Interleukin-1 and tumor necrosis factors-&agr; modulators,...

Details Interleukin-1 and tumor necrosis factors-&agr; modulators,... Interleukin-1 and tumor necrosis factors-&agr; modulators,...

2000-05-12

2002-04-02

Geist, Gary (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S116000, C562S499000, C562S498000, C514S510000, C514S577000

Reexamination Certificate

active

06365768

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to chemical compounds and pharmaceutical compositions, including novel chemical compounds and pharmaceutical compositions thereof, useful in the treatment of various diseases and disease states. The invention also relates to methods of synthesizing natural products and novel, structurally-related chemical compounds. More particularly, the present invention relates to novel analogs of and processes for the preparation of compounds and pharmaceutical compositions thereof useful in the treatment of, for example, inflammation, cancer, cachexia, cardiovascular disease, diabetes, otitis media, sinusitis and transplant rejection.
BACKGROUND OF THE INVENTION
Acanthopanax koreanum
Nakai (Araliaceae), which is found indigenously in Cheju Island, The Republic of Korea, has been used traditionally as a remedy for, for example, neuralgia, paralysis, and lumbago. Various useful components, including acanthoic acid, a compound having the chemical structure of Formula (I), have been isolated from the root bark of this tree. Furthermore, certain analogs of the compound of Formula (I), for example, wherein the COOH group is replaced by a methanolic group, by a methyl-acetyl ether, by a methyl group, and by a methyl-ester have each also been isolated from the root bark of
Acanthopanax koreanum
Nakai (Araliaceae). See Kim, Y. H. and Chung, B. S.,
J. Nat. Pro.,
51, 1080-83 (1988). (The proper chemical names of these analogs are provided in this reference.) This reference and all the other patents and printed publication cited herein are, in their entirety, incorporated by reference herein.
The compound of Formula (I), also known as acanthoic acid, has been reported to have certain pharmacological effects, including, for example, analgesic and anti-inflammatory activity. The compound of Formula (I) also exhibits very low toxicity; 1000 mg/kg is the minimum lethal dose (MLD) when administered to a rat. See Lee, Y. S., “Pharmacological Study for (−)-Pimara-9(11),15-Diene-19-oic Acid, A Component of
Acanthopanax koreanum
Nakai,” Doctorate Thesis, Dept. of Pharmacy, Seoul National University, Korea (1990). The compound of Formula (I) and/or its naturally-occurring analogs, may exhibit these known pharmacological effects by inhibiting leukocyte migration and prostaglandin E
2
(PGE
2
) synthesis, and is a suspected effector of both Interleukin-1 (IL-1) and Tumor Necrosis Factor-&agr; (TNF-&agr;) production. Additionally, a process for the preparation of acanthoic acid, and use of the acanthoic acid for treatment of immune disease is described in International Patent Publication WO 95/34300 (Dec. 21, 1995).
Also, the compound of Formula (IA), kauranoic acid, and the corresponding methyl-ester analog of the compound of Formula (IA), as well as methanolic reduction analogs of the compound of Formula (IA) have been isolated from the root bark of
Acanthopanax koreanum
Nakai (Araliaceae). See Kim, Y. H. and Chung, B. S.,
J. Nat. Pro.,
51, 1080 (1988). (The proper chemical name of kauranoic acid, (−)-kaur-16-en-19-oic acid, and of the known analogs of kauranoic acid are provided in this reference.)
Tumor Necrosis Factor-&agr; (herein “TNF-&agr;” or “TNF”) and/or Interleukin-1 (herein “IL-1”) are involved in various biochemical pathways and, thus modulators of TNF-&agr; and/or IL-1 activity or production, especially novel modulators of TNF-&agr; and/or IL-1 activity or novel compounds that influence the production of either IL-1 or TNF-&agr;, or both, are highly desired. Such compounds and classes of compounds would be valuable in maintaining the human immune system and in treating diseases such as for example, tuberculous pleurisy, rheumatoid pleurisy, and diseases not conventionally considered to be immune disorders, such as cancer, cardiovascular disease, skin redness, viral infection, diabetes, and transplant rejection.
Although numerous approaches to regulate the production of Tumor Necrosis Factor-&agr; and the interleukins are known, novel approaches, compounds, and pharmaceutical formulations to regulate the production of Tumor Necrosis Factor-&agr; and interleukins are highly desirable and have been long sought by those of skill in the art.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide processes for the synthetic and semi-synthetic preparation of the compounds of Formulae (I) and (IA) and their structural analogs, including novel analogs, of the compounds of Formulae (I) and (IA).
The compounds of the present invention include, for example, compounds having the chemical structure of Formula (II) and compounds having the chemical structure of Formula (IIA). Regarding compounds having the chemical structure of Formula (II), the invention includes:
wherein the R groups are defined as follows: If any R
3
-R
5
, R
7
, R
8
, R
11
-R
13
is not hydrogen, R
2
or R
6
or R
9
is not methyl, or R
10
is not CH
2
, then R
1
is selected from the group consisting of hydrogen, a halogen, COOH, C
1
-C
12
carboxylic acids, C
1
-C
12
acyl halides, C
1
-C
12
acyl residues, C
1
-C
12
esters, C
1
-C
12
secondary amides, (C
1
-C
12
)(C
1
-C
12
) tertiary amides, C
1
-C
12
alcohols, (C
1
-C
12
)(C
1
C
12
) ethers, C
1
-C
12
alkyls, C
1
-C
12
substituted alkyls, C
2
-C
12
alkenyls, C
2
-C
12
substituted alkenyls, and C
5
-C
12
aryls; however, if all R
3
-R
5
, R
7
, R
8
, R
11
-R
13
are hydrogen, R
2
, R
6
, and R
9
are each methyl, and R
10
is CH
2
, then R
1
is selected from hydrogen, a halogen, C
1
-C
12
carboxylic acids, C
1
-C
12
acyl halides, C
1
-C
12
acyl residues, C
2
-C
12
esters, C
2
-C
12
secondary amides, (C
1
-C
12
)(C
1
-C
12
) tertiary amides, C
2
-C
12
alcohols, (C
1
-C
12
)(C
1
-C
12
) ethers other than methyl-acetyl ether, C
2
-C
12
alkyls, C
1
-C
12
substituted alkyls, C
2
-C
12
alkenyls, C
2
-C
12
substituted alkenyls, and C
2
-C
12
aryls.
R
2
and R
9
are each separately selected from hydrogen, a halogen, C
1
-C
12
alkyl, C
1
-C
12
substituted alkyls, C
2
-C
12
alkenyl, C
2
-C
12
substituted alkenyl, C
2
-C
12
alkynyl, C
1
-C
12
acyl, C
1
-C
12
alcohol, and C
5
-C
12
aryl.
R
3
-R
5
, R
7
, R
8
, and R
11
-R
13
are each separately selected from hydrogen, a halogen, C
1
-C
12
alkyl, C
1
-C
12
substituted alkyls, C
2
-C
12
alkenyl, C
2
-C
12
substituted alkenyl, C
2
-C
12
alkynyl, and C
5
-C
12
aryl. In particularly preferred embodiments, R
11
is a C
1
-C
6
alkyl, or C
1
-C
6
substituted alkyl, and all other R groups are hydrogen.
R
6
is selected from hydrogen, a halogen, C
1
-C
12
alkyl, C
1
-C
12
substituted alkyls, C
2
-C
12
alkenyl, C
2
-C
12
substituted alkenyl, and C
2
-C
12
alkynyl.
R
10
is selected from hydrogen, a halogen, CH
2
, C
1
-C
6
alkyl, C
1
-C
6
substituted alkyl, C
2
-C
6
alkenyl, C
2
-C
6
substituted alkenyl, C
1
-C
12
alcohol, and C
5
-C
12
aryl.
R
14
and R
15
are separately selected from hydrogen, a halogen, CH
2
, C
1
-C
6
alkyl, C
1
-C
6
substituted alkyl, C
2
-C
6
alkenyl, C
2
-C
6
substituted alkenyl, C
1
-C
6
alcohol, and C
5
-C
6
aryl.
Regarding compounds having the chemical structure of Formula (IIA), the invention includes:
wherein, if any R
3
-R
5
, R
7
, R
8
, R
11
-R
13
is not hydrogen, R
2
or R
6
is not methyl, R
10
is not CH
2
, or if it is not true that R
10
is CH
2
OH and R
11
is OH, then R
1
is selected from the group consisting of hydrogen, a halogen, COOH, C
1
-C
12
carboxylic acids, C
1
-C
12
acyl halides, C
1
-C
12
acyl residues, C
1
-C
12
esters, C
1
C
12
secondary amides, (C
1
-C
12
)(C
1
-C
12
) tertiary amides, C
1
-C
12
alcohols, (C
1
-C
12
)(C
1
-C
12
) ethers, C
1
-C
12
alkyls, C
1
-C
12
substituted alkyls, C
2
-C
12
alkenyls, C
2
-C
12
substituted alkenyls; but
if all R
3
-R
5
, R
7
, R
8
, R
11
-R
13
are hydrogen, R
2
and R
6
are each methyl, and R
10
is CH
2
or CH
2
OH, then R
1
is selected from hydrogen, a halogen, C
1
-C
12
carboxylic acids, C
1
-C
12
acyl halides, C
1
-C
12
acyl residues, C
2
-C
12
esters, C
1
-C
12
secondary amides, (C
1
-C
12

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