Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-27
2001-04-03
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S280100, C544S238000, C544S333000, C544S405000
Reexamination Certificate
active
06211385
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a synthetic process for preparing benzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3-ene and benzo[1,2-g]-1,2-dihydroquinoline derivatives which bind to retinoid receptors and have retinoid-like, retinoid antagonist or retinoid inverse agonist-like biological activity. More specifically, the present invention relates to a synthetic process for preparing certain benzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3-ene and benzo[1,2-g]-1,2-dihydroquinoline derivatives which are described in U.S. Pat. No. 5,728,846 and which bind to retinoid receptors and primarily have retinoid antagonist or retinoid inverse agonist-like biological activity.
2. Background Art
U.S. Pat. No. 5,728,846 discloses substituted benzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3-ene and benzo[1,2-g]-1,2-dihydroquinoline derivatives which bind to retinoid receptors and have retinoid-like, retinoid antagonist or retinoid inverse agonist-like biological activity. Other examples of compounds having retinoid-like biological activity and condensed tricyclic or dihydronaphthalene structure are found in the following U.S. and foreign patent disclosures: U.S. Pat. Nos. 5,523,457; 5,559,248; 5,648,514; 5,877,207, WO 94/14777 and EPO 0 661-259 A1.
The publication Dawson and William H. Okamura,
Chemistry and Biology of Synthetic Retinoids
, published by CRC Press Inc., 1990, pages 334-335, 354 and 324-356 is of special interest as an overview of the chemistry and biology of retinoid-like compounds.
Among the compounds disclosed in U.S. Pat. No. 5,728,846, benzo[1,2-g]-chrom-3-ene derivatives, and particularly 4-[2,2-dialkyl-4-(aryl, heteroaryl or alkyl)-6,7-benzochrom-3-en-7-yl]benzoic acids or benzoic acid esters are of particular interest primarily as retinoid antagonist and/or retinoid inverse agonist compounds. Whereas U.S. Pat. No. 5,728,846 discloses synthetic processes for the preparation of these compounds, the present invention describes a different and significantly improved synthetic process for the preparation of this class of compounds.
SUMMARY OF THE INVENTION
The present invention relates to the synthetic process for making compounds of Formula 1,
where X is O, S, NH or N-lower alkyl of 1 to 6 carbons;
R is alkyl of 1 to 10 carbons, alkenyl of 1 to 10 carbons and of 1 to 3 double bonds, alkynyl of 1 to 10 carbons and of 1 to 3 triple bonds, (R
4
)
s
-aryl or (R4)
s
-heteroaryl where heteroaryl is selected from the group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl;
R
1
is lower alkyl of 1 to 6 carbons;
R
2
and R
4
independently are alkyl of 1 to 6 carbons, F, Cl, Br, I, NO
2
, N
3
, (CH
2
)
p
COOH, (CH
2
)
p
COOR
1
;
o, p and s are integers each independently having the value of 0 to 2;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R
2
groups, or Y is —(CR
3
═CR
3
)
2
—;
R
3
is H or lower alkyl of 1 to 6 carbons;
A is (CH
2
)
q
where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, with the proviso that when Y is —(CR
3
═CR
3
)
2
— then A is (CH
2
)
q
and q is 0;
B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR
8
, CONR
9
R
10
, —CH
2
OH, CH
2
OR
11
, CH
2
OCOR
11
, CHO, CH(OR
12
)
2
, CHOR
13
, —COR
7
, CR
7
(OR
12
)
2
, CR
7
OR
13
O, or Si(C
1-6
alkyl)
3
, where alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R
8
is an alkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R
8
is phenyl or lower alkylphenyl, R
9
and R
10
independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R
11
, is lower alkyl, phenyl or lower alkylphenyl, R
12
is lower alkyl, and R
13
is divalent alkyl radical of 2-5 carbons.
The inventive process comprises the steps shown in Reaction Scheme 1 where a condensed tricyclic ketone compound of Formula 2 is reacted with an organometal reagent under conditions in which the organometal reagent selectively reacts with the endocyclic ketone of the compound of Formula 2, in preference over reacting with the halogen substituent X
1
. The symbols X, R
1
, R
2
and R are defined in Reaction Scheme 1 as in connection with Formula 1. The resulting intermediate tertiary alcohol (not shown in the scheme) is dehydrated by treatment with acid to provide a benzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3-ene and benzo[1,2-g]-1,2-dihydroquinoline derivative of Formula 3 that still has the halogen substituent X
1
in the 7 position of the benzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3-ene and benzo[1,2-g]-1,2-dihydroquinoline nucleus. The numbering of these condensed tricyclic systems is shown in the specification of U.S. Pat. No. 5,768,646 which is expressly incorporated herein by reference.
In a subsequent step of the inventive process, either the X
1
halogen substituent of the 7-halogeno-benzo[1,2-g]-chrom-3-ene, benzo[1,2-g]-thiochrom-3-ene or benzo[1,2-g]-1,2-dihydroquinoline derivative of Formula 3 or the halogen substituent X
3
of the reagent X
3
—Y(R
2
)—A—B (X
3
is halogen, and the symbols Y, R
2
, A and B are defined as in connection with Formula 1) is converted to a metal, so that one of these two compounds becomes an organometal reagent. These two compounds, that is the organometal reagent derived either from the compound of Formula 3 or from the compound X
3
—Y(R
2
)—A—B and the other halogen substituted derivative are reacted, typically in the presence of a catalyst, to provide compounds of Formula 1 where the Y group is phenyl, naphthyl or heteroaryl. Typically the metal is zinc or lithium and the catalyst is a palladium complex, such as tetrakis-palladium(O)triphenylphosphine To obtain compounds of Formula 1 where Y is —(CR
3
═CR
3
)
2
—, the compond of Formula 3 is reacted with a butadiene derivative of the formula CHR
3
═CR
3
—CR
3
═CR
3
—B where the symbols R
3
and B are defined as in connection with Formula 1. The latter reaction is conducted under conditions of a Heck reaction, typically in the presence of palladium(2) acetate and triphenylphosphine.
DETAILED DESCRIPTION OF THE INVENTION
The compounds made in accordance with the novel synthetic process of the present invention are used as agents that bind to retinoid receptors, and act as retinoids, retinoid antagonists and or retinoid inverse agonists. The manner of using the compounds made by the process of the present invention is described in U.S. Pat. No. 5,728,846.
Reaction Scheme 1 that is described above in connection with the Summary of the Invention discloses the two most important steps utilized in the synthetic process for making the compounds defined by Formula 1. Reaction Scheme 2 discloses the synthetic route in more detail.
The starting compound in Reaction Scheme 2 is a 7-halogeno-2-naphthoic acid derivative (X
1
is Cl, Br or I) which is available in accordance with the chemical literature and wherein the symbols X, and R
2
are defined as in connection with Formula 1. An example for the starting compound of Formula 4 is 7-bromo-3-methoxy-2-naphthoic acid that is available in accordance with the publication Murphy, R. A. et al, J. Med. Chem. 1990 33, 171. Other examples are 7-bromo-3-methylthio-2-naphthoic acid and 7-bromo-3-methylamino-2-naphthoic acid. It will be recognized by those skilled in the art that instead of the 7-bromo derivativ
Chandraratna Roshantha A.
Vuligonda Vidyasagar
Allergan Sales Inc.
Baran Robert J.
Owens Amelia
Szekeres Gabor L.
Voet Martin A.
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