Hydronaphtalene compounds, prepared by a rhodium catalyzed...

Details Hydronaphtalene compounds, prepared by a rhodium catalyzed... Hydronaphtalene compounds, prepared by a rhodium catalyzed...

2001-02-27

2003-02-25

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S317000, C514S415000, C514S417000, C514S428000, C514S429000, C546S164000, C546S229000, C546S232000, C548S469000, C548S472000, C548S566000, C548S570000

Reexamination Certificate

active

06525068

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to methods for chemically synthesizing compounds containing a hydronaphthalene ring structure. It encompasses the compounds made by the methods, pharmaceutical preparations containing the compounds, and methods for treating patients using these pharmaceutical preparations.
BACKGROUND OF THE INVENTION
The hydronaphthalene structure can be found in many natural products and pharmaceutical agents. These include homochelidonine (structure 1 below; Slavik, J.; et al.,
Collect. Czech. Chem. Commun.
30:3697 (1965); Spath, E., et al.,
Ber.,
64:1123 (1931); Bersch, H. W.,
Arch. Pharm.
(Weinheim, Ger.), 2914:91 (1958)) an alkaloid isolated from Chelidonium plants, dihydrexidine (structure 2 below; Snyder, S. E.,
J. Med. Chem.,
38:2395 (1995)) which shows antiparkinsonian character, etoposide (structure 3 below; Kamal, A., et al.,
Tetrahedron Lett.
37:3359 (1996)) which is used in the treatment of various cancers, and SF-2315B (structure 4 below; Kim, K., et al.,
J. Org. Chem.
60:6866 (1995)) which is a viral reverse transcriptase inhibitor. In addition, CNS agents, immunoregulatory agents and antibiotics contain variations on this framework (Perrone. R., et al.,
J. Med. Chem.
38:942 (1995)).
Given the large number of pharmaceutically useful compounds which contain this core skeleton, new methodology which produces functionalized hydronaphthatene skeletons (structure 1) would clearly be of value.
Previous work on oxabicyclic ring opening reactions led to a catalytic enantioselective route to dihydronaphthol (Lautens, M., et al.,
Tetrahedron
54:1107 (1998)) which was a key step in the total synthesis of sertraline (Lautens, M., et al.,
J. Org. Chem.
63:5276 (1997)). However, little is known about the ring opening of oxabenzonorbornadiene or similar compounds with the incorporation of nucleophiles during the ring opening step. Duan and Chen developed a method of introducing aryl groups by using catalytic amounts of palladium (Duan, J.-P., et al.,
Tetrahedron Lett.,
34:4019 (1993); Duan, J.-P., et al.,
Organometallics
14:1608 (1995)). Moinet et al., later developed an enantioselective version of this reaction but the yields were low (
Tetrahedron Lett.,
36:2051 (1995)).
Catalytic organometallic processes that form carbon-heteroatom bonds are far fewer in number than those which form carbon-carbon bonds. The Wacker Process (Henry, P. M.,
Paladium Catalysed Oxidation of Hydrocarbons,
vol. 2, Reidel, Boston, (1980)), oxidative carbonylations of amines and alcohols (
Applied Homogeneous Catalysis with Organometallic Compounds: A Comprehensive Handbook in Two Volumes
(eds.: B. Cornils, W. A. Hermann), VCH, New York, (1984)) and the formation of arylamines and aryl ethers (Hartwig, J. F.,
Agnew. Chem. Int. Ed.
37:2046 (1998); Widenhoefer, R. A., et al.,
J. Am. Chem. Soc.
119:6787 (1997)) are a few that have been described to date.
SUMMARY OF THE INVENTION
The present invention is based upon the discovery of a rhodium catalyzed ring opening reaction of oxabenzonorbornadienes or azabicyclic compounds to produce a new carbon-oxygen bond via an intermolecular reaction with various alcohols. This reaction occurs in good yields with complete regio and diastereoselectivity and excellent enantioselectivity (e.g., eq. 1).
In the reaction above, Z is O or NR
a
. This reaction will work when oxabenzonor-bornadienes or azabicyclic compounds are reacted with nitrogen nucleophiles, carboxylate nucleophiles, carbon nucleophiles or phenol nucleophiles. The invention encompasses not only the chemical reactions but also the compounds made by the reactions and the use of such compounds in the treatment of a variety of diseases and conditions.
In its first aspect, the invention is directed to a compound according to formula I:
in which R is selected from the group consisting of:
(a) H;
(b) a C
1
-C
6
straight or branched alkyl;
(c) a straight or branched C
2
-C
6
alkenyl;
(d) —(CH
2
)
n
R
1
, wherein R
1
is a C
3
-C
6
aryl, optionally substituted at one or more positions with a group selected from: Cl; F; NO
2
; I; Br; a C
1
-C
3
alkyl; and a C
1
-C
3
alkoxy wherein n=0-3;
(e) —C(O)R
2
, wherein R
2
is selected from the group consisting of: H; —(CH
2
)
n
R
1
, wherein R
1
is as described above and n=0-3; and —(CH
2
)
n
C(O)R
3
, wherein R
3
is a C
1
-C
6
straight or branched alkyl and n=0-3;
(f) —C(O)(CH
2
)
p
—C(O)—O—R
4
, wherein R
4
is a straight or branched C
1
-C
6
alkyl and wherein p=0-3;
(g) —R
d
(CF
3
)
j
, wherein R
d
is a C
1
-C
3
straight or branched alkyl and j=1-3;
(h) —(CH
2
)
j
—TMS, wherein TMS is trimethylsilyl, and j=1-3;
X and Y are independently selected from the group consisting of H; NH
2
; F; Cl; Br; a C
1
-C
3
alkyl; and a C
1
-C
3
alkoxy;
or wherein the combination XY or YY together form a C
3
-C
6
carbocyclic ring or a C
3
-C
6
heterocyclic ring containing one or more heteroatoms selected from the group consisting of: O; N; and S; and
in which Z is selected from O or NR
a
, wherein R
a
is selected from:
(i) phenyl;
(j) (O)C—O—R
b
, wherein R
b
is a straight or branched C
1
-C
6
alkyl;
(k) —SO
2
—R
c
, wherein R
c
is selected from the group consisting of:
i) C
1
-C
6
straight or branched alkyl;
ii) —(CH
2
)
q
R
e
, wherein q=0-3 and R
e
is a C
3
-C
6
aryl, optionally substituted at one or more positions with a group selected from: Cl; F; NO
2
; CN;I; Br; a straight or branched C
1
-C
3
alkyl; a C
1
-C
3
alkoxy; and —C(O)R
f
, wherein R
f
is a C
1
-C
3
alkyl; —(CH
2
)
r
CF
3
, wherein r=0-3;
iii) —R
g
(CF
3
)
s
, wherein R
g
is a C
1
-C
3
straight or branched alkyl and s=1-3;
iv) —(CH
2
)
s
—TMS, wherein TMS=trimethylsilyl and s=1-3;
(l) —SO
2
—(CH
2
)
q
—Si(CH
3
)
3
wherein q is 1-3.
Preferably, R in formula I is —(CH
2
)
n
R
1
and R
1
is a C
3
-C
6
aryl optionally substituted at one or more positions with a group selected from: Cl; F; NO
2
; I; Br; a C
1
-C
3
alkyl; and a C
1
-C
3
alkoxy and wherein n=0-3. When Z is NR
a
, R
a
is preferably phenyl; (O)C—O—C—(CH
3
)
3
; —SO
2
—(CH
2
)
2
—Si(CH
3
)
3
; or —SO
2
—R
c
, wherein R
e
is —(CH
2
)
q
R
c
, wherein q=0-3 and R
e
is a C
3
-C
6
aryl, optionally substituted at one or more positions with a group selected from: Cl; F; NO
2
; CN; I; Br; a straight or branched C
1
-C
3
alkyl; a C
1
-C
3
alkoxy; and —C(O)R
f
, wherein R
f
is a C
1
-C
3
alkyl; —(CH
2
)
r
CF
3
, wherein r=0-3.
The compounds of formula I described above may be prepared by reacting a compound of formula ROH with a compound of formula V:
in which R, X, Y, and Z are as defined above. The reaction is catalyzed by [Rh(COD)Cl]
2
in the presence of a phosphine ligand, preferably selected from the group consisting of: DPPF; (R)-(S)-BPPFA; and (R)-(S)-PPF-P
t
Bu
2
In preferred reactions: (a) the compound made is (1R*,2R*)-acetic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl ester and ROH is acetic acid; (b) the compound made is (1R*,2R*)-propionic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl ester and ROH is propionic acid; (c) the compound made is (1R,2R)-benzoic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl-ester and ROH is benzoic acid; (d) the compound made is (1R*,2R*)-formic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl-ester and ROH is formic acid; (e) the compound made is (1R*,2R*)-2-methyl acrylic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl-ester and ROH is methacrylic acid; (f) the compound made is (1R*,2R*)-malonic acid ethyl-ester (1-hydroxy-1,2-dihydro-naphthalen-2-yl) ester and ROH is ethyl malonic acid; and (g) the compound made is (1R,2R)-2-(4-bromo-phenoxy)-1,2-dihydro-naphthalen-1-ol and ROH is p-bromophenol; (h) the compound made is N-[(1R,2S)-2-methoxy-1,2-dihydrohydro-1-naphthalenyl]-4-methylbenzene-sulfonamide and ROH is MeOH; (i) the compound made is 4-methyl-N-[(1R,2S)-2-phenoxy-1,2-dihydrohydro-1-naphthalenyl]benzenesulfonamide and the ROH is phenol; (j) the compound made is (1R,2S)-1-{[(4-methylphenyl

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