 10 h.
The reaction was quenched with saturated aqueous NH.sub.4Cl. The
aqueous solution was adjusted to pH=3 with 1M HCl and extracted
with EtOAc, 3.times.. The organic layers were combined and washed
with water (2.times.) and brine. The organic solution was dried
(NaSO.sub.4), filtered, and concentrated. Purification by silica
gel radial chromatography (20:1=hexanes:Et.sub.2O) gave
4-[2-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]-
benzoic acid, 317 mg (62%) as a colorless oil: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.14 (1/2ABq, J=8.4 Hz, 2H, ArH), 7.84
(1/2ABq, J=8.4 Hz, 2H, ArH), 7.47 (s, 1H, ArH), 6.81 (s, 1H, ArH),
3.80 (t, J=6.2 Hz, 2H, OCH.sub.2), 1.71 (m, 4H, 2CH.sub.2), 1.34
(m, 2H, CH.sub.2), 1.32 (s, 6H, 2CH.sub.3), 1.28 (s, 6H,
2CH.sub.3), 1.11 (m, 4H, 2CH.sub.2), 0.95 (m, 2H, CH.sub.2), 0.80
(t, J=7.1 Hz, 3H, CH.sub.3). The hexyloxyketo acid (87 mg, 0.19
mmol) in EtOH (2 mL) was converted into the oxime derivative as
described in Example 4 to provide, after recrystallization
(CH.sub.2Cl.sub.2/hexanes),
4-[(3hexloxy-5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-2-naphthyl)carbonyl]benzoic acid oxime (114), 312 mg (60%)
as a white solid: mp 197-199.degree. C. (d); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.14 (1/2ABq, J=8.5 Hz, 2H, ArH), 7.57 (1/2ABq,
J=8.5 Hz, 2H, ArH), 7.22 (s, 1H, ArH), 6.85 (s, 1H, ArH), 3.82 (t,
J=6.3 Hz, 2H, OCH.sub.2), 1.70 (m, 4H, 2CH.sub.2), 1.45 (m, 2H,
CH.sub.2), 1.32 (s, 6H, 2CH.sub.3), 1.25 (s, 6H, 2CH.sub.3), 1.13
(m, 6H, 3CH.sub.2), 0.80 (t, J=6.8 Hz, 3H, CH.sub.3); 13C NMR (100
MHz, CDCl.sub.3) .delta. 155.7, 153.8, 147.8, 141.1, 137.0, 130.3,
129.9, 128.4, 127.0, 118.5, 110.0, 68.3, 35.1, 35.0, 34.8, 33.8,
31.9, 31.8, 31.4, 29.0, 25.4, 22.5, 13.9.
EXAMPLE 15
[0155]
4-[(3-Heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)c-
arbonyl]benzoic Acid Oxime (Compound 115, Prepared as Illustrated
and Described in Scheme 1 and Scheme 3)
[0156] A solution of the
4-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramet-
hyl-2-naphthyl)carbonyl]benzoic acid methyl ester (from Example 7,
433 mg, 1.18 mmol) in DMSO (2 mL) was treated with KOH (1.5 mmol)
at 0.degree. C. and allowed to warm to ambient temperature over 1
h. The yellow solution was cooled again to 0.degree. C., and
treated with a solution of bromoheptane (174 mL, 1.30 mmol) in DMSO
(1 mL) and allowed to warm to ambient temperature and stirred for
10 h. The reaction was quenched with saturated aqueous NH.sub.4Cl.
The aqueous solution was adjusted to pH=3 with 1M HCl and extracted
with EtOAc, 3.times.. The organic layers were combined and washed
with water (2.times.) and brine. The organic solution was dried
(NaSO.sub.4), filtered, and concentrated. Purification by silica
gel radial chromatography (20:1 to 1:1=hexanes:Et.sub.2O) gave
4-[(3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbony-
l]benzoic acid 530 mg (99%) as a colorless solid: mp
154-158.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.14
(1/2ABq, J=8.3 Hz, 2H, ArH), 7.84 (1/2ABq, J=8.3 Hz, 2H, ArH), 7.46
(s, 1H, ArH), 6.81 (s, 1H, ArH), 3.80 (t, J=6.2 Hz, 2H, OCH.sub.2),
1.71 (m, 4H, 2CH.sub.2), 1.35 (m, 2H, CH.sub.2), 1.32 (s, 6H,
2CH.sub.3), 1.28 (s, 6H, 2CH.sub.3) 1.19 (m, 2H, CH.sub.2), 1.08
(m, 4H, 2CH.sub.2), 0.94 (m, 2H, CH.sub.2), 0.83 (t, J=7.2 Hz, 3H,
CH.sub.3); HRMS calcd. for C.sub.29H.sub.38O.sub.4 451.2848
(MH.sup.+), found 451.2818. The heptyloxykketo acid (30 mg, 0.07
mmol) in EtOH (1 mL) was converted into the oxime derivative as
described in Example 4 to provide, after recrystallization
(CH.sub.2Cl.sub.2/hexane- s),
4-[(3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carb-
onyl]benzoic acid oxime (115), 15 mg (46%) as a white solid: mp
200-205.degree. C., .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.97
(1/2ABq, J=7.7 Hz, 2H, ArH), 7.54 (1/2ABq, J=7.7 Hz, 2H, ArH), 7.16
(s, 1H, ArH), 6.87 (s, 1H, ArH), 3.83 (t, J=6.4 Hz, 2H, OCH.sub.2),
1.71 (m, 4H, 2CH.sub.2), 1.45 (m, 2H, CH.sub.2), 1.32 (s, 6H,
2CH.sub.3), 1.26 (s, 6H, 2CH.sub.3), 1.20 (m, 2H, CH.sub.2), 1.11
(m, 4H, 2CH.sub.2), 0.89 (m, 2H, CH.sub.2), 0.84 (t, J=7.0 Hz, 3H,
CH.sub.3); HRMS calcd. for C.sub.29H.sub.39NO.sub.4 466.2957
(MH.sup.+), found 466.2930.
EXAMPLE 16
[0157]
4-[(3-Heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)e-
thenyl]benzoic Acid (Compound 116, Prepared as Illustrated and
Described in Scheme 1 and Scheme 2)
[0158]
4-[3-Heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ca-
rbonyl]benzoic acid (from Example 15, 150 mg, 0.32 mmol) was
converted to the ethenyl compound as described in Example 2 to
afford, after preparative silica gel TLC
(1:1:1=hexanes:EtOAc:CH.sub.2Cl.sub.2+5% MeOH),
4-[(3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-
ethenyl]benzoic acid (116), 45 mg (31%) as a white solid: mp
153-155.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.01
(1/2ABq, J=8.3 Hz, 2H, ArH), 7.39 (1/2ABq, J=8.3 Hz, 2H, ArH), 7.20
(s, 1H, ArH), 6.72 (s, 1H, ArH), 5.67 (appparent s, 1H, olefinic),
5.43 (appparent s, 1H, olefinic), 3.71 (t, J=6.2 Hz, 2H,
OCH.sub.2), 1.70 (m, 4H, 2CH.sub.2), 1.32 (m, 2H, CH.sub.2), 1.30
(s, 6H, 2CH.sub.3), 1.28 (s, 6H, 2CH.sub.3), 1.22 (m, 2H,
CH.sub.2), 1.10 (m, 4H, 2CH.sub.2), 0.93 (m, 2H, CH.sub.2), 0.84
(t, J=7.2 Hz, 3H, CH.sub.3); HRMS calcd. for
C.sub.30H.sub.40O.sub.3 448.2978 (M.sup.+), found 448.2948.
EXAMPLE 17
[0159]
cis-4-[(3-Benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth-
yl)carbonyl]benzoic Acid Oxime (Compound 117, Prepared as
Illustrated and Described in Scheme 1 and Scheme 3)
[0160] A solution of the
4-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramet-
hyl-2-naphthyl)carbonyl]benzoic acid methyl ester (237 mg, 0.65
mmol) in DMF (1 mL) was treated with NaH (0.68 mmol) at 0.degree.
C. and allowed to warm to ambient temperature over 1 h. The yellow
solution was cooled again to 0.degree. C., and treated with a
solution of benzyl bromide (142 mg, 0.83 mmol) in DMF and allowed
to warm to ambient temperature and stirred for 10 h. The reaction
was quenched with saturated aqueous NH.sub.4Cl. The aqueous
solution was extracted with EtOAc, 3.times.. The organic layers
were combined and washed with water (2.times.) and brine. The
organic solution was dried (NaSO.sub.4), filtered, and concentrated
to give a colorless oil. Purification by silica gel flash
chromatography (20:1=hexanes:EtOAc) gave
4-[3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-2-naphthyl)carbonyl]benzoic acid methyl ester 242 mg (82%)
as a colorless oil: .sup.1H NM (400 MHz, CDCl.sub.3) .delta. 8.19
(1/2ABq, J=8.4 Hz, 2H, ArH), 7.81 (1/2ABq, J=8.4 Hz, 2H, ArH), 7.44
(s, 1H, ArH), 7.38 (m, 3H, ArH), 7.17 (m, 2H, ArH), 6.92 (s, 1H,
ArH), 4.93 (s, 2H, OCH.sub.2), 3.95 (s, 3H, OCH.sub.3), 1.67 (m,
4H, 2CH.sub.2), 1.29 (s, 6H, 2CH.sub.3), 1.26 (s, 6H, 2CH.sub.3).
The benzyloxy keto ester (204 mg, 0.46 mmol) in MeOH (2 mL) was
treated with hydroxylamine hydrochloride (97 mg, 1.4 mmol) and KOH
(156 mg, 2.8 mmol), and the mixture was heated at reflux for 3 h.
After 6 h, the mixture was cooled to room temperature and the
ethanol was removed in vacuo. The residue was taken-up in water and
the aqueous layer was adjusted to pH=4-5 with 1 M aqueous HCl. The
aqueous solution was extracted with EtOAc, 3.times.. The organic
layers were combined and washed with water (2.times.) and brine.
The organic solution was dried (Na.sub.2SO.sub.4), filtered, and
concentrated to give a white foamy solid. Recrystallization
(THF/hexanes) gave
cis-4-[(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthy-
l)carbonyl]benzoic acid oxime (117) 186 mg (88%) as awhite solid:
mp 199-205.degree. C. (d); IR (neat) 3500-3100 (br) m, 2963 s, 2934
s, 1694 s, 1613 w, 1505 w, 1321 m, 1265 m, 1024 w cm.sup.-1;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.00 (1/2ABq, J=8.4 Hz,
2H, ArH), 7.56 (1/2ABq, J=8.4 Hz, 2H, ArH), 7.20 (m, 3H, ArH), 7.15
(s, 1H, ArH), 7.08 (m, 2H, ArH), 6.91 (s, 1H, ArH), 4.96 (s, 2H,
OCH.sub.2), 1.69 (m, 4H, 2CH.sub.2), 1.27 (s, 6H, 2CH.sub.3), 1.24
(s, 6H, 2CH.sub.3); HRMS (EI.sup.-, 70 ev) calcd. for
C.sub.29H.sub.31NO.sub.4: 457.2253, found 457.2226, anal. calcd.
for C.sub.29H.sub.31NO.sub.4: C.sub.1 76.12; H.sub.1 6.83; N.sub.1
3.06, found C.sub.1 75.83; H.sub.1 6.95; N.sub.1 2.90.
EXAMPLE 18
[0161]
trans-4-[(3-Benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naph-
thyl)carbonyl]benzoic Acid Oxime (Compound 118, Prepared as
Illustrated and Described in Scheme 1 and Scheme 3).
[0162] The minor oxime isomer from the final product mixture of
Example 17 was isolated by successive recrystallizations
(CH.sub.2Cl.sub.2/hexanes) to give
trans-4-[(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-na-
phthyl)carbonyl]benzoic acid oxime (118) 21 mg (10%) as a white
solid: mp 220-222.degree. C. (d); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.99 (1/2ABq, J=8.2 Hz, 2H, ArH), 7.56 (1/2ABq, J=8.2 Hz,
2H, ArH), 7.38 (s, 1H, ArH), 7.21 (m, 3H, ArH), 6.85 (m, 2H, ArH),
6.78 (s, 1H, ArH), 4.77 (s, 2H, OCH.sub.2), 1.69 (m, 4H,
2CH.sub.2), 1.30 (s, 6H, 2CH.sub.3), 1.25 (s, 6H, 2CH.sub.3).
EXAMPLE 19
[0163] (2E, 4E,
6E)-7-[3-Butyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-na-
phthalen-2-yl]-3-methylocta-2,4,6-trienoic Acid (Compound 119,
Prepared as Illustrated and Described in Scheme 7)
[0164] A 200 mL round-bottomed flask equipped with stir bar and
reflux condenser was charged with a solution of n-butylbenzene
(14.7 g, 109 mmol, 17 mL) and 2,4-dichloro-2,4-dimethylhexane (10.0
g, 54.6 mmol) in dichloromethane (30 mL). Aluminum chloride (1.45
g, 10.9 mmol) was added slowly to the solution until the
spontaneous reflux had subsided and the solution became dark
red/brown in color. After stirring 10-15 min at room temperature,
the reaction was poured into ice water (30 mL) and the layers were
separated. The aqueous layer was extracted with EtOAc (5.times.20
mL). The combined organic extracts were washed with water and
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated to give
a yellow oil. Excess n-butylbenzene was removed by distillation at
1 mm Hg. The distillation residue corresponded to the product
6-butyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene 9.4 g
(70%) as an opaque oil: .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
7.21 (d, J=8.6 Hz, 1H, Ar--H), 7.00 (d, J=2.0 Hz, 1H, Ar--H), 6.95
(dd, J=2.0, 8.6 Hz, 1H, Ar--H), 2.56 (t, 2H, CH.sub.2), 1.67 (s,
4H, 2CH.sub.2), 1.55 (m, 2H, CH.sub.2), 1.35 (m, 2H, CH.sub.2),
1.26 (s, 6H, 2CH.sub.3), 1.25 (s, 6H, 2CH.sub.3), 0.93 (t, 3H,
CH.sub.3).
[0165] A solution of the n-butyltetrahydronaphthalene adduct (2.09
g, 8.55 mmol) and acetylchloride (0.79 g, 9.40 mmol, 0.67 mL) in
dichloromethane (10 mL) and hexanes (10 mL) was treated at room
temperature with aluminum chloride (1.14 g, 8.55 mmol). The
reaction solution was stirred at room temperature for 24 h and then
poured into ice water (20 mL), and the layers were separated. The
aqueous layer was extracted with EtOAc (3.times.20 mL) and the
combined organic extracts were washed with water and brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give the acylated
product 1-(3-butyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnap-
hthalen-2-yl)ethanone 2.46 g (100%) as an oil: .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 7.57 (s, 1H, Ar--H), 7.15 (s, 1H, Ar--H),
2.80 (t, 2H, CH.sub.2), 2.56 (s, 3H, CH.sub.3), 1.69 (s, 4H,
2CH.sub.2), 1.55 (m 2H, CH.sub.2), 1.35 (m, 2H, CH.sub.2), 1.26 (s,
6H, 2CH.sub.3), 1.25 (s, 6H, 2CH.sub.3), 0.93 (t, 3H,
CH.sub.3).
[0166] A flame-dried 50 mL round-bottomed flask equipped with
N.sub.2 bubbler, septa, and stir bar was charged with a 60%
dispersion of NaH in mineral oil (0.515 g, 12.9 mmol). The NaH was
rinsed free of mineral oil with hexanes (3.times.2 mL). THF (13 mL)
was added, followed by the dropwise addition of diethyl
cyanomethylphosphonate (3.04 g, 17.2 mmol, 2.82 mL) in THF (8 mL)
at room temperature and the solution was stirred for 30 min. The
acyl(N-butyl)naphthalene (2.46 g, 8.59 mmol) in THF (10 mL) was
added dropwise via cannula to the yellow solution. The solution was
stirred for 48 h and then concentrated. The residue was diluted
with water (25 mL), and the mixture was extracted with EtOAc
(3.times.20 mL). The combined organic extracts were washed with
water and brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated to give a dark brown/red oil which was purified by
radial chromatography (9:1=hexanes:Et.sub.2O) to give the product
3-(3-butyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaph-
thalen-2-yl)but-2-enenitrile 1.14 g (43%) as a yellow oil:
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.12 (s, 1H, Ar--H), 6.92
(s, 1H, Ar--H), 5.23 (s, 1H, CH), 2.49 (t, 2H, CH.sub.2), 2.37 (s,
3H, CH.sub.3), 1.67 (s, 4H, 2CH.sub.2), 1.53 (m, 2H, CH.sub.2),
1.35 (m, 2H, CH.sub.2), 1.27 (s, 6H, 2CH.sub.3), 1.25 (s, 6H,
2CH.sub.3), 0.93 (t, 3H, CH.sub.3).
[0167] A round-bottomed flask equipped with N.sub.2 bubbler, septa,
and stir bar was charged with a solution of the
cyano(n-butyl)naphthalene adduct (1.10 g, 3.71 mmol) in hexanes (5
mL) and toluene (5 mL). The solution was cooled to -78.degree. C.
and DIBAL (3.71 mL of a 1.0 M solution in toluene, 5.60 mmol) was
added dropwise via syringe. After stirring for 1.5 h at -78.degree.
C., the solution was quenched with aqueous sodium-potassium
tartrate solution (10 mL) and allowed to warm to room temperature
over 30 min. The aqueous layer was acidified (1.0 M HCl to pH=4)
and extracted with EtOAc (3.times.10 mL). The combined organic
extracts were washed with water and brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give the crude
aldehyde. Purification by radial chromatography
(5:1:0.5=hexanes:Et.sub.2O:CH.sub.2Cl.sub.2) gave the aldehyde
3-(3-butyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-- 2-yl)
but-2-enal 0.911 g (82%) as a yellow solid as a mixture of
trans:cis (5:1)isomers: 1H-NMR (trans isomer, CDCl.sub.3) .delta.
10.23 (d, 1H, CHO), 7.13 (s, 1H, Ar--H), 6.96 (s, 1H, Ar--H), 5.98
(d, 1H, olefinic), 2.55 (t, 2H, CH.sub.2), 2.50 (s, 3H, CH.sub.3),
1.67 (s, 4H, 2CH.sub.2), 1.53 (m, 2H, CH.sub.2), 1.35 (m, 2H,
CH.sub.2), 1.27 (s, 6H, 2CH.sub.3), 1.25 (s, 6H, 2CH.sub.3), 0.93
(t, 3H, CH.sub.3).
[0168] A flame-dried round-bottomed flask equipped with N.sub.2
bubbler, septa, and stir bar was charged with a solution of diethyl
3-ethoxycarbonyl-2-methyl prop-2-enylphosphonate (0.417 g, 1.58
mmol, 0.39 mL) in THF (2.0 mL) and DMPU (0.7 mL). The solution was
cooled to -78.degree. C., and n-BuLi (0.96 mL of a 1.5 M solution
in hexanes, 1.44 mmol) was added dropwise via syringe. The reaction
mixture was warmed to 0.degree. C. and stirred for 15 min. The red
solution was then cooled to -78.degree. C. and the above aldehyde
(0.430 g, 1.31 mmol) was added dropwise via cannula. The solution
was warmed to ambient temperature and gradually became a dark
brown-reddish color. After stirring for 1.5 h, the reaction was
quenched with water (15 mL), and the aqueous layer was extracted
with EtOAc (3.times.10 mL). The combined organic extracts were
washed with aqueous CuSO.sub.4, water, and brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give the crude
ester as an orange oil. The crude ester in MeOH (7 mL) was
hydrolyzed with KOH (excess) at reflux temperature. After 4 h, the
reaction was cooled to room temperature and quenched with 1M HCl (5
mL). The solution was concentrated, diluted with water (10 mL), and
the aqueous layer was extracted with EtOAc (3.times.15 mL). The
combined organic extracts were washed with water and brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give the crude
product as a mixture of geometric isomers (0.533 g, 94%) as a
yellow oil. .sup.1H-NNR indicated a 3:1 mixture of the trans to cis
isomers. A sample of the product mixture was purified by radial
chromatography (3:1:0.01=hexanes:Et.sub.2O MeOH) followed by
preparative silica gel TLC (1% MeOH/CHCl.sub.3) to give (2E, 4E,
6E)-7-[3-(butyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl-
]-3-methylocta-2,4,6-trienoic acid (119) as a yellow solid:
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.10 (s, 1H, Ar--H), 7.02
(dd, J=11.2, 15.2 Hz, 1H, olefinic), 6.97 (s, 1H, Ar--H), 6.28 (d,
J=15.2 Hz, 1H, olefinic), 6.10 (d, J=11.2 Hz, 1H, olefinic), 5.82
(s, 1H, olefinic), 2.52 (t, J=7.9 Hz, 2H, CH.sub.2), 2.40 (s, 3H,
CH.sub.3), 2.17 (s, 3H, CH.sub.3), 1.67 (s, 4H, 2CH.sub.2), 1.52
(m, 2H, CH.sub.2), 1.34 (m, 2H, CH.sub.2), 1.28 (s, 6H, 2CH.sub.3),
1.26 (s, 6H, 2CH.sub.3), 0.91 (t, J=7.3 Hz, 3H, CH.sub.3).
EXAMPLE 20
[0169] (2Z, 4E,
6E)-7-[3-(Butyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2--
naphthalen-2-yl]-3-methylocta-2,4,6-trienoic Acid (Compound 120,
Prepared as Illustrated and Described in Scheme 7)
[0170] The title compound was obtained from the final product
mixture of Example 19 by radial chromatography
(3:1:0.01=hexanes:Et.sub.9O:MeOH) followed by preparative silica
gel TLC (1% MeOH/CHCl.sub.3) to give (2Z, 4E,
6E)-7-[3-(butyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen--
2-yl]-3-methylocta-2,4,6-trienoic acid (120) as a yellow solid:
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.70 (d, J=15.4 Hz, 1H,
olefinic), 7.08 (s, 1H, Ar--H), 7.00 (dd, J=11.3, 15.4 Hz), 6.96
(s, 1H, Ar--H), 6.18 (d, J=11.3 Hz, 1H, olefinic), 5.30 (s, 1H,
olefinic), 2.52 (t, J=8.0 Hz, 2H, CH.sub.2), 2.16 (s, 3H,
CH.sub.3), 2.13 (s, 3H, CH.sub.3), 1.66 (s, 4H, 2CH.sub.2), 1.52
(m, 2H, CH.sub.2), 1.33 (m, 2H, CH.sub.2), 1.28 (s, 6H, 2CH.sub.3),
1.25 (s, 6H, 2CH.sub.3), 0.90 (t, J=7.3 Hz, 3H, CH.sub.3).
EXAMPLE 21
[0171] (2E, 4E,
6E)-7-[3-Propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2--
naphthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (Compound 121,
Prepared as Illustrated and Described in Scheme 7)
[0172] A 200 mL round-bottomed flask equipped with stir bar was
charged with a solution of phenol (10.2 g, 108 mmol) and
2,4-dichloro-2,4-dimethy- lhexane (21.8 g, 119 mmol) in
dichloromethane (50 mL) at 0.degree. C. Aluminum chloride (1.44 g,
10.8 mmol) was added slowly to the solution until the spontaneous
reflux had subsided and the solution became pale orange in color.
After stirring 10-15 min at 0.degree. C., the reaction was poured
into ice water (30 mL) and the layers were separated. The aqueous
layer was extracted with EtOAc (2.times.30 mL). The combined
organic extracts were washed with water and brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give a pale
yellow/white solid. Recrystallization from hexanes gave the product
5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-ol 18.25 g (83%)
as a white crystalline solid: .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 7.17 (d, J=8.5 Hz 1H, Ar--H), 6.76 (d, J=3.0 Hz, 1H,
Ar--H), 6.62 (dd, J=8.5 Hz, 3.0 Hz, 1H, Ar--H), 4.52 (s, 1H, OH),
1.65 (s, 4H, 2CH.sub.2), 1.26 (s, 6H, 2CH.sub.3), 1.24 (s, 6H,
2CH.sub.3).
[0173] A solution of the tetrahydronaphthol adduct (10.00 g, 49.0
mmol) and acetylchloride (4.62 g, 58.8 mmol, 4.18 mL) in
dichloromethane (30 mL) was treated at room temperature with
aluminum chloride (0.653 g, 4.90 mmol). The heterogenous reaction
solution was stirred at room temperature for 15 min and became
homogenous. Additional aluminum chloride (3.27 g, 25.0 mmol) was
added portionwise and the reaction solution was heated to reflux; a
final aliquot of aluminum chloride (3.27 g, 25.0 mmol) was added
over 1 h until the solution became a dark red/brown. The solution
was then poured into ice water and became yellow/orange. The
aqueous layer was extracted with EtOAc (3.times.20 mL) and the
combined organic extracts were washed with water and brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give the acylated
product
1-(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)ethano-
ne 9.45 g (78%) as a white crystalline solid: .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.66 (s, 1H, Ar--H), 6.89 (s, 1H, Ar--H), 2.61
(s, 3H, CH.sub.3), 1.68 (s, 4H, 2CH.sub.2), 1.29 (s, 6H,
2CH.sub.3), 1.27 (s, 6H, 2CH.sub.3).
[0174] Potassium hydroxide (pellets, 0.036 g, 0.634 mmol) was added
to a solution of the ketotetrahydronaphthol adduct (0.104 g, 0.423
mmol) in DMSO (5 mL) at room temperature. The reaction solution was
stirred for 30 min and became brown. Bromopropane (0.073 g, 0.592
mmol, 0.054 mL) was added dropwise at room temperature. The
solution was stirred for an additional 15 min and became orange.
Water was added and the aqueous layer was extracted with EtOAc
(3.times.20 mL). The combined organic extracts were washed with
water and brine, dried (Na.sub.2SO.sub.4), filtered, and
concentrated to give the crude ether. Crystallization from
EtOAc/hexanes gave
1-(3-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnap-
hthalen-2-yl)ethanone 0.122 g (100%) as a clear crystalline solid:
.sup.1H-NMR: (400 MHz, CDCl.sub.3) .delta. 7.74 (s, 1H, Ar--H),
6.81 (s, 1H, Ar--H), 4.00 (t, J=6.3 Hz, 2H, OCH.sub.2), 2.62 (s,
3H, CH.sub.3); 1.86 (m, 2H, CH.sub.2), 1.67 (s, 4H, 2CH.sub.2),
1.29 (s, 6H, 2CH.sub.3), 1.26 (s, 6H, 2CH.sub.3), 1.08 (t, J=7.5
Hz, 3H, CH.sub.3).
[0175] The above propoxyketone (0.120 g, 0.416 mmol) and diethyl
cyanomethylphosphonate (0.258 g, 1.46 mmol, 0.236 mL) were
condensed as described for Example 19. Aqueous work-up afforded a
dark brown/orange oil which was purified by flash chromatography
(9:1=hexanes:EtOAc) to give the product
3-(3-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naph-
thalen-2-yl)but-2-enenitrile 0.106 g (78%) as a yellow oil:
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.10 (s, 1H, Ar--H), 6.78
(s, 1H, Ar--H), 5.61 (s, 1H, olefinic), 3.92 (t, J=6.4 Hz, 2H,
OCH.sub.2), 2.44 (s, 3H, CH.sub.3), 1.81 (m, 2H, CH.sub.2), 1.67
(s, 4H, 2CH.sub.2), 1.28 (s, 6H, 2CH.sub.3), 1.25 (s, 6H,
2CH.sub.3), 1.04 (t, J=7.4 Hz, 3H, CH.sub.3).
[0176] The cyano(n-propoxyl)naphthalene adduct (0.100 g, 0.307
mmol) was reduced with DIBAL (0.614 mL of a 1.0 M solution in
hexanes, 0.641 mmol) as described for Example 19. Aqueous work-up
followed by radial chromatography (9:1=hexanes:Et.sub.2O) gave the
aldehyde of
3-(3-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)
but-2-enal 0.093 g (92%) as a yellow solid as a mixture of
trans:cis (5:1) isomers: .sup.1H-NMR (trans isomer, 400 MHz,
CDCl.sub.3) .delta. 10.16 (d, 1H CHO), 7.09 (s, 1H, Ar--H), 6.79
(s, 1H, Ar--H), 6.14 (d, J=7.9 Hz, 1H, olefinic), 3.93 (t, J=6.4
Hz, 2H, CH.sub.2), 2.56 (s, 3H, CH.sub.3), 1.81 (m, 2H, CH.sub.2),
1.67 (s, 4H, 2CH.sub.2), 1.29 (s, 6H, 2CH.sub.3), 1.25 (s, 6H,
2CH.sub.3), 1.03 (t, J=7.4 Hz, 3H, CH.sub.3); .sup.1H-NMR (cis
isomer, 400 MHz, CDCl.sub.3) .delta. 9.38 (d, 1H, CHO), 6.98 (s,
1H, Ar--H), 6.79 (s, 1H, Ar--H), 6.08 (d, 1H, olefinic), 3.91 (t,
2H, CH.sub.2), 2.29 (s, 3H, CH.sub.3), 1.81 (m, 2H, CH.sub.2), 1.61
(s, 4H, 2CH.sub.2), 1.24 (s, 6H, 2CH.sub.3), 1.23 (s, 6H,
2CH.sub.3), 1.01 (t, 3H, CH.sub.3).
[0177] The above aldehyde (0.090 g, 0.274 mmol) and diethyl
3-ethoxycarbonyl-2-methyl prop-2-enylphosphonate (0.181 g, 0.685
mmol, 0.168 mL) were condensed as described for Example 19. Aqueous
work-up afforded the ester (0.121 g, 100%) as a yellow oil.
Hydrolysis of the crude ester (0.121 g, 0.282 mmol) and aqueous
work-up gave the acids as a mixture of geometric isomers (1.06 g,
94%) as a yellow solid. Recrystallization from EtOAc/hexanes gave
(2E, 4E,
6E)-7-[3-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalen-2-yl-
]-3-methylocta-2,4,6-trienoic acid (121) as a yellow solid:
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.09 (s, 1H, Ar--H), 6.62
(dd, J=15.3, 10.9 Hz, 1H, olefinic), 6.75 (s, 1H, Ar--H), 6.32 (d,
J=15.2 Hz, 2H, olefinic), 6.32 (d, J=10.9 Hz, 2H, olefinic), 5.81
(s, 1H, olefinic), 3.90 (t, J=6.51 Hz, 2H, OCH.sub.2), 2.40 (s, 3H,
CH.sub.3), 2.24 (s, 3H, CH.sub.3) 1.79 (m, 2H, CH.sub.2), 1.67 (s,
4H, 2CH.sub.2), 1.29 (s, 6H, 2CH.sub.3), 1.27 (s, 6H, 2CH.sub.3),
1.03 (t, J=7.5 Hz, 3H, CH.sub.3).
EXAMPLE 22
[0178] (2E, 4E,
6Z)-7-[3-Propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2--
naphthalen-2-yl]-3-methylocta-2,4,6-trienoic Acid (Compound 122,
Prepared as Illustrated and Described in Scheme 8)
[0179] Phosphorous oxychloride (0.234 g, 0.142 mL, 1.52 mmol) was
added dropwise to DMF (4 mL) at room temperature under a nitrogen
atmosphere. The solution was stirred for 30 min. The
1-(3-propoxy-5,6,7,8-tetrahydro--
5,5,8,8-tetramethylnaphthalen-2-yl)ethanone (prepared as described
in Example 21, 0.110 g, 0.381 mmol) was added quickly (in one
portion) to the orange solution and the reaction solution was
heated to 60.degree. C. and stirred for 12 h. The dark brown
solution was poured into ice water and the aqueous layer was
adjusted to pH 7 with solid NaHCO.sub.3. EtOAc extraction afforded
the crude product, the chloro enal, 0.128 g, as an orange/brown
oil. To a 80.degree. C. solution of NaOH (0.061 g, 1.52 mmol) in
dioxane: H.sub.2O (3:2; 20 mL) was added the crude chloro enal in a
dioxane:water solution (3:2; 5 mL) in one portion and the yellow
reaction solution was stirred at 80.degree. C. for 2 h. The
resulting orange reaction solution was cooled to room temperature
and poured into brine and extracted with EtOAc. The organic
solution was dried (MgSO.sub.4), filtered, and concentrated to
afford an orange oil which was purified by radial chromatography
(10:1=Hex:EtOAc) to give the product
6-ethynyl-1,1,4,4-tetramethyl-7-propoxy-1,2,3,4-tetrahydronapthal-
ene 0.040 g (39%) as a yellow oil: .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.38 (s, 1H, Ar--H), 6.76 (s, 1H, Ar--H), 3.98
(t, J=6.6 Hz, 2H, OCH.sub.2), 3.19 (s, 1H, CH), 1.83 (m, 2H,
CH.sub.2), 1.66 m, 2H, 2CH.sub.2), 1.26 (s, 6H, 2CH.sub.3), 1.24
(s, 6H, 2CH.sub.3), 0.93 (t, J=7.4 Hz, 3H, CH.sub.3).
[0180] Ethyl magnesium bromide (3.33 mL of a 1.0 M solution in THF,
3.32 mmol) was added dropwsie to a room temperature solution of the
acetylene ether (0.450 g, 1.66 mmol) in THF (10 mL). The solution
was heated to reflux for 6 h and then cooled to room temperature.
Phenyl cyanate (0.40 g, 0.50 mL, 3.33 mmol) was added neat to the
reaction solution and reflux continued for an additional 2 h. The
reaction solution was cooled to room temperature and quenched with
a saturated ammonium chloride solution. Aqueous workup followed by
radial chromatography (20:1=hexanes:EtOAc) afforded the product
3-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydron-
apthalen-2-yl)-propynenitirle 0.393 g (80%) as a yellow solid:
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.44 (s, 1H, Ar--H), 6.78
(s, 1H, Ar--H), 3.97 (t, J=6.5 Hz, 2H, OCH.sub.2), 1.83 (m, 2H,
CH.sub.2), 1.67 (m, 2H, 2CH.sub.2), 1.27 (s, 6H, 2CH.sub.3), 1.24
(s, 6H, 2CH.sub.3), 1.03 (t, J=7.3 Hz, 3H, CH.sub.3).
[0181] A flame dried flask was charged with a suspension of copper
(I) iodide (0.057 g, 0.298 mmol) in THF (5 mL); the mixture was
stirred at 0.degree. C. under a nitrogen atmosphere. Methyl lithium
(0.43 mL of a 1.4 M solution in ether, 0.596 mmol) was added
dropwise to give a colorless solution. The solution was cooled to
-78.degree. C. and became a yellow/brown color. The acetylene
nitrile (0.040 g, 0.135 mmol) in THF (3.0 mL) was added dropwise
and the solution was stirred at -78.degree. C. for 45 min and then
quenched with MeOH (5 mL). An aqueous workup afforded the
cis-alkene nitrile 3-(3-propoxy-5,5,8,8-tetramethyl-5,6,7,8--
tetrahydro-naphthalen-2-yl)but-2-enenitrile 0.040 g (97%) as a
yellow oil: .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.19 (s, 1H,
Ar--H), 6.78 (s, 1H, Ar--H), 5.35 (s, 1H, olefinic), 3.92 (t, J=6.4
Hz, 2H, OCH.sub.2), 2.27 (s, 3H, CH.sub.3), 1.79 (m, 2H, CH.sub.2),
1.67 (s, 2H, 2CH.sub.2), 1.28 (s, 6H, 2CH.sub.3), 1.27 (s, 6H,
2CH.sub.3), 1.02 (t, J=7.4 Hz, 3H, CH.sub.3).
[0182] The above cis-alkene was reduced with DIBAL as described in
Example 19 to afford
cis-3-(3-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naph-
thalen-2-yl)but-2-enal as a yellow oil. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 9.36 (d, J=8.4 Hz, 1H, CHO), 6.99 (s, 1H,
Ar--H), 6.79 (s, 1H, Ar--H), 6.09 (s, J=8.4 Hz, 1H, olefinic), 3.90
(t, J=6.5 Hz, 2H, OCH.sub.2), 2.29 (s, 3H, CH.sub.3), 1.76 (m, 2H,
CH.sub.2), 1.68 (s, 2H, 2CH.sub.2), 1.30 (s, 6H, 2CH.sub.3), 1.24
(s, 6H, 2CH.sub.3), 1.00 (t, J=7.4 Hz, 3H, CH.sub.3).
[0183] The above cis-alkenal was converted into the title compound
by the procedure described in Example 19. The cis-triene acid was
purified by recrystallization to give (2E, 4E,
6Z)-7-[5,5,8,8-tetramethyl-3-propoxy-5-
,6,7,8-tetrahydro-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic
acid (122) as a pale yellow solid: mp 177-179.degree. C.;
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.95 (s, 1H, Ar--H), 6.79
(s, 1H, Ar--H), 6.62 (dd, J=15.3, 11.0 Hz, 1H, olefinic), 6.22
(appp br d, 27, 2.times. olefinic), 5.76 (s, 1H olefinic), 3.89 (t,
J=6.5 Hz, 2H, OCH.sub.2), 2.19 (s, 3H, CH.sub.3), 2.13 (s, 3H,
CH.sub.3), 1.77 (m, 2H, CH.sub.2), 1.68 (s, 4H, 2CH.sub.2), 1.30
(s, 6H, 2CH.sub.3), 1.23 (s, 6H, 2CH.sub.3), 1.01 (t, J=7.4 Hz, 3H,
CH.sub.3).
EXAMPLE 23
[0184] (2Z, 4E,
6E)-7-(3-Ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-n-
aphthalen-2-yl)-3-methylocta-2,4,6-trienoic Acid (Compound 123,
Prepared as Illustrated and Described in Scheme 7)
[0185]
1-(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)-
ethanone (3.00 g, 12.3 mmol) in DMSO was alkylated with ethyl
iodide (2.00 g, 12.9 mmol) as described in Example 21 to give
1-(3-ethoxy-5,6,7,8-tetr-
ahydro-5,5,8,8-tetramethylnaphthalen-2-yl)ethanone 3.0 g (88%) as a
yellow solid: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.72 (s,
1H, ArH), 6.81 (s, 1H, ArH), 4.21 (q, 2H, OCH.sub.2), 2.60 (s, 3H,
CH.sub.3), 1.67 (m, 4H, 2CH.sub.2), 1.45 (t, 3H, CH.sub.3), 1.28
(s, 6H, 2CH.sub.3), 1.26 (s, 6H, 2CH.sub.3).
[0186] The above ketone (3.0 g, 11.0 mmol) was condensed with
diethyl cyanomethylphosphonate (2.9 g, 16.5 mmol) as described in
Example 19 to give
3-(3-ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)bu-
t-2-enenitrile 2.9 g (93%) as a yellow solid: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.10 (s, 1H, ArH), 6.77 (s, 1H, ArH), 5.62 (s,
1H, olefinic), 4.05 (q, 2H, OCH.sub.2), 2.45 (s, 3H, CH.sub.3),
1.67 (m, 4H, 2CH.sub.2), 1.42 (t, 3H, CH.sub.3), 1.26 (s, 6H,
3CH.sub.3), 1.24 (d, 6H, 3CH.sub.3).
[0187] The nitrile olefin (2.8 g, 10.0 mmol) was readily reduced
with DIBAL (15.0 mL of a 1.0 M solution in hexanes, 15.0 mmol) as
described in Example 19 to yield the aldehyde
3-(3-ethoxy-5,6,7,8-tetrahydro-5,5,8,8-t-
etramethylnaphthalen-2-yl)but-2-enal 2.8 g (98%) as an orange
solid: .sup.1H.about.NMR (400 MHz, CDCl.sub.3) .delta. 10.15 (d,
1H, CHO), 7.10 (s, 1H, ArH), 6.80 (s, 1H, ArH), 6.15 (d, 1H,
olefinic), 4.05 (q, 2H, OCH.sub.2), 2.55 (s, 3H, CH.sub.3), 1.67
(m, 4H, 2CH.sub.2), 1.42 (t, 3H, CH.sub.3), 1.26 (s, 6H,
3CH.sub.3), 1.24 (d, 6H, 3CH.sub.3).
[0188] The above aldehyde (5.3 g, 20.0 mmol) was condensed with
diethyl 3-ethoxycarbonyl-2-methyl prop-2-enylphosphonate as
described in Example 19 to yield, after silica gel chromatography,
the triene ester (2Z, 4E, 6E)-7-(3-ethoxy-5,6,7,8-tetrahydro-5
5,8,8-tetramethyl-2-naphthalen-2-yl)- -3-methylocta-2,4,6-trienoic
acid ethyl ester 3.3 g (83%) as an orange oil: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.80 (s, 1H, olefinic), 7.10 (s, 1H, ArH),
6.83 (d, 1H, olefinic), 6.77 (s, 1H, ArH), 6.40 (d, 1H, olefinic),
5.67 (s, 1H, olefinic), 4.15 (q, 2H, OCH.sub.2), 4.03 (q, 2H,
OCH.sub.2), 2.24 (s, 3H, CH.sub.3), 2.10 (s, 3H, CH.sub.3), 1.67
(br s, 4H, 2CH.sub.2), 1.38 (t, 3H, CH.sub.3), 1.28 (t, 3H,
CH.sub.3), 1.26 (s, 6H, 3CH.sub.3), 1.24 (d, 6H, 3CH.sub.3).
[0189] The ester (2.8 g, 7.0 mmol) was hydrolyzed using the
standard conditions of Example 19 to yield after HPLC purification
the title acid (2Z, 4E,
6E)-7-(3-ethoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtha-
len-2-yl)-3-methylocta-2,4,6-trienoic acid (123) 2.5 g (93%) as a
light yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.75
(d, 1H, olefinic), 7.10 (s, 1H, ArH), 7.05 (dd, 1H, olefinic), 6.70
(s, 1H, ArH), 6.38 (d, 1H, olefinic), 5.67 (s, 1H, olefinic), 4.02
(q, 2H, OCH.sub.2), 2.23 (s, 3H, CH.sub.3), 2.13 (s, 3H, CH.sub.3),
1.67 (br s, 4H, 2CH.sub.2), 1.40 (t, 3H, CH.sub.3), 1.28 (s, 6H,
3CH.sub.3), 1.25 (d, 6H, 3CH.sub.3).
EXAMPLE 24
[0190] (2E, 4E,
6Z)-7-[3-Hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
-naphthalen-2-yl]-3-methylocta-2,4,6trienoic acid (Compound 124,
Prepared as Illustrated and Described in Scheme 7)
[0191]
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)-
ethanone (0.103 g, 0.418 mmol) in DMSO (1 mL) was alkylated with
bromohexane (0.097 g, 0.585 mmol, 0.082 mL) as described in Example
21. Aqueous workup gave
1-(3-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyln-
aphthalen-2-yl)ethanone 0.161 g (100% crude) as an orange oil:
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.74 (s, 1H, Ar--H), 6.82
(s, 1H, Ar--H), 4.02 (t, J=6.4 Hz, 2H, OCH.sub.2), 2.61 (s, 3H,
CH.sub.3), 1.83 (m, 2H, CH.sub.2), 1.67 (app br d, 4H, 2CH.sub.2),
1.50 (m, 2H, CH.sub.2), 1.36 (m, 4H, 2CH.sub.2), 1.29 (s, 6H,
2CH.sub.3), 1.26 (s, 6H, 2CH.sub.3), 0.91 (t, J=7.0 Hz, 3H,
CH.sub.3).
[0192] The above hexyloxyketone (0.160 g, 0.484 mmol) was condensed
with diethyl cyanomethylphosphonate (0.172 g, 0.968 mmol, 0.157 mL)
as described for Example 19. Aqueous work-up afforded the crude
product
3-(3-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)but-2-
-enenitrile 0.2711 g (123%) as a dark brown oil: .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 7.11 (s, 1H, Ar--H), 6.80 (s, 1H, Ar--H),
5.62 (s, 1H, olefinic), 3.96 (t, J=6.4 Hz, 2H, OCH.sub.2), 2.45 (s,
3H, CH.sub.3), 1.79 (m, 2H, CH.sub.2), 1.68 (s, 4H, 2CH.sub.2),
1.47 (m, 2H, CH.sub.2), 1.35 (m, 4H, 2CH.sub.2), 1.30 (s, 6H,
2CH.sub.3), 1.26 (s, 6H, 2CH.sub.3), 0.93 (t, J=6.87 Hz, 3H,
CH.sub.3).
[0193] The cyano(n-hexyloxy)naphthalene adduct (0.211 g, 0.597
mmol) was readily reduced with DIBAL (1.80 mL of a 1.0 M solution
in hexanes, 1.80 mmol) as described for Example 19. Aqueous work-up
gave the aldehyde
3-(3-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)but-2-
-enal 0.162 g (76%) as a yellow oil (mixture of trans:cis=4:1)
isomers: .sup.1H-NMR (trans isomer, CDCl.sub.3) .delta. 10.13 (d,
J=8.2 Hz, 1H, CHO), 7.08 (s, 1H, Ar--H), 6.78 (s, 1H, Ar--H), 6.13
(d, J=8.0 Hz, 1H, olefinic), 3.96 (t, J=6.4 Hz, 2H, OCH.sub.2),
2.55 (s, 3H, CH.sub.3), 1.77 (m, 2H, CH.sub.2), 1.67 (s, 4H,
2CH.sub.2), 1.45 (m, 2H, CH.sub.2), 1.33 (m, 4H, 2CH.sub.2), 1.29
(s, 6H, 2CH.sub.3), 1.25 (s, 6H, 2CH.sub.3), 0.90 (m, 3H,
CH.sub.3); .sup.1H-NMR (cis isomer, 400 MHz, CDCl.sub.3) .delta.
9.34 (d, 1H, CHO), 6.98 (s, 1H, Ar--H), 6.78 (s, 1H, Ar--H), 6.08
(d, 1H, olefinic), 3.94 (t, 2H, OCH.sub.2), 2.28 (s, 3H, CH.sub.3),
1.65 (m, 2H, CH.sub.2), 1.62 (s, 4H, 2CH.sub.2), 1.42 (m, 2H,
CH.sub.2), 1.32 (m, 4H, 2CH.sub.2), 1.29 (s, 6H, 2CH.sub.3), 1.22
(s, 6H, 2CH.sub.3), 0.90 (m, 3H, CH.sub.3).
[0194] The above aldehyde (0.097 g, 0.272 mmol) and diethyl
3-ethoxycarbonyl-2-methyl prop-2-enylphosphonate (0.180 g, 0.680
mmol, 0.167 mL) were condensed as described for Example 19. Aqueous
work-up afforded the ester (0.117 g, 94%) as a yellow oil. Standard
hydrolysis of the crude ester (0.117 g, 0.256 mmol) followed by the
typical aqueous work-up gave the acid as a mixture of geometric
isomers (0.110 g, 100%) as an orange oil. A sample of the product
mixture was purified by reverse phase HPLC (90% MeOH/10% 1 mM
NH.sub.4OAc with 0.5% AcOH) to give (2E, 4E,
6Z)-7-[3-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-
-2-yl]-3-methylocta-2,4,6-trienoic acid (124) as a yellow oil:
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.95 (s, 1H, Ar--H), 6.79
(s, 1H, Ar--H), 6.63 (dd, J=10.9, 15.4 Hz, 1H, olefinic), 6.23
(appp br d, 2H, 2.times. olefinic), 5.74 (s, 1H, olefinic), 3.92
(t, J=6.48, 2H, OCH.sub.2), 2.19 (s, 3H, CH.sub.3), 2.14 (s, 3H,
CH.sub.3), 1.74 (m, 2H, CH.sub.2), 1.68 (s, 4H, 2CH.sub.2), 1.42
(m, 2H, CH.sub.2), 1.30 (s, 6H, 2CH.sub.3), 1.29 (m, 4H,
2CH.sub.2), 1.23 (s, 6H, 2CH.sub.3), 0.88 (m, 3H, CH.sub.3).
EXAMPLE 25
[0195] (2E, 4E,
6E)-7-[3-Hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic Acid (Compound 125,
Prepared as Illustrated and Described in Scheme 7)
[0196] The final product mixture from Example 24 was purified by
reverse phase HPLC (85% MeOH/15% 1 mM NH.sub.4OAc with 0.5% AcOH)
to give the title compound (2E, 4E,
6E)-7-[3-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetr-
amethyl-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (125)
as a yellow oil: .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.08 (s,
1H, Ar--H, 7.06 (dd, J=11.4, 15.0 Hz, 1H, olefinic.), 6.75 (s, 1H,
Ar--H), 6.32 (d, J=15.0 Hz, 1H, olefinic), 6.31 (d, J=11.4 Hz, 1H,
olefinic), 5.83 (s, 1H, olefinic), 3.93 (t, J=6.4 Hz, 2H,
OCH.sub.2), 2.39 (s, 3H, CH.sub.3), 2.24 (s, 3H, CH.sub.3), 1.76
(m, 2H, CH.sub.2), 1.67 (s, 4H, 2CH.sub.2), 1.45 (m, 2H, CH.sub.2),
1.32 (m, 4H, 2CH.sub.2), 1.29 (s, 6H, 2CH.sub.3), 1.27 (s, 6H,
2CH.sub.3), 0.90 (m, 3H, CH.sub.3).
EXAMPLE 26
[0197] (2E, 4E,
6E)-7-[3-(3-Methylbut-2-enyloxy)-5,6,7,8-tetrahydro-5,5,8,-
8-tetramethyl-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic Acid
(Compound 126, Prepared as Illustrated and Described in Scheme
7)
[0198]
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)-
ethanone (0.125 g, 0.507 mmol) in DMSO (1 mL) was alkylated with
4-bromo-2-methyl-2-butene (0.106 g, 0.710 mmol, 0.082 mL) as
described in Example 21. Aqueous workup gave
1-[3-(3-methylbut-2-enyloxy)-5,6,7,8-tetr-
ahydro-5,5,8,8-tetramethylnaphthalen-2-yl]ethanone 0.201 g (100%
crude) as a clear yellow crystalline solid: .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.72 (s, 1H, Ar--H), 6.83 (s, 1H, Ar--H), 5.48
(m, 1H, olefinic), 4.59 (d, J=6.6 Hz, 2H, OCH.sub.2), 2.60 (s, 3H,
CH.sub.3), 1.79 (s, 3H, CH.sub.3), 1.76 (s, 3H, CH.sub.3), 1.67
(appp d, J=2.7 Hz, 4H, 2CH.sub.2), 1.28 (s, 6H, 2CH.sub.3), 1.26
(s, 6H, 2CH.sub.3).
[0199] The above prenyloxyketone (0.160 g, 0.509 mmol) and diethyl
cyanomethylphosphonate (0.315 g, 1.78 mmol, 0.288 mL) were
condensed as described for Example 19. Aqueous work-up afforded the
crude product
3-[3-(3-methylbut-2-enyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-
alen-2-yl]but-2-enenitrile 0.207 g as a yellow oil: .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. 7.10 (s, 1H, Ar--H), 6.80 (s, 1H,
Ar--H), 5.62 (s, 1H, olefinic), 5.42 (m, 1H, olefinic), 4.51 (d,
J=6.5 Hz, 2H, OCH.sub.2), 2.43 (s, 3H, CH.sub.3), 1.79 (s, 3H,
CH.sub.3), 1.74 (s, 3H, CH.sub.3), 1.67 (s, 4H, 2CH.sub.2), 1.28
(s, 6H, 2CH.sub.3), 1.25 (s, 6H, 2CH.sub.3).
[0200] The cyanoprenyloxynaphthalene adduct (0.207 g, 0.636 mmol)
was readily reduced with DIBAL (1.91 mL of a 1.0 M solution in
hexanes, 1.91 mmol) as described for Example 19. Aqueous work-up
gave the aldehyde
3-[3-(3-methylbut-2-enyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-
alen-2-yl]but-2-enal 0.168 g (80%) as a crude yellow oil:
.sup.1H-NMR (trans isomer, CDCl.sub.3) .delta. 10.14 (d, J=8.2 Hz,
1H, CHO), 7.09 (s, 1H, Ar--H), 6.80 (s, 1H, Ar--H), 6.13 (d, J=8.2
Hz, 1H, olefinic), 5.43 (m, 1H, olefinic), 4.52 (m, 2H, OCH.sub.2),
2.54 (s, 3H, CH.sub.3), 1.78 (s, 3H, CH.sub.3), 1.74 (s, 3H,
CH.sub.3), 1.68 (s, 4H, 2CH.sub.2), 1.29 (s, 6H, 2CH.sub.3), 1.26
(s, 6H, 2CH.sub.3).
[0201] The above aldehyde (0.168 g, 0.493 mmol) and diethyl
3-ethoxycarbonyl-2-methyl prop-2-enylphosphonate (0.326 g, 1.23
mmol, 0.302 mL) were condensed as described for Example 19. Aqueous
work-up afforded the crude ester as a yellow oil. Standard
hydrolysis of the ester (0.201 g, 0.467 mmol) and aqueous work-up
gave the acid as a mixture of geometric isomers (0.172 g, 87%) as
an orange oil. A sample of the product mixture was purified by
reverse phase HPLC (90% MeOH/10% 1 mM NH.sub.4OAc with 0.5% AcOH)
to give (2E, 4E, 6E)-7-[3-(3-methylbut-2-enyl-
oxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methylocta-
-2,4,6-trienoic acid (126) as a yellow oil: .sup.1H-NMR ((2E, 4E,
6E)-isomer, 400 MHz, CDCl.sub.3) .delta. 7.08 (s, 1H, Ar--H), 7.06
(dd, J=11.2, 15.1 Hz, 1H, olefinic.), 6.77 (s, 1H, Ar--H), 6.30
(dd, J=8.3, 15.1 Hz, 1H, olefinic), 5.81 (s, 1H, olefinic), 5.44
(m, 1H, olefinic), 4.50 (d, J=6.6 Hz, 2H, OCH.sub.2), 2.39 (s, 3H,
CH.sub.3), 2.23 (s, 3H, CH.sub.3), 1.77 (s, 3H, CH.sub.3), 1.72 (s,
3H, CH.sub.3), 1.67 (s, 4H, 2CH.sub.2), 1.28 (s, 6H, 2CH.sub.3),
1.27 (s, 6H, 2CH.sub.3).
EXAMPLE 27
[0202] (2E, 4E,
6E)-7-[3-Benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl--
2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic Acid (Compound 127,
Prepared as Illustrated and Described in Scheme 7)
[0203]
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)-
ethanone (0.103 g, 0.418 mmol) in DMSO (1 mL) was alkylated with
benzylbromide (0.100 g, 0.585 mmol, 0.070 mL) as described in
Example 21. Aqueous workup gave
1-(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-
naphthalen-2-yl)ethanone 0.106 g (75% crude) as a yellow oil:
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.74 (s, 1H, ArH), 7.45
(m, 5H, ArH), 6.88 (s, 1H, ArH), 5.12 (s, 2H, OCH.sub.2), 2.59 (s,
3H, CH.sub.3), 1.66 (br s, 4H, 2CH.sub.2), 1.28 (s, 6H, 2CH.sub.3),
1.25 (s, 6H, 2CH.sub.3).
[0204] The benzyloxyketone (0.106 g, 0.315 mmol) was condensed with
diethyl cyanomethylphosphonate (0.195 g, 1.10 mmol, 0.18 mL) as
described for Example 19. Aqueous work-up afforded the crude
product
3-(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)but--
2-enenitrile 0.047 g (41%) as a yellow oil: .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.36 (m, 5H, ArH), 7.11 (s, 1H, ArH), 6.85 (s,
1H, ArH), 5.58 (s, 1H, olefinic), 5.06 (s, 2H, OCH.sub.2), 2.43 (s,
3H, CH.sub.3), 1.66 (s, 4H, 2CH.sub.2), 1.25 (s, 6H, 2CH.sub.3),
1.24 (s, 6H, 2CH.sub.3).
[0205] The cyanobenzyloxy naphthalene adduct (0.047 g, 0.131 mmol)
was readily reduced with DIBAL (0.392 mL of a 1.0 M solution in
hexanes, 0.392 mmol) as described for Example 19. Aqueous work-up
gave the aldehyde
E-3-(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthale-
n-2-yl)but-2-enal 0.020 g (42%) as a yellow oil: .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 10.13 (d, J=8.0 Hz, 1H, CHO), 7.39 (m, 5H,
ArH), 7.10 (s, 1H, ArH), 6.86 (s, 1H, ArH), 6.14 (d, J=8.0 Hz, 1H,
olefinic), 5.06 (s, 2H, OCH.sub.2), 2.54 (s, 3H, CH.sub.3), 1.67
(s, 4H, 2CH.sub.2), 1.25 (s, 12H, 4CH.sub.3).
[0206] The above aldehyde (0.020 g, 0.0552 mmol) and diethyl
3-ethoxycarbonyl-2-methyl prop-2-enylphosphonate (0.031 g, 0.116
mmol, 0.029 mL) were condensed as described for Example 19. Aqueous
work-up afforded the ester (0.026 g, 100%) as a yellow oil.
Standard hydrolysis of the crude ester (0.026 g, 0.055 mmol)
followed by the typical aqueous work-up gave the acid as a mixture
of geometric isomers (0.022 g, 87%) as a yellow oil. A sample of
the product mixture was purified by reverse phase HPLC (88%
MeOH/12% 1 mM NH.sub.4OAc with 0.5% AcOH) to give (2E, 4E,
6E)-7-[3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthale-
n-2-yl]-3-methylocta-2,4,6-trienoic acid (127) as a yellow solid:
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.37 (m, 5H, ArH), 7.11
(s, 1H, ArH), 7.04 (dd, J=11.2, 15.2 Hz, 1H, olefinic), 6.83 (s,
1H, ArH), 6.33 (appp broad t, 2H, 2.times. olefinic), 5.84 (s, 1H,
olefinic), 5.05 (s,2H, OCH.sub.2), 2.38 (s, 3H, CH.sub.3), 2.25 (s,
3H, CH.sub.3), 1.67 (s, 4H, 2CH.sub.2), 1.27 (s, 6H, 2CH.sub.3),
1.25 (s, 6H, 2CH.sub.3).
EXAMPLE 28
[0207] (2E, 4E,
6Z)-7-[3-Benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl--
2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic Acid (Compound 128,
Prepared as Illustrated and Described in Scheme 7)
[0208] The final product mixture from Example 27 was purified by
reverse phase HPLC (88% MeOH/12% 1 mM NH.sub.4OAc with 0.5% AcOH)
to give the title compound (2E, 4E,
6Z)-7-[3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tet-
ramethyl-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (128)
as a yellow solid: .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.34
(m, 5H, ArH), 6.97 (s, 1H, ArH), 6.86 (s, 1H, ArH), 6.63 (dd,
J=11.1, 15.0 Hz, 1H, olefinic), 6.23 (appp b t, 2H, 2.times.
olefinic), 5.76 (s, 1H, olefinic), 5.05 (s, 2H, OCH.sub.2), 2.21
(s, 3H, CH.sub.3), 2.04 (s, 3H, CH.sub.3), 1.67 (s, 4H, 2CH.sub.2),
1.26 (s, 6H, 2CH.sub.3), 1.23 (s, 6H, 2CH.sub.3).
EXAMPLE 29
[0209] (2E, 4E,
6E)-7-[3-(4-Methylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-te-
tramethyl-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic Acid
(Compound 129, Prepared as Illustrated and Described in Scheme
7)
[0210]
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)-
ethanone (0.116 g, 0.471 mmol) was alkylated with
4-methylbenzylchloride (0.93 g, 0.659 mmol, 0.087 mL) as described
in Example 21. Aqueous workup gave
1-[3-(4-methylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnapht-
halen-2-yl]ethanone 0.217 g (131% crude) as a pale orange solid:
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.74 (s, 1H, ArH, 7.33
and 7.20 (d of ABq, J=7.8 Hz, 4H, Ar--H), 6.91 (s, 1H, ArH), 5.08
(s, 2H, OCH.sub.2), 2.56 (s, 3H, CH.sub.3), 2.35 (s, 3H,
ArCH.sub.3), 1.66 (br s, 4H, 2CH.sub.2), 1.28 (s, 6H, 2CH.sub.3),
1.25 (s, 6H, 2CH.sub.3).
[0211] The (4-methylbenzyloxy)ketone (0.217 g, 0.619 mmol) was
condensed with diethyl cyanomethylphosphonate (0.329 g, 1.86 mmol,
0.300 mL) as described for Example 19. Aqueous work-up afforded the
crude product
3-(4-methylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2--
yl]but-2-enenitrile 0.173 g (75%) as an orange oil: .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. 7.27 and 7.20 (d of ABq, J=7.8 Hz,
4H, Ar--H), 7.10 (s, 1H, ArH), 6.87 (s, 1H, ArH), 5.58 (s, 1H,
olefinic), 5.01 (s, 2H, OCH.sub.2), 2.42 (s, 3H, CH.sub.3), 2.37
(s, 3H, ArCH.sub.3), 1.67 (s, 4H, 2CH.sub.2), 1.26 (s, 6H,
2CH.sub.3), 1.25 (s, 6H, 2CH.sub.3).
[0212] The cyano(methylbenzyloxy)naphthalene adduct (0.173 g, 0.463
mmol) was readily reduced with DIBAL (1.39 mL of a 1.0 M solution
in hexanes, 1.39 mmol) as described for Example 19. Aqueous work-up
gave the aldehyde
3-(4-methylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2--
yl)but-2-enal 0.090 g (52%) as a yellow oil: .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 10.12 (d, J=8.2 Hz, 1H, CHO), 7.28 and 7.18 (d
of ABq, J=8.0 Hz, 4H, Ar--H), 7.10 (s, 1H, ArH), 6.87 (s, 1H, ArH),
6.11 (d, J=8.2 Hz, 1H, olefinic), 5.02 (s, 2H, OCH.sub.2), 2.53 (s,
3H, CH.sub.3), 2.36 (s, 3H, ArCH.sub.3), 1.67 (s, 4H, 2CH.sub.2),
1.26 (s, 6H, 2CH.sub.3), 1.25 (s, 6H, 2CH.sub.3).
[0213] The above aldehyde (0.090 g, 0.240 mmol) and diethyl
3-ethoxycarbonyl-2-methyl prop-2-enylphosphonate (0.0159 g, 0.601
mmol, 0.147 mL) were condensed as described for Example 19. Aqueous
work-up afforded the ester (0.099 g, 85%) as a yellow oil. Standard
hydrolysis of the crude ester (0.099 g, 0.203 mnol) followed by the
typical aqueous work-up gave the acid as a crude mixture of
geometric isomers (0.109 g, 117%) as a yellow oil. A sample of the
product mixture was purified by reverse phase HPLC (90% MeOH/10% 1
mM NH.sub.4OAc with 0.5% AcOH) to give (2E, 4E,
6E)-7-[3-(4-methylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramet-
hyl-2-naphthalen-2-yl]-3-methylocta-2,4,6-trienoic acid (129) as a
yellow solid: .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.30 and
7.17 (d of ABq, J=7.9 Hz, 4H, Ar--H), 7.10 (s, 1H, ArH), 7.02 (dd,
J=11.2, 15.1 Hz, 1H, olefinic), 6.87 (s, 1H, ArH), 6.11 (appp br t,
1H, olefinic), 5.80 (s, 1H, olefinic), 5.00 (s, 2H, OCH.sub.2),
2.38 (s, 3H, CH.sub.3), 2.37 (s, 3H, CH.sub.3), 2.23 (s, 3H,
CH.sub.3), 1.67 (s, 4H, 2CH.sub.2), 1.27 (s, 6H, 2CH.sub.3), 1.26
(s, 6H, 2CH.sub.3).
EXAMPLE 30
[0214] (2E, 4E,
6Z)-7-[3-(4-Methylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-te-
tramethyl-2-naphthalen-2-yl]-3methylocta-2,4,6-trenoic Acid
(Compound 130, Prepared as Illustrated and Described in Scheme
7)
[0215] The final product mixture from Example 29 was purified by
reverse phase HPLC (90% MeOH/10% 1 mM NH.sub.4OAc with 0.5% AcOH)
to give the title compound (2E, 4E,
6Z)-7-[3-(4-methylbenzyloxy)-5,6,7,8-tetrahydro-5-
,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methylocta-2,4,6trienoic
acid (130) as a yellow solid: .sup.1H-NMR (400 MHz CDCl.sub.3)
.delta. 7.27 and 7.15 (d of ABq, J=7.9 Hz, 4H, Ar--H), 6.96 (s, 1H,
ArH), 6.87 (s, 1H, ArH), 6.60 (dd, J=11.0, 14.9 Hz, 1H, olefinic),
6.23 (appp br d, 1H, olefinic), 5.80 (s, 1H, olefinic), 5.00 (s,
2H, OCH.sub.2), 2.34 (s, 3H, CH.sub.3), 2.19 (s, 3H, C.sub.3), 2.13
(s, 3H, CH.sub.3), 1.67 (s, 4H, 2CH.sub.2), 1.27 (s, 6H,
2CH.sub.3), 1.23 (s, 6H, 2CH.sub.3).
EXAMPLE 31
[0216]
4-(3,4,3,6,7,8-Hexahydro-5,5,8,8-tetramethyl-anthracen-1-ylmethyl)--
benzoic Acid (Compound 131, Prepared as Illustrated and Described
in Scheme 9)
[0217] To a solution of
1,2,3,4,6,7,8,9-octahydro-6,6,9,9-tetramethylanthr- acene (prepared
by Friedel-Crafts alkylation/annulation of
1,2,3,4-tetrahydronaphthalene with 2,5-dichloro-2,3-dimethylhexane
in the presence of aluminum trichloride at 0.degree. C. in
dichloromethane, 2.0 g, 8.3 mmol) in CH.sub.2Cl.sub.2 (100 mL) and
pyridine (15 mL) at 0.degree. C. was added CrO.sub.3 (8.26 g, 82.6
mmol) in several portions. The reaction mixture was stirred at
0.degree. C. for 30 min, then allowed to warm to room temperature
and stirred for 10 h. The reaction mixture was poured over an
ice-acid mixture (1N HCl, 100 mL), extracted with Et.sub.2O (200
mL), dried (MgSO.sub.4), concentrated, and purified by column
chromatography (25% ether in hexane) to give
3,4,5,6,7,8-hexaydro-5,5,8,8-tetramethyl-2H-anthracen-1-one (740
mg, 35%): .sup.1H NMR(400 MHz, CDCl.sub.3) .delta. 8.01(s, 1H,
ArH), 7.17(s, 1H, ArH), 2.90 (t, J=6.5 Hz, 2H, CH.sub.2), 2.60 (t,
J=6.3 Hz, 2H, CH.sub.2), 2.10 (m, 2H, CH.sub.2), 1.68 (s, 4H,
2CH.sub.2), 1.30 (s, 6H, 2CH.sub.3), 1.29 (s, 6H, 2CH.sub.3).
[0218] To a solution of
3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2H-anthr- acen-1-one (512
mg, 2 mmol) in MeOH (10 mL) w&s added NaBH.sub.4 (76 mg, 2
mmol) at 0.degree. C. The reaction mixture was stirred at 0.degree.
C. for 30 min, quenched with saturated aqueous NH.sub.4Cl (5 mL),
extracted with ether (50 mL), dried (MgSO.sub.4), The organic
layers were concentrated under reduced pressure to give the
corresponding tricyclic alcohol, which was used without further
purification. To the above alcohol (516 mg, 2 mmol) in MeOH (5 mL)
was added Ph.sub.3P--HBr (686 mg, 2 mmol) at rt. The mixture was
heated at 85.degree. C. for 5 h. Removal of the solvent, followed
by addition of hexane (100 mL) gave a white solid, which was then
filtered to give pure 3,4,5,6,7,8-hexahydro-5,5,8,8-
-tetramethyl-2H-anthracen-1-triphenylphosphonium bromide (697 mg,
60%). To a solution of the above phosphonium salt (581 mg, 1 mmol)
in THF (8 mL) was added n-BuLi (0.4 mL, 2.5 M, 1 mmol) at 0.degree.
C. and the resulting dark-red solution was stirred at that
temperature for 30 min to afford the ylide. To this freshly
prepared ylide was added methyl 4-formyl-benzoate (1.2 mmol) in THF
(3 mL) at -78.degree. C. The solution was allowed to warm to
ambient temperature and stirred for 6 h. The reaction was quenched
with saturated aqueous NH.sub.4Cl. The aqueous solution was
extracted with EtOAc, 3.times.. The organic layers were combined
and washed with water (2.times.) and brine. The organic solution
was dried (Na.sub.2SO.sub.4), filtered, and concentrated to give
the crude exocyclic ester product as a yellow solid (86%): m.p.
161-163.degree. C.
[0219] The ester (220 mg, 0.56 mmol) in methanol (10 mL) was
treated with concentrated HCl (0.05 mL) and the solution was
allowed to stir at 85.degree. C. for 8 h. The solution was quenched
with water and extracted with EtOAc (3.times.). The organic
solution was washed with saturated aqueous NaHCO.sub.3, water
(2.times.), and brine. The organic solution was dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give the
endocylcic ester product (95%) as a yellow oil: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.92 (1/2ABq, J=8.2 Hz, 2H, ArH), 7.33
(1/2ABq, J=8.2 Hz, 2H, ArH), 7.03 (s, 1H, ArH), 7.00 (s, 1H, ArH),
5.77 (broad t, 1H, olefinic), 3.90 (s, 3H, OCH.sub.3), 3.78 (s, 2H,
CH.sub.2), 2.72 (t, J=7.9 Hz, 2H, CH.sub.2), 2.30 (m, 2H,
CH.sub.2), 1.61 (s, 4H, 2CH.sub.2), 1.22 (s, 6H, 2CH.sub.3), 1.10
(s, 6H, 2CH.sub.3).
[0220] The ester (80 mg) was hydrolyzed in excess KOH/MeOH at
ambient temperature for 24 h. The methanol was removed in vacuo The
residue was taken-up in water and the aqueous layer was adjusted to
pH=4-5 with 1 M aqueous HCl. The aqueous solution was extracted
with EtOAc, 3.times.. The organic layers were combined and washed
with water (2.times.) and brine. The organic solution was dried
(Na.sub.2SO.sub.4), filtered, and concentrated to give
4-(3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-anthrac-
en-1-ylmethyl)-benzoic acid (131) 76 mg (96%) as a white solid:
m.p. 212-214.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.99 (1/2ABq, J=8.2 Hz, 2H, ArH), 7.36 (1/2ABq, J=8.2 Hz, 2H, ArH),
7.03 (s, 1H, ArH), 7.02 (s, 1H, ArH), 5.76 (broad t, 1H, olefinic),
3.81 (s, 2H, CH.sub.2), 2.72 (t, J=7.9 Hz, 2H, CH.sub.2), 2.31 (m,
2H, CH.sub.2), 1.60 (s, 4H, 2CH.sub.2), 1.23 (s, 6H, 2CH.sub.3),
1.10 (s, 6H, 2CH.sub.3).
EXAMPLE 32
[0221]
4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-3H-cyclopenta[b]naphthale-
n-1-ylmethyl)-benzoic Acid (Compound 132, Prepared as Illustrated
and Described in Scheme 9)
[0222] The title compound was prepared in a manner similar to that
of Example 30 using
2,3,5,6,7,8-hexahydro-5,5,8,8-tetramethylcyclopenta[b]-1- -one
[U.S. Pat. No. 2,815,382 (1957)] in place of the anthracen-1-one
for the NaBH.sub.4 reduction step.
4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl--
3H-cyclopenta[b]naphthalen-1-ylmethyl)-benzoic acid (132) (38%) was
obtained as a white, foamy solid .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.01 (1/2ABq, J=8.2 Hz, 2H, ArH), 7.39 (1/2ABq, J=8.2 Hz,
2H, ArH), 7.37 (s, 1H, ArH), 7.19 (s, 1H, ArH), 6.00 (broad t, 1H,
olefinic), 3.92 (broad s, 2H, CH.sub.2), 3.29 (broad s, 2H,
CH.sub.2), 1.67 (s, 4H, 2CH.sub.2), 1.28 (s, 6H, 2CH.sub.3), 1.24
(s, 6H, 2CH.sub.3).
EXAMPLE 33
[0223]
4-(6,7,8,9-Tetrahydro-6,6,9,9-tetramethyl-2H-benzo[g]chromen-4-ylme-
thyl)-benzoic Acid (Compound 133, Prepared as Illustrated and
Described in Scheme 9)
[0224] Aluminum trichloride (25 g, 0.18 mol) was added in portions
to a solution of phenol (49.5 g, 0.52 mol) and
2,5-dichloro-2,5-dimethylhexane (101.0 g, 0.55 mol) in
dichloromethane (700 mL). The reaction mixture was allowed to stir
at 25-40.degree. C. for 2 h, then the dark red mixture was poured
onto ice water. Aqueous work up (EtOAc extraction) gave
5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-ol 84.8 g (80%)
as a white solid, which was recrystallized from hexane to give the
product as colorless needles: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.17 (d, 1H, ArH), 6.78 (d, 1H, ArH), 6.62 (dd, 1H, ArH),
4.55 (s, 1H OH), 1.65 (s, 4H, 2CH.sub.2), 1.25 (s, 12H,
4CH.sub.3).
[0225] The hydroxynaphthalene (19.1 g, 93.6 mmol) was treated
dropwise with acetyl chloride (7.7 g, 98.2 mmol) in
1,2-dichloroethane (250 ml) at 0.degree. C. After completion of the
addition, aluminum chloride (10 g, 75.2 mmol) was added in portions
over 5 min. The mixture was heated at reflux for 10 h, then stirred
at 25.degree. C. for 8 h. GC analysis indicated the desired
keto-phenol was present in 98.6% purity. The reaction mixture was
poured onto ice water and aqueous work-up (EtOAc extraction) gave a
brown-black solid, which was dissolved in hot methanol, filtered,
and concentrated to give a brown viscous semi-solid. Flash
chromatography (15% EtOAc/hexane) gave
1-(3-hydroxy-5,5,8,8-tetrame-
thyl-5,6,7,8-tetrahydro-naphthalen-2-yl)ethanone as a light yellow
solid. Recrystallization from hexane afforded the product as white
crystals 15.2 g (66%): .sup.1H NMR (400 NHz, CDCl.sub.3) .delta.
7.63 (s, 1H, ArH), 6.9 (s, 1H, ArH), 2.61 (s, 3H, CH.sub.3), 1.67
(s, 4H, 2CH.sub.2), 1.29 (s, 6H, 2CH.sub.3), 1.27 (s, 6H,
2CH.sub.3).
[0226] A 200-mL round bottom flask was flame dried under nitrogen
and charged with sodium metal (3.2 g, 140 mmol). A solution of
1-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)ethan-
one (15 g, 61.0 mmol) in ethyl, formate (350 mL) was added dropwise
over 1 h. The resulting yellow solution was stirred at 35.degree.
C. for 4 h. The mixture was cooled to 25.degree. C. solution,
diluted with 1N HCl (20 mL) and extracted with ether. The extracts
were washed with water, brine, and dried over MgSO.sub.4. The
extracts were concentrated under vacuum to give
2-hydroxy-6,6,9,9-tetramethyl-2,3,6,7,8,9-hexahydrobenzo[g]chromen-4-
one: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.85 (s, 1H, ArH),
6.9 (s, 1H, ArH), 5.85 (t, 1H, CH), 3.32 (br s, 1H, OH), 2.9 (dd,
2H, CH.sub.2), 1.67 (s, 4H, 2CH.sub.2), 1.27 (s, 12H,
4CH.sub.3).
[0227] To a solution of above benzochromen-4-one (19.6 g, 71.5
mmol) in methanol (250 mL) was added concentrated HCl (0.5 mL)
dropwise. The mixture was stirred at 60.degree. C. for 2.5 h. TLC
analysis indicated the reaction was complete. The mixture was
cooled to 25.degree. C. and diluted with water (200 mL). A light
brown solid precipitate was collected by filtration and dissolved
in ether, washed with water, brine and dried over sodium sulfate.
Concentration under vacuum gave
6,6,9,9-tetramethyl-6,7,8,9-tetrahydro-benzo[g]chromen-4-one 13.3 g
(73%) as a light brown solid m.p. 201-202.degree. C.; .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.15 (s, 1H, ArH), 7.8 (d, 1H,
olefinic), 7.4 (s, 1H, ArH), 6.25 (d, 1H, olefinic), 1.75 (s, 4H,
2CH.sub.2), 1.35 (s, 12H, 4CH.sub.3).
[0228] A solution of
6,6,9,9-tetramethyl-6,7,8,9-tetrahydro-benzo[g]chrome- n-4-one (400
mg, 1.56 mmol) in EtOAc (30 mL) was hydrogenated (1 atm H.sub.2)
over 10% palladium on carbon for 3 h. The mixture was filtered
through Celite and the filter pad was rinsed with EtOAc (400 mL)
and concentrated to afford
6,6,9,9-tetramethyl-2,3,5,6,7,8,9-hexahydro-benzo[-
g]chromen-4-one, 379 mg (94%): .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.85 (s, 1H, ArH), 6.89 (s, 1H, ArH), 4.49 (t, 2H, J=6.4
Hz, ring CH.sub.2), 2.77 (t, 2H, J=6.4 Hz, ring CH.sub.2), 1.56 (s,
4H, 2CH.sub.2), 1.27 (s, 12H, 4CH.sub.3).
[0229] To the ketone (379 mg, 1.47 mmol) in methanol (20 mL) at
0.degree. C. was added NaBH.sub.4 (82 mg, 2.2 mmol) and the mixture
was allowed to stir for 30 min. The reaction was poured into 10%
HCl aqueous solution (100 mL), extracted with EtOAc (100 mL),
separated, and concentrated to give
6,6,9,9-tetramethyl-2,3,5,6,7,8,9-hexahydro-2H-benzo[g]chromen-4-ol
320 mg (84%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.26 (s,
1H, ArH), 6.79 (s, 1H, ArH), 4.76 (m, 1H, CH--OH), 2.10 (m, 2H,
ring CH.sub.2), 2.00 (m, 2H, ring CH.sub.2), 1.66 (s, 4H,
2CH.sub.2), 1.27 (s, 6H, 2CH.sub.3), 1.25 (s, 6H, 2CH.sub.3).
[0230] To a solution of triphenyl phosphine hydrobromide (424 mg,
1.2 mmol) in 25 mL of methanol was added the alcohol (320 mg, 1.2
mmol) in methanol (25 mL) and the solution was stirred at room
temperature for 4 h. The reaction was concentrated in vacuo to give
a white foam. Trituration with 20% etherihexane solution
(3.times.10 mL) gave the phosphorium salt as a yellow solid. The
phosphonium bromide in THF (10 mL) was treated with a solution of
n-BuLi (0.43 mL of a 2.5 M, 1.08 mmol) at -78.degree. C. and
allowed to stir for 30 minutes A solution of methyl-4-formyl
benzoate (177 mg, 1.08 mmol) in THF (20 mL) was added at
-78.degree. C. The reaction was warmed to ambient temperature then
quenched with aqueous, saturated NH.sub.4Cl. The solution was
extracted with ether (100 mL), concentrated, and dried (MgSO.sub.4)
to afford
4-(6,6,9,9-tetramethyl-6,7,8,9-tetrahydro-2H-benzo[g]chromen-4-ylidenemet-
hyl)-benzoic acid methyl ester (240 mg, 52%): .sup.1H NMR (400 MMz,
CDCl.sub.3) .delta. 8.02 (1/2ABq, 2H, J=8.3 Hz, ArH), 7.58 (s, 1H,
ArH), 7.38 (1/2ABq, 2H, J=8.3 Hz, ArH) 7.06 (s, 1H, olefinic) 6.80
(s, 1H, ArH), 4.15 (t, 2H, J=5.6 Hz, ring CH.sub.2), 2.89 (t, 2H,
J=5.6 Hz, ring CH.sub.2), 3.93 (s, 3H, CH.sub.3), 1.68 (s, 4H,
2CH.sub.2), 1.32 (s, 6H, 2CH.sub.3), 1.24 (s, 6H, 2CH.sub.3).
[0231] To a mixture of
4-(6,6,9,9-tetramethyl-6,7,8,9-tetrahydro-2H-benzo[-
g]chromen-4-ylidenemethyl)-benzoic acid methyl ester (220 mg, 0.56
mmol) in methanol (10 mL) was added concentrated HCl (0.05 mL) and
the solution was allowed to stir at 85.degree. C. for 12 h. The
solution was quenched with aqueous saturated NaHCO.sub.3 solution
(100 mL), extracted with EtOAc, dried (Na.sub.2SO.sub.4), and
concentrated. The acid was obtained by hydrolysis according to the
standard conditions and was purified by silica gel preparative TLC
(50% EtOAc/Hexane) to afford
4-(6,7,8,9-tetrahydro-6,6,9,9-tetramethyl-2H-benzo[g]chromen-4-ylmethyl)--
benzoic acid (133) (89%) as a white solid: m.p. 200-201.degree. C.;
IR (neat) 2969 s, 2958 s, 2922 s, 2361 m, 1689 s, 1608 m, 1419 s,
1408 s, 1286 m, 1174 s, 1018 s cm.sup.-1; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.04 (1/2ABq, 2H, J=8 0 Hz, ArH), 7.37 (1/2ABq,
2H, J=8.0 Hz, ArH), 6.98 (s, 1H, ArH), 6.74 (s, 1H, ArH), 5.43
(broad t, 1H, olefinic), 4.75 (m, 2H, ring CH.sub.2), 3.79 (s, 2H,
benzylic CH.sub.2), 1.59 (s, 4H, 2CH.sub.2), 1.22 (s, 6H,
2CH.sub.3), 1.13 (s, 6H, 2CH.sub.3).
EXAMPLE 34
[0232]
4-(3,4,6,7,8,9-Hexahydro-2-oxo-6,6,9,9-tetramethyl-2H-benzo[g]quino-
lin-1-ylmethyl)-benzoic Acid (Compound 134, Prepared as Illustrated
and Described in Scheme 10)
[0233] To a solution of
6,6,9,9-tetramethyl-3,4,6,7,8,9-hexahydro-1H-benzo-
[g]quinolin-2-one (130 mg, 0.50 mmol) in THF (4 mL) was added NaH
(18 mg, 0.76 mmol) in one portion at ambient temperature. To this
solution was added methyl 4-(bromomethyl)-benzoate (229 mg, 1.01
mmol) in THF (8 mL). The mixture was then heated at 60.degree. C.
for 8 h, cooled to ambient temperature, quenched with aqueous
saturated NH.sub.4Cl (20 mL), extracted with EtOAc (100 mL), dried
with (MgSO.sub.4), concentrated, and purified by column
chromatography (10% ether in hexane) to afford
4-(6,6,9,9-tetramethyl-3,4,6,7,8,9-hexahydro-1H-benzo[g]quinolin-1-ylmeth-
yl)benzoic acid methyl ester (120 mg, 58%): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.10 (1/2 ABq, 2H, J=8.0 Hz, ArH), 7.48
(1/2ABq, 2H, J=8.0 Hz, ArH), 7.08 (s, 1H, ArH), 6.70 (s, 1H, ArH),
5.20 (s, 2H, CH.sub.2), 4.51 (s, 3H, CH.sub.3), 2.91 (t, 2H, J=7.0
Hz, ring CH.sub.2), 2.81 (broad m, 2H, ring CH.sub.2), 1.60 (s, 4H,
2CH.sub.2), 1.23 (s, 12H, 4CH.sub.3).
[0234] The acid was obtained by hydrolysis according to the
standard conditions to yield
4-(3,4,6,7,8,9-hexahydro-2-oxo-6,6,9,9-tetramethyl-2H-
-benzo[g]quinolin-1-ylmethyl)-benzoic acid (134) 8.7 mg (10%) as a
yellow oil, IR (neat) 3398 m, 2928 m, 2914 m, 2870 m, 1682 m, 1670
m, 1651 s, 1612 s, 1423 s, 1363 s cm.sup.-1; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.04 (1/2ABq, 2H, J=8 Hz, ArH), 7.35 (1/2ABq,
2H, J=8 Hz, ArH), 7.07 (s, 1H, ArH), 6.68 (s, 1H, ArH), 5.22 (s,
2H, CH.sub.2), 2.94 (t, 2H, J=7 Hz, ring CH.sub.2), 2.80 (broad m,
2H, J=8, ring CH.sub.2), 1.23 (s, 4H, 2CH.sub.2), 1.04 (s, 12H,
4CH.sub.3).
EXAMPLE 35
[0235]
4-(3,4,6,7,8,9-Hexahydro-6,6,9,9-tetramethyl-2H-benzo[g]quinolin-1--
ylmethyl)-benzoic Acid (Compound 135, Prepared as Illustrated and
Described in Scheme 10)
[0236] To a solution of
6,6,9,9-tetramethyl-3,4,6,7-hexahydro-1H-benzo[g]q- uinolin-2-one
(1.0 g, 3.9 mmol, prepared by Friedel-Crafts alkylation/annulation
of 2-oxo-1,2,3,4-tetrahydroquinoline with
2,5-dichloro-2,5-dimethylhexane in the presence of aluminum
trichloride at ambient temperature in dichloromethane) in THF (10
mL) at ambient temperature was added LiAlH.sub.4 (11.7 mmol). The
reaction mixture was heated to 80.degree. C. and allowed to stir
for 30 minutes. The reaction mixture was poured into aqueous
saturated sodium potassium tartrate (100 mL), extracted with EtOAc
(100 mL), dried (MgSO.sub.4), and concentrated to give
6,6,9,9-tetramethyl-1,2,3,4,6,7,8,9-octahydrobenzo[g]quinoline 978
mg (99%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.88 (s, 1H,
ArH), 6.41 (s, 1H, ArH), 3,26 (t, 2H, J=6.2 Hz, ring CH.sub.2),
2.71 (t, 2H, J=4.0 Hz, ring, CH.sub.2), 1.92 (m, 2H, ring
CH.sub.2), 1.63 (s, 4H, 2CH.sub.2), 1.23 (s, 12H, 4CH.sub.3).
[0237] To a solution of
6,6,9,9-tetramethyl-1,2,3,4,6,7,8,9-octahydrobenzo- [g]quinoline
(200 mg, 0.823 mmol) in THF (4 mL) was added NaH (30 mg, 1.2 mmol)
in one portion at ambient temperature. To this solution was added
methyl 4-(bromomethyl)-benzoate (377 mg, 1.6 mmol) in THF (8 mL).
The mixture was then heated at 60.degree. C. for 8 h, cooled to
ambient temperature, quenched with aqueous saturated NH.sub.4Cl (20
mL), extracted with EtOAc (100 mL), dried (MgSO.sub.4),
concentrated, and purified by column chromatography (10% ether in
hexanes) to afford
4-(6,6,9,9-tetramethyl-3,4,6,7,8,9-hexahydro-2H-benzo[g]quinolin-1-ylmeth-
yl)-benzoic acid methyl ester 130 mg (40%): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.98 (1/2 ABq, 2H, J=9.0 Hz, ArH), 7.38
(1/2ABq, 2H, J=9.0 Hz, ArH), 6.91 (s, 1H, ArH), 6.33 (s, 1H, ArH)
4.45 (s, 2H, CH.sub.2), 3.90 (s, 3H, CH.sub.3), 3.2 (t, 2H, J=5.4
Hz, ring CH.sub.2), 2.79 (t, 2H, J=6.4 Hz, ring CH.sub.2), 2.02 (m,
2H, ring CH.sub.2), 1.59 (s, 4H, 2CH.sub.2), 1.22 (s, 6H,
2CH.sub.3), 1.06 (s, 6H, 2CH.sub.3).
[0238] The acid was prepared by hydrolysis according to the
standard conditions to yield
4-(3,4,6,7,8,9-hexahydro-6,9,9-tetramethyl-2H-benzo[g-
]quinolin-1-ylmethyl)-benzoic acid (135) 117 mg (40%) as a yellow
solid: m.p. 173-175.degree. C.; IR (neat) 2965 s, 2910 s, 2850 s,
1695 s, 1592 s, 1503 s, 1483 m, 1410 s cm.sup.-1, .sup.1H NMR (400
Hz, CDCl.sub.3) .delta. 8.04 (1/2 ABq, 2H, J=8.0 Hz, ArH), 7.42
(1/2ABq, 2H, J=8.0 Hz, ArH), 6.91 (s, 1H, ArH), 6.33 (s, 1H, ArH),
4.46 (s, 2H, CH.sub.2), 3.35 (t, J=7.0 Hz, 2H, ring CH.sub.2), 2.78
(t, 2H, J=6.0, CH.sub.2), 2.03 (m, 2H, ring CH.sub.2), 1.60 (s, 4H,
2CH.sub.2), 1.26 (s, 6H, 2CH.sub.3), 1.07 (s, 6H, 2CH.sub.3).
EXAMPLE 36
[0239]
4-(2,3,6,7,8,9-Hexahydro-6,6,9,9-tetramethyl-naphtho[2,3-b][1,4]oxa-
zin-4-ylmethyl)-benzoic Acid (Compound 136, Prepared as Illustrated
and Described in Scheme 10)
[0240] To a solution of
6,6,9,9-tetramethyl-6,7,8,9-tetrahydro-4H-naphtho[-
2,3-b][1,4]oxazin-3-one (400 mg, 1.5 mmol; prepared by Friedel
Crafts acylation/annulation of 2H-1,4-benzoxazin-3[4H]-one with
2,5-dichloro-2,5-dimethylhexane in the presence of aluminum
trichloride in dichloromethane) in THF (20 mL) at 0.degree. C. was
added LiAlH.sub.4 (4.6 mmol). The reaction was warmed to ambient
temperature then heated to 80.degree. C. for 1 h. The reaction was
then allowed to cool to ambient temperature, was quenched in
aqueous saturated sodium potassium tartrate (100 mL), extracted
with EtOAc, dried (MgSO.sub.4), and concentrated. The product was
washed with hexane and purified by column chromatography (30%
EtOAc/Hexane) to give
6,6,9,9-tetramethyl-3,4,6,7,8,9-hexanydro-2H-naphth-
o[2,3-b][1,4]oxazin 300 mg (70%): .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 6.71 (s, 1H, ArH), 6.52 (s, 1H, ArH), 4.22 (t, 2H, J=4.6
Hz, ring CH.sub.2), 3.39 (t, 2H, J=4.6 Hz, ring CH.sub.2), 1.63 (s,
4H, 2CH.sub.2), 1.22 (s, 12H, 4CH.sub.3).
[0241] To a pressure tube containing a solution of methyl
4-bromomethyl benzoate (187 mg, 0.82 mmol) in THF (20 mL) and NaH
(15 mg, 0.61 mmol) was added
6,6,9,9-tetramethyl-3,4,6,7,8,9-hexahydro-2H-naphtho[2,3-b][1,4-
]oxazine (100 mg, 0.41 mmol) in THF (5 mL). The reaction was heated
at 60.degree. C. for 12 h. The reaction was then cooled to ambient
temperature, quenched with aqueous saturated NH.sub.4Cl, extracted
with EtOAc (100 mL), concentrated, and purified by silica gel
preparative TLC (12% EtOAc/hexane) to give
4-(6,6,9,9-tetramethyl-2,3,6,7,8,9-hexahydro-n-
aphtho[2,3-b][1,4]oxazin-4-ylmethyl)-benzoic acid methyl ester 104
mg (65%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.01 (1/2ABq,
J=7.7 Hz, 2H, ArH), 7.4 0(1/2ABq, J=7.7 Hz, 2H, ArH), 6.74 (s, 1H,
ArH), 6.47 (s, 1H, ArH), 4.42 (s, 2H, CH.sub.2), 4.28 (t, 2H, J=4.5
Hz, ring CH.sub.2), 3.91 (s, 3H, CH.sub.3), 3.31 (t, 2H, J=4.5 Hz,
ring CH.sub.2), 1.60 (s, 4H, 2CH.sub.2), 1.22 (s, 6H, 2CH.sub.3),
1.09 (s, 6H, 2CH.sub.3).
[0242] The acid was obtained by hydrolysis according to the
standard conditions to afford
4-(2,3,6,7,8,9-hexahydro-6,6,9,9-tetramethyl-naphtho-
[2,3-b][1,4]oxazin-4-ylmethyl)-benzoic acid (136) 35 mg (35%) as an
off-white solid: m.p. 187.degree. C.; IR (neat) 2657 m, 2924 m,
2856 m, 1691 m, 1651 m, 1612 m, 1510 s, 1290 s, 1253 s cm.sup.-1;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.09(1/2ABq, 2H, J=8.0
Hz, ArH), 7.47 (1/2ABq, 2H, J=8.0 Hz, ArH), 6.76 (s, 1H, ArH), 6.50
(s, 1H, ArH), 4.51 (broad t, 2H, ring CH.sub.2), 4.32 (s, 2H,
CH.sub.2), 3.43 (broad t, 2H, ring CH.sub.2), 1.60 (s, 4H,
2CH.sub.2), 1.22 (s, 6H, 2CH.sub.3), 1.08 (s, 6H, 2CH.sub.3).
EXAMPLE 37
[0243]
4(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracene-1-car-
bonyl)-benzoic Acid (Compound 137, Prepared as Illustrated and
Described in Scheme 11)
[0244] A solution of
3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-2H-anthrace- n-1-one
(from Example 30, 1.0 g, 3.9 mmol) in EtOH (10 mL) was combined
with 4-toluenesulfonhydrazide (731 mg, 3.9 mmol). A catalytic
amount of concentrated HCl (100 mL) was added and the solution was
heated at reflux for 3 h. The mixture was cooled to ambient
temperature and the solid was collected by filtration. The solid
was recrystallized (EtOH) to yield the tricyclic hydrazone 2.18 g
(87%). The hydrazone (626 mg, 1.5 mmol) in THF (10 mL) was treated
directly with n-BuLi (2.5 M in hexanes, 2.36 mL, 6.0 mmol) at
0.degree. C. and the orange solution was allowed to warm to ambient
temperature and subsequently cooled at -78.degree. C. A solution of
methyl 4-formylbenzoate (366 mg, 2.25 mmol) in THF (3 mL) was added
dropwise to the solution of the vinyl anion. The resulting yellow
solution was allowed to warm to ambient temperature over 2 h and
then quenched with aqueous saturated NH.sub.4Cl. The aqueous
solution was extracted with EtOAc (3.times.). The organic layers
were combined, and washed with water (2.times.) and brine. The
organic solution was dried (Na.sub.2SO.sub.4), filtered, and
concentrated. The crude product was purified by silica gel
chromatography (10:1=hexanes:EtOAc) to give
4-(3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-anthracen-1-yl
hydroxymethyl)-benzoic acid methyl ester 350 mg (84%): .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.00 (1/2ABq, J=8.2 Hz, 2H, ArH),
7.55 (1/2ABq, J=8.2 Hz, 2H, ArH), 7.12 (s, 1H, ArH), 7.01 (s, 1H,
ArH), 6.05 (broad t, 1H, olefinic), 6.33 (broad s, 1H, CH), 3.90
(s, 3H, OCH.sub.3), 2.72 (t, J=7.9 Hz, 2H, CH.sub.2), 2.34 (m, 2H,
CH.sub.2), 1.63 (s, 4H, 2CH.sub.2), 1.22 (s, 6H, 2CH.sub.3), 1.15
(s, 3H, CH.sub.3), 1.05 (s, 3H, CH.sub.3).
[0245] The hydroxy ester (350 mg, 0.84 mmol) was oxidized directly
with MnO.sub.2 (350 mg.times.2) in dichloromethane (20 mL) at
ambient temperature for 3 h. The reaction mixture was filtered
through a pad of Celite and the pad was rinsed with EtOAc. The
organic solution was concentrated to give
4-(3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-anthrac-
ene-1-carbonyl)-benzoic acid methyl ester 306 mg (88%): .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.09 (1/2ABq, J=8.2 Hz, 2H, ArH),
7.83 (1/2ABq, J=8.2 Hz, 2H, ArH), 7.28 (s, 1H, ArH), 7.08 (s, 1H,
ArH 6.48 (broad t, 1H, olefinic), 3.93 (s, 3H, OCH.sub.3), 2.72 (t,
J=7.9 Hz, 2H, CH.sub.2), 2.50 (m, 2H, CH.sub.2), 1.65 (m, 4H,
2CH.sub.2), 1.30 (s, 6H, 2CH.sub.3), 1.13 (s, 6H, 2CH.sub.3).
[0246] Hydrolysis of the ester has described in Example 30 afforded
two products.
4-(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracene--
1-carbonyl)-benzoic acid (137) 6 mg (8%): IR (neat) 3500-3000 broad
m, 2960 m, 2926 m, 1726 s, 1633 m, 1597 s, 1568 m, 1253 s, 1215 s
cm.sup.-1; .sup.1H NMR (400 MHz, d.sub.6-acetone) .delta. 8.19
(1/2ABq, J=8.2 Hz, 2H, ArH), 7.92 (1/2ABq, J=8.2 Hz, 2H, ArH), 7.81
(s, 2H, ArH), 7.37 (app d, J=2.2 Hz, 1H, ArH), 7.22 (app d, J=2.2
Hz, 1H, ArH), 1.74 (m, 4H, 2CH.sub.2), 1.39 (s, 6H, CH.sub.3), 1.19
(s, 6H, 2CH.sub.3).
[0247] The other product isolated from the hydrolysis was
4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracene-1-carbonyl)-benzoic
acid 51 mg (68%): m.p. 190-193.degree. C.; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.18 (m, 3H, ArH), 7.93 (m, 3H, ArH), 7.84 (s,
1H, ArH), 7.52 (m, 1H, ArH), 7.38 (m, 1H, ArH), 1.74 (m, 4H,
2CH.sub.2), 1.39 (s, 6H, 2CH.sub.3), 1.24 (s, 6H, 2CH.sub.3).
EXAMPLE 38
[0248]
4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-anthracen-1-yl)-hydroxym-
ethyl]-benzoic Acid (Compound 138, Prepared as Illustrated and
Described in Scheme 12)
[0249] A solution of
4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracene--
1-carbonyl)-benzoic acid(from Example 36, 10 mg, 0.03 mmol) in MeOH
(2 mL) was treated with NaBH.sub.4 (5 mg) at ambient temperature
and the mixture was allowed to stir for 5 min. The reaction was
quenched with aqueous saturated NH.sub.4Cl. The aqueous solution
was extracted with EtOAc (3.times.). The organic layers were
combined and washed with water (2.times.) and brine. The organic
solution was dried (Na.sub.2SO.sub.4), filtered, and concentrated
to afford 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-anthracen-1-yl)-hydroxymethyl]-benzoic acid (138) 9.2 mg
(92%) as a colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.04 (1/2ABq, J=8.3 Hz, 2H, ArH), 7.95 (s, 1H, ArH), 7.76 (s, 1H,
ArH), 7.71 (d, J=82 Hz, 1H, ArH), 7.56 (1/2ABq, J=8.3 Hz, 2H, ArH),
7.43 (d, J=6.9 Hz, 1H, ArH), 7.34 (dd, J=6.9, 8.2 Hz, 1H, ArH),
6.48 (s, 1H, CH), 1.70 (broad s, 4H, 2CH.sub.2), 1.35 (s, 3H,
CH.sub.3), 1.34 (s, 3H, CH.sub.3), 1.24 (s, 3H, CH.sub.3), 1.19 (s,
3H, CH.sub.3).
EXAMPLE 39
[0250]
4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-anthracen-1-ylmethyl)-ben-
zoic Acid (Compound 139, Prepared as Illustrated and Described in
Scheme 12)
[0251] A solution of
4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracen--
1-yl)-hydroxymethyl]-benzoic acid (from Example 37, 30 mg, 0.07
mmol) in dichloromethane (5 mL) was treated with excess
triethylsilane (0.2 mL) and BF.sub.3-Et.sub.2O (0.16 mL) at
0.degree. C. The solution was allowed to stir for 10 min and then
EtOH was added. The mixture was diluted with water and EtOAc. The
organic solution was washed with water and brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated to yield
4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracen-1-ylmethyl)-benzoic
acid (139) 15 mg, (55%) as a colorless oil: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.01 (1/2Aq, J=8.2 Hz, 2H, ArH), 7.81 (s, 1H,
ArH), 7.77 (s, 1H, ArH), 7.66 (d, J=8.2 Hz, 1H, ArH), 7.32 (m, 3H,
ArH), 7.24 (s, 1H, ArH), 7.19 (d, J=6.7 Hz, 1H, ArH), 4.45 (s, 2H,
CH.sub.2), 1.72 (m, 4H, 2CH.sub.2), 1.35 (s, 6H, 2CH.sub.3), 1.24
(s, 6H, 2CH.sub.3).
EXAMPLE 40
[0252]
4-[1-Hydroxy-1-(5,6,7,8-Tetrahydro-(5,5,8,8-tetramethyl-anthracen-1-
-yl)-ethyl)]-benzoic Acid (Compound 140, Prepared as Illustrated
and Described in Scheme 13)
[0253] A solution of
4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracene--
1-carbonyl)-benzoic acid (from Example 36, 10 mg, 0.03 mmol) in
CH.sub.2Cl.sub.2 (2 mL) was treated with trimethylaluminum (0.4 mL)
at 0.degree. C. and the solution was allowed to stir for 1 h. The
reaction was quenched with aqueous saturated potassium sodium
tartrate. The aqueous solution was extracted with EtOAc (3.times.).
The organic layers were combined and washed with water (2.times.)
and brine. The organic solution was dried (Na.sub.2SO.sub.4),
filtered, and concentrated to afford
4-[1-hydroxy-1-(5,6,7,8-tetrahydro-5,5,8,3-tetramethyl-anthracen-1-
-yl)-ethyl)]-benzoic acid (140) 5.0 mg (55%) as a colorless oil:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.01 (1/2ABq, J=8.2 Hz,
2H, ArH), 7.74 (m, 3H, ArH), 7.53 (1/2ABq, J=8.2 Hz, 2H, ArH), 7.39
(t, J=7.7 Hz, 1H, ArH), 7.26 (s, 1H, ArH), 2.05 (s, 3H, CH.sub.3),
1.64 (m, 4H, 2CH.sub.2), 1.26 (s, 6H, 2CH.sub.3), 1.15 (s, 3H,
CH.sub.3), 0.77 (s, 3H, CH.sub.3).
EXAMPLE 41
[0254]
4-[1-Methoxy-1-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-anthracen-1--
yl)-ethyl)]-benzoic Acid (Compound 141, Prepared as Illustrated and
Described in Scheme 13)
[0255] A solution of
4-[1-hydroxy-1-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-
-anthracen-1-yl)-ethyl)-benzoic acid (from Example 39; 5 mg, 0.01
mmol) in MeOH (2 mL) was treated with concentrated HCl (0.25 mL) at
ambient temperature The solution was heated to 85.degree. C. and
allowed to stir for 1 h. The reaction was quenched with aqueous
saturated NH.sub.4Cl. The aqueous solution was extracted with EtOAc
(3.times.). The organic layers were combined and washed with water
(2.times.) and brine. The organic solution was dried
(Na.sub.2SO.sub.4), filtered, and concentrated to afford after
silica gel flash chromatography (70:30=EtOAc:hexanes),
4-[1-methoxy-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracen-1-yl)-et-
hyl)]-benzoic acid (141) 0.6 mg (12%) as a colorless oil: .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 8.02 (1/2ABq, J=8.2 Hz, 2H, ArH),
7.77 (m, 3H, ArH), 7.54 (1/2ABq, J=8.2 Hz, 2H, ArH), 7.36 (t, J=7.7
Hz, 1H, ArH), 7.25 (s, 1H, ArH), 3.90 (s, 3H, OCH.sub.3), 2.03 (s,
3H, CH.sub.3), 1.69 (m, 4H, 2CH.sub.2), 1.29 (s, 6H, 2CH.sub.3),
1.10 (s, 3H, CH.sub.3), 0.83 (s, 3H, CH.sub.3).
EXAMPLE 42
[0256]
4-[1-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-anthracen-1-yl)-vinyl)-
]-benzoic Acid (Compound 142, Prepared as Illustrated and Described
in Scheme 13)
[0257] The final product mixture from Example 40 was further
purified by preparative silica gel TLC (70:30=EtOAc:hexanes), to
afford
4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracen-1-yl)-vinyl)]-benz-
oic acid (142) 1 mg (20%) as a colorless oil: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.97 (1/2ABq, J=8.4 Hz, 2H, ArH), 7.75 (s, 1H,
ArH), 7.73 (m, 1H, ArH), 7.50 (s, 1H, ArH), 7.40 (1/2ABq, J=8.4 Hz,
2H, ArH), 7.35 (m, 2H, ArH), 5.98 (d, J=1.0 Hz, 1H, olefinic), 5.53
(app s, 1H, olefinic), 1.65 (m, 4H, 2CH.sub.2), 1.35 (s, 6H,
2CH.sub.3), 1.03 (s, 6H, 2CH.sub.3).
EXAMPLE 43
[0258]
(trans)4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-anthracene-1-carbo-
nyl oxime)-benzoic Acid (Compound 143, Prepared as Illustrated and
Described in Scheme 14)
[0259] A solution of
4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracene--
1-carbonyl)-benzoic acid (from Example 36, 18 mg, 0.04 mmol) in
EtOH (2 mL) and pyridine (0.05 mL) was treated with hydroxylamine
hydrochloride (5 mg, 0.07 mmol), and the mixture was heated at
reflux. After 6 h, the mixture was cooled to room temperature and
ethanol was removed in vacuo. The residue was taken-up in water and
the aqueous layer was adjusted to pH=4-5 with 1 M aqueous HCl. The
aqueous solution was extracted with EtOAc (3.times.). The organic
layers were combined and washed with water (2.times.) and brine.
The organic solution was dried (Na.sub.2SO.sub.4), filtered, and
concentrated to give a foamy white solid. Purification by silica
gel chromatography (1:1=hexanes:Et.sub.2O) (trans)-4-(5,6,7,8-tetr-
ahydro-5,5,8,8-tetramethyl-anthracene-1-carbonyl oxime)-benzoic
acid (143), 2.5 mg (16%) as a colorless film. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 8.04 (1/2ABq, J=8.5 Hz, 2H, ArH), 7.85 (d,
J=8.3 Hz, 1H, ArH), 7.83 (s, 1H, ArH), 7.60 (1/2ABq, J=8.5 Hz, 2H,
ArH), 7.51 (s, 1H, ArH), 7.44 (dd, J=8.3, 7.2 Hz, 1H, ArH), 7.26
(d, J=7.2 Hz, 1H, ArH), 1.70 (m, 4H, 2CH.sub.2), 1.38 (s, 12H,
4CH.sub.3).
EXAMPLE 44
[0260]
(cis)-4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-anthracene-1-carbon-
yl oxime)-benzoic acid (Compound 144, Prepared as Illustrated and
Described in Scheme 14)
[0261] The product mixture from Example 42 was purified by
preparative silica gel chromatography (Et.sub.2O) to afford
(cis)-4-(5,6,7,8-tetrahyd-
ro-5,5,8,38-tetramethyl-anthracene-1-carbonyl oxime)benzoic acid
(144) 0.5 mg (3%) as a colorless film: 1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.05 (1/2ABq, J=8.4 Hz, 2H, ArH), 7.99 (d, J=8.5 Hz, 1H,
ArH), 7.75 (s, 1H, ArH), 7.70 (1/2ABq, J=8.4 Hz, 2H, ArH), 7.65 (s,
1H, ArH), 7.59 (d, J=8.0 Hz, 1H, ArH), 7.38 (dd, J=8.5, 8.0 Hz, 1H,
ArH), 1.68 (m, 4H, 2CH.sub.2), 1.33 (s, 3H, CH.sub.3), 1.23 (s, 6H,
2CH.sub.3), 1.06 (s, 3H, CH.sub.3).
EXAMPLE 45
[0262]
(trans)-4-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-anthracene-1-carb-
onyl O-methyloxime)-benzoic Acid (Compound 145, Prepared as
Illustrated and Described in Scheme 14)
[0263] A solution of
4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-anthracene--
1-carbonyl)-benzoic acid (from Example 36, 21 mg, 0.04 mmol) in
EtOH (2 mL) was treated with methoxyl amine hydrochloride (12 mg,
0.15 mmol) and pyridine (0.05 mL), and the mixture was heated at
reflux for 5 h. The reaction was worked-up in a manner identical to
that described for Example 42 to give, after silica gel
chromatography (1:1=hexanes:Et.sub.2O)
(trans)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-
-anthracene-1-carbonyl O-methyloxime)-benzoic acid (145) 8.2 mg
(49%) as a colorless oil: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.04 (1/2ABq, J=8.5 Hz, 2H, ArH), 7.85 (d, J=8.3 Hz, 1H, ArH), 7.83
(s, 1H, ArH), 7.63 (1/2ABq, J=8.5 Hz, 2H, ArH), 7.51 (s, 1H, ArH),
7.44 (dd, J=8.3, 7.2 Hz, 1H, ArH), 7.20 (d, J=7.2 Hz, 1H, ArH),
3.98 (s, 3H, OCH.sub.3), 1.70 (m, 4H, 2CH.sub.2), 1.38 (s, 12H,
4CH.sub.3).
EXAMPLE 46
[0264] (2E, 4E,
6E)-7-(3,5-Diisopropyl-2-n-heptyloxyphenyl)-3-methylocta-2-
,4,6-trienoic Acid (Compound 146, Prepared as Illustrated and
Described in Scheme 15).
[0265] A solution of 3,5-diisopropyl-2-hydroxybenzoic acid (20.0 g,
90.1 mmol) in THF (100 mL) at -78.degree. C. was treated dropwise
with a solution of methyllithium (1.4 M in ether, 193 mL, 270
mmol). The reaction solution was allowed to warm to room
temperature and stirred for 30 min. The solution was poured into
saturated aqueous NH.sub.4Cl (200 mL), and the organic product was
extracted with 1:1=EtOAc:hexanes (2.times.100 mL), dried
(MgSO.sub.4), filtered, and concentrated. Distillation (1 mm Hg,
120.degree. C.) gave 3,5-diisopropyl-2-hydroxyacet- ophenone 12.0 g
(61%): TLC (5% EtOAc-95% hexanes) R.sub.f=0.4, .sup.1H-NMR
(CDCl.sub.3) .delta. 7.39 (s, 1H, ArH), 7.29 (s, 1H, ArH), 3.38 (m,
1H, CH), 2.87 (m, 1H, CH), 2.63 (s, 3H, CH.sub.3), 1.24 (d, J=14.0
Hz, 12H, 4CH.sub.3).
[0266] A solution of 3,5-diisopropyl-2-hydroxy-acetophenone (1.0 g,
4.54 mmol) DMSO (1 mL) was treated with n-heptylbromide (1 mL,
excess) and KOH (solid, 600 mg, 10.7 mmol) at ambient temperature.
The mixture was heated at 50.degree. C. for 12 h, cooled to room
temperature and diluted with water (5 mL) and hexanes (10 mL). The
organic layer was separated and washed with water (2.times.5 mL)
and brine (5 mL), dried (MgSO.sub.4), and concentrated to give
3,5-diisopropyl-2-n-heptyloxyacetophenone 1.3 g, (90%): 1H-NMR
(CDCl.sub.3) .delta. 7.23 (s, 1H, ArH), 7.21 (s, 1H, ArH), 3.71(t,
J=7.4 Hz, 2H, OCH.sub.2), 3.32 (m, 1H, CH), 2.87 (m, 1H, CH), 2.63
(s, 3H, CH.sub.3), 1.78 (m, 2H, CH.sub.2), 1.31 (m, 8H, 4CH.sub.2),
1.27 (d, J=14.0 Hz, 6H, 2CH.sub.3), 1.24 (d, J=14.0 Hz, 6H,
2CH.sub.3), 0.89 (t, J=7.5 Hz, 3H, CH.sub.3).
[0267] A solution of diethylcyanomethyl phosphonate (200 g, 11.18
mmol) in THF (10 mL) at -78.degree. C. was treated dropwise with
n-BuLi (2.5 M in hexanes, 4.4 mL, 11.0 mmol). The reaction solution
was allowed to warm to ambient temperature and stirred for 30 min.
A solution of the unpurified
3,5-diisopropyl-2-n-heptyloxyacetophenone (1.0 g, 3.14 mmol) in THF
(5 mL) was added dropwise to the ylide solution. After stirring for
1 h at ambient temperature, the reaction solution was diluted with
saturated aqueous NH.sub.4Cl (20 mL) and extracted with hexanes
(2.times.20 mL). The organic extracts were combined and washed with
water (2.times.5 mL) and brine (5 mL), dried (MSO.sub.4), filtered,
and concentrated to give
3-(3,5-diisopropyl-2-n-heptyloxyphenyl)-but-2-enenitrile 900 mg
(32%), predominantly as the trans isomer: TLC (5% EtOAc-95%
hexanes) R.sub.f=0.9; .sup.1H-NMR (CDCl.sub.3), .delta. 7.11(s, 1H,
ArH), 6.81 (s, 1H, ArH), 5.57 (s, 1H, olefinic), 3.61(t, J=7.4 Hz,
2H, OCH.sub.2), 3.32 (m, 1H, CH), 2.84 (m, 1H, CH), 2.46 (s, 3H,
CH.sub.3), 1.73 (m, 2H, CH.sub.2), 1.31 (m, 8H, 4CH.sub.2), 1.27
(d, J=14.0 Hz, 6H, 2CH.sub.3), 1.24 (d, J=14.0 Hz, 6H, 2CH.sub.3),
0.89 (t, J=7.5 Hz, 3H, CH.sub.3).
[0268] A solution of
3-(3,5-diisopropyl-2-n-heptyloxyphenyl)-but-2-enenitr- ile (900 mg,
2.64 mmol) in hexanes (8 mL) was treated with DIBAL (1.5 M in
toluene, 2.0 mL, 7.95 mmol) at -78.degree. C. After stirring for 15
min at -78.degree. C., the reaction solution was quenched with a
saturated aqueous sodium-potassium tartrate solution (20 mL) and
allowed to warm to room temperature over 30 min. The product was
extracted with ether (2.times.40 mL), and the organic solution was
washed with water (2.times.5 mL) and brine (5 mL), dried
(MgSO.sub.4), filtered, concentrated. Purification by silica gel
flash chromatography (3% EtOAc-hexanes) gave the unsaturated
aldehyde 3-(3,5-diisopropyl-2-n-hepty- loxyphenyl)-but-2-enal 800
mg (90%): TLC (10% EtOAc-90% hexanes) R.sub.f=0.7, .sup.1H-NMR
(CDCl.sub.3) .delta. 10.17 (d, J=8.0 Hz, 1H, CHO), 7.11(s, 1H, ArH
), 6.82 (s, 1H, ArH),6.17 (d, J=8 Hz, 1H, olefinic), 3.65 (t, J=7.4
Hz, 2H, OCH.sub.2), 3.32 (m, 1H, CH), 2.84 (m, 1H, CH), 2.57 (s,
3H, CH.sub.3), 1.73 (m, 2H, CH.sub.2), 1.31 (m, 8H, 4CH.sub.2),
1.27 (d, J=14.0 Hz, 6H, 2CH.sub.3), 1.24 (d, J=14.0 Hz, 6H,
2CH.sub.3), 0.89 (t, J=7.5 Hz, 3H, CH.sub.3).
[0269] A solution of diethyl-3-ethoxycarbonyl-2-methyl
prop-2-enylphosphonate (1.0 g, 3.79 mmol) and DMPU (4 mL) in THF (4
mL) was cooled in a -78.degree. C. bath and treated with n-BuLi
(2.5 M solution in hexanes, 1.5 mL, 3.75 mmol). The reaction
solution was allowed to warm to room temperature and stirred for 15
min. A solution of
3-(3,5-diisopropyl-2-n-heptyloxyphenyl)-but-2-enal (820 mg, 2.38
mmol) in THF (10 mL) was added and the resulting solution was
allowed to stir for 1 h at room temperature. The reaction was
quenched with saturated aqueous NH.sub.4Cl (20 mL) and extracted
with ether (2.times.20 mL). The combined organic extracts were
washed with water (2.times.5 mL) and brine (5 mL), dried
(MgSO.sub.4), filtered, concentrated and purified by silica gel
flash column chromatography (5% EtOAc-hexanes) to give ethyl-(2E,
4E,
6E)-7-(3,5-diisopropyl-2-n-heptyloxyphenyl)-3-methylocta-2,4,6-trienoate
1.0 g (92%): TLC (5% EtOAc-95% hexanes) R.sub.f=0.8, .sup.1H-NMR
(CDCl.sub.3) .delta. 7.01 (s, 1H, ArH), 6.99 (m, 1H, olefinic),
6.84 (s, 1H, Ar), 6.35 (d, J=11.0 Hz, 1H, olefinic), 6.30 (d,
J=15.0 Hz, 1H, olefinic), 5.79 (s, 1H, olefinic), 4.18 (m, 2H,
OCH.sub.2), 3.65 (t, J=7.4 Hz, 2H, OCH.sub.2), 3.32 (m, 1H, CH),
2.84 (m, 1H, CH), 2.37 (s, 3H, CH.sub.3), 2.19 (s, 3H, CH.sub.3),
1.66 (m, 2H, CH.sub.2), 1.31 (m, 8H, 4CH.sub.2), 1.29 (t, J=14.0
Hz, 3H, CH.sub.3), 1.27 (d, J=14.0 Hz, 6H, 2CH.sub.3), 1.24 (d,
J=14.0 Hz, 6H, 2CH.sub.3), 0.89 (t, J=7.5 Hz, 3H, CH.sub.3).
[0270] A solution of the crude ethyl-(2E, 4E,
6E)-7-(3,5-diisopropyl-2-n-h-
eptyloxyphenyl)-3-methylocta-2,4,6-trienoate (500 mg, 1.10 mmol) in
methanol (5 mL) was hydrolyzed with NaOH (1 mL of 5N aqueous
solution) at reflux temperature. After 10 min, the mixture was
cooled to room temperature and acidified with a 20% aqueous HCl
solution. The solution was concentrated and the aqueous residue was
extracted with EtOAc (2.times.10 mL). The EtOAc layer was washed
with water (2.times.5 mL) and brine (5 mL), dried (MgSO.sub.4),
filtered and concentrated. The major product (highest running spot
by TLC) was isolated by preparative TLC (20% EtOAC-80% hexanes) to
give (2E, 4E, 6E)-7-(3,5-diisopropyl-2-n-hepty-
loxyphenyl)-3-methylocta-2,4,6-trienoic acid (146) 220 mg (47%):
TLC (10% MeOH-90% CHCl.sub.3) R.sub.f=0.6, .sup.1H-NMR (CDCl.sub.3)
.delta. 7.04 (m, 1H, olefinic), 7.01(s, 1H, ArH), 6.84 (s, 1H,
ArH), 6.35 (d, J=11.0 Hz, 1H, olefinic), 6.30 (d, J=15.0 Hz, 1H,
olefinic), 5.79 (s, 1H, olefinic), 3.65 (t, =7.4 Hz, 2H,
OCH.sub.2), 3.32 (m, 1H, CH), 2.84 (m, 1H, CH), 2.37 (s, 3H,
CH.sub.3), 2.19 (s, 3H, CH.sub.3), 1.66 (m, 2H, CH.sub.2), 1.31 (m,
8H, 4CH.sub.2), 1.27 (d, J=14.0 Hz, 6H, 2CH.sub.3), 1.24 (d, J=14.0
Hz, 6H, 2CH.sub.3), 0.89 (t, J=7.5 Hz, 3H, CH.sub.3).
EXAMPLE 47
[0271] (2E, 4E,
6Z)-7-(3,5-Diisopropyl-2-n-heptyloxyphenyl)-3-methylocta-2-
,4,6-trienoic Acid (Compound 147, Prepared as Illustrated and
Described in Scheme 15).
[0272] The final product mixture from Example 46 was purified by
preparative silica gel thin layer chromatography (20%
EtOAc:hexanes) to give the title compound (2E, 4E,
6Z)-7-(3,5-diisopropyl-2-n-heptyloxyphen-
yl)-3-methylocta-2,4,6-trienoic acid (147) as a colorless oil: TLC
(10% MeOH-90% CHCl.sub.3) R.sub.f=0.6, .sup.1H-NMR (CDCl.sub.3)
.delta. 7.26 (d, J=2.3 Hz, 1H, Ar--H), 7.03 (d, J=2.3 Hz, 1H,
Ar--H), 6.73 (m, 1H, olefinic), 6.24 (d, J=15.2 Hz, 1H, olefinic),
6.21 (d, J=10.2 Hz, 1H, olefinic), 5.72 ( s, 1H, olefinic), 3.61
(t, J=6.5 Hz, 2H, OCH.sub.2), 3.34 (m, 1H, CH), 2.85 (m, 1H, CH),
2.21 (s, 3H, CH.sub.3), 2.14 (s, 3H, CH.sub.3), 1.64 (m, 2H,
CH.sub.2), 1.50 (m, 2H, CH.sub.2), 1.37 (m, 6H, 3CH.sub.3), 1.27
(d, J=4.7 Hz, 6H, 2CH.sub.3), 1.21 (d, J=4.7 Hz, 6H, 2CH.sub.3),
0.88 (t, J=6.5 Hz, 3H, CH.sub.3).
EXAMPLE 48
[0273] (2E,
4E,)-7-(3,5-Diisopropyl-2-n-heptyloxyphenyl)-3-methylocta-2,4--
dienoic Acid (Compound 148, Prepared as Illustrated and Described
in Scheme 16).
[0274] To a solution of
3-(3,5-di-t-butyl-2-n-heptyloxyphenyl)-but-2-eneni- trile (900 mg,
2.64 mmol) in EtOAc (5 mL) was added 10% Pd on carbon (20 mg,
catalytic amount). The mixture was placed under vacuum for 1 min
followed by addition of H.sub.2. After stirring for 24 h under an
atmosphere of H.sub.2, the solution was filtered through celite.
The celite washed with EtOAc (3.times.5 mL) and the solution was
concentrated to give the reduced product
3-(3,5-di-t-butyl-2-n-heptyloxyphenyl)butyron- itrile 880 mg (97%):
TLC (5% EtOAc-95% hexanes) R.sub.f0.8; .sup.1H-NMR (CDCl.sub.3)
.delta. 7.00 (d, J=2.2 Hz, 1H, Ar--H), 6.89 (d, J=2.2 Hz, 1H,
Ar--H), 3.73 (t, J=6.5 Hz, 2H, OCH.sub.2), 3.52 (m, 1H, CH), 3.27
(m, 1H, CH), 2.86 (m, 1H, CH), 2.63 (m, 2H, CH.sub.2CN), 1.79 (m,
2H, CH.sub.2), 1.50 (m, 2H, CH.sub.2), 1.44 (m, 6H, 3CH.sub.2),
1.39 (d, J=13.2 Hz, 3H, CH.sub.3), 1.27 (d, J=4.7 Hz, 2CH.sub.3),
1.21 (d, J=4.7 Hz, 2CH.sub.3), 0.89 (t, J=6.6 Hz, 3H,
CH.sub.3).
[0275] To a solution of the (3,5-di-t-butyl-2-n-heptyloxyphenyl)
butyronitrile (200 mg, 0.58 mmol) in hexanes (5 mL) at -78.degree.
C. was added DIBAL (1.5 M solution in toluene, 1.20 mL, 1.80 mmol).
The reaction was stirred for 5 min, quenched with saturated aqueous
NH.sub.4Cl (10 mL), extracted with ether (2.times.20 mL), dried
(MgSO.sub.4), filtered, concentrated and purified by chromatography
(SiO.sub.2, 5% EtOAc-hexanes) to give the aldehyde
3-(3,5-di-t-butyl-2-n-heptyloxyphenyl) butyroacetal 60 mg (30%):
TLC (5% EtOAc-95% hexanes) R.sub.f0.8; .sup.1H-NMR (CDCl.sub.3)
.delta. 9.70 (t, J=2.3 Hz, 1H, CHO), 6.96 (d, J=2.2 Hz, 1H, Ar--H),
6.86 (d, J=2.2 Hz, 1H, Ar--H), 3.74 (t, J=6.5 Hz, 2H, OCH.sub.2),
3.39 (m, 1H, CH), 3.26 (m, 1H, CH), 2.82 (m, 1H, CH), 2.64 (m, 2H,
CH.sub.2), 1.50 (m, 2H, CH.sub.2), 1.40 (m, 6H, 3CH.sub.2), 1.32
(d, J=13.2 Hz, 3H, CH.sub.3), 1.27 (d, J=4.7 Hz, 2CH.sub.3), 1.21
(d, J=4.7 Hz, 2CH.sub.3), 0.88 (t, J=6.6 Hz, 3H, CH.sub.3).
[0276] In a manner similar to that described in Example 46, the
intermediate aldehyde was converted to ethyl (2E,
4E)--[7-(3,5-di-t-butyl-
-2-n-heptyloxyphenyl)-3-methyl]-octa-2,4-dienoate: TLC (5%
EtOAc-95% hexanes) R.sub.f0.9; .sup.1H-NMR (CDCl.sub.3) .delta.
6.93 (d, J=2.2 Hz, 1H, Ar--H), 6.86 (d, J=2.2 Hz, 1H, Ar--H), 6.06
(m, 2H, 2.times. olefinic), 5.65 (s, 1H, olefinic), 4.16 (m, 2H,
--CH.sub.2CH.sub.3), 3.68 (t, J=6.5 Hz, 2H, OCH.sub.3), 3.32 (m,
1H, CH), 2.84 (m, 1H, CH), 2.46 (m, 1H CH), 2.37 (m, 2H, CH.sub.2),
2.22 (s, 3H, CH.sub.3), 1.79 (m, 2H, CH.sub.2), 1.47 (m, 2H,
CH.sub.2), 1.32 (d, J=13.2 Hz, 3H, CH.sub.3), 1.31 (m, 6H,
3CH.sub.2), 1.29 (t, J=7.0 Hz, 3H, CH.sub.3), 1.27 (d, J=4.7 Hz,
6H, 2CH.sub.3), 1.21 (d, J=4.7 Hz, 6H, 2CH.sub.3), 0.89 (t, J=7.0
Hz, 3H, CH.sub.3).
[0277] The ester was hydrolyzed as described in Example 46 to give
(2E,
4E)-7-(3,5-di-t-butyl-2-n-heptyloxyphenyl)-3-methylocta-2,4-dienoic
acid (148): TLC (10% MeOH-90% CHCl.sub.3) R.sub.f0.5, .sup.1H-NMR
(CDCl.sub.3) .delta. 6.94 (d, J=2.2 Hz, 1H, Ar--H), 6.86 (d, J=2.2
Hz, 1H, Ar--H), 6.11 (m, 2H, 2.times. olefinic), 5.68 (s, 1H,
olefinic), 3.68 (t, J=6.5 Hz, 2H, OCH.sub.3), 3.28 (m, 1H, CH),
2.82 (m, 1H, CH), 2.43 (m, 1H, CH), 2.38 (m, 2H CH.sub.2), 2.23 (s,
3H, CH.sub.3), 1.77 (m, 2H, CH.sub.2), 1.43 (m, 2H, CH.sub.2), 1.34
(m, 6H, 3CH.sub.2), 1.32 Hz, 3H, CH.sub.3), 1.27 (t, J=4.7 Hz, 3H,
CH.sub.3), 1.21 (d, J=4.7 Hz, 6H, 2CH.sub.3), 0.88 (t, J=6.6 Hz,
3H, CH.sub.3).
EXAMPLE 49
[0278] (2Z,
4E,)-7-(3,5-Diisopropyl-2-n-heptyloxyphenyl)-3-methylocta-2,4,-
dienoic Acid (Compound 149, Prepared as Illustrated and Described
in Scheme 16).
[0279] The final product mixture from Example 48 was purified by
preparative silica gel thin layer chromatography (20%
EtOAc-hexanes) to give the title compound (2Z,
4E,)-7-(3,5-diisopropyl-2-n-heptyloxyphenyl)-
-3-methylocta-2,4,dienoic acid (149) as a colorless oil: TLC (10%
MeOH-90% CHCl.sub.3) R.sub.f0.6; .sup.1H-NMR (CDCl.sub.3) .delta.
7.52 (d, J=15.8 Hz, 1H, olefinic), 6.93 (d, J=2.2 Hz, 1H, Ar--H),
6.89 (d, J=2.2 Hz, 1H, Ar--H), 6.10 (s, 1H, olefinic), 5.60 (s, 1H,
olefinic), 3.68 (t, J=6.5 Hz, 2H, OCH.sub.3), 3.28 (m 1H, CH), 3.28
(m, 1H, CH), 2.85 (m, 1H, CH), 2.49 (m, 3H, CH--CH.sub.2), 1.97 (s,
3H, CH.sub.3), 1.77 (m, 2H, CH.sub.2), 1.47 (m, 2H, CH.sub.2), 1.31
(m, 6H, 3CH.sub.2), 1.27 (d, J=13.2 Hz, 3H, CH.sub.3), 1.24 (t,
J=4.7 Hz, 3H, CH.sub.3), 1.21 (d, J=4.7 Hz, 6H, 2CH.sub.3), 0.88
(t, J=6.6 Hz, 3H, CH.sub.3).
EXAMPLE 50
[0280] (2E, 4E,
6E)-7-(3,5-Diisopropyl-2-benzyloxyphenyl)-3-methylocta-2,4-
,6-trienoic Acid (Compound 150, Prepared as Illustrated and
Described in Scheme 15).
[0281] The title compound was prepared in an analogous manner as
described in Example 46 using
3,5-diisopropyl-2-benzyloxyacetophenone instead of
3,5-diisopropyl-2-n-heptyloxyacetophenone to give (2E, 4E,
6E)-7-(3,5-diisopropyl-2-benzyloxyphenyl)-3-methylocta-2,4,6-trienoic
acid (150): TLC (10% MeOH-90% CHCl.sub.3) R.sub.f=0.5; .sup.1H-NMR
(CDCl.sub.3) .delta. 7.74 (m, 5H, Ar--H), 7.05 (m, 1H, olefinic),
7.03(s, 1H, ArH), 6.90 (s, 1H, ArH), 6.43 (d, J=11.0 Hz, 1H,
olefinic), 6.34 (d, J=15.0 Hz, 1H, olefinic), 5.83 (s, 1H,
olefinic), 4.71 (s, 2H, OCH.sub.2), 3.39 (m, 1H, CH), 2.88 (m, 1H,
CH), 2.40 (s, 3H, CH.sub.3), 2.26 (s, 3H, CH.sub.3), 1.26 (m, 12H,
4CH.sub.3).
EXAMPLE 51
[0282] (2E, 4E,
6E)-7-(3,5-Diisopropyl-2-n-butyloxyphenyl)-3-methylocta-2,-
4,6-trienoic Acid (Compound 151, Prepared as Illustrated and
Described in Scheme 15).
[0283] The title compound was prepared in an analogous manner as
described in Example 46 using
3,5-diisopropyl-2-butyloxyacetophenone instead of
3,5-diisopropyl-2-n-heptyloxyacetophenone to give (2E, 4E,
6E)-7-(3,5diisopropyl-2-n-butyloxyphenyl)-3-methylocta-2,4,6-trienoic
acid (151): TLC (10% MeOH-90% CHCl.sub.3) R.sub.f=0.6; .sup.1H-NMR
(CDCl.sub.3) .delta. 7.05 (m, 1H, olefinic), 7.03(s, 1H, ArH), 6.85
(s, 1H, ArH), 6.36 (d, J=11.0 Hz, 1H, olefinic), 6.30 (d, J=15.0
Hz, 1H, olefinic), 5.83 (s, 1H, olefinic), 3.66 (t, J=7.4 Hz, 2H,
OCH.sub.2), 3.32 (m, 1H, CH), 2.84 (m, 1H, CH), 2.40 (s, 3H,
CH.sub.3), 2.26 (s, 3H, CH.sub.3), 1.67 (m, 2H, CH.sub.2), 1.44 (m,
8H, 4CH.sub.2), 1.25 (d, J=14.0 Hz, 6H, 2CH.sub.3), 1.23 (d, J=14.0
Hz, 6H, 2CH.sub.3), 0.92 (t, J=7.5 Hz, 3H, CH.sub.3).
EXAMPLE 52
[0284] (2E,
4E)-6-[2-(5,5,8,8-Tetramethyl-3-propyloxy-5,6,7,8-tetrahydrona-
phthalen-2-yl) cyclopropan-1-yl]-3-methyl Hexadienoic Acid
(Compound 152, Prepared as Illustrated and Described in Scheme
17)
[0285] To a solution of 2-bromophenol (10 g, 57.8 mmol) and
2,5-dichloro-dimethyl hexane (13.04 g, 69.36 mmol) in 160 mL
anhydrous CH.sub.2Cl.sub.2 at 5.degree. C. was added, portionwise,
AlCl.sub.3 (2.31 g, 17.34 mmol). Upon addition of AlCl.sub.3, HCl
gas evolution was observed. The solution changed from yellow to
reddish orange. The reaction solution was kept at 5-20.degree. C.
for two hours and then allowed to stir at room temperature
overnight. The reaction mixture was poured into 160 g of ice and
extracted with 160 mL. CHCl.sub.3. The organic phase was washed
with water, aqueous saturated NaHCO.sub.3, saturated NaCl and dried
(Na.sub.2SO.sub.4). The organic solution was then concentrated in
vacuo and chromatographed (5 to 10% EtOAc/hexane) to provide 12.83
g of 2-bromo-3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahyd-
ronaphthalene as a white solid in 80% yield. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.34 (s, 1H, aromatic), 6.93 (s, 1H, aromatic),
5.24 (s, 1H, phenolic OH), 1.64 (s, 4H, 2CH.sub.2), 1.23 (s, 6H,
2CH.sub.3), 1.22 (s, 6H, 2CH.sub.3).
[0286] A mixture of tetrahydrobromonaphthol (3.0 g, 10.38 mmol),
iodopropane (1.42 mL, 14.53 mmol), and K.sub.2CO.sub.3 (2.3 g,
16.61 mmol) were mixed together in 100 mL of acetone a allowed to
reflux overnight. The solvent was removed in vacuo and then 100 mL
of water was added. The aqueous phase was extracted with EtOAc
(3.times.50 mL), washed with brine, and dried (Na.sub.2SO.sub.4).
The organic phase was concentrated in vacuo to afford 3.29 g of of
2-bromo-3-propyloxy-5,5,8,8--
tetramethyl-5,6,7,8-tetrahydronaphthalene as a brownish oil (97%).
The crude material was carried on to the next step without fiurther
purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.41 (s,
1H, aromatic), 6.78 (s, 1H, aromatic), 3.97 (t, J=6.4 Hz, 2H,
CH.sub.2), 1.86 (m, 2H, CH.sub.2), 1.67 (s, 4H, 2CH.sub.2), 1.25
(s, 6H, 2CH.sub.3), 1.23 (s, 6H, 2CH.sub.3), 1.08 (t, J=7.4 Hz, 3H,
CH.sub.3).
[0287] To a solution of the above aryl bromide (12 g, 36.89 mmol)
in 200 mL of anhydrous THF at -78.degree. C., was added n-BuLi
(16.23 mL, 40.58 mmol), generating a pale yellow solution. This
reaction solution was stirred at -78.degree. C. for 15-20 minutes.
Trimethyl borate (4.19 mL, 36.89 mmol) was then added via a
syringe. The reaction mixture was allowed to warm to room
temperature and stirred overnight. It was then cooled to 0.degree.
C. and acidified with 5% HCl to pH=6. The organic phase was
concentrated in vacuo and the residue was diluted with 200 mL of
water and extracted with CH.sub.2Cl.sub.2 ( 3.times.100 mL). The
organic phase was washed with brine and dried (MgSO.sub.4). After
removal of the solvent, 9.5 g of the boronic acid was isolated as
an off-white solid in 82% yield. To a solution of
tetrakistriphenylphosphine palladium (0.032 g, 0.03 mmol) in 2 mL
of toluene under N.sub.2 was added 2-bromopropene (0.82 mL, 0.92
mmol) at room temperature. The mixture was allowed to stir for 10
min. The above boronic acid (0.399 g, 1.37 mmol) in 1 mL of ethanol
was added, followed by 1.38 mL of an aqueous 2M solution of
Na.sub.2CO.sub.3. The reaction mixture was then refluxed for three
hours after, which the solvent was removed in vacuo to give an oil.
The residue was then dissolved in 15 mL of EtOAc and 15 mL of
water. The aqueous phase was extracted with EtOAc (2.times.10 mL).
The combined organic solution was washed with water and saturated
NaCl, dried (Na.sub.2SO.sub.4) and concentrated in vacuo to an oil
that was subjected to chromatography (5% EtOAc/95% hexane) to give
0.366 g (93%) of
2-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)-pro-
pene. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.11 (s, 1H,
aromatic), 6.73 (s, 1H, aromatic), 5.07 (s, 2H, olefinic), 3.90 (t,
J=6.5 Hz, 2H, CH.sub.2), 2.14 (s, 3H, allylic CH.sub.3), 1.81 (sx,
J=6.8 Hz, 2H, CH.sub.2), 1.66 (s, 4H, 2CH.sub.2), 1.28 (s, 6H, 2X
CH.sub.3), 1.26 (s, 6H, 2CH.sub.2) and 1.03 (t, J=7.4 Hz, 3H,
CH.sub.3).
[0288] Into a 5 mL round-bottom flask was introduced selenium
dioxide (71 mg, 0.64 mmol), 1 mL of dichloromethane, and 90%
t-butyl hydroperoxide (0.284 mL, 2.56 mmol). After the mixture had
been stirred for 30 min. at room temperature,
2-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydrona-
phthalen-2-yl)-propene (366 mg, 1.28 mmol) in 1 mL of
dichloromethane was slowly added. The mixture was stirred at room
temperature for 3 h. Then quenched with aqueous saturated
NaHCO.sub.3. The mixture was extracted with dichloromethane
(2.times.10 mL), washed with water (10 mL) and brine (10 mL), and
the combined organic phase dried (Na.sub.2SO.sub.4). Concentrated
in vacuo to give an oil which was subjected to chromatography (10%
EtOAc/90% hexane) to give 149 mg (40%) of
2-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydro
naphthalen-2-yl)-propen-1-ol. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.14 (s, 1H, aromatic), 6.76 (s, 1H, aromatic), 5.36 (s,
1H, vinylic), 5.22 (s, 1H, vinylic), 4.44 (d, J=6.1 Hz,
CH.sub.2OH), 3.93 (t, J=6.5 Hz, 2H, CH.sub.2), 2.19 (t, J=6.1 Hz,
1H, OH), 1.82 (sx, J=6.8 Hz, 2H, CH.sub.2), 1.66 (s, 4H,
2CH.sub.2), 1.28 (s, 6H, 2CH.sub.3), 1.26 (s, 3H, CH.sub.3), 1.25
(s, 3H, CH.sub.3) and 1.0, (t, J=7.3 Hz, 3H, CH.sub.3).
[0289] A 15 mL round bottom flask (oven dried and under argon) was
charged with 1 mL anhydrous dichloroethane and diethyl zinc) 1M in
hexane, 0.660 mL, 0.66 mmol). The mixture was cooled to 0.degree.
C. and chloroiodomethane (0.096 mL, 1.32 mmol) was slowly added via
a syringe. The reaction mixture was stirred at 0.degree. C. for 5
min. and a solution of the above allylic alcohol (0.100 g, 0.33
mmol) in 1 mL dichloroethane was slowly added. The reaction mixture
was stirred at 0.degree. C. for 20 min. and quenched with aqueous
saturated NH.sub.4Cl and the aqueous phase was extracted with EtOAc
(2.times.10 mL). The organic phase was then washed with saturated
NaCl, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The
resulting oil was subjected to chromatography (10% EtOAc/90%
hexane) to provide 56 mg (54%) of
[1-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)-
-cyclopropyl]methanol. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.17 (s, 1H, aromatic), 6.72 (s, 1H, aromatic), 3.94 (t, J=6.3 Hz,
2H, CH.sub.2), 3.56 (d, J=5.2 Hz, 2H, CH.sub.2), 2.63 (t, J=5.3 Hz,
1H, OH), 1.84 (sx, J=6.5 Hz, 2H, CH.sub.2), 1.65 (s, 4H,
2CH.sub.2), 1.26 (s, 6H, 2CH.sub.3), 1.24 (s, 6H, 2CH.sub.3), 1.08
(t, J=7.4 Hz, 3H, CH.sub.3) and 0.82 (m, 4H, cyclopropyl
CH.sub.2).
[0290] To a solution of the above cyclopropyl alcohol (56 mg, 0.177
mmol) in 3 mL CH.sub.2Cl.sub.2 at room temperature was added celite
(0.13 g, 2.times.wt. PCC) and PCC (60 mg, 0.282 mmol). The reaction
mixture was stirred for 4 hours and then filtered and rinsed with
15%) EtOAc/hexane through a pad of celite/silica gel. The solvent
was removed in vacuo to provide 49 mg of
1-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydronap-
hthalen-2-yl)-cyclopropane carboxaldehyde as a white solid in 95%
yield. 1H NMR (400 MHz, CDCl.sub.3) .delta. 9.39 (s, 1H, aldehyde),
7.06 (s, 1H, aromatic), 6.77 (s, 1H, aromatic), 3.91 (t, J=6.2 Hz,
2H, CH.sub.2), 1.75 (sx, J=6.4 Hz, 2H, CH.sub.2), 1.66 (s, 4H,
2CH.sub.2), 1.53 (m, 2H, cyclopropyl CH.sub.2), 1.29 (s, 6H,
2CH.sub.3), 1.26 (m, 2H, cyclopropyl CH.sub.2), 1.23 (s, 6H,
2CH.sub.3) and (t, J=7.4 Hz, 3H, CH.sub.3).
[0291] A solution 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate
(123 mg, 0.47 mmol) in THF/DMPU (1:1; 2 mL) was treated with n-BuLi
(2.5 M in hexane; 0.190 mL, 0.47 mmol) at -78.degree. C. The
reaction mixture was stirred for ten minutes. The above
cyclopropane carboxaldehyde (49 mg, 0.155 mmol) in THF/DMPU (2 mL
of 1:1 mixture) was added. The reaction mixture was warmed to
0.degree. C. and monitored by TLC. The reaction was complete in 30
minutes and was quenched with saturated aqueous NH.sub.4Cl. The
aqueous layer was extracted with EtOAc (2.times.10 mL). The
combined organic solution was washed with saturated NaCl and dried
(Na.sub.2SO.sub.4). The recovered oil was then filtered through a
short plug of silica gel and further rinsed with 5% ethyl
acetate/hexane to remove DMPU. A mixture of isomers (52 mg) of
ethyl-6-[(5,5,8,8-tetramethy-
l-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropan-1-yl]-3-methyl-
-2,4-hexadienoate was recovered in 82% yield.
[0292] To a solution of the above ester (52 mg, 0.127 mmol) in 2 mL
of MeOH was added 12 drops of 6.4M KOH (excess). The reaction
mixture was allowed to reflux for three hours. The MeOH was then
evaporated in vacuo and the residue was diluted in 3 mL of water.
The aqueous phase was neutralized with 5% HCl to pH=6. The aqueous
phase was then extracted with EtOAc (2.times.15 mL). The organic
phase was washed with brine, dried (Na.sub.2SO.sub.4), and
concentrated in vacuo. The final product was recrystallized from
Et.sub.2O/hexane (1.2) to give 23 mg (46%) of (2E,
4E)-6-[2-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthal-
en-2-yl)-cyclopropan-1-yl]-3-methylhexadienoic acid (152) as a
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.09 (s, 1H,
aromatic), 6.71 (s, 1H, aromatic) 5.98 (d, J=15.6 Hz, 1H, vinylic),
5.63 (d, J=15.5 Hz, 1H, vinylic), 5.54 (s, 1H, vinylic), 3.88 (t,
J=6.2 Hz, CH.sub.2), 2.23 (s, 3H, CH.sub.3), 1.74 (sx, J=6.2 Hz,
2H, CH.sub.2), 1.67 (s, 4H, 2CH.sub.2), 1.29 (s, 6H, 2CH.sub.3),
1.24 (s, 6H, 2CH.sub.3), 1.17 (m, 2H, cyclopropyl CH.sub.2), 1.06
(m, 2H, cyclopropyl CH.sub.2), 0.98 (t, J=7.4 Hz, 3H,
CH.sub.3).
EXAMPLE 53
[0293] (2E,
4E)-6-[2-(5,5,3,8-Tetramethyl-3-heptyloxy-5,6,7,8-tetrahydrona-
phthalen-2-yl) cyclopropan-1-yl]-3-methyl Hexadienoic Acid
(Compound 153, Prepared as Illustrated and Described in Scheme
17)
[0294] The heptyloxy boronic acid (prepared as described in Example
52, 2.92 g, 8.03 mmol) was coupled with 2-bromopropene as described
in Example 52 to give 1.65 g of
2-(5,5,8,8-tetramethyl-3-heptyloxy-5,6,7,8-t-
etrahydronaphthalen-2-yl)-propene as a colorless oil in 57% yield
after column chromatography (hexane). .sup.1H (400 MHz, CDCl.sub.3)
.delta. 7.11 (s, 1H, aromatic), 6.74 (s, 1H, aromatic), 5.07 (s,
2H, olefinic CH.sub.2), 3.94 (t, J=6.5 Hz, 2H, CH.sub.2), 2.13 (s,
3H, CH.sub.3), 1.77 (m, 2H, CH.sub.2), 1.66 (m, 4H, 2CH.sub.2),
1.45 (m, 2H, CH.sub.2), 1.33 (m, 6H, 3CH.sub.2), 1.28 (s, 6H,
2CH.sub.3), 1.26 (s, 6H, CH.sub.3), 0.89 (t, J=6.7 Hz, 3H,
CH.sub.3).
[0295] The above 2-propene derivative (1.0 g, 3.0 mmol) was oxidize
as described in Example 52 to give
2-(5,5,8,8-tetramethyl-3-heptyloxy-5,6,7,-
8-tetrahydronaphthalen-2-yl)-2-propen-1-ol as a white solid in 53%
yield after column chromatography (15% EtOAc/hexane). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.13 (s, 1H, aromatic), 6.75 (s, 1H,
aromatic), 5.35 (s, 1H, vinylic), 5.23 (s, 1H, vinylic), 4.43 (d,
J=6.5 Hz, 2H, CH.sub.2), 3.96 (t, J=6.6 Hz, 2H, CH.sub.2), 2.20 (t,
J=6.6 Hz, 1H, OH), 1.79 (m, 2H, CH.sub.2), 1.66 (m, 4H, 2CH.sub.2),
1.45 (m, 2H, CH.sub.2), 1.35 (m, 6H, 3CH.sub.2), 1.28 (s, 6H,
2CH.sub.3), 1.26 (s, 6H, CH.sub.3), 0.89 (t, J=6.9 Hz, 3H,
CH.sub.3).
[0296] The above alcohol (0.57 g, 1.59 mmol) was cyclopropanated as
described in Example 52 to give
[1-(5,5,8,8-tetramethyl-3-heptyloxy-5,6,7-
,8-tetrahydronaphthalen-2-yl)-cyclopropyl]-methanol as a pale
yellow oil in 73% yield. The cyclopropyl alcohol (0.43 g, 1-20
mmol) was oxidized as described in Example 52 to give
1-(5,5,8,8-tetramethyl-3-heptyloxy-5,6,7,-
8-tetrahydronaphthalen-2-yl)-cyclopropanecarboxaldehyde as a
colorless oil in 87%; yield. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.37 (s, 1H, CHO), 7.06 (s, 1H, aromatic), 6.77 (s, 1H,
aromatic), 3.94 (t, J=6.4 Hz, 2H, CH.sub.2), 1.74 (m, 2H,
CH.sub.2), 1.67 (s, 4H, 2 CH.sub.2), 1.53 (m, 2H, CH.sub.2), 1.40
(m, 2H, CH.sub.2), 1.34 (m, 8H, 4CH.sub.2), 1.29 (s, 6H,
2CH.sub.3), 1.24 (s, 6H, 2CH.sub.3), 0.89 (t, J=6.5 Hz, 3H,
CH.sub.3).
[0297] The above cyclopropyl aldehyde (0.40 g, 1.10 mmol) and
3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (912 mg, 3.3 mmol)
were condended as described for Example 52 to give
ethyl-6-[(5,5,8,8-tetrameth-
yl-3-heptyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)-cyclopropan-1-yl]-3-meth-
yl-2,4-hexanedienoate as a pale yellow oil in 78% yield. The
resulting ethyl ester (0.41 g, 0.846 mmol) in 9 mL MeOH was
hydrolyzed as described in Example 52 to give the crude acid. The
crude mixture was recrystallized from Et.sub.2O/hexane (1:2) to
give 205 mg (53%) of
(2E,4E)-6-[2-(5,5,8,8-tetramethyl-3-heptyloxy-5,6,7,8-tetrahydronaphthale-
n-2-yl)cyclopropan-1-yl]-3-methyl-2,4-heptadienoic (153).
mp=152-153.degree. C. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.09 (s, 1H, aromatic), 6.71 (s, 1H, aromatic), 5.97 (d, J=15.6 Hz,
1H, olefinic CH), 5.63 (d, J=15.6 Hz, 1H, olefinic CH), 5.52 (s,
1H, olefinic CH), 3.91 (t, J=6.2 Hz, 2H, CH.sub.2), 2.23 (s, 3H,
CH.sub.3), 1.71 (m, 2H, CH.sub.2), 1.66 (s, 4H, 2CH.sub.2), 1.40
(m, 2H, CH.sub.2), 1.29 (s, 6H, 2CH.sub.3), 1.27 (m, 6H,
3CH.sub.2), 1.24 (s, 6H, 2CH.sub.3), 1.16 (m, 2H, CH.sub.2), 1.05
(m, 2H, CH.sub.2), 0.87 (t, J=6.5 Hz, 3H, CH.sub.3).
EXAMPLE 54
[0298] (2E,
4E)-6-[2-(5,5,8,8-Tetramethyl-3-benzyloxy-5,6,7,8-tetrahydrona-
phthalen-2-yl) cyclopropan-1-yl]-3-methyl Hexadienoic Acid
(Compound 154 Prepared as Illustrated and Described in Scheme
17)
[0299] The benzyloxy boronic acid (prepared as described in Example
52, 1.31 g, 3.95 mmol) was coupled with 2-bromopropene as described
in Example 52 to give 400 mg of
2-(5,5,8,8-tetramethyl-3-benzyloxy-5,6,7,8-t-
etrahydronaphthalen-2-yl)-propene as a colorless oil in 39% yield
after column chromatography (hexane). .sup.1H NMR NMR (400 MHz,
CDCl.sub.3) .delta. 7.45-7.18 (m, 5H, aromatic), 7.14 (s, 1H,
aromatic), 6.81 (s, 1H, aromatic), 5.10 (s, 2H, benzylic CH.sub.2),
5.06 (s, 2H, olefinic CH.sub.2), 2.15 (s, 3H, CH.sub.3), 1.66 (s,
4H, 2CH.sub.2), 1.27 (s, 6H, 2CH.sub.3), 1.24 (s, 6H,
2CH.sub.3).
[0300] The above 2-propene derivative (0.34 g, 0.96 mmol) was
oxidize as described in Example 52 to give 130 mg of
2-(5,5,8,8-tetramethyl-3-benzyl-
oxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-propen-1-ol as a white
solid in 36% yield after column chromatography (15% EtOAc/hexane).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.43-7.31 (m, 5H,
aromatic), 7.15 (s, 1H, aromatic), 6.84 (s, 1H, aromatic), 5.37 (d,
J=1.5 Hz, 1H, olefinic CH), 5.75 (d, J=1.5 Hz, 1H, olefinic CH),
5.06 (s, 2H, benzylic CH.sub.2), 4.43 (d, J=6.5 Hz, 2H, CH.sub.2),
1.97 (t, J=6.5 Hz, 1H, alcohol), 1.67 (s, 4H, 2CH.sub.2), 1.26 (s,
6H, 2CH.sub.3), 1.25 (s, 6H, 2CH.sub.3).
[0301] The above alcohol (0.13 g, 0.35 mmol) was cyclopropanated as
described in Example 52 to give
[1-(5,5,8,8-tetramethyl-3-benzyloxy-5,6,7-
,8-tetrahydronaphthalen-2-yl)-cyclopropyl]-methanol as a pale
yellow oil in 73% yield. The cyclopropyl alcohol (50 mg, 0.131
mmol) was oxidized as described in Example 52 to give
1-(5,5,8,8-tetramethyl-3-benzyloxy-5,6,7,-
8-tetrahydronaphthalen-2-yl)-cyclopropanecarboxaldehyde as a
colorless oil in 92% yield. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.35 (s, 1H, aldehyde), 7.52-7.29 (m, 5H, aromatic), 7.09
(s, 1H, aromatic), 6.84 (s, 1H, aromatic), 5.07 (s, 2H, benzylic
CH.sub.2), 1.66 (s, 4H, 2CH.sub.2), 1.56 (dd, J=4.0, 3.1 Hz, 2H,
CH.sub.2), 1.30 (dd, J=4.0, 3.1 Hz, 2H, 2CH.sub.2), 1.25 (s, 6H,
2CH.sub.3), 1.24 (s, 6H, 2CH.sub.3).
[0302] The above cyclopropyl aldehyde (45 mg, 0.12 mmol) and
3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (190 mg, 0.72 mmol)
were condended as described for Example 52 to give
ethyl-6-[(5,5,8,8-tetrameth-
yl-3-benzyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)-cyclopropan-1-yl]-3-meth-
yl-2,4-hexanedienoate as a pale yellow oil in 77% yield. The
resulting ethyl ester (36 mg, 0.10 mmol) in 2 mL MeOH was
hydrolyzed as described in Example 52 to give the crude acid. The
crude mixture was recrystallized from Et.sub.2O/hexane (1:2) to
give 18 mg (52%) of
(2E,4E)-6-[2-(5,5,8,8-tetramethyl-3-benzyloxy-5,6,7,8-tetrahydronaphthale-
n-2-yl)-cyclopropan-1-yl]-3-methyl-2,4heptadienoic (154).
mp=210.degree. C. (dec.) .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.40-7.27 (m, 5H, aromatic), 7.13 (s, 1H, aromatic), 6.78 (s, 1H,
aromatic), 5.99 (d, J=15.5 Hz, 1H, olefinic CH), 5.66 (d, J=15.5
Hz, 1H, olefinic CH), 5.53 (s, 1H, olefinic CH), 5.06 (s, 2H,
benzylic CH.sub.2), 2.24 (s, 3H, CH.sub.3), 1.66 (s, 4H,
2CH.sub.2), 1.24 (s, 12H, 4CH.sub.3), 1.21 (dd, J=4.0, 3.1 Hz, 2H,
CH.sub.2), 1.10 (dd, J=4.0, 3.1 Hz, 2H, CH.sub.2).
EXAMPLE 55
[0303] (2E,
4E)-7-[(5,5,8,8-Tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaph-
tha-len-2-yl) cyclopropan-1-yl]-3-methyl Heptadienoic Acid
(Compound 155, Prepared as Illustrated and Described in Scheme
18)
[0304] The propyloxy boronic acid (prepared as described in Example
52, 0.70 g, 2.39 mmol) in toluene (6 mL) was coupled to
3-bromo-3-buten-1-ol (0.16 mL, 1.59 mmol) as described in Example
52 to provide, after column chromatography (10 to 15%
EtOAc/hexane), 0.16 g of
2-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)-3-b-
uten-1-ol as a pale yellow oil in 31% yield. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.03 (s, 1H, aromatic), 6.74 (s, 1H, aromatic),
5.22 (d, J=1.1 Hz, 1H, olefinic CH), 5.13 (d, J=1.9 Hz, 1H,
olefinic CH), 3.91 (t, J=6.6 Hz, 2H, CH.sub.2), 3.61 (dd, J=6.1,
6.0 Hz, 2H, CH.sub.2), 2.71 (dd, J=5.9, 5.8 Hz, 2H, CH.sub.2), 1.88
(t, J=6.2 Hz, 1H, alcohol), 1.79 (m, 2H, CH.sub.2), 1.66 (s, 4H,
2CH.sub.2), 1.28 (s, 6H, 2CH.sub.3), 1.24 (s, 6H, 2CH.sub.3), 1.02
(t, J=7.5 Hz, 3H, CH.sub.3).
[0305] In a 15 mL round-bottom flask (oven dried and under argon)
was added anhydrous dichloroethane (2 mL) and diethyl zinc (0.11 mL
1.08 mmol). The mixture was cooled to 0.degree. C. and
chloroiodomethane (0.14 mL, 1.96 mmol) was slowly added via
syringe. The reaction mixture was stirred at 0.degree. C. for 5
min. and a solution of the above homoallylic alcohol (0.16 g, 0.49
mmol) in dichloroethane (2 mL) was slowly added. The mixture was
allowed to warm to room temperature and stirred for one hour. The
reaction mixture was then quenched with saturated NH.sub.4Cl and
the aqueous phase was extracted with EtOAc (2.times.15 mL). The
organic solution was washed with saturated NaCl, dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. Crude
[1-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)-cy-
clopropyl]ethanol was recovered in 89% yield (0.15 g) and carried
directly on to the next step. To a solution of the above
cyclopropyl alcohol (0.06 g, 0.19 mmol) in 5 mL CH.sub.2Cl.sub.2 at
room temperature was added celite (0.13 g, 2.times.wt. PCC) and PCC
(0.07 g, 0.30 mmol). The reaction mixture was stirred for 4 hours
and then filtered and rinsed with 15% EtOAc/hexane through a pad of
celite/silica gel. Solvent was removed in vacuo to provide 60 mg of
1-(5,5,8,8-tetramethyl-3-propyloxy-5-
,6,7,8-tetrahydronaphthalen-2-yl)-cyclopropaneacetaldehyde as a
white solid in 95% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
9.75 (t, J=2.9 Hz, 1H, aldehyde), 7.17 (s, 1H, aromatic), 6.67 (s,
1H, aromatic), 3.91 (t, J=6.3 Hz, 2H, CH.sub.2), 2.50 (d, J=2.9 Hz,
2H, CH.sub.2), 1.83 (m, 2H, CH.sub.2), 1.64 (s, 4H, 2CH.sub.2),
1.26 (s, 6H, 2CH.sub.3), 1.08 (t, J=7.4 Hz, 3H, CH.sub.3), 0.89
(dd, J=6.4, 4.3 Hz, 2H, CH.sub.2), 0.80 (dd, J=6.4, 4.3 Hz, 2H,
CH.sub.2).
[0306] The above propyloxy cyclopropyl aldehyde (0.06 g, 0.18 mmol)
and 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (285 mg, 1.08
mmol) were condensed as described in Example 52 to give 70 mg of
ethyl-7-[2-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen--
2-yl)-cyclopropyl]-3-methyl-2,4-heptadienoate as a pale yellow oil
in 97% yield. The resulting ethyl ester (70 mg, 0.17 mmol) in 2.5
mL MeOH was hydrolyzed as described in Example 52 to give the crude
acid. The crude mixture was recrystallized from Et.sub.2O/hexane
(1:2) to give 31 mg (45%) of (2E,
4E)-6-[2-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydr-
onaphthalen-2-yl)-cyclopropyl]-3-methyl-2,4-heptadienoic acid
(155). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.03 (s, 1H,
aromatic), 6.68 (s, 1H, aromatic), 6.11 (m, 1H, olefinic CH), 5.96
(d, J=15.6 Hz, 1H, olefinic CH), 5.65 (s, 1H, olefinic CH), 3.92
(t, J=6.3 Hz, 2H, CH.sub.2), 2.38 (d, J=7.1 Hz, 2H, CH.sub.2), 2.20
(s, 3H, CH.sub.3), 1.83 (m, 2H, CH.sub.2), 1.64 (s, 4H, 2CH.sub.2),
1.26 (s, 6H, 2CH.sub.3), 1.21 (s, 6H, 2CH.sub.3), 1.09 (t, J=7.5
Hz, 3H, CH.sub.3), 0.74 (dd, J=6.4, 4.3 Hz, 2H, CH.sub.2), 0.66
(dd, J=6.4, 4.3 Hz, 2H, CH.sub.2).
EXAMPLE 56
[0307] (2E,
4E)-7-[(5,5,8,8-Tetramethyl-3-heptyloxy-5,6,7,8-tetrahydronaph-
tha-len-2-yl) cyclopropan-1-yl]-3-methyl Heptadienoic Acid
(Compound 156, Prepared as Illustrated and Described in Scheme
18)
[0308] The tetrahydrobromonaphthol (Example 52, 1.5 g, 5.19 mmol)
was alkylated with heptyl bromide (1.14 mL, 7.27 mmol) as described
for Example 52 to provide 2.1 g of
2-bromo-3-heptyloxy-5,5,8,8-tetramethyl-5,-
6,7,8-tetrahydronaphthalene as a clear oil in quantitative yield.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.41 (s, 1H, aromatic),
6.77 (s, 1H, aromatic), 3.98 (t, J=6.5 Hz, 2H CH.sub.2), 1.85-1.78
(m, 2H, CH.sub.2), 1.65 (s, 4H 2CH.sub.2), 1.53-1.29 (m, 10H
aliphatic CH.sub.2), 1.26 (s, 6H, 2CH.sub.3), 1.24 (s, 6H,
2CH.sub.3), 0.89 (t, J=6.0 Hz, 3H, CH.sub.3).
[0309] The
2-bromo-3-heptyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro
naphthalene (2.1 g, 5.42 mmol) was converted to the corresponding
boronic acid as described for Example 52 to give 1.74 g of a brown
residue in 79% yield. The crude mixture was carried on to the next
step.
[0310] The above heptyloxy boronic acid (0.90 g, 2.18 mmol) was
coupled with 3-bromo-3-butenol as described in Example 55 to give
270 mg of
2-(5,5,8,8-tetramethyl-3-heptyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)-3-b-
uten-1-ol as a white solid in 42% yield after column chromatography
(10 to 15% EtOAc/hexane). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.02 (s, 1H, aromatic), 6.74 (s, 1H, aromatic), 5.23 (d, J=2.2 Hz,
1H, olefinic CH), 5.12 (d, J=2.2 Hz, 1H, olefinic CH), 3.93 (t,
J=6.5 Hz, 2H CH.sub.2), 3.60 (q, J=6.1 Hz, 2H, CH.sub.2), 2.70 (t,
J=5.9 Hz, 2H, CH.sub.2), 1.84 (t, J=6.3 Hz, 1H, alcohol), 1.76 (m,
2H, CH.sub.2), 1.66 (s, 4H, 2CH.sub.2), 1.54-1.30 (m, 8H, aliphatic
CH.sub.2), 1.28 (s, 6H, 2CH.sub.3), 1.24 (s, 6H, 2CH.sub.3), 0.88
(t, J=6.7 Hz, 3H, CH.sub.3).
[0311] The above unsaturated alcohol (0.27 g, 0.61 mmol) was
converted to the cyclopropyl alcohol as described in Example 55 to
give 190 mg of
1-(5,5,8,8-tetramethyl-3-heptyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)-cyc-
lopropyl]-ethanol as a pale yellow oil in 69% yield. The above
cyclopropyl alcohol (0.19 g, 0.41 mmol) was oxidized as described
in Example 55 to give 170 mg of
1-(5,5,8,8-tetramethyl-3-heptyloxy-5,6,7,8-tetrahydronapht-
halen-2-yl)-cyclopropaneacetaldehyde as a white solid in 92% yield.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.75 (t, J=2.9 Hz, 1H,
CHO), 7.17 (s, 1H, aromatic), 6.67 (s, 1H, aromatic), 3.94 (t,
J=6.3 Hz, 2H, CH.sub.2), 2.49 (d, J=2.9 Hz, 2H, CH.sub.2), 1.80 (m,
2H, CH.sub.2), 1.53 (s, 4H, 2CH.sub.2), 1.50-1.32 (m, 8H, aliphatic
CH.sub.2), 1.26 ( s, 6H, 2CH.sub.3), 1.23 (s, 6H 2CH.sub.3), 0.91
(t, J=6.7 Hz, 3H, CH.sub.3), 0.88 (dd, J=6.3, 4.2 Hz, 2H, CH.sub.2)
0.79 (dd, J=6.3, 4.2 Hz, 2H, CH.sub.2).
[0312] The above cyclopropyl aldehyde (0.17 g, 0.38 mmol) and
3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (285 mg, 1.08 mmol)
were condensed as described for Example 52 to give 220 mg of
ethyl-7-[2-(5,5,8,8-tetramethyl-3-heptyloxy-5,6,7,8-tetrahydronaphthalen--
2-yl)-cyclopropyl]-3-methyl-2,4-heptadienoate as a pale yellow oil
in quantitative yield.
[0313] The above ethyl ester (0.22 g, 0.44 mmol) in 8 mL MeOH was
hydrolyzed as described for Example 52 to give the crude acid. The
crude mixture was recrystallized from Et.sub.2O/Hex (1:2) to give
130 mg (63%) of (2E,
4E)-6-[2-(5,5,8,8-tetramethyl-3-heptyloxy-5,6,7,8-tetrahydro
naphthalen-2-yl)-cyclopropyl]-3-methyl-2,4-heptadienoic acid (156).
.sup.1H NMR NMR (400 MHz, CDCl.sub.3) .delta. 7.03 (s, 1H,
aromatic), 6.68 (s, 1H, aromatic), 6.11 (m, 1H, olefinic CH), 5.96
(d, J=15.6 Hz, 1H, olefinic CH), 5.64 (s, 1H, olefinic CH), 3.94
(t, J=6.2 Hz, 2H, CH.sub.2), 2.37 (d, J=7.1 Hz, 2H, CH.sub.2), 2.20
(s, 3H, CH.sub.3), 1.82 (m, 2H, CH2), 1.64 (s, 4H, 2CH2), 1.54-1.29
(m, 8H, aliphatic CH2), 1.26 (s, 6H, 2CH.sub.3), 1.21 (s, 6H,
2CH.sub.3), 0.90 (t, J=6.8 Hz, 3H, CH.sub.3), 0.74 (dd, J=6.3, 4.0
Hz, 2H, CH.sub.2), 0.66 (dd, J=6.3, 4.0 Hz, 2H, CH.sub.2).
EXAMPLE 57
[0314] (2E,
4E)-7-[(5,5,8,8-Tetramethyl-3-benzyloxy-5,6,7,8-tetrahydronaph-
tha-len-2-yl) cyclopropan-1-yl]-3-methyl Heptadienoic Acid
(Compound 157, Prepared as Illustrated and Described in Scheme
18)
[0315] The tetrahydrobromonaphthol (Example 52, 3.0 g, 10.38 mmol)
was alkylated with benzyl bromide (1.73 mL, 14.53 mmol) as
described for Example 52 to provide 4.21 g of
2-bromo-3-benzyloxy-5,5,8,8-tetramethyl-5-
,6,7,8-tetrahydronaphthalene as a clear oil in quantitative yield.
.sup.1H NMR (400 MHz, CDCl.sub.3) d7.48 (d, J=7.48 Hz, 2H,
aromatic), 7.44 (s, 1H, aromatic), 7.38 (dd, J=8.6, 1.6 Hz, 2H,
aromatic), 7.31 (dd, J=7.1, 2 2 Hz, 1H, aromatic), 6.82 (s, 1H,
aromatic), 5.12 (s, 2H, benzylic CH.sub.2), 1.64 (s, 4H,
2CH.sub.2), 1.24 (s, 6H, 2CH.sub.3), 1.20 (s, 6H, 2CH.sub.3).
[0316] The
2-bromo-3-benzyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro
naphthalene (1.57 g, 4.14 mmol) was converted to the corresponding
boronic acid as described for Example 52 to give 1.31 g of a brown
residue in 79% yield. The crude mixture was carried on to the next
step.
[0317] The above benzyloxy boronic acid (1.04 g, 2.93 mmol) was
coupled with 3-bromo-3-butenol as described in Example 55 to give
370 mg of
2-(5,5,8,8-tetramethyl-3-heptyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)-3-b-
uten-1-ol as a white solid in 49% yieid after column chromatography
(10 to 15% EtOAc/hexane). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.42-7.35 (m, 5H, aromatic), 7.05 (s, 1H, aromatic), 6.81 (s, 1H,
aromatic), 5.23 (d, J=1.5 Hz, 1H, olefinic CH), 5.16 (d, J=2.0 Hz,
1H, olefinic CH), 5.04 (s, 2H, benzylic CH.sub.2), 3.59 (q, J=6.1
Hz, 2H, CH.sub.2), 2.71 (t, J=6.0 Hz, 2H, CH.sub.2), 1.66 (s, 4H,
2CH.sub.2), 1.25 (s, 6H, 2CH.sub.3), 1.24 (s, 6H, 2CH.sub.3).
[0318] The above unsaturated alcohol (0.37 g, 0.96 mmol) was
converted to the cyclopropyl alcohol as described in Example 55 to
give 190 mg of
[1-(5,5,8,8-tetramethyl-3-heptyloxy-5,6,7,8-tetrahydronaphthalen-2-yl)-cy-
clopropyl]-ethanol as a pale yellow oil in 52% yield. The above
cyclopropyl alcohol (0.19 g, 0.48 mmol) was oxidized as described
in Example 55 to give 180 mg of
1-(5,5,8,8-tetramethyl-3-benzyloxy-5,6,7,8-t-
etrahydronaphthalen-2-yl)-cyclopropaneacetaldehyde as a white solid
in 95% yield. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.72 (d,
J=3.2 Hz, 1H, CHO), 7.47 (d, J=7.2 Hz, 2H, aromatic), 7.40 (dd,
J=8.6, 1.6 Hz, 2H, aromatic), 7.32 (dd, J=7.1, 2.2 Hz, 1H,
aromatic), 7.20 (s, 1H, aromatic), 6.76 (s, 1H, aromatic), 5.07 (s,
2H, benzylic CH.sub.2), 1.64 (s, 4H, 2CH.sub.2), 1.23 (s, 12H,
4CH.sub.3), 0.94 (dd, J=6.4, 4.2 Hz, 2H, CH.sub.2), 0.82 (dd,
J=6.4, 4.2 Hz, 2H CH.sub.2).
[0319] The above cyclopropyl aldehyde (0.18 g, 0.46 mmol) and
3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (322 mg, 1.43 mmol)
were condensed as described for Example 52 to give 230 mg of
ethyl-7-[2-(5,5,8,8-tetramethyl-3-benzyloxy-5,6,7,8-tetrahydronaphthalen--
2-yl)-cyclopropyl]-3-methyl-2,4heptadienoate as a pale yellow oil
in quantitative yield.
[0320] The above ethyl ester (0.23 g, 0.46 mmol) in 8 mL MeOH was
hydrolyzed as described for Example 52 to give the crude acid. The
crude mixture was recrystallized from Et.sub.2O/Hex (1:2) to give
91 mg (43%) of (2E,
4E)-6-[2-(5,5,8,8-tetramethyl-3-benzyloxy-5,6,7,8-tetrahydronapht-
halen-2-yl)-cyclopropyl]-3-methyl-2,4heptadienoic acid (157).
.sup.1H NMR NMR (400 MHz, CDCl.sub.3) .delta. 7.50 (d, J=7.3 Hz,
2H, aromatic), 7.39 (dd, J=6.8, 1.3 Hz, 2H, aromatic), 7.32 (dd,
J=7.4, 2.3 Hz, 1H, aromatic), 7.07 (s, 1H, aromatic), 6.77 (s, 1H,
aromatic), 6.11 (m, 1H, olefinic CH), 5.94 (d, J=15.7 Hz, 1H,
olefinic CH), 5.64 (s, 1H, olefinic CH), 5.09 (s, 2H, benzylic
CH.sub.2), 2.41 (d, J=7.2 Hz, 2H CH.sub.2), 2.16 (s, 3H, CH.sub.3),
1.64 (s, 4H, 2CH.sub.2), 1.25 (s, 6H, 2CH.sub.3), 1.22 (s, 6H,
2CH.sub.3), 0.80 (dd, J=6.5, 3.8 Hz, 2H, CH.sub.2), 0.71 (dd,
J=6.4, 4.0 Hz, 2H, CH.sub.2).
EXAMPLE 58
[0321] (2E,
4E)-5-[2-(5,5,8,8-Tetramethyl-3-propyloxy-5,6,7,8-tetrahydrona-
phthalen-2-yl) cyclopent-1-en-1-yl]-3-methyl Pentadienoic Acid
(Compound 158, Prepared as Illustrated and Described in Scheme
19)
[0322] To a solution of tetrakistriphenylphosphine palladium (0.035
g, 0.03 mmol) in 4 mL of toluene under N.sub.2 was added
1,2-dibromocyclopentene (0.66 mL, 5.55 mmol) at room temperature.
The mixture was allowed to stir for 10 min. Then boronic acid (see
Example 52, 0.28 g, 1.11 mmol) in 1 mL of ethanol was added,
followed by an aqueous 2M solution of Na.sub.2CO.sub.3. The
reaction mixture was then refluxed for three hours after which the
solvent was removed in vacuo to give an oil. The residue was then
dissolved in 15 mL of EtOAc and 15 mL of water. The aqueous phase
was extracted with EtOAc (2.times.10 mL). The combined organic
solution was washed with water and saturated NaCl, dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to give 0.255 g (59%)
of
1-[2-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphth-2-yl]-2-br-
omocyclopentene as an oil that was used directly in the next
step.
[0323] To a solution of the above cyclopentyl bromide (0.255 g,
0.65 mmol) in 6 mL of anhydrous ether, at -78.degree. C., was added
t-BuLi (0.84 mL, 1.43 mmol) dropwise. The mixture was stirred at
-78.degree. C. for one hour. Then anhydrous DMF (0.055 mL, 0.72
mmol) was added and the reaction mixture was stirred at room
temperature 30 min. The reaction mixture was cooled to 0.degree. C.
and quenched with 2 mL of water. The aqueous phase was extracted
with ether (2.times.15 mL). The combined organic phase was washed
with water and satd NaCl, dried (Na.sub.2SO.sub.4), and
concentrated in vacuo. The desired product was purified by
chromatography (5% EA/Hex) to give 0.168 g (76%) of the
1-[2-(5,5,8,8-tetramethyl-3-prop-
yloxy-5,6,7,8-tetrahydronaphthalen-2-yl]cyclopentene-2-carboxaldehyde.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.66 (s, 1H, CHO), 7.06
(s, 1H, aromatic), 6.80 (s, 1H, aromatic), 3.90 (t, J=6.4 Hz, 2H,
CH.sub.2), 2.99 (dd, J=7.4, 2.4 Hz, 2H, CH.sub.2), 2.70 (dd, J=7.4,
2.4 Hz, 2H, CH.sub.2), 1.98 (m, 2H, CH.sub.2), 1.76 (m, 2H,
CH.sub.2), 1.68 (s, 4H, 2CH.sub.2), 1.30 (s, 6H, 2CH.sub.3), 1.24
(s, 6H, 2CH.sub.3), 1.00 (t, J=7.4 Hz, 3H, CH.sub.3).
[0324] A solution 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate
(0.07 g, 0.26 mmol) in THF/DMPU (1:1, 2 mL) was treated with BuLi
(1.6M, 0.163 mL) at -78.degree. C. The reaction mixture was stirred
for ten minutes. The above cyclopentene aldehyde (0.03 g, 0.09
mmol) in THF/DMPU (1 mL of 1:1) was added. The reaction mixture was
warmed to 0.degree. C. and monitored by TLC. The reaction was
complete in 30 minutes and was quenched with saturated aqueous
NH.sub.4Cl. The aqueous layer was extracted with EtOAc (2.times.10
mL). The combined organic phase was then washed with saturated NaCl
and dried (Na.sub.2SO.sub.4). Concentration in vacuo provided an
oil which was then filtered through a short pad of silica gel and
rinsed with 5% ethyl acetatelhexane to remove DMPU. The isolated
mixture of isomers (44 mg) of
ethyl-5-[2-(5,5,8,8-tetramethyl-3-propyloxy-
-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopent-1-en-1-yl]-3-methyl
2,4-pentadienoate was recovered in quantitative yield. To a
solution of the cyclopentene ethyl ester (0.044 g, 0.01 mmol) in 2
mL of MeOH was added 12 drops of 6.4 M KOH (excess). The reaction
mixture was heated at reflux for three hours. The MeOH was then
evaporated in vacuo and the residue was diluted in 3 mL of water.
The aqueous phase was then neutralized with 5% HCl to pH=6. The
aqueous phase was then extracted with EtOAc (2.times.15 mL). The
organic phase was subsequently washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. The final product was
recrystallized from Et.sub.2O/hexane (1:2) to give 23 mg (55%) of
(2E,4E)-5-[2-(5,5,8,8-Tetramethyl-3-propyloxy-5,6,7,8-tetrahydro-
naphthalen-2-yl) cyclopent-1-en-1-yl]-3-methyl pentadienoic acid
(158). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm) 7.01 (s, 1H,
aromatic), 6.94 (d, J=15.7 Hz, 1H, olefinic CH), 6.79 (s, 1H,
aromatic), 6.25 (d, J=15.7 Hz, 1H, olefinic CH), 5.82 (s, 1H,
olefinic CH), 3.89 (t, J=6.4 Hz, 2H, CH.sub.2), 2.92 (dd, J=7.4,
2.1 Hz, 2H, CH.sub.2), 2.65 (dd, J=7.4, 2.1 Hz, 2H, CH.sub.2), 2.23
(s, 3H, CH.sub.3), 1.98 (m, 2H, CH.sub.2), 1.78 (m, 2H, CH.sub.2),
1.68 (s, 4H, 2CH.sub.2), 1.31 (s, 6H, 2CH.sub.3), 1.25 (s, 6H,
2CH.sub.3), 1.01 (t, J=7.5 Hz, 3H, CH.sub.3).
EXAMPLE 59
[0325] cis (2E,
4E)-5-[2-(5,5,8,8-Tetramethyl-3-propyloxy-5,6,7,3-tetrahyd-
ro-2-naphthyl) cyclopentan-1-yl]-3-methyl Pentadienoic Acid
(Compound 159, Prepared as Illustrated and Described in Scheme
20)
[0326]
1-[2-(5,5,8,8-tetramethyl-3-propyloxy-5,6,7,8-tetrahydronaphthalen--
2-yl] cyclopentene-2-carboxaldehyde (from Example 58, 0.09 g, 0.27
mmol) and 5% Pd on C (0.01 g) was taken-up in 3 mL of EtOAc. The
reaction mixture was kept under an atmosphere of hydrogen. After 16
h of stirring, the reaction mixture was then filtered through a
short plug of celite and the solvent was removed in vacuo.
Chromatography (5% EtOAc/95% hexane) afforded 78 mg (83%) of the
desired 1-[2-(5,5,8,8-tetrarnethyl-3-propylox-
y-5,6,7,8-tetrahydronaphthalen-2-yl] cyclopentane-2-carboxaldehyde.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.20 (d, J=2.1 Hz, 1H,
aldehyde), 7.04 (s, 1H, aromatic), 6.68 (s, 1H, aromatic), 3.93 (m,
2H, CH.sub.2), 3.65 (m, 1H, CH), 3.21 (m, 1H, CH), 2.15-1.78 (m,
8H, 4CH.sub.2), 1.62 (s, 4H, 2CH.sub.2), 1.26 (s, 6H, 2CH.sub.3),
1.24 (s, 6H, 2CH.sub.3), 1.06 (t, J=7.4 Hz, 3H, CH.sub.3).
[0327] A solution 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate
(0.67 g, 0.25 mmol) in THF/DMPU (1:1, 2 mL) was treated with BuLi
(1.6M, 0.151 mL) at -78.degree. C. The reaction mixture was stirred
for ten minutes. The above cyclopentane aldehyde (0.03 g, 0.09
mmol) in THF/DMPU (1 mL of 1:1) was added. The reaction mixture was
warmed to 0.degree. C. and monitored by TLC. The reaction was
complete in 30 minutes and was quenched with saturated aqueous
NH.sub.4Cl. The aqueous layer was extracted with EtOAc (2.times.10
mL). The combined organic phase was then washed with saturated NaCl
and dried (Na.sub.2SO.sub.4). Concentration in vacuo provided an
oil which was then filtered through a short plug of silica gel and
rinsed with 5% ethyl acetate/hexane to remove DMPU. The isolated
mixture of isomers (44 mg) of
ethyl-5-[2-(5,5,8,8-tetramethyl-3-propyloxy-
-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentan-1-yl]-3-methyl
2,4-pentadienoate was recovered in quantitative yield
[0328] To a solution of the cyclopentane ethyl ester (0.044 g, 0.01
mmol) in 2 mL of MeOH was added 12 drops of 6.4 M KOH (excess). The
reaction mixture was heated at reflux for three hours. The MeOH was
then evaporated in vacuo and the residue was diluted in 3 mL of
water. The aqueous phase was then neutralized with 5% HCl to pH=6.
The aqueous phase was then extracted with EtOAc (2.times.15 mL).
The organic phase was subsequently washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. The final product was
recrystallized from Et.sub.2O/hexane (1:2) to give 23 mg (55%) of
cis-(2E,4E)-5-[2-(5,5,8,8-tetramethyl-3-prop-
yloxy-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentan-1-yl]-3-methylpentadie-
noic acid (159). .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 6.99 (s,
1H, aromatic), 6.64 (s, 1H, aromatic), 5.83 (d, J=15.7 Hz, 1H,
olefinic CH), 5.74 (dd, J=15.7, 8.1 Hz, 1H, olefinic CH), 5.52 (s,
1H, olefinic CH), 3.85 (t, J=6.6 Hz, 2H, CH.sub.2), 3.62 (m, 1H,
CH), 3.03 (m, 1H, CH), 1.98-1.78 (m, 6H, 3CH.sub.2), 1.63 (s, 4H,
2CH.sub.2), 1.23 (s, 6H, 2CH.sub.3), 1.22 (s, 6H, 2CH.sub.3), 1.05
(t, J=7.4 Hz, 3H, CH.sub.3).
EXAMPLE 60
[0329]
4-[(3-(4-t-Butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
-naphthyl)carbonyl]benzoic Acid Oxime (Compound 160, Prepared as
Illustrated and Described in Scheme 1 and Scheme 3)
[0330] A solution of the
4-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramet-
hyl-2-naphthyl)carbonyl]benzoic acid methyl ester (from Example 7;
225 mg, 0.61 mmol) in acetone (3 mL) was stirred with
K.sub.2CO.sub.3 (1.0 mmol) at room temperature for one hour. The
yellow solution was treated with a solution of
4-t-butylbenzylbromide (168 mg, 0.74 mmol) and allowed to stir for
10 h. The reaction was quenched with saturated aqueous NH.sub.4Cl.
The aqueous solution was extracted 3 times with EtOAc, the organic
layers were combined, and washed with water (2.times.) and brine.
The organic solution was dried (NaSO.sub.4), filtered, and
concentrated. Purification by crystallization
(CH.sub.2Cl.sub.2/hexanes) gave
4-[(3-(4-t-butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napht-
hyl)carbonyl]benzoic acid methyl ester 298 mg (95%) as a white
solid. mp 168-169.5.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.04 (1/2ABq, J=8.5 Hz, 2H, ArH), 7.81 (1/2ABq, J=8.5 Hz,
2H, ArH), 7.44 (s, 1H, ArH), 7.19 (1/2ABq, J=8.2 Hz, 2H, ArH),
6.89(s, 1H, ArH), 6.87 (1/2ABq, J=8.4 Hz, 2H, ArH), 4.89 (s, 2H,
OCH.sub.2), 3.94(s, 3H, OCH.sub.3), 1.69 (m, 4H, 2CH.sub.2), 1.28
(s, 6H, 2CH.sub.3), 1.26 (s, 6H, 2CH.sub.3), 1.25 (s, 9H,
3CH.sub.3).
[0331] The above 4-t-butylbenzyloxy keto ester was hydrolyzed as
described for Example 1 to give
4-[(3-(4-t-butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8-
,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid as a white solid
(90%): mp 218-219.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.11(1/2ABq, J=8.4 Hz, 2H, ArH), 7.84 (1/2ABq, J=8.4 Hz,
2H, ArH), 7.47 (s, 1H, ArH), 7.20 (1/2ABq, J=8.2 Hz, 2H, ArH), 6.90
(s, 1H, ArH), 6.88 (1/2ABq, J=8.3 Hz, 2H, ArH), 4.89 (s, 2H,
OCH.sub.2), 1.70 (m, 4H, 2CH.sub.2), 1.29 (s, 6H, 2CH.sub.3), 1.28
(s, 6H, 2CH.sub.3), 1.26 (s, 9H, 3CH.sub.3); .sup.13C NMR (100 MHz,
CDCl.sub.3) .delta. 196.4, 170.6, 155.0, 151.0, 150.9, 143.8,
138.1, 133.6, 132.1, 301.1, 129.6, 129.3, 126.9, 126.4, 125 4,
111.1, 70.4, 35.2, 35.1, 35.0, 34.7, 34.1, 32.1, 31.9, 31.5.
[0332] The above acid was condensed with hydroxylamine
hydrochloride as described for Example 4 to give
4-[(3-(4-t-butylbenzyloxy)-5,6,7,8-tetrah-
ydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime
(160) as a white solid (97%): mp 223-366.degree. C. d; .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.11(1/2ABq, J=8.4 Hz, 2H, ArH), 7.59
(1/2ABq, J=8.4 Hz, 2H, ArH), 7.24 (s, 1H, ArH), 7.20 (1/2ABq, J=8.1
Hz, 2H, ArH), 7.00 (1/2ABq, J=8.2 Hz, 2H, ArH), 6.93 (s, 1H, ArH),
4.93 (s, 2H, OCH.sub.2), 1.69 (m, 4H, 2CH.sub.2), 1.28 (s, 6H,
2CH.sub.3), 1.25 (s, 6H, 2CH.sub.3), 1.24 (s, 9H, 3CH.sub.3).
EXAMPLE 61
[0333]
4-[(3-(4-Bromobenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-n-
aphthyl)carbonyl]benzoic Acid Oxime (Compound 161, Prepared as
Illustrated and Described in Scheme 1 and Scheme 3)
[0334] The
4-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl-
)carbonyl]benzoic acid methyl ester (from Example 7) was alkylated
with 4-bromobenzylbromide as described for Example 60 to give
4-[(3(-4-bromobenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthy-
l)carbonyl]benzoic acid methyl ester (60%): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.03 (1/2ABq, 2H, J=8.4 Hz, ArH), 7.80 (1/2ABq,
2H, J=8.4 Hz, ArH), 7.46 (s, 1H, ArH), 7.29 ({fraction (1/2)}ABq,
2H, J=8.4 Hz, ArH), 6.87 (s, 1H, ArH), 6.81 (1/2ABq, 2H, J=8.4 Hz,
ArH), 4.87 (s, 2H, OCH.sub.2), 3.97 (s, 3H, OCH.sub.3), 1.70 (m,
4H, 2CH.sub.2), 1.30 (s, 6H, 2CH.sub.3), 1.27 (s, 6H,
2CH.sub.3).
[0335] The above 4-bromobenzyloxy keto ester was hydrolyzed as
described for Example 1 to give
4-[(3-(4-t-butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8-
,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid as a white solid
(90%): mp 218-219.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.08 (1/2ABq, 2H, J=8.1 Hz, ArH), 7.82 (1/2ABq, 2H, J=8.1
Hz, ArH), 7.44 (s, 1H, ArH), 7.31 (1/2ABq;, 2H, J=8.3 Hz, ArH),
6.88 (s, 1H, ArH), 6.82 (1/2ABq, 2H, J=8.3 Hz, ArH), 4.89 (s, 2H,
OCH.sub.2), 1.70 (m, 4H, 2CH.sub.2), 1.30 (s, 6H, 2CH.sub.3), 1.27
(s, 6H, 2CH.sub.3).
[0336] The above acid was condensed with hydroxylamine
hydrochloride as described for Example 4 to give
4-[(3-(4-bromobenzyloxy)-5,6,7,8-tetrahyd-
ro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime (161)
as a white solid (97%): mp 222-223.5.degree. C. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.99 (1/2ABq, 2H, J=8.4 Hz, ArH), 7.55
(1/2ABq, 2H, J=8.4 Hz, ArH), 7.33 (1/2ABq, 2H, J=8.4 Hz, ArH), 7.15
(s, 1H, ArH), 6.95 (1/2ABq, 2H, J=8.4 Hz, ArH), 6.88 (s, 1H, ArH),
4.91 (s, 2H, OCH.sub.2), 1.70 (s, 4H, 2CH.sub.2), 1.28 (s, 6H,
2CH.sub.3), 1.25 (s, 6H, 2CH.sub.3).
EXAMPLE 62
[0337]
cis-4-[(3-Benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth-
yl)carbonyl]benzoic Acid O-methyloxime (Compound 162, Prepared as
Illustrated and Described in Scheme 1 and Scheme 4)
[0338] A solution of
4-[3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-
-2-naphthyl)carbonyl]benzoic acid methyl ester in MeOH was
hydrolyzed as described for Example 1 to give
4-[(3-(benzyloxy)-5,6,7,8-tetrahydro-5,5,-
8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid as a white solid:
mp 211.5-213.degree. C.; IR (thin film) 2961, 2926, 1696, 1661,
1602, 1240, 735 cm.sup.-1; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.11 (1/2ABq, J=8.4 Hz, 2H, aromatic), 7.85 (1/2ABq, J=8.4
Hz, 2H, aromatic), 7.48 (s, 1H, aromatic), 7.19 (m, 3H, aromatic),
6.94 (m, 2H, aromatic), 6.90 (s, 1H, aromatic), 4.93 (s, 2H,
OCH.sub.2), 1.70 (m, 4H 2CH.sub.2), 1.29 (s, 6H, 2CH.sub.3), 1.28
(s, 6H, 2CH.sub.3); 13C NMR (100 MHz, CDCl.sub.3) .delta. 196.1,
170.5, 154.6, 150.8, 143.6, 138.0, 136.3, 129.9, 129.3, 129.1,
128.2, 127.7, 126.8, 126.2, 110.7, 70.3, 35.0, 34.9, 34.8, 33.8,
31.8, 31.7. HRMS (EI, 70 eV) calcd for C.sub.29H.sub.30O.sub.4
(M.sup.+) 442.2144. Found: 442.2126.
[0339] The above benzyloxy ketoacid (45 mg, 0.101 mmol) was
converted to the O-methyloxime derivative as described for Example
8 (87%). Purification by reverse phase HPLC (90% MeOH/10%
NH.sub.4OAc with 0.5% AcOH) ave
cis-4-[(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-na-
phthyl)carbonyl]benzoic acid O-methyloxime (162) as a white solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.93 (m, 2H, ArH), 7.46
(m, 2H, ArH), 7.34 (s, 1H, ArH), 7.17 (m, 3H, ArH), 6.83 (m, 2H,
ArH), 6.74 (s, 1H, ArH), 4.74 (s, 2H, OCH.sub.2), 3.93 (s, 3H,
OCH.sub.3), 1.65 (s, 4H, 2CH.sub.2), 1.27 (s, 6H, 2CH.sub.3), 1.20
(s, 6H, 2CH.sub.3); .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.
155.6, 154.6 148.1, 138.9, 137.6, 136.8, 129.4, 129.3, 128.3,
127.8, 127.4, 123.7, 110.7, 70.3, 62.4, 35.3, 35.2, 34.9, 33.9,
32.1, 32.0.
EXAMPLE 63
[0340]
trans-4-[(3-Benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naph-
thyl)carbonyl]benzoic Acid O-methyloxime (Compound 163, Prepared as
Illustrated and Described in Scheme 1 and Scheme 4)
[0341] HPLC purification (reverse phase; 90% Me-OH/10% NH.sub.4OAc
with 0.5% AcOH) of the crude product mixture from Example 62
yielded
trans-4-[(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)c-
arbonyl]benzoic acid O-methyloxime (163) as a white soid: .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.96 (br s, 2H, ArH), 7.56 (br s,
2H, ArH), 7.19 (m, 3H, ArH), 7.08 (s, 1H, ArH), 7.06 (m, 2H, ArH),
6.87 (s, 1H, ArH), 4.93 (s, 2H, OCH.sub.2), 3.97 (s, 3H,
OCH.sub.3), 1.67 (m, 4H, 2CH.sub.2), 1.26 (s, 6H, 2CH.sub.3), 1.22
(s, 6H, 2CH.sub.3); .sup.13C NMR (100 MHz, CDCl.sub.3), .delta.
154.3, 153.4, 147.4, 137.6, 137.4, 128.7, 128.5, 127.8, 127.5,
127.2, 120.1, 110.9, 70.4, 62.8, 35.3, 34.9, 34.0, 32.2, 32.0,
29.9.
EXAMPLE 64
[0342]
4-[2-(3-Benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl-
)-[1,3]dioxolan-2-yl]benzoic Acid (Compound 164, Prepared as
Illustrated and Described in Scheme 5)
[0343] A solution of
4-[3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-
-2-naphthyl)carbonyl]benzoic acid (from Example 62; 102 mg, 0.23
mmol) in benzene (2 mL) was treated with ethylene glycol (0.7 mmol)
and p-toluenesulfonic acid (20 mg). The solution was heated at
reflux with azeotropic distillation for 12 h. The solution was
cooled to ambient temperature, water was added, and the mixture was
extracted with EtOAc. The organic solution was washed with water
and brine, dried (MgSO.sub.4), filtered, and concentrated. The
crude product was purified by silica gel chromatography to give
4-[2-(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetra-
methyl-2-naphthyl)-[1,3]dioxolan-2-yl]benzoic acid as a white solid
(40%): mp 222-228.degree. C. d; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.93 (1/2ABq, 2H, J=8.4 Hz, ArH), 1.63 (s, 1H, ArH), 7.50
(1/2ABq, 2H, J=8.4 Hz, ArH), 7.22 (m, 3H, ArH), 6.98 (m, 2H, ArH),
6.72 (s, 1H, ArH), 4.84 (s, 2H, OCH.sub.2), 4.06 (m, 4H,
2OCH.sub.2), 1.65 (s, 4H, 2CH.sub.2), 1.28 (s, 6H, 2CH.sub.3), 1.18
(s, 6H, 2CH.sub.3).
EXAMPLE 65
[0344]
4-[2-Methyl-1-(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
-naphthyl)propenyl]benzoic Acid (Compound 165, Prepared as
Illustrated and Described in Scheme 6)
[0345] A solution of
4-[3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-
-2-naphthyl)carbonyl]benzoic acid methyl ester (201 mg, 0.44 mmol)
in THF (1 mL) was cooled with an ice/water bath and treated
dropwise with isopropylmagnesium bromide (0.53 mmol). The mixture
was allowed to warm to room temperature and stirred for 2 h.
Concentrated sulfuric acid (0.2 mL) was added and the mixture was
stirred for an additional 2 h. Water was added and the mixture was
extracted with EtOAc. The organic solution was washed with water
and brine, dried (MgSO.sub.4), filtered, and concentrated. The
crude product was purified by silica gel chromatography to give
4-[2-methyl-1-(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-
-2-naphthyl)propenyl]benzoic acid methyl ester (37%): .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.89 (1/2ABq, 2H, J=8.3 Hz, ArH),
7.25 (m, 3H, ArH), 7.22 (1/2ABq, 2H, J=8.3 Hz, ArH), 7.07 (m, 2H,
ArH), 7.05 (s, 1H, ArH), 6.72 (s, 4H, ArH), 4.84 (s, 2H,
OCH.sub.2), 3.89 (s, 3H, OCH.sub.3), 1.81 (s, 3H, CH.sub.3), 1.72
(s, 3H, CH.sub.3), 1.65 (s, 4H, 2CH.sub.2), 1.24 (s, 6H,
2CH.sub.3), 1.21 (s, 6H, 2CH.sub.3).
[0346] The above ester was hydrolyzed as described for Example 1 to
give
4-[2-methyl-1-(3-benzyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napht-
hyl)propenyl]benzoic acid (165) as a white solid (91%): .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.94 (1/2ABq, 2H, J=8.3 Hz, ArH),
7.25 (m, 3H, ArH), 7.22 (1/2ABq, 2H, J=8.3 Hz, ArH), 7.06 (m, 3H,
ArH), 6.72 (s, 1H, ArH), 4.84 (s, 2H, OCH.sub.2), 1.82 (s, 3H,
CH.sub.3) 1.73 (s, 3H, CH.sub.3), 1.65 (s, 4H, 2CH.sub.2), 1.25 (s,
6H, 2CH.sub.3), 1.21 (s, 6H, 2CH.sub.3).
EXAMPLE 66
[0347] (2E, 4E,
6E)-7-[3-(4-tert-butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,-
8-tetramethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic Acid.
(Compound 166, Prepared as Illustrated and Described in Scheme
7)
[0348]
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl-
)-ethanone (0.285 g, 1.16 mmol) was alkylated with
t-butylbenzylbromide (0.368 g, 1.62 mmol, 0.30 mL) as described in
Example 21. Aqueous workup gave
1-[3-(4-t-butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-nap-
hthalen-2-yl]-ethanone 0.452 g (99%) as a brown/orange oil:
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.74 (s, 1H, Ar--H), 7.43
(d of ABq, J=8.4 Hz, 2H), 7.38 (d of ABq, J=8.4 Hz, 2H), 6.91 (s,
1H, Ar--H), 5.11 (s, 2H, OCH.sub.2), 2.60 (s, 3H, CH.sub.3), 1.67
(m, 4H, 2CH.sub.2), 1.33 (s, 9H, 3CH.sub.3), 1.27 (s, 6H,
2CH.sub.3), 1.26 (s, 6H, 2CH.sub.3).
[0349] The above 3-(4-t-butylbenzyloxy)-2-acyltetrahydronapthalene
(0.440 g, 1.12 mmol) was condensed with diethyl
cyanomethylphosphonate (0.417 g, 2.35 mmol, 0.381 mL) as described
for Example 19. Aqueous work-up afforded the crude product
3-[3-(4-t-butylbenzyloxy)-5,6,7,8-tetrahydro-5-
,5,8,8-tetramethyl-naphthalen-2-yl]-but-2-enenitrile 0.391 g (84%)
as a pale orange oil: .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
7.42 (d of ABq, J=8.4 Hz, 2H), 7.32 (d of ABq, J=8.4 Hz, 2H), 7.13
(s, 1H, Ar--H), 6.90 (s, 1H, Ar--H), 5.59 (s, 1H, olefinic), 5.02
(s, 2H, OCH.sub.2), 2.44 (s, 3H, CH.sub.3), 1.66 (s, 4H,
2CH.sub.2), 1.33 (s, 9H, 3CH.sub.3), 1.32 (s, 6H, 2CH.sub.3), 1.27
(s, 6H, 2CH.sub.3).
[0350] The cyano(4-t-butylbenzyloxy)naphthalene adduct (0.525 g,
1.26 mmol) was reduced with DIBAL (2.65 mL of a 1.0 M solution in
hexanes, 2.65 mmol) as described for Example 19. Aqueous work-up
gave the aldehyde
3-[3-(4-t-butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthal-
en-2-yl]-but-2-enal 0.347 g (66%) as a yellow oil: .sup.1H-NMR
(trans isomer, CDCl.sub.3) .delta. 10.13 (d, J=8.1 Hz, 1H, CHO),
7.41 (d of ABq, J=8.4 Hz, 2H), 7.33 (d of ABq, J=8.4 Hz, 2H), 7.10
(s, 1H, Ar--H), 6.86 (s, 1H, Ar--H), 6.14 (d, J=8.1 Hz, 1H,
olefinic), 5.03 (s, 2H, OCH.sub.2), 2.55 (s, 3H, CH.sub.3), 1.67
(s, 4H, 2CH.sub.2), 1.33 (s, 9H, 3CH.sub.3), 1.26 (s, 6H,
2CH.sub.3), 1.25 (s, 6H, CH.sub.3).
[0351] The above aldehyde (0.347 g, 0.829 mmol) and
diethyl-3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (0.350 g,
1.33 mmol, 0.325 mL) were condensed as described for Example 19.
Aqueous work-up afforded the ester (0.381 g, 87%) as a yellow oil.
Standard hydrolysis of the crude ester (0.117 g, 0.256 mmol)
followed by the typical aqueous work-up gave the acid as a mixture
of geometric isomers (0.222 g, 62%). The product mixture was
crystallized with hexanes to give (2E, 4E,
6E)-7-[3-(4-tert-butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetr-
amethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid (166)
as a yellow solid: mp=188-190.degree. C.; .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.40 (d of ABq, J=8.4 Hz, 2H), 7.35 (d of ABq,
J=8.4 Hz, 2H), 7.11 (s, 1H, Ar--H), 7.05 (dd, J=15.3, 11.3 Hz, 1H,
CH), 6.83 (s, 1H, Ar--H), 6.33 (app br t, 2H, 2.times. olefinic),
5.81 (s, 1H, olefinic), 5.01 (s, 2H, OCH.sub.2), 2.39 (s, 3H,
CH.sub.3), 2.26 (s, 3H, CH.sub.3), 1.67 (s, 4H, 2CH.sub.2), 1.33
(s, 9H, 3CH.sub.3), 1.27 (s, 6H, 2CH.sub.3), 1.26 (s, 6H,
2CH.sub.3); .sup.13C-NMR (400 MHz, CDCl.sub.3) .delta. 171.2,
155.7, 154.0, 151.0, 145.8, 142.5, 137.5, 135.0, 134.6, 132.4,
131.8, 128.8, 127.5, 127.4, 125.6, 117.4, 110.8, 70.6, 35.4, 35.3,
34.8, 34.7, 34.0, 32.1, 32.0, 31.6, 18.4, 14.3.
EXAMPLE 67
[0352] (2E, 4E,
6Z)-7-[3-(4-tert-butylbenzyloxy)-5,6,7,8-tetrahydro-5,5,8,-
8-tetramethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic Acid.
(Compound 167, Prepared as Illustrated and Described in Scheme
7)
[0353] The final product mixture from Example 66 was purified by
reverse phase HPLC (90% MeOH/10% NH.sub.4OAc with 0.3% AcOH) to
give the title compound (2E, 4E,
6Z)-7-[3-(4-tert-butylbenzyloxy)-5,6,7,8-tetrahydro-5,5-
,8,8-tetramethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic
acid (167) as a pale yellow solid: .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.38 (d of ABq, J=8.4 Hz, 2H), 7.32 (d of ABq,
J=8.4 Hz, 2H), 6.97 (s, 1H, Ar--H), 6.86 (s, 1H, Ar--H), 7.05 (dd,
J=15.3, 11.3 Hz, 1H, CH), 6.23 (app br t, 2H, 2.times.olefinic),
5.76 (s, 1H olefinic), 5.01 (s, 2H, OCH.sub.2), 2.21 (s, 3H,
CH.sub.3), 2.14 (s, 3H CH.sub.3), 1.67 (s, 4H, 2CH.sub.2), 1.31 (s,
9H, 3CH.sub.3), 1.26 (s, 6H, 2CH.sub.3), 1.24 (s, 6H,
2CH.sub.3).
EXAMPLE 68
[0354] (2E, 4E,
6E)-7-[3-isobutyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethy-
l-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic Acid. (Compound
168, Prepared as Illustrated and Described in Scheme 7)
[0355]
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl-
)-ethanone (0.250 g, 1.01 mmol) was alkylated with isobutylbromide
(0.195 g, 1.42 mmol, 0.154 mL) as described in Example 21. Aqueous
workup gave
1-[3-isobutyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl]--
ethanone 0.322 g (crude) as an orange oil: .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.74 (s, 1H, Ar--H), 6.81 (s, 1H, Ar--H), 4.13
(d, J=6.2 Hz, 2H, OCH.sub.2), 2.62 (s, 3H, CH.sub.3), 2.16 (m, 1H,
CH), 1.68 (app br d, 4H, 2CH.sub.2), 1.30 (s, 6H, 2CH.sub.3), 1.28
(s, 6H, 2CH.sub.3), 1.08 (d, J=6.7 Hz, 6H, 2CH.sub.3).
[0356] The above 3-isobutyloxy-2-acyltetrahydronapthalene (0.307 g,
1.01 mmol) and diethyl cyanomethylphosphonate (0.378 g, 2.13 mmol,
0.345 mL) were condensed as described for Example 19. Aqueous
work-up afforded the crude product
3-[3-isobutyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-nap-
hthalen-2-yl]-but-2-enenitrile 0.569 g (crude) as an orange oil:
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.10 (s, 1H, Ar--H), 6.77
(s, 1H, Ar--H), 5.61 (s, 1H, olefinic), 3.73 (d, J=6.3 Hz, 2H,
OCH.sub.2), 2.45 (s, 3H, CH.sub.3), 2.09 (m, 1H, CH), 1.68 (app br
s, 4H, 2CH.sub.2), 1.29 (s, 6H, 2CH.sub.3), 1.26 (s, 6H,
2CH.sub.3), 1.02 (d, J=6.7 Hz, 6H, 2CH.sub.3)
[0357] The cyanoisobutyloxynaphthalene adduct (0.560 g, 1.72 mmol)
was reduced with DIBAL (3.44 mL of a 1.0 M solution in hexanes,
3.44 mmol) as described for Example 19. Aqueous work-up gave the
aldehyde
3-[3-isobutyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl]--
but-2-enal 0.255 g (45%) as a brown oil: .sup.1H-NMR (trans isomer,
CDCl.sub.3) .delta. 10.15 (d, J=8.3 Hz, 1H, CHO), 7.09 (s, 1H,
Ar--H), 6.76 (s, 1H, Ar--H), 6.14 (d, J=8.3 Hz, 1H, olefinic), 3.73
(d, J=6.4 Hz, 2H, OCH.sub.2), 2.57 (s, 3H, CH.sub.3), 2.09 (m 1H,
CH), 1.66 (app br s, 4H, 2CH.sub.2), 1.30 (s, 6H, 2CH.sub.3), 1.25
(s, 6H, 2CH.sub.3), 1.01 (d, J=6.7 Hz, 6H, 2CH.sub.3).
[0358] The above aldehyde (0.255 g, 0.776 mmol) and
diethyl-3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (0.328 g,
1.24 mmol, 0.304 mL) were condensed as described for Example 19.
Aqueous work-up afforded the crude ester as an orange oil. Standard
hydrolysis of the ester (0.280 g) and aqueous work-up gave the acid
as a mixture of geometric isomers. The product mixture was
recrystallized with EtOAc/hexanes to give (2E,
4E,6E)-7-[3-isobutyloxy-5,6,7,8-tetrahydro-5,5-
,8,8-tetramethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic
acid (168) as a yellow solid: mp=179-181.degree. C., .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. 7.09 (s, 1H, Ar--H), 7.06 (dd,
J=15.3, 11.1 Hz, 1H, olefinic), 6.74 (s, 1H, Ar--H), 6.32 (app br
d, J=14.6 Hz, 2H, 2.times. olefinic), 5.81 (s, 1H, olefinic), 3.70
(d, J=6.3 Hz, 2H, OCH.sub.2), 2.40 (s, 3H, CH.sub.3), 2.25 (s, 3H,
CH.sub.3), 2.07 (m, 1H, CH), 1.67 (s, 4H, 2CH.sub.2), 1.29 (s, 6H,
2CH.sub.3), 1.27 (s, 6H, 2CH.sub.3), 1.02 (d, J=6.7 Hz, 6H,
2CH.sub.3).
EXAMPLE 69
[0359] (2E, 4E,
6Z)-7-[3-isobutyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethy-
l-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic Acid. (Compound
169, Prepared as Illustrated and Described in Scheme 7)
[0360] A sample of the product mixture from Example 68 was purified
by reverse phase HPLC (90% MeOH/10% ammonium acetate with 0.3%
AcOH) to give (2E, 4E,
6Z)-7-[3-isobutylomy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-na-
phthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid (169) as a pale
yellow solid: .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.95 (s,
1H, Ar--H), 6.77 (s, 1H, Ar--H), 6.64 (dd, J=15.3, 10.9 Hz, 1H,
olefinic), 6.23 (app br d, J=14.6 Hz, 2H, 2.times. olefinic), 5.75
(s, 1H, olefinic), 3.69 (d, J=6.3 Hz, 2H, OCH.sub.2), 2.20 (s, 3H,
CH.sub.3), 2.14 (s, 3H, CH.sub.3), 2.04 (m, 1H, CH), 1.67 (s, 4H,
2CH.sub.2), 1.31 (s, 6H, 2CH.sub.3), 1.23 (s, 6H, 2CH.sub.3), 1.00
(d, J=6.7 Hz, 6H, 2CH.sub.3).
EXAMPLE 70
[0361] (2E, 4E,
6E)-7-[3-pentyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl--
2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic Acid. (Compound
170, Prepared as Illustrated and Described in Scheme 7).
[0362]
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl-
)-ethanone (0.316 g, 1.28 mmol) was alkylated with n-bromopentane
(0.271 g, 1.80 mmol, 0.223 mL) as described in Example 21. Aqueous
workup gave
1-[3-pentyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl]-et-
hanone 0.461 g (crude) as an orange oil: .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.74 (s, 1H, Ar--H), 6.82 (s, 1H, Ar--H), 4.03
(t, J=6.3 Hz, 2H, OCH.sub.2), 2.61 (s, 3H, CH.sub.3), 1.84 (m, 2H,
CH.sub.2) 1.67 (app br d, 4H, 2CH.sub.2), 1.39 (m, 4H, 2CH.sub.2),
1.29 (s, 6H, 2CH.sub.3), 1.26 (s, 6H, 2CH.sub.3), 0.94 (t, J=7.1
Hz, 3H, CH.sub.3).
[0363] The above 3-pentyloxy-2-acyltetrahyronapthalene (0.450 g,
1.42 mmol) and diethyl cyanomethylphosphonate (0.529 g, 2.98 mmol,
0.483 mL) were condensed as described for Example 19. Aqueous
work-up afforded the product
3-[3-pentyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen--
2-yl]-but-2-enenitrile 0.595 g (crude) as an orange oil:
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.10 (s, 1H, Ar--H), 6.78
(s, 1H, Ar--H), 5.61 (s, 1H, olefinic), 3.95 (t, J=6.4 Hz, 2H,
OCH.sub.2), 2.44 (s, 3H, CH.sub.3), 1.78 (m, 2H, CH.sub.2), 1.67
(app br s, 4H, 2CH.sub.2), 1.39 (m, 4H, 2CH.sub.2), 1.28 (s, 6H,
2CH.sub.3), 1.25 (s, 6H, 2CH.sub.3), 0.94 (t, J=6.9 Hz, 3H,
CH.sub.3).
[0364] The above cyanopentyloxynaphthalene adduct (0.148 g, 0.436
mmol) was reduced with DIBAL (0.872 mL of a 1.0 M solution in
hexanes, 0.872 mmol) as described for Example 1. Aqueous work-up
gave the aldehyde
3-[3-pentyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl]-bu-
t-2-enal 0.136 g (91%) as a yellow oil: .sup.1H-NMR (trans isomer,
CDCl.sub.3) .delta. 10.16 (d, J=8.0 Hz, 1H, CHO), 7.09 (s, 1H,
Ar--H), 6.78 (s, 1H, Ar--H), 6.14 (d, J=6.8 Hz, 1H, olefinic), 3.95
(t, J=6.4 Hz, 2H, OCH.sub.2), 2.44 (s, 3H, CH.sub.3), 1.78 (m, 2H,
CH.sub.2), 1.67 (app br s, 4H, 2CH.sub.2), 1.39 (m, 4H, 2CH.sub.2),
1.28 (s, 6H, 2CH.sub.3), 1.25 (s, 6H, 2CH.sub.3), 0.94 (t, J=6.9
Hz, 3H, CH.sub.3).
[0365] The above aldehyde (0.090 g, 0.263 mmol) and
diethyl-3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (0.111 g,
0.420 mmol, 0.103 mL) were condensed as described for Example 19.
Aqueous work-up afforded the crude,ester (0.100 g, 83%). Standard
hydrolysis of the ester (0.100 g, 0.221 mmol) and aqueous work-up
gave the acid as a mixture of geometric isomers (0.093 g, 87%). A
sample of the product mixture was purified by reverse phase HPLC
(92% MeOH/8% ammonium acetate with 0.3% AcOH) to give (2E, 4E,
6E)-7-[3-pentyloxy-5,6,7,8-tetrahydro-5,-
5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic
acid (170) as a pale yellow oil: .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. 7.08 (s, 1H, Ar--H), 7.06 (dd, J=15.1, 11.5 Hz, 1H,
olefinic), 6.75 (s, 1H, Ar--H), 6.33 (d, J=5.3 Hz, 1H, olefinic),
6.30 (s, 1H, olefinic), 5.87 (s, 1H, olefinic), 3.93 (t, J=6.5 Hz,
2H, OCH.sub.2), 2.40 (s, 3H, CH.sub.3), 2.24 (s, 3H, CH.sub.3),
1.75 (m, 2H, CH.sub.2), 1.67 (s, 4H, 2CH.sub.2), 1.39 (m, 4H,
2CH.sub.2), 1.29 (s, 6H, 2CH.sub.3), 1.26 (s, 6H, 2CH.sub.3), 0.92
(t, J=7.2 Hz, 3H, CH.sub.3).
EXAMPLE 71
[0366] (2E, 4E,
6Z)-7-[3-pentyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl--
2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic Acid. (Compound
171, Prepared as Illustrated and Described in Scheme 7.)
[0367] A sample of the product mixture from Example 70 was purified
by reverse phase HPLC (92% MeOH/8% ammonium acetate with 0.3% AcOH)
to give (2E, 4E,
6Z)-7-[3-pentyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naph-
thalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid (171) as a pale
yellow solid: .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.08 (s,
1H, Ar--H), 6.95 (s, 1H, Ar--H), 6.64 (dd, J=15.5, 10.8 Hz, 1H,
olefinic), 6.23 (app br d, 2H, 2.times. olefinic), 5.75 (s, 1H,
olefinic), 3.93 (t, J=6.6 Hz, 2H, OCH.sub.2), 2.19 (s, 3H,
CH.sub.3), 2.14 (s, 3H, CH.sub.3), 1.75 (m, 2H, CH.sub.2), 1.68 (s,
4H, 2CH.sub.2), 1.39 (m, 4H, 2CH.sub.2), 1.30 (s, 6H, 2CH.sub.3),
1.23 (s, 6H, 2CH.sub.3), 0.90 (t, J=7.2 Hz, 3H, CH.sub.3).
EXAMPLE 72
[0368] (2E, 4E,
6E)-7-[3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl--
2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic Acid. (Compound
172, Prepared as Illustrated and Described in Scheme 7)
[0369]
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl-
)-ethanone (0.410 g, 01.66 mmol) was alkylated with n-bromoheptane
(0.417 g, 2.33 mmol, 0.366 mL) as described in Example 21. Aqueous
workup cave
1-[3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl]-et-
hanone 0.629 g (crude) as an orange oil which was used without
further purification. The 3-n-heptyloxy-2-acyltetrahydronapthalene
(0.625 g, 1.81 mmol) and diethyl cyanomethylphosphonate (0.705 g,
3.98 mmol, 0.644 mL) were condensed as described for Example 19.
Aqueous work-up afforded the crude product
3-[3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-napht-
halen-2-yl]-but-2-enenitrile 0.915 g as an orange oil: .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. 7.10 (s, 1H, Ar--H), 6.78 (s, 1H,
Ar--H), 5.61 (s, 1H, olefinic), 3.95 (t, J=6.4 Hz, 2H, OCH.sub.2),
2.44 (s, 3H, CH.sub.3), 1.78 (m, 4H, 2CH.sub.2), 1.67 (app br s,
4H, 2CH.sub.2), 1.39 (m, 2H, CH.sub.2), 1.30 (m, 4H, 2CH.sub.2),
1.28 (s, 6H, 2CH.sub.3), 1.25 (s, 6H, 2CH.sub.3), 0.94 (t, 3H,
CH.sub.3).
[0370] The above cyanoheptyloxynaphthalene adduct (0.915 g, 2.48
mmol) was reduced with DIBAL (5.21 mL of a 1.0 M solution in
hexanes, 5.21 mmol) as described for Example 19. Aqueous work-up
gave the aldehyde
3-[3-isobutyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl]--
but-2-enal 0.452 g (49%) as an orange oil which was used without
further purification. The aldehyde (0.452 g, 1.22 mmol) and
diethyl-3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (0.514 g,
1.95 mmol, 0.477 mL) were condensed as described for Example 19.
Aqueous work-up afforded the crude ester (0.458, 78%) as a yellow
oil. Standard hydrolysis of the ester (0.458 g, 0.952 mmol) and
aqueous work-up gave the crude acid as a mixture of geometric
isomers. A sample of the product mixture was purified by
preparative TLC to give (2E, 4E,
6E)-7-[3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2--
yl]-3-methyl-octa-2,4,6-trienoic acid (172) as a yellow-oil:
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.08 (s, 1H, Ar--H), 7.06
(dd, J=15.2, 11.4 Hz, 1H, olefinic), 6.75 (s, 1H, Ar--H), 6.33
(broad t, 2H, 2.times. olefinic), 5.81 (s, 1H, olefinic), 3.92 (t,
J=6.5 Hz, 2H, OCH.sub.2), 2.39 (s, 3H, CH.sub.3), 2.23 (s, 3H,
CH.sub.3), 1.68 (m, 4H, 2CH.sub.2), 1.67 (s, 4H, 2CH.sub.2), 1.41
(m, 2H, CH.sub.2), 1.30 (m, 4H, 2CH.sub.2), 1.28 (s, 6H,
2CH.sub.3), 1.26 (s, 6H, 2CH.sub.3), 0.88 (t, 3H, CH.sub.3).
EXAMPLE 73
[0371] (2E, 4E,
6Z)-7-[3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl--
2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic Acid. (Compound
173, Prepared as Illustrated and Described in Scheme 7)
[0372] A sample of the product mixture from Example 72 was purified
by reverse phase HPLC (92% MeOH/8% ammonium acetate with 0.3% AcOH)
to give (2E, 4E,
6Z)-7-[3-heptyloxy-5,6,7,8-tetrahydro-5,5,8,3-tetramethyl-2-naph-
thalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid (173) as a yellow
oil: .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.95 (s, 1H, Ar--H),
6.79 (s, 1H, Ar--H), 6.64 (dd, J=15.5, 10.8 Hz, 1H, olefinic), 6.23
(app br d, 2H, 2.times. olefinic), 5.74 (s, 1H, olefinic), 3.92 (t,
J=6.6 Hz, 2H, OCH.sub.2), 2.19 (s, 3H, CH.sub.3), 2.14 (s, 3H,
CH.sub.3), 1.75 (m, 2H, CH.sub.2), 1.70 (s, 4H, 2CH.sub.2), 1.39
(m, 4H, 2CH.sub.2), 1.30 (s, 6H, 2CH.sub.3), 1.23 (s, 6H,
2CH.sub.3), 0.89 (t, J=6.6 Hz, 3H, CH.sub.3).
EXAMPLE 74
[0373] (2E, 4E,
6E)-7-[3-(4-methoxybenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-t-
etramethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic Acid.
(Compound 174, Prepared as Illustrated and Described in Scheme
7)
[0374]
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl-
)-ethanone (0.315 g, 1.28 mmol) was alkylated with
4-methoxybenzylchloride (0.280 g, 1.79 mmol, 0.24. mL) as described
in Example 21. Aqueous workup gave
1-[3-(4-methoxybenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-nap-
hthalen-2-yl]-ethanone 0.606 g (crude) as an orange oil:
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.74 (s, 1H, Ar--H), 7.39
(d of ABq, J=8.6 Hz, 2H), 6.92 (d, of ABq, J=8.6 Hz, 2H), 6.91 (s,
1H, Ar--H), 5.06 (s, 2H, OCH.sub.2), 3.82 (s, 3H, OCH.sub.3), 2.55
(s, 3H, CH.sub.3), 1.67 (m, 4H, 2CH.sub.2), 1.27 (s, 6H,
2CH.sub.3), 1.26 (s, 6H, 2CH.sub.3).
[0375] The above 4-methoxybenzyloxy-2-acyltetrahydronapthalene
(0.606 g, 1.65 mmol) was condensed with diethyl
cyanomethylphosphonate (0.644 g, 3.64 mmol, 0.588 mL) as described
for Example 19. Aqueous work-up and flash chromatography
(10:1=hexanes:EtOAc) afforded the product
3-[3-(4-methoxybenzyloxy)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthal-
en-2-yl]-but-2-enenitrile 0.218 g (34%) as a clear oil: .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. 7.32 (d of ABq, J=8.6 Hz, 2H), 7.11
(s, 1H, Ar--H), 6.93 (d of ABq, J=8.6 Hz, 2H), 6.88 (s, 1H, Ar--H),
5.59 (s, 1H, olefinic), 4.99 (s, 2H, OCH.sub.2), 3.83 (s, 3H,
OCH.sub.3), 2.42 (s, 3H, CH.sub.3), 1.68 (s, 4H, 2CH.sub.2), 1.27
(s, 6H, 2CH.sub.3), 1.26 (s, 6H, 2CH.sub.3).
[0376] The cyano(4-methoxybenzyloxy)naphthalene adduct (0.525 g,
1.26 mmol) was reduced with DIBAL (2.65 mL of a 1.0 M solution in
hexanes, 2.65 mmol) as described for Example 19. Aqueous work-up
gave the crude aldehyde
3-(3-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen--
2-yl)-but-2-enal 0.203 g (92%) as a yellow oil: .sup.1H-NMR (trans
isomer, CDCl.sub.3) .delta. 10.11 (d, J=8.2 Hz, 1H, CHO), 7.32 (d
of ABq, J=8.5 Hz, 2H), 7.09 (s, 1H, Ar--H), 6.90 (d of ABq, J=8.5
Hz, 2H, 6.88 (s, 1H, Ar--H), 6.13 (d, J=8.2 Hz, 1H, olefinic), 4.99
(s, 2H, OCH.sub.2), 3.82 (s, 3H, OCH.sub.3), 2.52 (s, 3H,
CH.sub.3), 1.67 (s, 4H, 2CH.sub.2), 1.27 (s, 6H, 2CH.sub.3), 1.26
(s, 6H, 2CH.sub.3).
[0377] The above aldehyde (0.203 g, 0.517 mmol) and
diethyl-3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (0.218 g,
0.828 mmol, 0.203 mL) were condensed as described for Example 19.
Aqueous work-up and flash chromatography (10:1=hexanes:EtOAc)
afforded the ester (0.078 g, 30%) as a yellow oil. Standard
hydrolysis of the crude ester (0.078 g, 0.155 mmol) followed by the
typical aqueous work-up gave the acid as a mixture of geometric
isomers. The product mixture was crystallized with hexanes to give
(2E, 4E, 6E)-7-[3-(4-methoxybenzyloxy)--
5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalen-2-yl]-3-methyl-octa-2,-
4,6-trienoic acid (174) as a pale yellow solid: .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. 7.30 (d of ABq, J=8.6 Hz, 2H), 6.96 (s,
1H, Ar--H), 6.88 (d of ABq, J=8.6 Hz, 2H), 6.88 (s, 1H, Ar--H),
6.62 (dd, J=15.5, 10.9 Hz, 1H, CH), 6.22 (app br d, J=14.6 Hz, 2H,
2.times. olefinic), 5.74 (s, 1H, olefinic), 4.97 (s, 2H,
OCH.sub.2), 3.80 (s, 3H, OCH.sub.3), 2.19 (s, 3H, CH.sub.3), 2.13
(s, 3H, CH.sub.3), 1.67 (s, 4H, 2CH.sub.2), 1.28 (s, 6H,
2CH.sub.3), 1.23 (s, 6H, 2CH.sub.3).
EXAMPLE 75
[0378] (2E,
4E)-7-[3-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naph-
thalen-2-yl]-3-methyl-octa-2,4-dienoic Acid. (Compound 175,
Prepared as Illustrated and Described in Scheme 7 and Scheme
16)
[0379] The propoxy nitrile (prepared as described in Example 19)
(0.503 g, 1.61 mmol) was stirred at room temperature in a
EtOAc:EtOH (1:1) solution. 10% Pd/C was added and the black mixture
was stirred under atmospheric H.sub.2 for 36 h. The reaction
solution was filtered through Celite, and the pad was rinsed with
EtOAc. Concentration of the filtrate gave
3-[3-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl]-
-butyronitrile 0.478 g (95%) as a turbid oil: .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. 7.09 (s, 1H, Ar--H), 6.63 (s, 1H, Ar--H), 3.42
(m, 1H benzylic), 2.72 (dd, J=16.7, 5.4 Hz, 1H, CHCN), 2.62 (dd,
J=16.7, 8.0 Hz, 1H, CHCN), 1.65 (s, 4H, 2CH.sub.2), 1.46 (d, J=7.1
Hz, 3H CH.sub.3), 1.25 (s, 6H, 2CH.sub.3), 1.24 (d, J=1.9 Hz, 6H,
2CH.sub.3).
[0380] The above cyanopropoxynaphthalene adduct (0.475 g, 1.39
mmol) was reduced with DIBAL (2.78 mL of a 1.0 M solution in
hexanes, 2.78 mmol) as described for Example 19. Aqueous work-up
gave the aldehyde
3-[3-propoxy-5,6,7,8-tetrahydro-5,3,8,8-tetramethyl-naphthalen-2-yl]-buty-
raldehyde 0.341 g (71%) as a pale yellow turbid oil: .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. 9.70 (app d, 1H, CHO), 7.05 (s, 1H,
Ar--H), 6.71 (s, 1H, Ar--H), 3.90 (m, 2H, OCH.sub.2), 3.65 (m, 1H,
benzylic), 2.75 (dd, J=16.7, 5.2 Hz, 1H, CHCHO), 2.62 (dd, J=16.7,
8.4 Hz, 1H, CHCHO), 1.80 (m, 2H, CH.sub.2), 1.65 (s, 4H,
2CH.sub.2), 1.30 (d, J=7.0 Hz, 3H, CH.sub.3), 1.28 (s, 6H,
2CH.sub.3), 1.27 (s, 6H, 2CH.sub.3), 1.05 (t, J=7.4 Hz, 3H,
CH.sub.3).
[0381] The above aldehyde (0.341 g, 1.08 mmol) and
diethyl-3-ethoxycarbony- l-2-methylprop-2-enylphosphonate (0.455 g,
1.72 mmol, 0.422 mL) were condensed as described for Example 21.
Aqueous work-up afforded the crude ester as a clear oil. Standard
hydrolysis of the ester (0.302 g, 0.682 mmol) and aqueous work-up
gave the acid as a mixture of geometric isomers. A sample of the
product mixture was purified by prep TLC (10:1=hexanes:EtOAc) to
give (2E, 4E)-7-[3-propoxy-5,6,7,8-tetrahydro-5,5-
,8,8-tetramethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4-dienoic acid
(175), as a yellow oil: .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
7.51 (d, J=15.9 Hz, 1H, olefinic), 7.01 (s, 1H, Ar--H), 6.67 (s,
1H, Ar--H), 6.10 (m, 1H, olefinic), 5.59 (s, 1H, olefinic), 3.87
(t, J=6.6 Hz, 2H, OCH.sub.2), 3.21 (m, 1H, benzylic), 2.55 (m, 1H,
CH), 2.40 (m, 1H, CH), 1.94 (s, 3H, CH.sub.3), 1.78 (m, 2H,
CH.sub.2), 1.62 (s, 4H, 2CH.sub.2), 1.24 (s, 6H, 2CH.sub.3), 1.21
(m, 9H, 3CH.sub.3), 1.03 (t, J=7.4 Hz, 3H, CH.sub.3).
[0382] Evaluation of Retinoid Receptor Subfamily Activity
[0383] Utilizing the "cis-trans" or "co-transfection" assay
described by Evans et al., Science, 240:889-95 (May 13, 1988), the
disclosure of which is herein incorporated by reference, the
dimer-selective RXR modulator compounds of the present invention
were tested and found to have strong, specific activity as
selective RXR modulators, including activity as full agonists,
partial agonists and/or full antagonists of RXR homodimers and/or
heterodimers. This assay is described in further detail in U.S.
Pat. Nos. 4,981,784 and 5,071,773, the disclosures of which are
incorporated herein by reference.
[0384] The co-transfection assay provides a method for identified
functional agonists which mimic, or antagonists which inhibit, the
effect of native hormones, and quantifying their activity for
responsive IR proteins. In this regard, the co-transfection assay
mimics an in vivo system in the laboratory. Importantly, activity
in the co-transfection assay correlates very well with known in
vivo activity, such that the co-transfection assay functions as a
qualitative and quantitative predictor of a tested compounds in
vivo pharmacology. See, e.g., T. Berger et al. 41 J. Steroid
Biochem. Molec. Biol. 773 (1992), the disclosure of which is herein
incorporated by reference.
[0385] In the co-transfection assay, cloned cDNA for one or more
IRs (e.g., human, murine or rat RXR.alpha., RXR.beta., RXR.gamma.,
PPAR.alpha., VDR, LXR), alone or in combination (i.e. for
heterodimer assays) under the control of a constitutive promoter
(e.g., the SV 40, RSV or CMV promoter) is introduced by
transfection (a procedure to introduce exogenous genes into cells)
into a background cell substantially devoid of endogenous IRs.
These introduced gene(s) direct the recipient cells to make the IR
protein(s) of interest. A further gene is also introduced
(co-transfected) into the same cells in conjunction with the IR
gene(s). This further gene, comprising the cDNA for a reporter
protein, such as firefly luciferase (LUC), controlled by an
appropriate hormone responsive promoter containing a hormone
response element (HRE). This reporter plasmid functions as a
reporter for the transcriptional-modulating activity of the target
IR(s). Thus, the reporter acts as a surrogate for the products
(mRNA then protein) normally expressed by a gene under control of
the target receptor(s) and their native hormone(s).
[0386] The co-transfection assay can detect small molecule agonists
or antagonists, including partial agonists and antagonist, of
target IRs. Exposing the transfected cells to an agonist ligand
compound increases reporter activity in the transfected cells. This
activity can be conveniently measured, e.g., by increasing
luciferase production and enzymatic activity, which reflects
compound-dependent, IR-mediated increases in reporter
transcription. To detect antagonists, the co-transfection assay is
carried out in the presence of a constant concentration of an known
agonist to the target IR (e.g.,
4-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzoic
acid (LGD1069, Ligand Pharmaceuticals, Inc.) for RXR.alpha.) known
to induce a defined reporter signal. Increasing concentrations of a
suspected antagonist will decrease the reporter signal (e.g.,
luciferase production). The co-transfection assay is therefore
useful to detect both agonists and antagonists of specific IRs.
Furthermore, it determines not only whether a compound interacts
with a particular IR, but whether this interaction mimics
(agonizes) or blocks (antagonizes) the effects of native or
synthetic regulatory molecules on target gene expression, as well
as the specificity and strength of this interaction.
[0387] The activity of the dimer-selective RXR retinoid modulator
compounds of the present invention were evaluated utilizing the
co-transfection assay according to the following illustrative
Examples.
EXAMPLE 76
[0388] RXR Homodimer Co-Transfection Assay
[0389] CV-1 cells (African green monkey kidney fibroblasts) were
cultured in the presence of Dulbecco's Modified Eagle Medium (DMEM)
supplemented with 10% charcoal resin-stripped fetal bovine serum
then transferred to 96-well microtiter plates one day prior to
transfection.
[0390] To determine agonist and antagonist activity of the
modulator compounds of the present invention, the CV-1 cells or
Schneider cells were transiently transfected by calcium phosphate
coprecipitation according to the procedure of Berger et al., 41 J.
Steroid Biochem. Mol. Biol., 733 (1992) with one or more of the
following receptor expressing plasmids: pRShRAR.alpha.: Giguere et
al., 330 Nature 624 (1987); pRShRAR.beta. and pRShRAR.gamma.,
Ishikawa et al., 4 Mol. Endocrin., 837 (1990); pRhRXR.alpha.;
Mangelsdorf et al., 345 Nature, 224 (1990); and pRSmRXR.beta. and
pRSmRXR.gamma., Mangelsdorf et al, 6 Genes & Devel., 329
(1992), the disclosures of which are herein incorporated by
reference. Each of these receptor expressing plasmids was
co-transfected at a concentration of 5 ng/well, along with a basal
reporter plasmid at 100 ng/well, the internal control plasmid
pRS-.beta.-Gal at 50 ng/well and filler DNA, pGEM at 45
ng/well.
[0391] The basal reporter plasmid .DELTA.-MTV-LUC (Hollenberg and
Evans, 55 Cell, 899 (1988), the disclosure of which is herein
incorporated by reference) containing an RARE which is referred to
as two copies of the TRE-palindromic response element described in
Umesono et al., 336 Nature, 262 (1988), the disclosure of which is
herein incorporated by reference, was used in transfections for the
RARs, and the reporter plasmid CRBPIITKLUC, which contains an RXRE
(retinoid X receptor response element, as described in Mangelsdorf
et al, 66 Cell, 555 (1991), the disclosure of which is herein
incorporated by reference), was used in transfections for the RXRs.
Each of these reporter plasmids contains the cDNA for firefly
luciferase (LUC) under the control of a promoter containing the
appropriate RAR or RXR response element. As noted above,
pRS-.beta.-Gal, coding for constitutive expression of E. coli
.beta.-galactosidase (.beta.-Gal), was included as an internal
control for evaluation of transfection efficiency and compound
toxicity.
[0392] Six hours after transfection, media was removed and the
cells were washed with phosphate-buffered saline (PBS). Media
containing compounds of the present invention in concentrations
ranging from 10.sup.-12 to 10.sup.-5 M were added to the cells.
Similarly, the reference compounds all-trans retinoic acid
(ATRA)(Sigma Chemical), a known RAR selective agonist compound, and
9-cis retinoic acid (9-cis) (as described in Heyman et al., Cell,
68:397-406 (1992)), a compound with known agonist activity on RXRs,
were added at similar concentrations to provide a reference point
for analysis of the agonist activity of the compounds of the
present invention. When determining the antagonist activity of the
compounds of the present invention, the compounds were added to the
cells in the presence of a fixed concentration (3.2.times.10.sup.-8
M) of the known RXR agonist LGD1069
(4-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-
-naphthyl)ethenyl]benzoic acid: Ligand Pharmaceuticals, Inc.) or
the known RAR/RXR panagonist compound
(2E,4E,6Z)-7-[5,6,7,8-tetrahydro-5,5,8,8-tetr-
amethyl-2-naphthalen-2-yl]-3-methyl-octa-2,4,6-trienoic acid
(Hoffmann LaRoche, Inc.). Retinoid purity was established as
greater than 99% by reverse phase high-performance liquid
chromatography. Retinoids were dissolved in dimethylsulfoxide for
use in the transcriptional activation assays. Three to four
replicates were used for each sample. Transfections and subsequent
procedures were performed on a Biomek 1000 automated work
station.
[0393] After 40 hours, the cells were washed with PBS, lysed with a
Triton X-100-based buffer and assayed for LUC and .beta.-Gal
activities using a luminometer or spectrophotometer, respectively.
For each replicate, the normalized response (NR) was calculated
as:
LUC response/.beta.-Gal rate
[0394] where .beta.-Gal
rate=.beta.-Gal.multidot.1.times.10.sup.-5/.beta.-- Gal incubation
time.
[0395] The mean and standard error of the mean (SEM) of the NR were
calculated. Data was plotted as the response of the compound
compared to the reference compounds over the range of the
dose-response curve. For the agonist activity of the compounds of
the present invention, the effective concentration that produced
50% of the maximum response (EC.sub.50) was quantified. Antagonist
activity was determined by testing the amount of LUC expression in
the presence of the RAR and/or RXR agonists described above at the
EC.sub.50 concentration for such known compounds. The concentration
of compounds of the present invention that inhibited 50% of LUC
expression induced by the reference agonist was quantified
(IC.sub.50). In addition, the efficacy of antagonists was
determined as a function (%) maximal inhibition.
[0396] RXR and RAR Binding
[0397] In addition to the cotransfection data, the binding of
selected compounds of the present invention to the RAR and RXR
receptors was also investigated according to the methodology
described in M. F., Boehm, et al., "Synthesis and
Structure-Activity Relationships of Novel Retinoid X Receptor
Selective Retinoids", 37 J. Med. Chem., 2930 (1994); M. F. Boehm,
et al., "Synthesis of High Specific Activity [.sup.3H]-9-cis
Retinoic Acid and Its Application for Identifying Retinoids with
Unusual Binding Properties", 37 J. Med. Chem., 408 (1994), and E.
A. Allegretto, et al., "Characterization and Comparison of
Hormone-Binding and Transactivation Properties of Retinoic Acid and
Retinoid X Receptors Expressed in Mammalian Cells and Yeast", 268
J. Biol. Chem., 22625 (1993), the disclosures of which are herein
incorporated by reference.
[0398] Non-specific binding was defined as that binding remaining
in the presence of 500 nM of the appropriate unlabelled compound.
At the end of the incubation period, bound from free ligand were
separated. The amount of bound tritiated retinoids was determined
by liquid scintillation counting of an aliquot (700 .mu.l) of the
supernatant fluid or the hydroxylapatite pellet.
[0399] After correcting for non-specific binding, IC.sub.50 values
were determined. The IC.sub.50 value is defined as the
concentration of competing ligand needed e specific binding by 50%.
The IC.sub.50 value was determined graphically from a log-logit
plot of the data. The K.sub.d values were determined by application
of the Cheng-Prussof equation to the IC.sub.50 values, the labeled
ligand concentration and the K.sub.d of the labeled ligand.
[0400] The IC.sub.50 antagonist potency (nM) and binding activity
(Kd in nM) of selected retinoid modulator compounds of the present
invention on RXR.alpha.,.beta.,.gamma. are shown in Table 1 below.
In this regard, all of the dimer-selective RXR modulator compounds
of the present invention displayed occassionally weak, but most
often negligible, if any, agonist activity (i.e. EC.sub.50) on all
of the RAR and RXR receptors. Accordingly, only RXR antagonist
co-transfection data and RXR binding data is provided in Table
1.
1TABLE 1 Antagonist potency (IC.sub.50 in nM) in the presence of
the known RXR agonist LGD 1069, and binding (Kd in nM-v-tritiated
LGD 1069 and tritiated 9-cis retinoic acid) of selected
dimer-selective RXR modulator compounds of the present invention.
RXR.alpha. RXR.alpha. RXR.beta. RXR.beta. RXR.gamma. RXR.gamma.
Cmpd. Potency Binding Potency Binding Potency Binding No. IC.sub.50
in nM Kd in nM IC.sub.50 in nM Kd in nM IC.sub.50 in nM Kd in nM
102 386 282 659 426 1668 683 103 498 389 701 846 1669 936 109 210
37 193 33 394 47 110 80 40 217 77 211 66 114 126 9 197 12 206 38
117 81 3 234 17 155 17 122 21 11 101 29 29 33 125 188 56 276 145
265 186 128 50 9 67 23 120 27 131 528 140 1409 105 1264 107 135 334
163 236 155 620 181 141 258 49 184 13 234 70 142 673 27 1828 90
1764 50 146 85 46 29 100 98 116 147 5 3 4 8 8 6 148 89 53 66 87 122
84 149 88 16 129 37 149 42 152 195 8 337 45 428 21 155 24 9 53 9 37
8 156 18 11 62 7 47 9 158 38 21 136 53 144 106 163 22 2 162 6 50 6
169 29 5 93 14 45 31 170 23 11 40 41 42 78 173 34 4 111 12 43 21
174 50 5 166 43 40 46 175 39 11 79 21 60 31
[0401] As can be seen in Table 1, the RXR modulator compounds of
the present invention act as antagonists in the context of an
RXR:RXR homodimer, with Compound 147 being an especially potent
antagonist, both in terms of binding and repression of
transactivation of the RXR:RXR homodimer.
[0402] Furthermore, as can be seen in FIG. 1A, Compound 122 binds
RXR (See Table 1) but is unable to activate RXR homodimers. In
contrast, the known RXR agonist, LG100268, is a potent activator
and produces a concentration dependent activation (EC.sub.50
value=4 nM) which is consistent with its ligand binding affinity.
In addition, Compound 122 antagonizes the transcriptional
activation of an RXR homodimer produced with a known RXR activator,
LGD1069 (FIG. 1B), producing a concentration dependent inhibition
of transactivation (IC.sub.50 value=20 nM). Further, Compound 122
also antagonizes transactivation of RXR homodimers in the presence
of other known RXR activators, i.e., LG100268 and 9-cis retinoic
acid (9-cis RA) (FIG. 1C). Thus, Compound 122 of the present
invention has properties that are distinct from LG100268, in that
it is transcriptionally neutral by itself and functions as a
competitive RXR antagonist in the context of RXR homodimers.
EXAMPLE 77
[0403] RXR Heterodimer Co-Transfection Assay
[0404] The cotransfection assay was utilized with CV-1 cells as
described in Example 76. Additional IR expression plasmids and
reporter plasmids employed included: pCMVhPPAR.alpha. expression
plasmid with the pPREA3-tk-LUC reporter plasmid: Kliewer et al.,
358 Nature 771-774 (1992) and Jow & Mukherjee, 270 Journ. Biol.
Chem., 3836-3840 (1994) and references cited therein, the
disclosures of which are herein incorporated by reference.
Co-transfections were performed as described in Mukherjee et al. 51
Journ. Steroid Biochem. Molec. Biol., 157-166 (1994), the
disclosure of which is herein incorporated by reference. Reference
agonists employed included clofibric acid (Sigma Chemical) for
PPAR.alpha. and LGD1069 (Ligand Pharmacueticals, Inc.) for
RXR.alpha..
[0405] Table 2 below shows the relative normalized response of
reporter activity, both in terms of EC.sub.50 and fold induction
values generated in response to the added compounds in a CV-1 cell
transfected with both RXR.alpha. and PPAR.alpha. and a reporter
containing the PPAR.alpha. response element indicated above.
2TABLE 2 Agonist potency (EC.sub.50 in nM) and fold induction of
dimer-selective RXR modulator compounds of the present invention in
comparison to the known RXR.alpha. agonist LGD 1069 and known
PPAR.alpha. agonist clofibric acid. Fold Activation = Normalized
luciferase values at 10-5 M (for RXR modulators and LGD 1069) or at
10-4 M (for clofibric acid) divided by normalized luciferase values
with vehicle. EC.sub.50 values were calculated as described in
example 76. Compound EC.sub.50 [M] Fold activation 131 8 .times.
10-7 7 135 10-6 5 114 2 .times. 10-7 4 117 9 .times. 10-7 9 122 3
.times. 10-7 7.5 128 2 .times. 10-7 4 LGD1069 3 .times. 10-7 9
Clofibric acid 4 .times. 10-5 6.5
[0406] As can be seen in Table 2, the known RXR agonist LGD1069
induces transactivation of the RXR.alpha.:PPAR.alpha. heterodimer
as does the fibrate derivative clofibric acid. In addition, the
dimer-selective RXR modulator compounds of the present invention
also all induce transcription of the RXR.alpha.:PPAR.alpha.
heterodimer. Thus, in the context of this heterodimer, these
compounds function as RXR.alpha.:PPAR.alpha. agonists in a
cotransfection assay in a similar manner to LGD1069, however, as
noted above in Table 1, Example 76, Compounds 114, 117, 122, 131,
and 135 in the context of an RXR.alpha.:RXR.alpha. homodimer
function as antagonists.
[0407] The result is further supported by a comparison of the
activities of Compound 122 of the present invention and the known
RXR agonist, LG100268, in the context of PPAR.alpha.:RXR.alpha. and
RAR.alpha.:RXR.alpha. heterodimer pairs. RXR:PPAR heterodimers have
previously been shown to be responsive to both RXR and PPAR
ligands. Kliewer, et al., Nature 358, 771-774 (1992). Accordingly,
as shown in FIG. 2A, LG100268 (.diamond-solid.) activates the
RXR.alpha.:PPAR.alpha. heterodimer, producing a maximal induction
of 4.5 fold at 1 mM. Unexpectedly, Compound 122 (.box-solid.)
activates the heterodimer and, in fact, is a stronger and more
efficacious activator than LG100268 producing a 13 fold induction
at 1 mM. Thus, Compound 122, along with other compounds of the
present invention, have the unique properties of functioning as
antagonists of RXR homodimers and a transcriptionally active
agonist of RXR.alpha.:PPAR.alpha. heterodimers. Although ligands
with mixed agonist/antagonist function have been reported for
estrogen receptors, See Danielian, P. S., et al. Mol Endocrinol. 7,
232-240 (1993), the compounds of the present invention, including
Compound 122, are the first examples of mixed function retinoids
whose activity is dimer selective.
[0408] In contrast to PPAR, RAR suppresses RXR ligand binding and
transactivation of typical RXR agonists (e.g., LGD1069, LG100268)
via allosteric interactions. Forman, B. M., Umesono, K., Chen, J.,
& Evans, R. M., Cell 81, 541-550 (1995) and Kurokawa, R., et.
al Nature 371, 528-531 (1994). However, when RAR is occupied,
typical RXR agonists activate the heterodimer. Forman, B. M.,
Umesono, K., Chen, J., & Evans, R. M., Cell 81, 541-550 (1995)
and Roy, B., Taneja, R., & Chambon, P., Mol. Cell. Biol .15,
6481-6487 (1995). To examine the effects of LG100268 and Compound
122 on the transcriptional properties of the RXR.alpha.:RAR.alpha.
a heterodimer cotransfection assays as described above was
employed. As shown in FIG. 2B, whereas RXR agonists, such as
LG100268 by themselves, do not activate the wild-type
RXR.alpha.:RAR.alpha. heterodimer, Compound 122 or the RAR
selective agonist, TTNPB, strongly transactivate this heterodimer
pair. Interestingly, the addition of both Compound 122 and TTNPB
further enhance the transactivation in a greater than additive
manner (FIG. 2B). This suggests that Compound 122 is active on
RXR:RAR heterodimers, and either receptor within this dimer can be
activated by its ligand while the partner remains unoccupied.
EXAMPLE 78
[0409] The activity of the dimer-selective RXR modulator compounds
of the present invention was further tested in an
RXR.alpha.:RAR.alpha. heterodimer assay. A slightly modified assay
to the one described in Example 76 was employed by using
Gal4-receptor chimeras in which the DNA binding domain of the
receptor was replaced by that of Gal4 to generate a fusion protein
according to Nagpal et al, 12 EMBO Journal, 2349 (1993), the
disclosure of which is herein incorporated by reference. Briefly,
CV-1 cells were transfected in 12 well multi-well plates using 0.1
.mu.g of each receptor and 0.1 .mu.g of reporter per well. Each
well was also transfected with 0.5 .mu.g of the .beta.-Gal
expression plasmid as an internal control for transfection
efficiency. Total plasmid per well was 2 .mu.g made up using the
plasmid pGEM. In this regard, the Gal4 plasmids contained 1-147
amino acids of Gal4 driven by the CMV (cytomegalovirus) promoter.
Receptor ligand binding domains (LBDs) were fused in-frame
downstream to the Gal4 cDNA to produce Gal4-receptor fusion
proteins. To express only the receptor LBDs, the LBD was cloned
directly downstream to the CMV promoter.
[0410] Cells were plated in the morning at a density of
.about.6.times.10.sup.4 cells/well and allowed to attach for
.about.5-6 hours. Cell were then transfected using the calcium
phosphate method and precipitates as described in Example 76 and
allowed to incubate with the cells for 12-14 hours following which
cells were washed 2.times. with phosphate buffered saline (PBS) and
incubated with the tested compounds at either 100 nM for LGD 1057
(9-cis retinoic acid: Ligand Pharmaceuticals, Inc.), LG100268
(6-[1-(3,5,5,8,-pentamethyl-5,6,7,8-tetr-
ahydronaphthalen-2-yl)cyclopropyl]nicotinic acid. Ligand
Pharmaceuticals, Inc.) and LGD 1069(Ligand Pharmaceuticals, Inc.),
500 nM for Compounds 117, 122 and 130 or 1 mM for Compound 131 in
charcoal stripped medium for 20-24 hours. Cells were then washed
2.times. with PBS and lysed using Promegca lysis buffer and assayed
for luciferase activity and .beta.-galactosidase activity. All
results were normalized against .beta.-Gal. Each set was done in
triplicates and each experiment was carried out at least 3 separate
times with similar results.
[0411] The above assay system was used because reporter activity is
dependent upon the binding of the Gal4 DNA binding domain to copies
of its binding site, the UAS (upstream activation sequence),
located upstream of the luciferase cDNA. Nagpal et al (1993). Since
endogenous receptors lack the Gal4 DNA binding domain, no
background activation of the reporter is observed, however,
Gal4-receptor LBD fusion proteins can bind the Gal4 site and be
activated in a receptor ligand dependent manner. This system,
therefore, completely eliminates the low background activity of
endogenous receptors in CV-1 cells making it possible to test
compound activity on exogenously added receptors.
[0412] Although all of the compounds tested, directly and
specifically bind RXR, they manifest distinct properties in the
RXR:RAR heterodimer assay as compared to the RXR:RXR homodimer
assay. The distinct properties appear to be regulated through the
binding of the RXR partner. Specifically, when tested on
RXR.alpha.:PPAR.alpha. heterodimers, Compounds 130, 122, 117 and
111 displayed similar agonist activity to LGD1069, albeit to
different degrees (See Example 77, Table 2). A summary of the
effects of the various modulator compounds on RXR.alpha.:RAR.alpha.
heterodimers and RXR homodimers in the present transactivation
assay is shown below in Table 3 and Table 4.
3TABLE 3 Agonist potency and antagonist potency in terms of fold
induction and fold repression respectively for dimer-selective RXR
modulator compounds of the present invention in comparison to the
known RXR.alpha. agonists LGD 1069 and LG100268 on an
RXR.alpha.:RAR.alpha. heterodimer. Com- Fold Com- Fold Com- Fold
pound Activation pound Activation pound Repression 122 50 LG100268
n.e. 117 1.4 130 25 117 n.e. 131 25 LG1069 5 n.e. = no effect
[0413]
4TABLE 4 Agonist potency and antagonist potency in terms of fold
induction and fold repression respectively for dimer-selective RXR
modulator compounds of the present invention in comparison to the
known RXR.alpha. agonists LGD 1069 and LG100268 on an
RXR.alpha.:RXR.alpha. homodimer. Com- Fold Com- Fold Com- Fold
pound Activation pound Activation pound Repression LG100268 50-75
130 n.e. 130 25-75 LGD1069 50-75 117 n.e. 117 1.5 131 n.e. 131 1.3
122 n.e. 122 75 n.e. = no effect.
[0414] As noted above in Table 3, when tested on
RXR.alpha.:RAR.alpha. heterodimers, Compounds 130, 131 and 122 were
potent agonists, whereas the known RXR agonist LGD1069 functioned
as a weaker agonist, and LG100268 and Compound 117 appeared to be
inactive. The RAR selective activator TTNPB
((E)4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphth-
alenyl)-1-propenyl]benzoic acid: Hoffman LaRoche, Inc.) activates
the RXR.alpha.:RAR.alpha. heterodimer. (Data not shown). When the
dimer-selective RXR modulator compounds of the present invention
were combined with the RXR:RAR activator, TTNPB, there was a slight
increase in activation with Compounds 130, 122 and 131, further
suggesting that in the context of a RXR.alpha.:RAR.alpha.
heterodimer, all three function as agonists. (Data not shown).
However, in combination with TTNPB, Compound 117 acted as a weak
repressor, indicating that it could antagonize the properties
associated with a RXR.alpha.:RAR.alpha. heterodimer. Thus, there
appears to be a continuum of activities from the dimer-selective
RXR modulator compounds of the present invention, such that: (a)
Compounds 117, 112, 130, and 131 function as agonists, (b) LGD1069
functions as a partial agonist, (c) LG100268 is inactive, and (d)
Compound 117 is also inactive but, can display some partial
antagonist activity.
[0415] Finally, we tested the same RXR modulator compounds on RXR
homodimers in the GAL4 transfection assay. As can be seen in Table
4, only LGD1069 and LG100268 were agonists, whereas Compounds 130,
117,122 and 131 were inactive. When tested in combination with
either LGD1069 or LG100268, Compounds 130 and 122 functioned as
strong antagonists (repressors) of RXR homodimer activity.
Additionally, Compound 117 was a moderate antagonist and Compound
131 was a weak antagonist. These data employing the Gal4RXR
chimeric receptors are entirely consistent with the assays
employing the wild type receptors shown in Table 1. Thus, the
various RXR modulator compounds of the present invention have a
range of distinct activities when compared with each other, such
that their actual function as either agonist, partial agonist
and/or antagonists change depending upon the RXR partner.
EXAMPLE 79
[0416] Compounds of the present invention, including Compound 122
were tested for their ability to induce NB4 myeloid leukemic cells
to differentiate according to the procedure described by Lanotte et
al., Blood 77, 1080-1086 (1991), the disclosure of which is herein
incorporated by reference. All points were performed in triplicate
for each experiment and varied less than 20%. Each experiment was
repeated at least three times with similar results.
[0417] As can be seen in FIG. 3, Compound 122 was equally, if not
more effective in promoting differentiation of NB4 cells than the
known RAR activator TTNPB and the known RAR/RXR panagonist
compound, 9-cis retinoic acid. Surprisingly, RXR in a complex with
Compound 122 escapes suppression by RAR, and promotes cellular
differentiation in a similar manner to compounds that exert their
activity through the RAR side of the heterodimer. In contrast, the
known RXR agonist, LG100268, does not promote NB4 differentiation,
and in fact cannot interact with the RXR side of the heterodimer
unless jointly administered with an RAR active compound (Data not
shown). Thus, this data further supports the novel activity of
these dimer-selective RXR modulators.
EXAMPLE 80
[0418] The following examples provide illustrative pharmacological
composition formulations:
[0419] Hard gelatin capsules are prepared using the following
ingredients:
5 Quantity (mg/capsule) Compound 101 140 Starch, dried 100
Magnesium stearate 10 Total 250 mg
[0420] The above ingredients are mixed and filled into hard gelatin
capsules in 250 mg quantities.
[0421] A tablet is prepared using the ingredients below:
6 Quantity (mg/tablet) Compound 101 140 Cellulose, microcrystalline
200 Silicon dioxide, fumed 10 Stearic acid 10 Total 360 mg
[0422] The components are blended and compressed to form tablets
each weighing 360 mg.
[0423] Tablets, each containing 60 mg of active ingredient, are
made as follows:
7 Quantity (mg/tablet) Compound 101 60 Starch 45 Cellulose,
microcrystalline 35 Polyvinylpyrrolidone (PVP) 4 (as 10% solution
in water) Sodium carboxymethyl starch (SCMS) 4.5 Magnesium stearate
0.5 Talc 1.0 Total 150 mg
[0424] The active ingredient, starch, and cellulose are passed
through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution
of PVP is mixed with the resultant powders, which are then passed
through a No. 14 mesh U.S. sieve. The granules so produced are
dried at 50.degree. C. and passed through a No. 18 mesh U.S. sieve.
The SCMS, magnesium stearate, and talc, previously passed through a
No. 60 mesh U.S. sieve, are then added to the granules which, after
mixing, are compressed on a tablet machine to yield tablets each
weighing 150 mg.
[0425] Suppositories, each containing 225 mg of active ingredient,
may be made as follows:
8 Compound 101 225 mg Saturated fatty acid glycerides 2,000 mg
Total 2,225 mg
[0426] The active ingredient is passed through a No. 60 mesh U.S.
sieve and suspended in the saturated fatty acid glycerides
previously melted using the minimum heat necessary. The mixture is
then poured into a suppository mold of normal 2 g capacity and
allowed to cool.
[0427] An intravenous formulation may be prepared as follows:
9 Compound 101 100 mg Isotonic saline 1,000 ml Glycerol 100 ml
[0428] The compound is dissolved in the glycerol and then the
solution is slowly diluted with isotonic saline. The solution of
the above ingredients is then administered intravenously at a rate
of 1 ml per minute to a patient.
[0429] While in accordance with the patent statutes, description of
the preferred embodiments and processing conditions have been
provided, the scope of the invention is not to be limited thereto
or thereby. Various modifications and alterations of the present
invention will be apparent to those skilled in the art without
departing from the scope and spirit of the present invention.
[0430] Consequently, for an understanding of the scope of the
present invention, reference is made to the following claims.
* * * * *