6-methoxy-2-naphthylacetic acid prodrugs

Details 6-methoxy-2-naphthylacetic acid prodrugs 6-methoxy-2-naphthylacetic acid prodrugs

2001-03-30

2003-04-22

Cook, Rebecca (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

Reexamination Certificate

active

06552078

ABSTRACT:

FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to pharmaceutical compositions useful for treatment of inflammation in humans utilizing compounds that are prodrugs of 6-methoxy-2-naphthylacetic acid (hereinafter “6MNA”).
Various naphthalene derivatives are known to be useful for the treatment of inflammation and for various rheumatic and arthritic conditions. For example, Naproxen having the formula (I):
as described in U.S. Pat. No. 4,009,197 to Fried et al. Compound (I) can, however, cause severe irritation of the gastrointestinal tract at dosages only slightly greater than the excess of the therapeutic dose.
Another naphthalene derivative is nabumetone having the formula (II):
as described in U.S. Pat. Nos. 4,061,779 and 4,420,639 to Lake et al. Nabumetone works by inhibiting cyclooxygenase, an enzyme responsible for making prostaglandins which are mediators of inflammation. Nabumetone is a prodrug which undergoes hepatic biotransformation to the active component, 6-methoxy-2-naphthylacetic acid, Formula (III):
(See Haddock, R. E. et al; Metabolism of Nabumetone (BRL 14777 by various species including man,″
Xenobiotica;
14(4): 327-337 (1984)). Nabumetone is commercially available as Relafen® from Smithkline Beecham, Inc. However, only about 35 percent of orally administered nabumetone is transferred in vivo into 6MNA.
It is therefore an object of the present invention to provide 6MNA prodrugs which are more readily transformed into 6MNA than nabumetone. It is believed that improvement in the body's ability to hydrolyze and solubilize the prodrug can contribute to this transformation. Thus, it is another object to improve the hydrolysis and solubility of the prodrug to provide better transformation to 6MNA.
Another concern with 6MNA and its related prodrugs is that the presence of the carboxylic acid moiety can cause stomach irritation and/or ulceration. Thus, it is another object of the present invention that provides prodrugs of 6MNA having a reduced propensity to cause stomach irritation.
SUMMARY OF THE INVENTION
The present invention provides compositions useful for the treatment of inflammation in humans, and related methods of treatment for the same. In one embodiment the composition is
wherein R is selected from the group consisting of (CH
2
)
m
O(CH
2
)
n
; (CH
2
)
m
(OC
2
H
4
)
p
O(CH
2
)
n
; (CH
2
)
m
(CHOH)
r
(CHOH)
s
, and the (R) and (S) enantiomers, and mixtures thereof; and CH
2
COR′; wherein m is an integer from 2 to 4, n and p are integers from 1 to 4 and r and s are integers from 1 to 2, and R′ is selected from the group consisting of C
1
to C
6
alkyl, (CH
2
)
m
O(CH
2
)
n
, CH
2
(OC
2
H
4
)
p
O(CH
2
)
n
, and CH
2
(OC
2
H
4
)
p
. Noting that as recognized by one skilled in the art that when an alkyl group is defined as “(CH
2
)
n
”, the actual structure will be (CH
2
)
n-1
CH
3
. In another embodiment, R is selected from the group consisting of (CH
2
)
a
C(O)R′ wherein R′ is selected from the group consisting of C
1
to C
6
alkyl and hydroxy, (OC
2
H
4
)
b
CH
3
, (OC
2
H
4
)
c
(CH
2
)
d
CH
3
, (OC
2
H
4
)
e
ONO
2
, (CH
2
)
f
O(CH
2
)
g
ONO
2
and wherein a is an integer from 0 to 4, b, c, d, e and f individually are integers from 1 to 5 and g is an integer from 2 to 5.
In yet another embodiment, the composition is a pharmaceutical composition useful for treatment of inflammation in humans comprising a therapeutically effective amount of a compound of the formula:
wherein X is O or N, n is from 0 to 5 and R is —OCH
3
or —ONO
2
.
In still another embodiment of the present invention, the composition is a pharmaceutical composition useful for treatment of inflammation in humans comprising a therapeutically effective amount of a compound of the formula:
wherein R″ is selected from the group consisting of C
1
to C
6
alkyl, CH
2
(OC
2
H
4
)
n
O(CH
2
)
n
, CH
2
(OC
2
H
4 )
p
OCH
3
, (OC
2
H
4
)
n
ONO
2
, (OC
2
H
4
)
n
O(CH
2
)
n
, (CH
2
)
n
(OC
2
H
4
)
m
ONO
2
, (OC
2
H
4
)
n
O(CH
2
)
m
OH, NH(CH
2
)
m
(OC
2
H
4
)
n
, NH(CH
2
)
m
(OC
2
H
4
)
m
ONO
2
, NHO(CH
2
)
n
CH
3,
, NH(CH
2
)
m
(OC
2
H
4
)
p
OCH
3
, and NH(OC
2
H
4
)
p
OCH
3
, wherein m is an integer from 0 to 4, and n and p are integers from 1 to 4 noting as recognized by one skilled in the art that when an alkyl group is defined as “(CH
2
)
n
, the actual structure will be (CH
2
)
n-1
CH
3
. Alternately R” is selected from the group consisting of NH(CH
2
)
a
OCH
3
, NH(CH
2
)
a
O(CH
2
)
b
CH
3
, NHOCH
3
, NH(CH
2
CH
2
O)
c
CH
3
, NHO(CH
2
)
d
CH
3
, NH(CH
2
CH
2
O)
c
(CH
2
)
e
CH
3
and NH(CH
2
CH
2
O)
c
H wherein a is an integer from 2 to 4 and b, c, d and e are individually integers from 1 to 4.
In yet another embodiment, the composition is
wherein R′″ is selected from the group consisting of hydrogen, O(CH
2
)
n
CH
3
, C
1
to C
6
alkyl, (CH
2
)
m
(OC
2
H
4
)
p
O(CH
2
)
n
, (CH
2
)
m
(OC
2
H
4
)
p
, (CH
2
)
m
(OC
2
H
4
)
n
ONO
2
(CH
2
)
m
(OC
2
H
4
)
p
O(CH
2
)
m
OH, and (CH
2
)
m
NHO(CH
2
)
n
CH
3
wherein m is an integer from 2 to 4, and n and p are integers from 1 to 4 noting as recognized by one skilled in the art that when an alkyl group is defined as “(CH
2
)
n
”, the actual structure will be (CH
2
)
n-1
CH
3
. In another embodiment, R′″ is selected from the group consisting of hydroxy, O(CH
2
)
a
CH
3
, (CH
2
)
b
OCH
3
, (CH
2
)
b
O(CH
2
)
c
CH
3
, (OC
2
H
4
)
d
H, CH
2
COO(CH
2
)
e
CH
3
, CH
2
COOH, CH
2
COOCH
3
and (CH
2
)
f
O(CH
2
)
g
ONO
2
and wherein a is an integer from 0 to 4, b, f and g are integers from 2 to 4 and c, d and e are integers from 1 to 4.
Additional alternative embodiments are R or R″ are therapeutic moieties. In another embodiment optionally there may be linking groups G connecting the therapeutic moiety to the end group.
The compositions summarized above can be used in methods of treating inflammation.


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