6-Methoxy-2-naphthylacetic acid prodrugs

Details 6-Methoxy-2-naphthylacetic acid prodrugs 6-Methoxy-2-naphthylacetic acid prodrugs

2002-08-19

2004-03-30

Cook, Rebecca (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S534000, C514S622000

Reexamination Certificate

active

06713510

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 CHCOR′; 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
.
In another embodiment, the composition is
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 2 to 4, and n and p are 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.
Additional alternative embodiments are R or R″ that are therapeutic moieties. Such compositions can be used in methods of treating inflammation.


REFERENCES:
patent: 3883662 (1975-05-01), Henzl et al.
patent: 3904682 (1975-09-01), Fried et al.
patent: 3978116 (1976-08-01), Fried et al.
patent: 4009197 (1977-02-01), Fried et al.
patent: 4061779 (1977-12-01), Lake et al.
patent: 4246164 (1981-01-01), Felder et al.
patent: 4246193 (1981-01-01), Holton
patent: 4268442 (1981-05-01), Kondo et al.
patent: 4270004 (1981-05-01), Rose et al.
patent: 4327022 (1982-04-01), Bailey
patent: 4328356 (1982-05-01), Giordano et al.
patent: 4420639 (1983-12-01), Lake et al.
patent: 4423244 (1983-12-01), Cannata et al.
patent: 4501913 (1985-02-01), Giordano et al.
patent: 4515811 (1985-05-01), Holton
patent: 4542237 (1985-09-01), Schloemer
patent: 4546201 (1985-10-01), Piccolo et al.
patent: 4550191 (1985-10-01), Castaldi et al.
patent: 4608441 (1986-08-01), Citterio et al.
patent: 4611088 (1986-09-01), Ohara et al.
patent: 4654438 (1987-03-01), Schloemer
patent: 4661524 (1987-04-01), Thomson et al.
patent: 4661525 (1987-04-01), Grazioso et al.
patent: 4670586 (1987-06-01), Yabe et al.
patent: 4670603 (1987-06-01), Piccolo et al.
patent: 4709089 (1987-11-01), Shimizu et al.
patent: 4723033 (1988-02-01), Erickson
patent: 4724102 (1988-02-01), Cannata et al.
patent: 4814494 (1989-03-01), Shimizu et al.
patent: 4851426 (1989-07-01), Ladkani et al.
patent: 4865770 (1989-09-01), Piselli
patent: 4922009 (1990-05-01), Villa et al.
patent: 4937379 (1990-06-01), Giordano et al.
patent: 4970336 (1990-11-01), Yoshioka et al.
patent: 5004832 (1991-04-01), Castaldi et al.
patent: 5068458 (1991-11-01), Dales et al.
patent: 5132466 (1992-07-01), Dales et al.
patent: 5145993 (1992-09-01), Kim et al.
patent: 5179208 (1993-01-01), Kim et al.
patent: 5200555 (1993-04-01), Kessels
patent: 5202495 (1993-04-01), Callander
patent: 5223640 (1993-06-01), Tafesh et al.
patent: 5225603 (1993-07-01), Aslam et al.
patent: 5248815 (1993-09-01), Paradies
patent: 5278333 (1994-01-01), Loosen et al.
patent: 5306833 (1994-04-01), Vallejos et al.
patent: 5426243 (1995-06-01), Lecouve
patent: 5539000 (1996-07-01), Leonard
patent: 5600009 (1997-02-01), Fritch et al.
patent: 5621000 (1997-04-01), Arena et al.
patent: 5695774 (1997-12-01), Clark
patent: 5700947 (1997-12-01), Soldato
patent: 5703073 (1997-12-01), Garvey et al.
patent: 5741938 (1998-04-01), Belmont
patent: 5750764 (1998-05-01), Marais et al.
patent: 5750793 (1998-05-01), Cannata et al.
patent: 5756851 (1998-05-01), Becnel et al.
patent: 5777170 (1998-07-01), Bellani
patent: 5780495 (1998-07-01), Del Soldato
patent: 5792886 (1998-08-01), Sabahi et al.
patent: 5840996 (1998-11-01), Sabahi
patent: 5847225 (1998-12-01), Ramachandran et al.
patent: 5861538 (1999-01-01), Theriot
patent: 5907069 (1999-05-01), Becnel et al.
patent: 5955635 (1999-09-01), Cabri et al.
patent: 6057347 (2000-05-01), Garvey et al.
patent: 2 051 012 (1972-04-01), None
patent: 0974584 (2000-01-01), None
patent: 2 060 332 (1970-04-01), None
patent: WO 94/04484 (1994-03-01), None
patent: WO 94/12463 (1994-06-01), None
patent: WO 95/30641 (1995-11-01), None
patent: WO 97/31654 (1997-09-01), None
Medline AN 85255717, Palmer D et al, Clin. & Experim. Rheumatology Apr.-Jun. 1985 3(2) 111-5, abstract.*
Benoni, et al.,Plasma Concentrations and Pharmacokinetic Parameters of Nitrofenac Using a Simple and Sensitive HPLC Method,Journal of Pharmaceutic Sciences, vol. 84, No. 1, Jan. 1995 (pp. 93-95).
Brett, et al.,Nabutemone, Evidence for the Lack of Enterohepatic Circulation of the Active Metabolite 6-MNA in Humans,Drugs 40 (Suppl. 5), 1990 (pp. 67-70).
Dahl, Stephen L.,Nabumetone: A ‘Nonacidic’ Nonsteroidal Antiinflammatory Drug,The Annals of Pharmacology, 27: 456-463 (Apr. 1993).
Hellberg et al.,Novel Esters and Amides of Nonsteroidal Aniinflammatory Carboxylic Acids as Antioxidants and Antiproliferative Agents, J. Med. Chem.,42(2): 267-276 (1999).
Hyneck, Martha,An Overview of the Clinical Pharmacokinetics of Nabumetone, The Journal of Rheumatology,19(36): 20-24 (1992).
Jeremy, et al.,Effects of Prodrug Nabumetone, and its Active Metabolite, 6-MNA, on Human and Rat Gastric Mucosal Prostanoids and Platelet Function,Drugs 40 (Suppl. 5), 1990 (pp. 53-56).
Mangan, et al.,Preclinical Overview of Nabumetone,The American Journal of Medicine, vol. 83 (suppl. 4B), Oct. 1987 (pp. 6-10).
Paris et al.,Glycerides as Prodrugs. 4. Synt

Affiliated with

Also associated with

Rating

6-Methoxy-2-naphthylacetic acid prodrugs does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with 6-Methoxy-2-naphthylacetic acid prodrugs, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 6-Methoxy-2-naphthylacetic acid prodrugs will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3196395